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Purpose: Intratumoral tavokinogene telseplasmid delivered by electroporation (TAVO-EP) results in localized expression of IL-12 within the tumor microenvironment (TME). This study evaluated neoadjuvant TAVO-EP combined with intravenous nivolumab followed by surgery and adjuvant nivolumab in patients with operable, locoregionally advanced melanoma., Patients and Methods: The neoadjuvant phase comprised up to 3 × 4-week cycles during which TAVO-EP was given intratumorally on days 1, 8, and 15 (optional) concurrently with 480 mg nivolumab intravenously on day 8 of each 4-week cycle. Surgery followed, and adjuvant nivolumab was initiated after surgery. The primary endpoint was pathologic complete response (pCR). Secondary endpoints included major pathologic response (MPR; pCR or near pCR)., Results: Sixteen patients were enrolled, and the preoperative radiological response rate was 63%. One patient declined surgery after experiencing a significant clinical response. Among the remaining 15 patients, the pCR rate was 60% and the MPR was 80%. No patient with MPR has had disease recurrence with a median follow-up from the date of surgery of 15.4 months. At baseline, most patients exhibited low CD8+ tumor-infiltrating lymphocytes, PD-L1, and IFN-γ gene expression signature. There was enhanced immune activation following treatment in the TME and blood, including increased immune-related gene expression, CD8+ tumor-infiltrating lymphocytes, and proliferating immune cell subsets., Conclusions: The clinical efficacy of neoadjuvant intratumoral TAVO-EP + nivolumab is promising with 80% of patients achieving an MPR. Evidence of potent immune activation both systemically and within the TME along with a favorable safety profile supports the activity of local IL-12 and anti-PD-1 based regimens., (©2024 American Association for Cancer Research.)

Purpose: In phase III CheckMate 238, adjuvant nivolumab significantly improved recurrence-free survival compared with ipilimumab in patients with resected stage IIIB-C/IV melanoma without a significant difference in overall survival (OS). Here, we investigate progression-free survival (PFS) and OS after postrecurrence systemic therapy., Patients and Methods: Patients 15 years or older with resected stage IIIB-C/IV melanoma were stratified by stage and tumor PD-L1 status and randomly assigned to receive nivolumab 3 mg/kg every 2 weeks, or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks for 1 year or until disease recurrence, unacceptable toxicity, or withdrawal of consent. Patients with recurrence in each group were assessed for PFS and OS from subsequent systemic therapy (SST) initiation per recurrence timing (≤12 months [early] v >12 months [late] from initial therapy)., Results: Recurrences occurred in 198 (44%) of 453 nivolumab-treated patients (122 early, 76 late) and 232 (51%) of 453 ipilimumab-treated patients (160 early, 72 late). Median PFS on next-line systemic therapy for nivolumab-treated patients recurring early versus late was 4.7 versus 12.4 months (24-month rates, 16% v 31%); median OS was 19.8 versus 42.8 months (24-month rates: 37% v 73%). In response to subsequent therapy, patients on nivolumab with late versus early recurrence were more likely to benefit from anti-PD-1 monotherapy. Nivolumab-treated patients with either an early or late recurrence benefitted from an ipilimumab-based therapy or targeted therapy, each with similar OS., Conclusion: Postrecurrence survival was longer for patients who recurred >12 months. Patients on nivolumab who recurred early benefitted from SST but had better survival with ipilimumab-based regimens or targeted therapy compared with anti-PD-1 monotherapy.

IFx-Hu2.0 was designed to encode part of the Emm55 protein contained within a plasmid in a formulation intended for transfection into mammalian cells. IFx-Hu2.0 promotes both adaptive and innate immune responses in animal studies. Furthermore, previous studies have demonstrated safety/efficacy in equine, canine, and murine species. We present the first-in-human study of IFx-Hu2.0, administered by intralesional injection into melanoma tumors of seven patients with stage III/IV unresectable melanoma. No dose-limiting toxicities attributable to IFx-Hu2.0 were observed. Grade 1/2 injection site reactions were observed in five of seven patients. IgG and IgM responses to Emm55 peptides and known melanoma antigens were seen in the peripheral blood, suggesting that IFx-Hu2.0 acts as an individualized "in situ vaccine." Three of four patients previously refractory to anti-PD1 experienced clinical benefit upon subsequent anti-PD1-based treatment. Therefore, this approach is feasible, and clinical/correlative outcomes warrant further investigation for treating patients with metastatic melanoma with an immune priming agent., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: Little is known about late and long-term patient-reported outcomes (PROs) of immune checkpoint modulators (ICMs) outside clinical trials. We conducted a cross-sectional, mixed-methods study to describe long-term PROs among advanced melanoma patients who began standard of care treatment with ICMs at least 1 year previously., Methods: All participants completed the Functional Assessment of Cancer Therapy-Immune Checkpoint Modulator (FACT-ICM), assessing 46 immune-related side effects on a 5-point Likert scale, and a subset completed individual interviews. Descriptive statistics were computed for quantitative data and applied thematic analysis was used to examine qualitative data., Results: Participants (N = 80) had a mean age of 67 years, and the majority were male (66%), non-Hispanic White (96%), and college graduates (61%). Single-agent nivolumab was the most common first (47%) and current/recent ICM (64%). On the FACT-ICM, 98% of participants reported at least one side effect, and 78% reported moderate or severe side effects. The most common moderate or severe side effects were aching joints (43%) and fatigue (38%). In interviews (n = 20), we identified five themes regarding patients' longer-term experiences after ICMs: lasting fatigue or decline in functioning, minimal side effects, manageable thyroid and pituitary dysfunction, skin conditions can be difficult to manage, and treating the cancer is worth the side effects., Conclusions: Nearly all patients reported side effects of ICMs at least 1 year after starting treatment. Our findings suggest that ICM side effect screening and management-especially for aching joints and fatigue-are indicated during long-term care of people living with advanced melanoma., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Cancer-related mortality rates among kidney transplant recipients (KTR) are high, but these patients have largely been excluded from trials of immune checkpoint inhibitors because of immunosuppression and risk of treatment-related allograft loss (TRAL). We conducted a prospective clinical trial testing nivolumab (NIVO) + tacrolimus (TACRO) + prednisone (PRED) ± ipilimumab (IPI) in KTR with advanced cutaneous cancers., Methods: Adult KTR with advanced melanoma or basal, cutaneous squamous, or Merkel cell carcinomas were eligible. Immunosuppression was standardized to TACRO (serum trough 2-5 ng/mL) + PRED 5 mg once daily. Patients then received NIVO 480 mg IV once every 4 weeks. The primary composite end point was partial or complete (tumor) response (CR) or stable disease per RECIST v1.1 without allograft loss at 16W. Patients with progressive disease (PD) could receive IPI 1 mg/kg IV + NIVO 3 mg/kg once every 3 weeks × 4 followed by NIVO. Donor-derived cell-free DNA (dd-cfDNA) levels were measured approximately once every 2 weeks as a potential predictor of allograft rejection., Results: Among eight evaluable patients, none met the trial's primary end point. All eight patients experienced PD on NIVO + TACRO + PRED; TRAL occurred in one patient. Six patients then received IPI + NIVO + TACRO + PRED. Best overall responses: two CR (one with TRAL) and four PD (one with TRAL). In total, 7 of 8 pre-NIVO tumor biopsies contained a paucity of infiltrating immune cells. In total, 2 of 5 on-NIVO biopsies demonstrated moderate immune infiltrates; both patients later experienced a CR to IPI + NIVO. In 2 of 3 patients with TRAL, dd-cfDNA elevations occurred 10 and 15 days before increases in serum creatinine., Conclusion: In most KTR with advanced skin cancer, TACRO + PRED provides insufficient allograft protection and compromises immune-mediated tumor regression after administration of NIVO ± IPI. Elevated dd-cfDNA levels can signal treatment-related allograft rejection earlier than rises in serum creatinine.

Background: Resistance to immune checkpoint inhibitors and targeted treatments for cancer is common; thus, novel immunotherapy agents are needed. Urelumab is a monoclonal antibody agonist that binds to CD137 receptors expressed on T cells. Here, we report two studies that evaluated urelumab in combination with cetuximab or nivolumab in patients with select, advanced solid tumors., Methods: CA186-018: Patients with metastatic colorectal cancer or metastatic squamous cell carcinoma of the head and neck (SCCHN) were treated in a dose-evaluation phase with urelumab 0.1 mg/kg (urelumab-0.1) every 3 weeks (Q3W)+cetuximab 250 mg/m 2 (cetuximab-250) weekly; and in a dose-expansion phase with urelumab 8 mg flat dose (urelumab-8) Q3W+cetuximab-250 weekly. CA186-107: The dose-escalation phase included patients with previously treated advanced solid tumors (or treated or treatment-naive melanoma); patients received urelumab 3 mg flat dose (urelumab-3) or urelumab-8 every 4 weeks+nivolumab 3 mg/kg (nivolumab-3) or 240 mg (nivolumab-240) every 2 weeks. In the expansion phase, patients with melanoma, non-small cell lung cancer, or SCCHN were treated with urelumab-8+nivolumab-240. Primary endpoints were safety and tolerability, and the secondary endpoint included efficacy assessments., Results: CA186-018: 66 patients received study treatment. The most frequent treatment-related adverse events (TRAEs) were fatigue (75%; n=3) with urelumab-0.1+cetuximab-250 and dermatitis (45%; n=28) with urelumab-8+cetuximab-250. Three patients (5%) discontinued due to TRAE(s) (with urelumab-8+cetuximab-250). One patient with SCCHN had a partial response (objective response rate (ORR) 5%, with urelumab-8+cetuximab-250).CA186-107: 134 patients received study treatment. Fatigue was the most common TRAE (32%; n=2 with urelumab-3+nivolumab-3; n=1 with urelumab-8+nivolumab-3; n=40 with urelumab-8+nivolumab-240). Nine patients (7%) discontinued due to TRAE(s) (n=1 with urelumab-3+nivolumab-3; n=8 with urelumab-8+nivolumab-240). Patients with melanoma naive to anti-PD-1 therapy exhibited the highest ORR (49%; n=21 with urelumab-8+nivolumab-240). Intratumoral gene expression in immune-related pathways (CD3, CD8, CXCL9, GZMB) increased on treatment with urelumab+nivolumab., Conclusions: Although the addition of urelumab at these doses was tolerable, preliminary response rates did not indicate an evident additive benefit. Nevertheless, the positive pharmacodynamics effects observed with urelumab and the high response rate in treatment-naive patients with melanoma warrant further investigation of other anti-CD137 agonist agents for treatment of cancer., Trial Registration Numbers: NCT02110082; NCT02253992., Competing Interests: Competing interests: NIK reports consulting fees from Bristol Myers Squibb, Merck, Jounce, Novartis, Regeneron, Genzyme, Iovance, Castle Biosciences, Nektar, Replimune, and Instil Bio; research funding (to institute) from Bristol Myers Squibb, Merck, Celgene, Novartis, GSK, HUYA, Regeneron, Replimune, Modulation Therapeutics; participation on a data safety monitoring board with Incyte, AstraZeneca; participation in a study steering committee with Bristol Myers Squibb, Nektar, Regerenon, Replimune; and ownership of common stock in Bellicum, Amarin, and Asensus Surgical. PAO reports grants from Bristol Myers Squibb, Neon Therapeutics, Merck, Pfizer, Novartis, Celldex, Xencor, Roche/Genentech, Oncorus; consulting fees from Bristol Myers Squibb, Evaxion, Merck, Roche/Genentech, Novartis, Immunetune, LG Chem; leadership or fiduciary role with NCCN. RF reports grants or contracts from AstraZeneca/MedImmune, Bristol Myers Squibb, Merck, Novasenta, Tesaro; consulting fees with Adagene, Aduro Biotech, Bicara Therapeutics, Brooklyn ImmunoTherapeutics, Catenion, EMD Serono, Everest Clinical Research Corporation, F. Hoffman-La Roche Ltd., Federation Bio, Genocea Biosciences, Kowa Research Institute, Mirati Therapeutics, Nanobiotix, Novartis, Novasenta, PPD Development, Sanofi, Zymeworks; participation on a data safety monitoring or advisory board with Coherus BioSciences, Eisai Europe Ltd., Genmab, Hookipa, Instil Bio, Lifescience Dynamics, MacroGenics, MeiraGtx, Merck, Mirror Biologics, Numab Therapeutics AG, OncoCyte, Pfizer, Rakuten Medical, Seagen, SIRPant Immunotherapeutics, Vir Biotechnology, stock or stock options with Novasenta. TC reports speaker fees/honoraria from AstraZeneca, Bristol Myers Squibb, Clinical Care Options, IDEOlogy Health, Mark Foundation for Cancer Research, Medscape, OncLive, PeerView, Physicians’ Education Resource, Roche, and Society for Immunotherapy of Cancer; advisory role/consulting fees from Arrowhead Pharmaceuticals, Bristol Myers Squibb, Genentech, MedImmune/AstraZeneca, Merck, Pfizer, and Regeneron; institutional research funding from Bristol Myers Squibb, EMD Serono, and MedImmune/AstraZeneca; and travel, food and/or beverage expenses from AstraZeneca, Bristol Myers Squibb, Dava Oncology, Genentech, IDEOlogy Health, International Association for the Study of Lung Cancer, OncLive, Parker Institute for Cancer Immunotherapy, Physicians’ Education Resource, and Society for Immunotherapy of Cancer. DS reports research funding to the institution from Bristol Myers Squibb, MSD, Novartis, Amgen, Roche, Array; patient fees to the institution for clinical studies from Bristol Myers Squibb, MSD, Novartis, Merck-EMD, Philogen, Pfizer, Array, InflaRX, Nektar, Sun Pharma; consulting fees/honoraria from Bristol Myers Squibb, MSD, Novartis, Merck-EMD, Philogen, Pfizer, Array, InflaRX, Nektar, Sun Pharma, OncoSec, Replimune, NeraCare, Sandoz, Ultimovacs; reimbursement from the Society for Immunotherapy of Cancer, Bristol Myers Squibb, Roche, Medscape Oncology and PeerView Institute for travel; nonfinancial support from Bristol Myers Squibb, MSD, Novartis, Merck-EMD, Pierre-Fabre, Pfizer, InFlaRX, NeraCare, Nektar, Sun Pharma, Sandoz; consulting/advisory role fees from MedImmune, AstraZeneca, Bristol Myers Squibb, Merck& Co., Genentech, Arrowhead Pharmaceuticals, and EMD Serono; institutional clinical research funding from Boehringer Ingelheim, MedImmune, AstraZeneca, EMD Serono, and Bristol Myers Squibb. DTL reports serving on advisory boards for Merck, Bristol Myers Squibb, Nouscom, G1 Therapeutics, and Janssen; receiving research funding from Merck, Bristol Myers Squibb, Curegenix, Nouscom, and AbbVie; speaking honoraria from Merck; being an inventor of licensed intellectual property related to technology for mismatch repair deficiency for diagnosis and therapy (WO2016077553A1) from Johns Hopkins University. MRS reports support for present manuscript from Bristol Myers Squibb; participation on a data safety monitoring or advisory board with Pilant Therapeutics; stock or stock options with Bristol Myers Squibb. FB reports financial interest with AbbVie, ACEA, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd., Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, MedImmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, Takeda. WS reports grants and personal fees from Bristol Myers Squibb, Merck, and Novartis; personal fees from Regeneron; and grants from Genentech. JJL reports grants or contracts from AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono, F-star, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, MacroGenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, Xencor; consulting fees from 7 Hills, Bright Peak, Exo, F-star, Inzen, RefleXion, Xilio, Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, Stipe, Tempest, AbbVie, Alnylam, Atomwise, Bayer, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, MacroGenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Ribon, Roivant, Servier, Stingthera, Synlogic, Synthekine; provisional patents in cancer immunotherapy (serial no. 15/612,657) and microbiome biomarkers for anti-PD-1/PD-L1 responsiveness: diagnostic, prognostic, and therapeutic uses thereof (PCT/US18/36052); participation on a data safety monitoring board or advisory board with AbbVie, Immutep, Evaxion; leadership or fiduciary role with Society for Immunotherapy of Cancer; stock or stock options with Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, STipe, Tempest. IM reports support for the current manuscript from Bristol Myers Squibb; grants or contracts from Bristol Myers Squibb, Roche, Genmab, Highlight Therapeutics, AstraZeneca; consulting fees from Bristol Myers Squibb, Roche, Genmab, Merus, Pieris, AstraZeneca, Numab, Highlight Therapeutics; payment or honoraria from Bristol Myers Squibb; support for attending meetings and/or travel from Bristol Myers Squibb and Roche. DL, JN and JH are employees and stock owners of Bristol Myers Squibb. AS is an employee of Boston Scientific. SS, AS, RS and SE report employment with Bristol Myers Squibb. NHS reports consulting fees from ABL Bio, Agenus, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Numab, Puretech, Regeneron, Revitope, and Roche/Genentech; and research funding from Agenus, AstraZeneca, Bristol Myers Squibb, Immunocore, Merck, Pfizer, Puretech, Regeneron, and Roche/Genentech., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Upfront dual checkpoint blockade with immune checkpoint inhibitors (ICI) has demonstrated efficacy for treating melanoma brain metastases (MBM) in asymptomatic patients. Whether the combination of stereotactic radiosurgery (SRS) with dual checkpoint blockade improves outcomes over dual-checkpoint blockade alone is unknown. We evaluated clinical outcomes of patients with MBM receiving ICI with nivolumab and ipilimumab, with and without SRS., Methods: 49 patients with 158 MBM receiving nivolumab and ipilimumab for untreated MBM between 2015 and 2022 were identified at our institution. Patient and tumor characteristics including age, Karnofsky Performance Status (KPS), presence of symptoms, cancer history, MBM burden, and therapy course were recorded. Outcomes measured from initiation of MBM-directed therapy included overall survival (OS), local control (LC), and distant intracranial control (DIC). Time-to-event analysis was conducted with the Kaplan-Meier method., Results: 25 patients with 74 MBM received ICI alone, and 24 patients with 84 MBM received concurrent SRS. Median follow-up was 24 months. No differences in age (p = 0.96), KPS (p = 0.85), presence of symptoms (p = 0.79), prior MBM (p = 0.68), prior MBM-directed surgery (p = 0.96) or SRS (p = 0.68), MBM size (p = 0.67), or MBM number (p = 0.94) were seen. There was a higher rate of nivolumab and ipilimumab course completion in the SRS group (54% vs. 24%; p = 0.029). The SRS group received prior immunotherapy more often than the ICI alone group (54% vs. 8.0%; p < 0.001). There was no significant difference in 1-year OS (72% vs. 71%, p = 0.20) and DIC (63% v 51%, p = 0.26) between groups. The SRS group had higher 1-year LC (92% vs. 64%; p = 0.002). On multivariate analysis, LC was improved with combination therapy (AHR 0.38, p = 0.01)., Conclusion: In our analysis, patients who received SRS with nivolumab and ipilimumab had superior LC without increased risk of toxicity or compromised immunotherapy treatment completion despite the SRS cohort having higher rates of prior immunotherapy. Further prospective study of combination nivolumab and ipilimumab with SRS is warranted., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: The OPTIMIzE registry study evaluated real-world outcomes in patients with advanced melanoma receiving immuno-oncology therapies. Materials and methods: Data were collected for patients treated with anti-programmed death 1 (PD-1) monotherapy (nivolumab or pembrolizumab; n = 147) or nivolumab plus ipilimumab (n = 81) from 2015-2017 and followed for ≥3 years. Results: Nivolumab plus ipilimumab versus anti-PD-1 monotherapy was associated with a nonsignificantly lower risk of death (adjusted HR: 0.83; 95% CI: 0.54-1.28; p = 0.41), higher disease control rate (72 vs 56%; p = 0.04), and stable quality of life, but more grade 3-4 treatment-related adverse events (54 vs 26%; p < 0.0001). Conclusion: These results support the use of immuno-oncology therapy in advanced melanoma.

Background: Resistance to BRAF and MEK inhibitors in BRAF V600-mutant melanoma is common. Multiple resistance mechanisms involve heat-shock protein 90 (HSP90) clients, and a phase 1 study of vemurafenib with the HSP90 inhibitor XL888 in patients with advanced melanoma showed activity equivalent to that of BRAF and MEK inhibitors., Methods: Vemurafenib (960 mg orally twice daily) and cobimetinib (60 mg orally once daily for 21 of 28 days) with escalating dose cohorts of XL888 (30, 45, 60, or 90 mg orally twice weekly) was investigated in a phase 1 trial of advanced melanoma, with a modified Ji dose-escalation design., Results: Twenty-five patients were enrolled. After two dose-limiting toxicities (DLTs) (rash and acute kidney injury) in the first cohort, lower doses of vemurafenib (720 mg) and cobimetinib (40 mg) were investigated with the same XL888 doses. Three DLTs (rash) were observed in 12 patients in the XL888 60-mg cohort, and this was determined as the maximum tolerated dose. Objective responses were observed in 19 patients (76%), and the median progression-free survival was 7.6 months, with a 5-year progression-free survival rate of 20%. The median overall survival was 41.7 months, with a 5-year overall survival rate of 37%. Single-cell RNA sequencing was performed on baseline and on-treatment biopsies; treatment was associated with increased immune cell influx (CD4-positive and CD8-positive T cells) and decreased melanoma cells., Conclusions: Combined vemurafenib and cobimetinib plus XL888 had significant toxicity, requiring frequent dose reductions, which may have contributed to the relatively low progression-free survival despite a high tumor response rate. Given overlapping toxicities, caution must be used when combining HSP90 inhibitors with BRAF and MEK inhibitors., (© 2023 American Cancer Society.)

Purpose: To provide guidance to clinicians regarding the use of systemic therapy for melanoma., Methods: American Society of Clinical Oncology convened an Expert Panel and conducted an updated systematic review of the literature., Results: The updated review identified 21 additional randomized trials., Updated Recommendations: Neoadjuvant pembrolizumab was newly recommended for patients with resectable stage IIIB to IV cutaneous melanoma. For patients with resected cutaneous melanoma, adjuvant nivolumab or pembrolizumab was newly recommended for stage IIB-C disease and adjuvant nivolumab plus ipilimumab was added as a potential option for stage IV disease. For patients with unresectable or metastatic cutaneous melanoma, nivolumab plus relatlimab was added as a potential option regardless of BRAF mutation status and nivolumab plus ipilimumab followed by nivolumab was preferred over BRAF/MEK inhibitor therapy. Talimogene laherparepvec is no longer recommended as an option for patients with BRAF wild-type disease who have progressed on anti-PD-1 therapy. Ipilimumab- and ipilimumab-containing regimens are no longer recommended for patients with BRAF -mutated disease after progression on other therapies.This full update incorporates the new recommendations for uveal melanoma published in the 2022 Rapid Recommendation Update.Additional information is available at www.asco.org/melanoma-guidelines.

Purpose: Despite marked advances in the treatment of unresectable or metastatic melanoma, the need for novel therapies remains. Bempegaldesleukin (BEMPEG), a pegylated interleukin-2 (IL-2) cytokine prodrug, demonstrated efficacy in the phase II PIVOT-02 trial. PIVOT IO 001 (ClinicalTrials.gov identifier: NCT03635983) is a phase III, randomized, open-label study that builds on the PIVOT-02 results in first-line melanoma., Methods: Patients with previously untreated, unresectable, or metastatic melanoma were randomly assigned 1:1 to receive BEMPEG plus nivolumab (NIVO) or NIVO monotherapy. Primary end points were objective response rate (ORR) and progression-free survival (PFS) by blinded independent central review and overall survival (OS). Secondary and exploratory end points included additional efficacy measures, safety, and pharmacokinetics (PKs) and pharmacodynamics analyses., Results: In 783 patients (n = 391, BEMPEG plus NIVO; n = 392, NIVO monotherapy), the median follow-up was 11.6 months in the intent-to-treat population. The ORR with BEMPEG plus NIVO was 27.7% versus 36.0% with NIVO (two-sided P = .0311). The median PFS with BEMPEG plus NIVO was 4.17 months (95% CI, 3.52 to 5.55) versus 4.99 months (95% CI, 4.14 to 7.82) with NIVO (hazard ratio [HR], 1.09; 97% CI, 0.88 to 1.35; P = .3988). The median OS was 29.67 months (95% CI, 22.14 to not reached [NR]) with BEMPEG plus NIVO versus 28.88 months (95% CI, 21.32 to NR) with NIVO (HR, 0.94; 99.929% CI, 0.59 to 1.48; P = .6361). Grade 3-4 treatment-related adverse events (AEs) and serious AE rates were higher with the combination (21.7% and 10.1%, respectively) versus NIVO (11.5% and 5.5%, respectively). BEMPEG PK exposure and absolute lymphocyte count changes after BEMPEG plus NIVO were comparable between PIVOT IO 001 and PIVOT-02., Conclusion: The PIVOT IO 001 study did not meet its primary end points of ORR, PFS, and OS. Increased toxicity was observed with BEMPEG plus NIVO versus NIVO.

Background: Immunotherapy and targeted BRAF/MEK inhibitors (i) have revolutionised the systemic management of advanced melanoma. Given the role of stereotactic radiosurgery (SRS) in the local management of brain metastases, we sought to evaluate clinical outcomes in patients with melanoma brain metastases (MBM) treated with SRS and various systemic therapies., Methods: Patients were included if MBM were diagnosed and treated with SRS within 3 months of receiving anti-PD-1+CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, or conventional chemotherapy. Comparisons between groups were made for overall survival (OS), distant MBM control, local MBM, systemic progression-free survival (sPFS), and neurotoxicity., Results: In total, 257 patients with 1048 MBM treated over 368 SRS sessions between 2011 and 2020 were identified. On MVA, treatment with anti-PD1+anti-CTLA-4, anti-PD-1, and BRAF/MEK-i improved distant intracranial control over conventional chemotherapy. No significant differences were noted in local control (LC) between groups (p = 0.78). Kaplan-Meier OS at 12 months for anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, and conventional chemotherapy was 68%, 59%, 45%, 62%, 21%, and 15%, respectively (p = <0.0001). The sPFS rates at 12 months were 57%, 53%, 42%, 45%, 14%, and 6% (p = <0.0001). No significant differences were noted in rates of radiation necrosis (p = 0.93)., Conclusions: This is among the largest series evaluating MBM treated with SRS and various systemic therapy regimens. Our analysis noted significant differences in OS, distant MBM control, and sPFS by systemic therapy. No differences in LC or radiation necrosis risk were noted., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests. Hsiang-Hsuan Michael Yu has received speaker’s honoraria from BrainLab and is on the advisory boards of Novocure and AbbVie. Michael A. Vogelbaum has indirect equity and royalty interests in Infuseon Therapeutics, Inc and has received honoraria from Tocagen, Inc and Celgene. Peter A. Forsyth has received funding from Pfizer and Celgene and is on the advisory boards of Novocure, BTG, Inovio, AbbVie, Ziopharm, Tocagen, and Pfizer. Kamran A. Ahmed has received research funding to the institution from Bristol-Myers Squibb, Eli Lilly, and Genentech and is on the advisory board of Castle Biosciences. Evan Wuthrick reports being a member of the advisory board for Viewray, Varian, Alphatau, Castle Biosciences, and Teiko. Nikhil Khushalani reports being a member of the advisory board for Bristol Myers-Squibb, Regeneron, Merck, Jounce Therapeutics, Iovance Biotherapeutics, Genzyme, Novartis, Castle Biosciences, Nektar, and Instill Bio; being a member of the steering or scientific committee for Nektar, Regeneron, Replimune, Bristol Myers-Squibb, and National Comprehensive Cancer Network via Pfizer; being on the data safety monitoring committee for AstraZeneca and Incyte; research support to his institution from Bristol Myers-Squibb, Merck, Celgene, Regeneron, Replimune, Novartis, HUYA Bioscience, and GlaxoSmithKline); and common stock from Bellicum, Amarin, Asensus Surgical. Ammoren E. Dohm, Justyn Y. Nakashima, Hruday Kalagotla, Shirley X. Jiang, Joseph D. Tang, Menal Bhandari, Youngchul Kim, Jasmine A. Graham, Arnold B. Etame, James K. Liu, Nam D. Tran, and Daniel E. Oliver report no conflicts to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: In the phase III CheckMate 238 study, adjuvant nivolumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab in patients with resected stage IIIB-C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings., Patients and Methods: Patients with resected stage IIIB-C/IV melanoma were stratified by stage and baseline programmed death cell ligand 1 (PD-L1) expression and received nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS., Results: At a minimum follow-up of 62 months, RFS with nivolumab remained superior to ipilimumab (HR = 0.72; 95% confidence interval, 0.60-0.86; 5-year rates of 50% vs. 39%). Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) rates were 76% with nivolumab and 72% with ipilimumab (75% data maturity: 228 of 302 planned events). Higher levels of tumor mutational burden (TMB), tumor PD-L1, intratumoral CD8+ T cells and IFNγ-associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both nivolumab and ipilimumab, albeit with limited clinically meaningful predictive value., Conclusions: Nivolumab is a proven adjuvant treatment for resected melanoma at high risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with ipilimumab and high OS rates. Identification of additional biomarkers is needed to better predict treatment outcome. See related commentary by Augustin and Luke, p. 3253., (©2023 The Authors; Published by the American Association for Cancer Research.)

In this randomized phase 2 trial, blockade of cytotoxic T-lymphocyte protein 4 (CTLA-4) with continuation of programmed death protein 1 (PD-1) blockade in patients with metastatic melanoma who had received front-line anti-PD-1 or therapy against programmed cell death 1 ligand 1 and whose tumors progressed was tested in comparison with CTLA-4 blockade alone. Ninety-two eligible patients were randomly assigned in a 3:1 ratio to receive the combination of ipilimumab and nivolumab, or ipilimumab alone. The primary endpoint was progression-free survival. Secondary endpoints included the difference in CD8 T cell infiltrate among responding and nonresponding tumors, objective response rate, overall survival and toxicity. The combination of nivolumab and ipilimumab resulted in a statistically significant improvement in progression-free survival over ipilimumab (hazard ratio = 0.63, 90% confidence interval (CI) = 0.41-0.97, one-sided P = 0.04). Objective response rates were 28% (90% CI = 19-38%) and 9% (90% CI = 2-25%), respectively (one-sided P = 0.05). Grade 3 or higher treatment-related adverse events occurred in 57% and 35% of patients, respectively, which is consistent with the known toxicity profile of these regimens. The change in intratumoral CD8 T cell density observed in the present analysis did not reach statistical significance to support the formal hypothesis tested as a secondary endpoint. In conclusion, primary resistance to PD-1 blockade therapy can be reversed in some patients with the combination of CTLA-4 and PD-1 blockade. Clinicaltrials.gov identifier: NCT03033576 ., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Immune checkpoint inhibitors (ICIs) have substantially improved overall survival in patients with advanced melanoma; however, the lack of biomarkers to monitor treatment response and relapse remains an important clinical challenge. Thus, a reliable biomarker is needed that can risk-stratify patients for disease recurrence and predict response to treatment., Methods: A retrospective analysis using a personalized, tumor-informed circulating tumor DNA (ctDNA) assay on prospectively collected plasma samples (n = 555) from 69 patients with advanced melanoma was performed. Patients were divided into three cohorts: cohort A (N = 30), stage III patients receiving adjuvant ICI/observation; cohort B (N = 29), unresectable stage III/IV patients receiving ICI therapy; and cohort C (N = 10), stage III/IV patients on surveillance after planned completion of ICI therapy for metastatic disease., Results: In cohort A, compared to molecular residual disease (MRD)-negative patients, MRD-positivity was associated with significantly shorter distant metastasis-free survival (DMFS; hazard ratio [HR], 10.77; p = .01). Increasing ctDNA levels from the post-surgical or pre-treatment time point to after 6 weeks of ICI were predictive of shorter DMFS in cohort A (HR, 34.54; p < .0001) and shorter progression-free survival (PFS) in cohort B (HR, 22; p = .006). In cohort C, all ctDNA-negative patients remained progression-free for a median follow-up of 14.67 months, whereas ctDNA-positive patients experienced disease progression., Conclusion: Personalized and tumor-informed longitudinal ctDNA monitoring is a valuable prognostic and predictive tool that may be used throughout the clinical course of patients with advanced melanoma., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Immunotherapy offers deep and durable disease control to some patients, but many tumors do not respond to treatment with single-agent immune checkpoint inhibitors (ICIs). One strategy to enhance responses to immunotherapy is via combinations with signal transduction inhibitors, such as antiangiogenic therapies, which not only directly target cancer cells but also could potentially favorably modulate the tumor immune microenvironment. Combination strategies with ICIs have demonstrated enhanced antitumor activity compared with tumor-targeted or antiangiogenic therapy alone in randomized trials in a variety of solid tumor settings, leading to regulatory approval from the US Food and Drug Administration and agencies in other countries for the treatment of endometrial cancer, kidney cancer, melanoma, and hepatocellular carcinoma. Despite improved survival and response rates for some patients when antiangiogenic or targeted therapies are administered with ICIs, many patients continue to progress after combination treatment and urgently need new strategies to address this manifestation of resistance to immunotherapy. Previously, the Society for Immunotherapy of Cancer (SITC) published consensus definitions for resistance to single-agent anti-PD-(L)1. To provide guidance for clinical trial design and to support analyses of emerging molecular and immune profiling data surrounding mechanisms of resistance to ICI-based combinations, SITC convened a follow-up workshop in 2021 to develop consensus definitions for resistance to multiagent ICI combinations. This manuscript reports the consensus clinical definitions for combinations of anti-PD-(L)1 ICIs and targeted therapies. Definitions for resistance to ICIs in combination with chemotherapy and with other ICIs will be published in companion volumes to this paper., Competing Interests: Competing interests: MBA—Consulting fees: Aveo, Bristol Myers Squibb, Eisai, Exelixis, Genentech, Iovance, Merck, Novartis, Pfizer, Roche, Pyxis, Werewolf, Asher Bio, Calithera, Idera, Agenus, Apexigen, Neoleukin, Adagene, AstraZeneca, Elpis, ScholarRock, Surface, ValoHealth, Sanofi, Fathom; Ownership interest less than 5%: Werewolf, Pyxis, Elpis. DF—Salary and employment: Palleon Pharmaceuticals; Ownership interest less than 5%: Palleon Pharmaceuticals. DBJ—IP rights: MHC-II for use as immunotherapy biomarker, Abatacept as treatment for irAEs; Consulting fees: Bristol Myers Squibb, Catalyst, Iovance, Jansen, Mallinckrodt, Merck, Mosaic ImmunoIngineering, Novartis, Oncosec, Pfizer, Targovax; Contracted research: Bristol Myers Squibb, Incyte. JS—Consulting fees: Array, Nektar, Jazz, Iovance, Apexigen, Eisai; Contracted research: Bristol Myers Squibb, Amphivena, PACT. NIK—Consulting fees: Bristol Myers Squibb, Merck, Jounce, Iovance, Regeneron, Genzyme, NCCN (via Pfizer), Novartis, Nektar, Castle Biosciences, Instil Bio, Immunocore; Contracted research: Bristol Myers Squibb, Merck, Celgene, GSK, HUYA, Replimune, Novartis, Regeneron, Amgen; Data safety Montioring board: AstraZeneca, Incyte; Study steering committee: Nektar, Bristol Myers Squibb, Regeneron, Replimune; Ownership interest less than 5%: Bellicum Pharaceuticals, Asensus Surgical (formerly TransEnterix), Amarin. PAA—Consulting fees: Bristol Myers Squibb, Roche, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, Medimmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandox, Immunocore, 4SC, Italfarmaco, Mektar, Boehringer Ingelheim, Eisai, Renegeron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, SeaGen, iTEOS, Medicenna; Contracted research: Bristol Myers Squibb, Genentech/Roche, Array, Sanofi. TAY—Consulting fees: AstraZeneca, Almac, Aduro, Artios, Athena, Atrin, Axiom, Bayer, Bristol Myers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, F-Star, GLG, Guidepoint, Ignyta, I-Mab, ImmuneSensor, Jansen, Merck, Pfizer, Repare, Roche, Schrodinger, Seattle Genetics, Varian, Zai Labs, ZielBio; Contracted research: AstraZeneca, Artios, Bayer, Beigene, BioNTech, Bristol Myers Squibb, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech/Roche, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Novartis, Pfizer, Repare, Ribon Therapeutics, Regeneron, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, Vivace. HK—Consulting fees: Iovance, Immunocore, Celldex, Array Biopharma, Merck, Elevate Bio, Instil Bio, Bristol Myers Squibb, Clinigen, Shionogi, Chemocentryx, Calithera, Signatero. RJS—Consulting fees: Asana Biosciences, AstraZeneca, Bristol Myers Squibb, Eisai, Iovance, Merck, Novartis, OncoSec, Pfizer, Replimune; Contracted research: Merck, Amgen. HT—Consulting fees: Genentech/Roche, Bristol Myers Squibb, Novartis, Merck, Pfizer, Eisai, Karyopharm, Boxer Capital; Contracted research: Genentech/Roche, Bristol Myers Squibb, Novartis, Merck, GSK. JLG—Nothing to disclose. SITC Staff: SMW, PI—Nothing to disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Metastatic melanoma is a tumor amenable to immunotherapy in part due to the presence of antigen-specific tumor-infiltrating lymphocytes (TIL). These T cells can be activated and expanded for adoptive cell transfer (ACT), which has resulted in relatively high rates of clinical responses. Similarly, immune checkpoint inhibitors, specifically programmed cell death protein 1 (PD-1) blocking antibodies, augment antitumor immunity and increase the influx of T cells into tumors. Thus, we hypothesized that addition of PD-1 inhibition may improve the outcomes for patients undergoing ACT with TILs., Patients and Methods: Patients with stage III/IV metastatic melanoma with unresectable disease who were anti-PD-1 treatment-naïve were enrolled. TILs were generated in the presence of anti-4-1BB antibody in vitro and expanded for ACT. Patients in cohort 1 received TIL infusion followed by nivolumab. Patients in cohort 2 also received nivolumab prior to surgical harvest and during TIL production., Results: A total of 11 patients were enrolled, all of whom were evaluated for response, and nine completed ACT. Predominantly CD8+ TILs were successfully expanded from all ACT-treated patients and were tumor reactive in vitro. The trial met its safety endpoint, as there were no protocol-defined dose-limiting toxicity events. The objective response rate was 36%, and median progression-free survival was 5 months. Two nonresponders who developed new metastatic lesions were analyzed to determine potential mechanisms of therapeutic resistance, which included clonal divergence and intrinsic TIL dysfunction., Conclusions: Combination therapy with TILs and nivolumab was safe and feasible for patients with metastatic melanoma and provides important insights for future therapeutic developments in ACT with TILs., (©2022 American Association for Cancer Research.)

Background: Patients with advanced melanoma have limited treatment options after progression on immune checkpoint inhibitors (ICI). Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, demonstrated an investigator-assessed objective response rate (ORR) of 36% in 66 patients who progressed after ICI and targeted therapy. Herein, we report independent review committee (IRC)-assessed outcomes of 153 patients treated with lifileucel in a large multicenter Phase 2 cell therapy trial in melanoma., Methods: Eligible patients had advanced melanoma that progressed after ICI and targeted therapy, where appropriate. Melanoma lesions were resected (resected tumor diameter ≥1.5 cm) and shipped to a central good manufacturing practice facility for 22-day lifileucel manufacturing. Patients received a non-myeloablative lymphodepletion regimen, a single lifileucel infusion, and up to six doses of high-dose interleukin-2. The primary endpoint was IRC-assessed ORR (Response Evaluation Criteria in Solid Tumors V.1.1)., Results: The Full Analysis Set consisted of 153 patients treated with lifileucel, including longer-term follow-up on the 66 patients previously reported. Patients had received a median of 3.0 lines of prior therapy (81.7% received both anti-programmed cell death protein 1 and anti-cytotoxic lymphocyte-associated protein 4) and had high disease burden at baseline (median target lesion sum of diameters (SOD): 97.8 mm; lactate dehydrogenase (LDH) >upper limit of normal: 54.2%). ORR was 31.4% (95% CI: 24.1% to 39.4%), with 8 complete responses and 40 partial responses. Median duration of response was not reached at a median study follow-up of 27.6 months, with 41.7% of the responses maintained for ≥18 months. Median overall survival and progression-free survival were 13.9 and 4.1 months, respectively. Multivariable analyses adjusted for Eastern Cooperative Oncology Group performance status demonstrated that elevated LDH and target lesion SOD >median were independently correlated with ORR (p=0.008); patients with normal LDH and SOD 30); and being on the speaker’s bureau for Bristol-Myers Squibb, Regeneron, and Castle Biosciences. ST reports honoraria, consulting or advisory role, research funding, speaker’s bureau, and travel, accommodations, expenses with Bristol-Myers Squibb, Merck, Pfizer, Ipsen, Amgen, Genentech, and Foundation One. MW reports receiving honoraria from Novartis, Pfizer, and Roche; consulting or advisory role with Bristol-Myers Squibb, Novartis, Pfizer, Cellex GmbH, Eli Lilly, Boehringer Ingelheim, ISA Pharmaceuticals, GEMoaB, Roche, MSD, AstraZeneca, Amgen, and Immatics; research funding from Roche; and travel, accommodations, and expenses from Pfizer, Bristol-Myers Squibb, AstraZeneca, Roche, Amgen, and GEMoaB. MC reports speaker’s bureau participation with Sirtex Medical. ED-M reports receiving honoraria from Castle Biosciences; consulting or advisory role and speaker’s bureau with Regeneron; and research funding from Clinigen. GQP reports honoraria from IBSA; consulting or advisory role with Acella, Amneal, and Terns; and patents, royalties, or other intellectual property with Virginia Commonwealth University. JMK reports consulting role with Amgen, Ankyra Therapeutics, Applied Clinical Intelligence, Axio Research, Becker Pharmaceutical Consulting, Bristol-Myers Squibb, Cancer Network, Checkmate Pharmaceuticals, DermTech, Fenix Group International, Harbour BioMed, Immunocore, Iovance Biotherapeutics, IQVIA, Istari Oncology, Merck, Natera, Novartis, Oncocyte, OncoSec, Pfizer, Replimune, Scopus BioPharma, SR One Capital Management LP, Takeda Development Center Americas, and Takeda Pharmaceutical Company; and research trial support to institution from Amgen, Bristol-Myers Squibb, Checkmate Pharmaceuticals, Harbour BioMed, ImmVira, Immunocore, Iovance Biotherapeutics, Novartis, Takeda, and Verastem. JCH reports honorarias for talks from Almirall, Amgen, Bristol-Myers Squibb, GSK, JSD Pharma, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma; advisory boards for GSK, MSD, Pierre Fabre, Sun Pharma (personal), and Bristol-Myers Squibb, Immunocore, Nektar, Novartis, and Philogen (institution); research funding from Bristol-Myers Squibb, Sun Pharma, and Sanofi; and travel, accommodations, and expenses from Sun Pharma. MO reports consulting or advisory role with TriSalus, Immunocore, Ideaya, and Delcath, and her husband is an employee of GSK. JL reports receiving honoraria from Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, and Bristol-Myers Squibb; consulting or advisory role with iOnctura, Apple Tree, Merck, Bristol-Myers Squibb, Eisai, Debiopharm, and Incyte; research funding from Bristol-Myers Squibb, MSD, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar, Covance, Immunocore, Pharmacyclics, and Aveo; and travel, accommodations, and expenses from Pierre Fabre, Roche, and GSK. JW reports stock or other ownership with Biond, Instil Bio, OncoV4, and Evaxion; honoraria and consulting or advisory role with Bristol-Myers Squibb, GSK, Pfizer, Sellas, Biond, OncoC4, ImCheck, Genentech, AstraZeneca, Regeneron, Instil Bio, Iovance Biotherapeutics, Evaxion, and Ultimovacs; research funding from Bristol-Myers Squibb, Moderna, Merck, Incyte, and Genentech; patents, royalties, or other intellectual property with Moffitt Cancer Center and Biodesix. AJSF reports consulting or advisory role with Immunocore and GSK; speaker’s bureau participation with Bristol-Myers Squibb, Ipsen, and Eisai; and travel, accommodations, and expenses from ESMO. NIK reports stock and other ownership interest with Bellicum Pharmaceuticals, Amarin Corporation, and Asensus Surgical; consulting or advisory role with Bristol-Myers Squibb, AstraZeneca, Regeneron, Array BioPharma, Immunocore, Merck, Incyte, Jounce Therapeutics, Iovance Biotherapeutics, NCCN/Pfizer, Genzyme, Novartis, Nektar, Castle Biosciences, and InstilBio; research funding from Bristol-Myers Squibb, Merck, Novartis, GSK, HUYA Bioscience International, Amgen, Regeneron, Celgene, and Replimune; and other relationships with Nektar, Regeneron, Bristol-Myers Squibb/Celgene, and Replimune. TM reports consulting or advisory role with Merck, Bristol-Myers Squibb, Iovance Biotherapeutics, Moderna, Nektar, Regeneron, Exicure, Checkmate Pharmaceuticals, BioAtla, Xencor, Replimune, Day One Biopharmaceuticals, Pfizer, and Taiga. MEE reports consultant or advisory role with Iovance Biotherapeutics and receiving research funding from SkylineDx. FGF, MJ, PH, GS, WS, and XW are employees of Iovance Biotherapeutics and hold stock and/or stock options. Further, FGF is in a leadership position at Iovance Biotherapeutics; owns stocks from Adverum Biotechnologies, Roche, Bristol-Myers Squibb, and Johnson & Johnson; and holds patents, royalties, or other intellectual property rights with Bristol-Myers Squibb. PH additionally reports receiving honoraria from Janssen, Amgen, Karyopharm, Bristol-Myers Squibb, and Sanofi; has been paid for a consultant or advisory role by Janssen, Amgen, Karyopharm, Bristol-Myers Squibb, and Allogen; and received travel, accommodations, and expenses from Johnson & Johnson, Bristol-Myers Squibb, and Sanofi. AS reports honoraria and consulting or advisory role with Iovance Biotherapeutics, Guidepoint, Defined Health, Huron Consulting Group, KeyQuest Health, Istari, Gerson Lehrman Group, Physicians’ Educational Resource, Medscape and MedStar Health; and holds patents, royalties, or other intellectual property rights with Moffitt Cancer Center, Iovance Biotherapeutics, and Provectus., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Currently accepted principles of surgical management-margin width, use of sentinel node biopsy, performance of radical node dissections for node-positive cases-and some aspects of postoperative management (use of radiation for desmoplastic melanoma primaries and for clinically node-positive disease) will change in the future with the potential widespread adoption of adjuvant and neoadjuvant therapies., (© 2022 American Cancer Society.)

Background: Adjuvant therapy for high-risk resected melanoma with programmed cell-death 1 blockade results in a median relapse-free survival (RFS) of 5 years. The addition of low dose ipilimumab (IPI) to a regimen of adjuvant nivolumab (NIVO) in CheckMate-915 did not result in increased RFS. A pilot phase II adjuvant study of either standard dose or low dose IPI with NIVO was conducted at two centers to evaluate RFS with correlative biomarker studies., Methods: Patients with resected stages IIIB/IIIC/IV melanoma received either IPI 3 mg/kg and NIVO 1 mg/kg (cohort 4) or IPI 1 mg/kg and NIVO 3 mg/kg (cohorts 5 and 6) induction therapy every 3 weeks for 12 weeks, followed by maintenance NIVO. In an amalgamated subset of patients across cohorts, peripheral T cells at baseline and on-treatment were assessed by flow cytometry and RNA sequencing for exploratory biomarkers., Results: High rates of grade 3-4 adverse events precluded completion of induction therapy in 50%, 35% and 7% of the patients in cohorts 4, 5 and 6, respectively. At a median of 63.9 months of follow-up, 16/56 patients (29%) relapsed. For all patients, at 5 years, RFS was 71% (95% CI: 60 to 84), and overall survival was 94% (95% CI: 88 to 100). Expansion of CD3+CD4+CD38+CD127-GARP- T cells, an on-treatment increase in CD39 expression in CD8+ T cells, and T-cell expression of phosphorylated signal-transducer-and-activator-of-transcription (STAT)2 and STAT5 were associated with relapse., Conclusions: Adjuvant IPI/NIVO at the induction doses used resulted in promising relapse-free and overall survival, although with a high rate of grade 3-4 adverse events. Biomarker analyses highlight an association of ectoenzyme-expressing T cells and STAT signaling pathways with relapse, warranting future validation., Trial Registration Number: NCT01176474 and NCT02970981., Competing Interests: Competing interests: Conflicts of Interest Disclosures: NIK: Advisory Board (Bristol Myers Squibb, Regeneron, Merck, Jounce Therapeutics, Iovance Biotherapeutics, Genzyme, Novartis, Castle Biosciences, Nektar, Instill Bio); Steering or Scientific Committee Member (Nektar, Regeneron, Replimmune, Bristol Myers Squibb, National Comprehensive Cancer Network via Pfizer); Data Safety Monitoring Committee (AstraZeneca, Incyte); Research support (all to institution—Bristol Myers Squibb, Merck, Celgene, Regeneron, Replimmune, Novartis, HUYA Bioscience, GlaxoSmithKline); Common stock (Bellicum, Amarin, Asensus Surgical). ZE: Advisory Board (Pfizer, Array, OncoSec, Regeneron, Genentech, Novartis, Eisai, Natera); Research funding (Novartis, Pfizer). YK: No disclosures to report. BC: No disclosures to report. JDG: President, Statistical Science and Technology Associates; Consultant (Tizona); BMS retirement W2 income; Pfizer pension. MV: No disclosures to report. RF: No disclosures to report. KM: No disclosures to report. TK: No disclosures to report. PB: No disclosures to report. AS: No disclosures to report. EM: No disclosures to report. CMA: No disclosures to report. GTG: Consulting fees from Bristol Myers Squibb, Merck, Regeneron, Esai, Genentech, Novartis, Sapience Therapeutics and Exicure; Institutional research support from Exelixis and Lucerno Dynamics. RK: Advisory Board (Bristol Myers Squibb, Regeneron, Merck, InstilBio, Novartis, Pfizer); Research funding from Bristol Myers Squibb, Regeneron, Merck). JM: Support by NIH/NCI K08CA252164; Research support to Moffitt Cancer Center from Microba Life Science, Morphogenesis, Dr Miriam and Sheldon Adelson Medical Research Foundation, and The Jackson Laboratory. ASB: Advisory board (Deciphera, Bayer). AP: Consultant for BMS, Merck and Regeneron. AR: No disclosures to report. DMW: Owns stocks in BMS (less than $1000). JW: Received less than $10,000 dollars per annum from Merck, Genentech, AstraZeneca, GSK, Novartis, Nektar, Celldex, Incyte, Biond, ImCheck, Sellas, Evaxion and EMD Serono and $10,000–$25,000 dollars from BMS for membership on Advisory Boards; Equity in Biond, Evaxion, OncoC4, Instil Bio and Neximmune; on scientific advisory boards for CytoMx, Incyte, ImCheck, Biond, Sellas, Instil Bio OncoC4 and Neximmune and was remunerated between $10,000–$75,000 dollars; NYU, but not me personally, received research support from BMS, Merck, GSK, Moderna, Pfizer, Novartis and AstraZeneca; Moffitt Cancer Center filed a patent on an IPILIMUMAB biomarker and on TIL preparation that I am named on, and Biodesix filed a PD-1 patent that I was named on; I receive less than $6000 yearly in royalties., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Nivolumab was approved as adjuvant therapy for melanoma based on data from CheckMate 238, which enrolled patients per American Joint Committee on Cancer version 7 (AJCC-7) criteria. Here, we analyse long-term outcomes per AJCC-8 staging criteria compared with AJCC-7 results to inform clinical decisions for patients diagnosed per AJCC-8., Patients and Methods: In a double-blind, phase 3 trial (NCT02388906), patients aged ≥15 years with resected, histologically confirmed AJCC-7 stage IIIB, IIIC, or IV melanoma were randomised to receive nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for 4 doses and then every 12 weeks, both intravenously ≤1 year. Recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were assessed in patients with stage III disease, per AJCC-7 and AJCC-8., Results: Per AJCC-7 staging, 42.4% and 57.3% of patients were in substage IIIB and IIIC, respectively; per AJCC-8, 1.1%, 30.4%, 62.8%, and 5.0% were in IIIA, IIIB, IIIC, and IIID. After 4 years' minimum follow-up, the AJCC-7 superior efficacy of nivolumab over ipilimumab in patients with resected stage III melanoma was preserved per AJCC-8 analysis. No statistically significant difference in RFS between stage III substage hazard ratios was observed per AJCC-7 or -8 staging criteria (interaction test: AJCC-7, P = 0.8115; AJCC-8, P = 0.1051; P = 0.8392 ((AJCC-7) and P = 0.8678 (AJCC-8) for DMFS)., Conclusions: CheckMate 238 4-year RFS and DMFS outcomes are consistent per AJCC-7 and AJCC-8 staging criteria. Outcome benefits can therefore be translated for patients diagnosed per AJCC-8., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JLa has worked in a consulting/advisory role for iOnctura, Apple Tree, Merck, Bristol Myers Squibb (BMS), Eisai, Debipharm, and Incyte; has received honoraria from AstraZeneca, BMS, Eisai, EUSA Pharma, GlaxoSmithKline (GSK), Incyte, Ipsen, Merck, touchEXPERTS, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, Merck Sharp & Dohme (MSD), Novartis, Aptitude, Pierre Fabre, Pfizer, Roche, Seagen, Inselgruppe, eCancer, Ultimovacs, Calithera, and Goldman Sachs; and has received research/grant support from Achilles Therapeutics, BMS, Immunocore, Aveo, Pharmacyclics, MSD, Nektar Therapeutics, Covance, Novartis, Pfizer, and Roche. JW has worked in a consulting/advisory role for, received honoraria from, and received institutional research/grant support from BMS; and is named on a patent for a PD-1 biomarker not used in the current trial. MDV has worked in a consulting/advisory role for and received honoraria from BMS, MSD, Novartis, and Pierre Fabre. HG has worked in a consulting/advisory role for Amgen, BMS, MSD, and Replimune; has received honoraria from BMS, MSD, Novartis, Sanofi, and Pierre Fabre; and has received research/grant support from Amgen, BMS, Iovance, MSD, Pfizer, and Replimune. AMA has worked in a consulting/advisory role for, and received honoraria from Pierre Fabre, Novartis, BMS, Merck, Roche, MSD, and Sanofi; and has served as a speaker/provided expert testimony for BMS, Merck, Pierre Fabre, Novartis, MSD, Sanofi, and Roche. SD has received research/grant support from BMS and MSD; has received travel/congress support from BMS; and has worked in an advisory role for MSD. CLC has worked in a consulting/advisory role for Merck, Novartis, Pfizer, Sanofi, and Eisai. MS has received research/grant support from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BMS, BeiGene, Bioven, Clovis Pharmaceutical, Daiichi Sankyo, Eli Lilly, Gilead, GSK, Merck Serono, MSD, Mylan, Novartis, Pfizer, Regeneron, Roche, Sanofi, and Tesaro. J-JG has worked in a consulting/advisory role for Amgen, BMS, MSD, Novartis, Philogen, Pierre Fabre, Roche, and Sanofi. VC-S has received honoraria from Pierre Fabre, Novartis, and BMS; and has received travel/congress support from Novartis and Pierre Fabre. IM-R has worked in a consulting/advisory role for AstraZeneca, Amgen, BMS, Incyte, Merck Serono, MSD, Novartis, Pierre Fabre, Roche, Sun Pharma, Highlight Therapeutics, Regeneron, and Sanofi; has received honoraria from BMS, MSD, Roche, Pierre Fabre, Novartis, and Sun Pharma; and has received travel/congress support from BMS, MSD, Novartis, Pierre Fabre, Roche, and Sun Pharma. MOB has worked in a consulting/advisory role for BMS, GSK, Immunocore, Merck, Novartis, Pfizer, Adaptimmune, Sun Pharma, Instil Bio, IOVANCE, Medison, LaRoche Possey, and Sanofi; has received research/grant support from Merck, Takara Bio, and Novartis; has received honoraria from Sanofi, BMS, Merck, and Novartis; and has served on the safety review board for Adaptimmune, and GSK. AMDG has worked in a consulting/advisory role for BMS, MSD, Pierre Fabre, Novartis, and Sanofi; has received honoraria from BMS, MSD, Pierre Fabre, and Sanofi; and has received travel/congress support from Pierre Fabre. MRM has worked in a consulting/advisory role for Novartis, BioLineRx, BMS, Immunocore, Kineta, Merck, and Silicon Therapeutics; and has received institutional research/grant support from Roche, Astrazeneca, GSK, Immunocore, BioLineRx, Pfizer, Regeneron, Replimune, and GRAIL. LDlC-M has received honoraria from BMS, Merck, MSD, Roche, AstraZeneca, and Gilead; and has received travel/congress support from Gilead. VA has worked in a consulting/advisory role for BMS, MSD, Nektar Therapeutics, Novartis, Pierre Fabre, and Q Biotics; has received honoraria from BMS, MSD, Novartis, Pierre Fabre, Nektar Therapeutics, and Q Biotics; and has given expert testimony for BMS. AH is an employee of Tasman Oncology; has received honoraria from BMS; has received travel/congress support from BMS and Merck; and holds stock in Tasman Oncology. LAF has worked in a consulting/advisory role for Elsevier, and Via Oncology; has received cooperative group research/grant support from Array BioPharma and Pfizer; has received institutional research/grant support from Array BioPharma, BMS, EMD Serono, Incyte, Kartos Therapeutics, Merck, and Pfizer; has received honoraria from ASCO, and the Michigan Society of Hematology and Oncology; and has served on the data and safety monitoring board of the Hoosier Cancer Research Network. MMi has worked in a consulting/advisory role for BMS, Novartis, Roche, MSD, The Limbic, Takeda, Guardant Health, Beigene, Amgen, Merck, and Lilly; has received honoraria from BMS, Roche, and The Limbic; has received travel/congress support from AstraZeneca; and has served in a leadership position for Melanoma and Skin Cancer Trials Australia. NIK has received institutional research/grant support from Amgen, BMS, Celgene, GSK, HUYA Bioscience, Merck, Novartis, Regeneron, and Replimune; had received honoraria from Novartis and Replimune; holds stock in Amarin, Asensus, Bellicum, and Mazor Robotics; has served on the data and safety monitoring or advisory board of AstraZeneca, BMS, Castle Biosciences, Genzyme, Incyte, Instil Bio, Iovance, Merck, NCCN, Nektar Therapeutics, Novartis, and Regeneron; and has served in a leadership position for BMS, NCCN, Nektar Therapeutics, Regeneron, and Replimune. PQ has received honoraria from and served on the data safety monitoring board or advisory board of Novartis, Sun Pharma, Pierre Fabre, BMS, MSD, Merck, Sanofi, and Roche; and has received travel/congress support from MSD. GVL has worked in a consulting/advisory role for Agenus, Amgen, Array Biopharma, Boehringer Ingelheim, BMS, Evaxion, Hexal AG, Highlight Therapeutics, MSD, Novartis, OncoSec, Pierre Fabre, Provectus Australia, QBiotics, and Regeneron; and has received honoraria from BMS and Pierre Fabre. ML and MA are employees of BMS. PAA has worked in a consulting/advisory role for Array BioPharma, AstraZeneca, Boehringer Ingelheim, BMS, Idera Pharmaceuticals, Immunocore, Italfarmaco, Nektar, Pfizer, Lunaphore, Medicenna, Bio-AI Health, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, iTeos, 4SC, MSD, Merck Serono, Novartis, Pierre Fabre, Roche/Genentech, Sandoz, Sanofi, and Sun Pharma; and has received research/grant support from Array BioPharma, Pfizer, BMS, Sanofi, and Roche/Genentech. MMan has worked in a consulting/advisory role for BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sun Pharma; has received honoraria from Novartis, BMS, MSD, Pierre Fabre, Sanofi, and Sun Pharma; and has received research/grant support from Novartis. All remaining authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Until recently, most patients with sentinel lymph node-positive (SLN+) melanoma underwent a completion lymph node dissection (CLND), as mandated in published trials of adjuvant systemic therapies. Following multicenter selective lymphadenectomy trial-II, most patients with SLN+ melanoma no longer undergo a CLND prior to adjuvant systemic therapy. A retrospective analysis of clinical outcomes in SLN+ melanoma patients treated with adjuvant systemic therapy after July 2017 was performed in 21 international cancer centers. Of 462 patients who received systemic adjuvant therapy, 326 patients received adjuvant anti-PD-1 without prior immediate (IM) CLND, while 60 underwent IM CLND. With median follow-up of 21 months, 24-month relapse-free survival (RFS) was 67% (95% CI 62% to 73%) in the 326 patients. When the patient subgroups who would have been eligible for the two adjuvant anti-PD-1 clinical trials mandating IM CLND were analyzed separately, 24-month RFS rates were 64%, very similar to the RFS rates from those studies. Of these no-CLND patients, those with SLN tumor deposit >1 mm, stage IIIC/D and ulcerated primary had worse RFS. Of the patients who relapsed on adjuvant anti-PD-1, those without IM CLND had a higher rate of relapse in the regional nodal basin than those with IM CLND (46% vs 11%). Therefore, 55% of patients who relapsed without prior CLND underwent surgery including therapeutic lymph node dissection (TLND), with 30% relapsing a second time; there was no difference in subsequent relapse between patients who received observation vs secondary adjuvant therapy. Despite the increased frequency of nodal relapses, adjuvant anti-PD-1 therapy may be as effective in SLN+ pts who forego IM CLND and salvage surgery with TLND at relapse may be a viable option for these patients., Competing Interests: Competing interests: ZE: Advisory boards: Array, Pfizer, OncoSec, Regeneron, Genentech, Novartis, Natera. Research funding: Novartis, Pfizer, Boehringer-Ingelheim. JFT: Advisory boards: BMS Australia, MSD Australia, GSK, Provectus Inc. Travel support: GSK, Provectus Inc and Novartis. TJH: Research funding: Genentech, SkylineDX. EKB: Research funding: SkylineDx, Honorarium: Excite International inc. DEG: Honoraria: BMS, Novartis, Q biotics. GK; Advisory Board: Merck. AVA: Advisory Boards: Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Provectus, Sanofi, Sirius Medical, 4SC Research funding: Amgen, Merck-Pfizer. JV: Speaker: Caste Biosciences. GB: Research funding: Istari Oncology, Delcath, Oncosec Medical, Replimune, Checkmate Pharmaceuticals. ROB: Advisory boards: Amgen, BD/BARD, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche and Sanofi Genzyme. Research funding: Bristol-Myers Squibb, SkyLineDx. Speaker honorarium: Roche and Pfizer. Shareholder in SATMEG Ventures AB. NIK: Advisory boards: Bristol-Myers Squibb, AstraZeneca, Regeneron, Array, Immunocore, Merck, Incyte, Jounce Therapeutics,Pfizer,Novartis, Nektar,Castle Biosciences, Instil Bio. Research funding: Bristol-Myers Squibb, Merck, Novartis, Celgene, Replimune, Amgen, Regneron, HUYA, GlaxoSmithKline Stocks: Bellicum Pharmaceuticals, Amarin Corporation, Asensus Surgical., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Acral melanoma is a rare subtype of melanoma that arises on the non-hair-bearing skin of the palms, soles, and nail beds. In this study, we used single-cell RNA sequencing (scRNA-seq) to map the transcriptional landscape of acral melanoma and identify novel immunotherapeutic targets., Experimental Design: We performed scRNA-seq on nine clinical specimens (five primary, four metastases) of acral melanoma. Detailed cell type curation was performed, the immune landscapes were mapped, and key results were validated by analysis of The Cancer Genome Atlas (TCGA) and single-cell datasets. Cell-cell interactions were inferred and compared with those in nonacral cutaneous melanoma., Results: Multiple phenotypic subsets of T cells, natural killer (NK) cells, B cells, macrophages, and dendritic cells with varying levels of activation/exhaustion were identified. A comparison between primary and metastatic acral melanoma identified gene signatures associated with changes in immune responses and metabolism. Acral melanoma was characterized by a lower overall immune infiltrate, fewer effector CD8 T cells and NK cells, and a near-complete absence of γδ T cells compared with nonacral cutaneous melanomas. Immune cells associated with acral melanoma exhibited expression of multiple checkpoints including PD-1, LAG-3, CTLA-4, V-domain immunoglobin suppressor of T cell activation (VISTA), TIGIT, and the Adenosine A2A receptor (ADORA2). VISTA was expressed in 58.3% of myeloid cells and TIGIT was expressed in 22.3% of T/NK cells., Conclusions: Acral melanoma has a suppressed immune environment compared with that of cutaneous melanoma from nonacral skin. Expression of multiple, therapeutically tractable immune checkpoints were observed, offering new options for clinical translation., (©2022 American Association for Cancer Research.)

The Great Debate session at the 2021 Melanoma Bridge virtual congress (December 2-4) featured counterpoint views from experts on seven important issues in melanoma. The debates considered the use of adoptive cell therapy versus use of bispecific antibodies, mitogen-activated protein kinase (MAPK) inhibitors versus immunotherapy in the adjuvant setting, whether the use of corticosteroids for the management of side effects have an impact on outcomes, the choice of programmed death (PD)-1 combination therapy with cytotoxic T-lymphocyte-associated antigen (CTLA)-4 or lymphocyte-activation gene (LAG)-3, whether radiation is needed for brain metastases, when lymphadenectomy should be integrated into the treatment plan and then the last debate, telemedicine versus face-to-face. As with previous Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their respective personal view. Audiences voted both before and after each debate., (© 2022. The Author(s).)

Advances in melanoma treatments over the past decade have changed the course of survival for patients. Several adjuvant therapies have been approved and are now considered standard of care for high-risk patients. These therapies have shown improvements for recurrence-free survival and distant metastases-free survival, but not overall survival, as the data are maturing. The 5-year recurrence-free survival in the COMBI-AD study, which compared dabrafenib and trametinib with placebo, was 65% and 58%, respectively. In the KEYNOTE-054 study, the recurrence-free survival at 3 years was 63.7% versus 41%. Despite these advances, approximately 50% of patients will succumb to their disease. Adjuvant therapy is considered potentially curative and avoids the morbidity of relapsed disease and the poor outcomes seen in metastatic disease. However, the lack of overall survival benefit in clinical trials of patients with high-risk stage II and stage III disease raises the question of whether it is more efficacious to treat when there is residual microscopic disease, or to wait until the disease recurs to avoid treating those who may have been cured by surgery alone. Immunotherapy also has the potential for substantial toxicity that may be lifelong; hence, discussion of risks and benefits of therapy is warranted because there should be less tolerance for substantial toxicity in the adjuvant setting. Adjuvant trials are needed that will integrate biomarkers to allow for better selection of patients who will truly benefit from adjuvant therapy.

Bempegaldesleukin (BEMPEG: NKTR-214) is an immunostimulatory IL-2 cytokine prodrug engineered to deliver a controlled, sustained and preferential IL-2 pathway signal. Nivolumab (NIVO), a PD-1 inhibitor, has been shown to prolong survival in patients with advanced melanoma and recurrence-free survival in the adjuvant setting. PIVOT-02 showed that BEMPEG plus NIVO was well-tolerated and demonstrated clinical activity as first-line therapy in metastatic melanoma. PIVOT-12 is a randomized, phase III, global, multicenter, open-label study comparing adjuvant therapy with BEMPEG plus NIVO versus NIVO alone in adult and adolescent patients with completely resected cutaneous stage III/IV melanoma at high risk of recurrence. The primary objective is to compare the efficacy, as measured by recurrence-free survival, of BEMPEG plus NIVO versus NIVO.

We conducted a randomized phase III trial to evaluate whether adjuvant pembrolizumab for one year (647 patients) improved recurrence-free survival (RFS) or overall survival (OS) in comparison with high-dose IFNα-2b for one year or ipilimumab for up to three years (654 patients), the approved standard-of-care adjuvant immunotherapies at the time of enrollment for patients with high-risk resected melanoma. At a median follow-up of 47.5 months, pembrolizumab was associated with significantly longer RFS than prior standard-of-care adjuvant immunotherapies [HR, 0.77; 99.62% confidence interval (CI), 0.59-0.99; P = 0.002]. There was no statistically significant association with OS among all patients (HR, 0.82; 96.3% CI, 0.61-1.09; P = 0.15). Proportions of treatment-related adverse events of grades 3 to 5 were 19.5% with pembrolizumab, 71.2% with IFNα-2b, and 49.2% with ipilimumab. Therefore, adjuvant pembrolizumab significantly improved RFS but not OS compared with the prior standard-of-care immunotherapies for patients with high-risk resected melanoma., Significance: Adjuvant PD-1 blockade therapy decreases the rates of recurrence, but not survival, in patients with surgically resectable melanoma, substituting the prior standard-of-care immunotherapies for this cancer. See related commentary by Smithy and Shoushtari, p. 599. This article is highlighted in the In This Issue feature, p. 587., (©2021 American Association for Cancer Research.)

Background: Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial., Methods: This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5-3·0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0-2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting ≥6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov, NCT02320058., Findings: Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34·3 months [IQR 14·7-36·4]) and 18 were symptomatic (cohort B; median follow-up 7·5 months [1·2-35·2]). Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% [95% CI 47·2-67·2]) of 101 patients in cohort A and three (16·7% [3·6-41·4]) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53·5% [43·3-63·5]) patients in cohort A and three (16·7% [3·6-41·4]) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator-assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54·1% (95% CI 42·7-64·1) and overall survival was 71·9% (61·8-79·8). For patients in cohort B, 36-month intracranial progression-free survival was 18·9% (95% CI 4·6-40·5) and overall survival was 36·6% (14·0-59·8). The most common grade 3-4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five [5%] of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A)., Interpretation: The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination., Funding: Bristol Myers Squibb., Competing Interests: Declaration of interests HAT worked in a consulting/advisory role for Array BioPharma, Bristol Myers Squibb (BMS), Genentech/Roche, Merck, and Novartis; participated in a scientific advisory board for Kayopharm; received research/grant support from BMS, Celgene, Genentech/Roche, GlaxoSmithKline (GSK), and Merck; and received honoraria from Eisai. PAF worked in a consulting role for AbbVie, Boehringer Ingelheim, NCI Neuro-Oncology Branch Peer Review, Novellus, Physical Sciences Oncology Network, Tocagen, and Ziopharm; received honoraria from BTG, NCRI, Tocagen, and Ziopharm; worked in an advisory role for Bayer, Inovio, Novocure, and BTG; and received research/grant support from CDMRP, NIH/NCI, Department of Defense, Pfizer, State of Florida Bankhead Coley, and Moffitt Center of Excellence Celgene Project. FSH worked in a consulting role for BMS, Corner Therapeutics, Eisai, EMD Serono, Genentech/Roche, Gossamer, Idera, Kairos, Merck, Novartis, Psioxus Therapeutics, Pieris Pharmaceutical, Takeda, and Sanofi; worked in an advisory role for 7 Hills Pharma, Aduro, Apricity, Bicara, Checkpoint Therapeutics, Pionyr, and Torque; received research/grant support from BMS and Novartis; received royalties from BMS and Novartis; and holds equity in Apricity. APA worked in an advisory role for Array BioPharma, OncoSec Medical, and Regeneron; received research/grant support from Acerta, Amgen, AstraZeneca, BMS, Dynavax, Genentech, Idera, Incyte, ISA, LOXO, Merck, Novartis, OncoSec Medical, Regeneron, Sensei, and Tessa; received travel/accommodations/expenses support from OncoSec Medical; and holds stock in OncoSec Medical and Valitor Biosciences. OH worked in a consulting role for and received research/grant support from Aduro, Akeso, Amgen, Beigene, Bioatla, BMS, Genentech, GSK, Immunocore, Idera, Incyte, Janssen, Merck, NextCure, Novartis, Pfizer, Sanofi Regeneron, Seagen, Tempus, and Zelluna; received research/grant support from BMS; and served as a speaker for BMS, Novartis, Pfizer, and Sanofi Regeneron. CDL received research/grant support from Novartis and Merck; worked in an advisory role for BMS and Immunocore; and received travel/accommodations/expenses support from BMS and Immunocore. SJM received research/grant support from Amgen, Merck, and Syndax Pharmaceuticals; worked in a consulting role for iTeos Therapeutics and EMD Serono; and participated in a Data Safety Monitoring board for IQVIA. MBA worked in a consulting role for Adagene, Agenus, AstraZeneca, Calithera, Exelixis, Idera, Immunocore, Iovance, Neoleukin, Sanofi, SeaGen, and Takeda; and worked in an advisory role for Apexigen, Aveo, BMS, Eisai, Elpis, Genentech/Roche, Leads Biopharma, Merck, Novartis, Pfizer, PACT, Pyxis Oncology, and Werewolf Therapeutics. KL received research/grant support from BMS, Merck, Roche/Genentech, Pfizer, and Regeneron; and worked in a consulting role for Merck, Roche/Genentech, and Pfizer. MAP worked in a consulting/advisory role for Aduro, BMS, Eisai, Incyte, Merck, NewLink Genetics, Novartis, and Pfizer; received research/grant support from Array BioPharma, AstraZeneca, BMS, Infinity, Merck, Novartis, and RGenix; and received honoraria from BMS and Merck. SJ worked in a consulting/advisory role for Array Biopharma, BMS, EMD Sorono, Genentech, Novartis, Sanofi, Sun Biopharma, and Pfizer. NIK worked in an advisory role for Array BioPharma, BMS, EMD Serono, Genentech, HUYA Bioscience International, Immunocore, Merck, Regeneron, and Jounce; received research/grant support from Amgen, BMS, Celgene, GSK, HUYA Bioscience International, Merck, Novartis, Replimmune, and Regeneron; received honoraria from BMS and Sanofi; holds stock in Amarin Corporation, Bellicum Pharmaceuticals, Mazor Robotics, and Asensus Surgical (formerly TransEnterix); participated in a Data Safety Monitoring board for AstraZeneca and Incyte; and participated in the Scientific Review Committee for NCCN (from Pfizer) and study steering committees for BMS, Regeneron, and Nektar. ACP worked in a consulting/advisory role for BMS, Merck, Regeneron, and Sanofi/Regeneron; received research/grant support from BMS, Merck, Regeneron, and Replimune; and worked on a speaker's bureau for BMS. MSE participated in a Data Safety Monitoring board for BMS; and holds stock or stock options in BMS. DAR worked in a consulting/advisory role for AbbVie, Advantagene, Agenus, Amgen, Bayer, BMS, Boston Biomedical, Celldex, DelMar, EMD Serono, Genentech/Roche, Inovio, Medicenna, Merck, Merck KGaA, Monteris, Oncorus, Oxigene, Novocure, Regeneron, Stemline, and Taiho; and received research/grant support from Tragara, Acerta Pharmaceuticals, Agenus, Celldex, EMD Serono, Incyte, Inovio, Midatech, and Omniox. RK worked in a consulting/advisory role for Array BioPharma, BMS, Immunocore, Merck, Novartis, Pfizer, and Regeneron; received research/grant support from BMS, Merck, and Regeneron; received honoraria from Array BioPharma and BMS; and received travel/accommodations/expenses support from BMS. AT worked in a consulting/advisory role for Array Biopharma, BioNTech, BMS, Clinigen, EMD Serono, Genentech/Roche, Immunocore, Merck, NewLink Genetics, Novartis, Partner Therapeutics, Pfizer, and Sanofi-Genzyme/Regeneron; and received research/grant support from BMS, Genentech/Roche, OncoSec Medical, Merck, Sanjofi-Genzyme, Regeneron, Clinigen, and CheckMate. CC received research/grant support from Siemens Healthineers and Raysearch Laboratories; and received honorarium from Elekta. CR and PD are employees of BMS and hold BMS stock or stock options. MA is an employee of BMS. IP worked in a consulting role for Amgen, Merck, and Nouscom. KAM worked in a consulting/advisory role for ImaginAb, Oncosec, Werewolf, Xilio, and Tentarix; participated in a Data Safety Monitoring board for CheckMate Pharmaceuticals; and received research/grant support from ImaginAb. RPT and JG report no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: In patients with melanoma and asymptomatic brain metastases (MBM), nivolumab plus ipilimumab provided an intracranial response rate of 55%. Here, we present the first report for patients who were symptomatic and/or required corticosteroids and updated data for asymptomatic patients., Methods: Patients with measurable MBM, 0.5-3.0 cm, were enrolled into Cohort A (asymptomatic) or Cohort B (stable neurologic symptoms and/or receiving corticosteroids). Nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg, were given intravenously every 3 weeks ×4, followed by nivolumab, 3 mg/kg, every 2 weeks until progression, unacceptable toxicity, or 24 months. The primary endpoint was intracranial clinical benefit rate (CBR; complete response [CR], partial response [PR], or stable disease ≥6 months)., Results: Symptomatic patients (N = 18) received a median of one nivolumab and ipilimumab combination dose and had an intracranial CBR of 22.2%. Two of 12 patients on corticosteroids had CR; 2 responded among the 6 not on corticosteroids. Median intracranial progression-free survival (PFS) and overall survival (OS) were 1.2 and 8.7 months, respectively. In contrast, with 20.6 months of follow-up, we confirmed an intracranial CBR of 58.4% in asymptomatic patients (N = 101); median duration of response, PFS, and OS were not reached. No new safety signals were observed., Conclusions: Nivolumab plus ipilimumab provides durable clinical benefit for asymptomatic patients with MBM and should be considered for first-line therapy. This regimen has limited activity in MBM patients with neurologic symptoms and/or requiring corticosteroids, supporting the need for alternative approaches and methods to reduce the dependency on corticosteroids. Clinical trial registration. ClinicalTrials.gov, NCT02320058., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Purpose: Effective treatment options are limited for patients with advanced (metastatic or unresectable) melanoma who progress after immune checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes has demonstrated efficacy in advanced melanoma. Lifileucel is an autologous, centrally manufactured tumor-infiltrating lymphocyte product., Methods: We conducted a phase II open-label, single-arm, multicenter study in patients with advanced melanoma who had been previously treated with checkpoint inhibitor(s) and BRAF ± MEK targeted agents. Lifileucel was produced from harvested tumor specimens in central Good Manufacturing Practice facilities using a streamlined 22-day process. Patients received a nonmyeloablative lymphodepletion regimen, a single infusion of lifileucel, and up to six doses of high-dose interleukin-2. The primary end point was investigator-assessed objective response rate (ORR) per RECIST, version 1.1., Results: Sixty-six patients received a mean of 3.3 prior therapies (anti-programmed death 1 [PD-1] or programmed death ligand 1 [PD-L1]: 100%; anticytotoxic T-lymphocyte-associated protein-4: 80%; BRAF ± MEK inhibitor: 23%). The ORR was 36% (95% CI, 25 to 49), with two complete responses and 22 partial responses. Disease control rate was 80% (95% CI, 69 to 89). Median duration of response was not reached after 18.7-month median study follow-up (range, 0.2-34.1 months). In the primary refractory to anti-PD-1 or PD-L1 therapy subset, the ORR and disease control rate were 41% (95% CI, 26 to 57) and 81% (95% CI, 66 to 91), respectively. Safety profile was consistent with known adverse events associated with nonmyeloablative lymphodepletion and interleukin-2., Conclusion: Lifileucel demonstrated durable responses and addresses a major unmet need in patients with metastatic melanoma with limited treatment options after approved therapy, including the primary refractory to anti-PD-1 or PD-L1 therapy subset., Competing Interests: Amod A. SarnaikHonoraria: Physicans' Education ResourceConsulting or Advisory Role: B4CC, Iovance Biotherapeutics, Guidepoint Global, Defined Health, Gerson Lehrman GroupResearch Funding: Provectus, Genentech, Iovance BiotherapeuticsPatents, Royalties, Other Intellectual Property: Compositions and methods for improving tumor-infiltrating lymphocytes for adoptive cell therapy, filed March 20, 2014 US Patent Application No. 61/955,970 and second Application No. 61/973,002Travel, Accommodations, Expenses: Iovance Biotherapeutics Omid HamidHonoraria: Bristol Myers Squibb, Novartis, Sanofi/Regeneron, PfizerConsulting or Advisory Role: Amgen, Novartis, Roche, Bristol Myers Squibb, Merck, Aduro Biotech, Akeso Biopharma, BeiGene, Genentech, GlaxoSmithKline, Immunocore, Incyte, Janssen, NextCure, Regeneron, Sanofi, Seattle Genetics, Tempus, Zelluna, BioAtla, Idera, PfizerSpeakers' Bureau: Bristol Myers Squibb, Novartis, Sanofi/Regeneron, PfizerResearch Funding: Bristol Myers Squibb, Genentech, Immunocore, Incyte, Merck, Merck Serono, Novartis, Pfizer, Roche, Amgen, CytomX Therapeutics, Iovance Biotherapeutics, NextCure, GlaxoSmithKline, Arcus Biosciences, Aduro Biotech, Akeso Biopharma, Exelixis, Moderna Therapeutics, Regeneron, Sanofi, Seattle Genetics, Torque, Zelluna, Bioatla, Idera Nikhil I. KhushalaniStock and Other Ownership Interests: Bellicum Pharmaceuticals, Mazor Robotics, Amarin Corporation, Asensus SurgicalHonoraria: SanofiConsulting or Advisory Role: Bristol Myers Squibb, AstraZeneca, Regeneron, Array BioPharma, Immunocore, Merck, Incyte, Jounce Therapeutics, Iovance Biotherapeutics, NCCN/PfizerResearch Funding: Bristol Myers Squibb, Merck, Novartis, GlaxoSmithKline, HUYA Bioscience International, Amgen, Regeneron, Celgene, Replimune Karl D. LewisHonoraria: Array BioPharma, Iovance BiotherapeuticsConsulting or Advisory Role: Array BioPharma, Merck, Roche, Regeneron, Sanofi, Iovance BiotherapeuticsResearch Funding: Roche/Genentech, Merck, Array BioPharma, Incyte, Nektar, Iovance Biotherapeutics, Bristol Myers Squibb, Kartos Therapeutics, OncoSec, Regeneron, Alkermes, Neon Therapeutics, Ultimovacs, Senhwa Biosciences, Replimune, AmgenTravel, Accommodations, Expenses: Merck, Roche/Genentech, Regeneron, Neon Therapeutics, AlkermesUncompensated Relationships: Roche/Genentech, Regeneron Theresa MedinaConsulting or Advisory Role: Bristol Meyer Squibb, Iovance BiotherapeuticsResearch Funding: Merck, Replimune, Bristol Myers Squibb, Iovance Biotherapeutics, Nektar, Immunocore, Checkmate Pharmaceuticals, BioAtla Harriet M. KlugerConsulting or Advisory Role: Nektar, Celldex, Iovance Biotherapeutics, Merck, Immunocore, Array BioPharma, ElevateBio, Instil Bio, Clinigen Group, Shionogi, Bristol Myers SquibbResearch Funding: Merck, Bristol Myers Squibb, ApexigenTravel, Accommodations, Expenses: Apexigen Sajeve S. ThomasSpeakers' Bureau: BMS, Merck, Genentech, Ipsen, Amgen, Pfizer, Novartis Evidio Domingo-MusibayHonoraria: RegeneronConsulting or Advisory Role: Sanofi/Regeneron, Castle BiosciencesSpeakers' Bureau: Sanofi/RegeneronResearch Funding: Clinigen Group, Iovance Biotherapeutics, Nektar Anna C. PavlickConsulting or Advisory Role: Bristol Myers Squibb, Merck, Regeneron, Sanofi/RegeneronResearch Funding: Bristol Myers Squibb, Merck, Millennium, Regeneron, Replimune Eric D. WhitmanConsulting or Advisory Role: Merck Sharp & Dohme, Bristol Myers Squibb, Castle Biosciences, Novartis, Eisai, PfizerSpeakers' Bureau: Bristol Myers Squibb, Merck Sharp & Dohme, Castle Biosciences, Sanofi/RegeneronResearch Funding: Bristol Myers Squibb, Merck Sharp & Dohme, Castle Biosciences, Genentech/Roche, Amgen, TRACON Pharma, AstraZeneca/MedImmune, Provectus, Oncolys BioPharma, Iovance Biotherapeutics, Dynavax Technologies, OncoSec, Toray Industries, Array BioPharmaPatents, Royalties, Other Intellectual Property: Nerve monitoring dissection device, Lighted Polyhedral surgical retractor Salvador Martin-AlgarraConsulting or Advisory Role: MSD Oncology, Sanofi, Regeneron, AstraZenecaSpeakers' Bureau: Bristol Myers Squibb, MSD Oncology, AstraZeneca, Novartis, Roche, Sanofi/RegeneronTravel, Accommodations, Expenses: Pierre Fabre, Roche, MSD Oncology Pippa CorrieHonoraria: Novartis, Merck Sharp & Dohme, Pierre Fabre, Bristol Myers SquibbConsulting or Advisory Role: Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Incyte, Pierre Fabre, Roche, MicrobioticaSpeakers' Bureau: Merck Sharp & Dohme, Novartis, Bristol Myers SquibbResearch Funding: MSD, Bristol Myers Squibb, Novartis, Array BioPharma, Celgene, Halozyme, Iovance Biotherapeutics, LillyTravel, Accommodations, Expenses: Bristol Myers Squibb, Merck Sharp & Dohme Brendan D. CurtiHonoraria: Clinigen Group, NektarConsulting or Advisory Role: MerckResearch Funding: Bristol Myers Squibb, Galectin Therapeutics, Clinigen GroupPatents, Royalties, Other Intellectual Property: Biomarkers for OX40 responseTravel, Accommodations, Expenses: Agonox Jose LutzkyConsulting or Advisory Role: Castle Biosciences, Iovance Biotherapeutics, Replimune, RegeneronResearch Funding: Bristol Myers Squibb, Novartis, Iovance Biotherapeutics, Immunocore, Regeneron, Replimune, Vyriad Jeffrey S. WeberStock and Other Ownership Interests: CytomX Therapeutics, Biond Biologics, Protean Biodiagnostics, NeximmuneHonoraria: Bristol Myers Squibb, Merck, Genentech, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Amgen, Roche, Celldex, CytomX Therapeutics, Novartis, Sellas Life Sciences, WindMIL, Takeda, Moderna Therapeutics, Jounce Therapeutics, Kirin Pharmaceuticals, Regeneron, Idera, OncosecConsulting or Advisory Role: Celldex, Bristol Myers Squibb, Merck, Genentech, Roche, Amgen, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, CytomX Therapeutics, Novartis, Sellas Life Sciences, WindMIL, Jounce Therapeutics, Moderna Therapeutics, Kirin Pharmaceuticals, Protean Biodiagnostics, Idera, OncosecResearch Funding: Bristol Myers Squibb, Merck, GlaxoSmithKline, Genentech, Astellas Pharma, Incyte, Roche, Novartis, NextCure, Moderna TherapeuticsPatents, Royalties, Other Intellectual Property: Named on a patent submitted by Moffitt Cancer Center for an IPILIMUMAB biomarker, named on a patent from Biodesix for a PD-1 antibody biomarker, named on a patent for 41BB induced TIL by Moffitt Cancer CenterTravel, Accommodations, Expenses: Bristol Myers Squibb, GlaxoSmithKline, Roche, Celldex, Amgen, Merck, AstraZeneca, Genentech, Novartis James M. G. LarkinHonoraria: Eisai, Bristol Myers Squibb, MSD, GlaxoSmithKline, Pfizer, Novartis, Roche/Genentech, Pierre Fabre, EUSA Pharma, Achilles Therapeutics, AstraZeneca, Boston Biomedical, Ipsen, Imugene, Incyte, iOncologi, Merck Serono, Nektar, Vitaccess, Kymab, SecarnaConsulting or Advisory Role: Eisai, Bristol Myers Squibb, MSD, GlaxoSmithKline, Pfizer, Novartis, Roche/Genentech, Pierre Fabre, EUSA Pharma, Achilles Therapeutics, AstraZeneca, Boston Biomedical, Ipsen, Imugene, Incyte, iOncologi, Merck Serono, Nektar, Vitaccess, Secarna, KymabResearch Funding: Pfizer, Novartis, MSD, Bristol Myers Squibb, Achilles Therapeutics, Roche, Nektar, Covance, Immunocore, AVEOTravel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Boston Biomedical, Incyte, GlaxoSmithKline, Pierre Fabre, Merck Serono Wen ShiEmployment: Iovance BiotherapeuticsStock and Other Ownership Interests: Iovance BiotherapeuticsTravel, Accommodations, Expenses: Iovance Biotherapeutics Toshimi TakamuraEmployment: Iovance Biotherapeutics Inc Madan JagasiaEmployment: Iovance BiotherapeuticsStock and Other Ownership Interests: Iovance BiotherapeuticsConsulting or Advisory Role: Kadmon Harry QinEmployment: Iovance BiotherapeuticsStock and Other Ownership Interests: Iovance Biotherapeutics Xiao WuEmployment: Iovance BiotherapeuticsStock and Other Ownership Interests: Iovance BiotherapeuticsTravel, Accommodations, Expenses: Iovance Biotherapeutics Cecile ChartierEmployment: Iovance BiotherapeuticsLeadership: Iovance BiotherapeuticsPatents, Royalties, Other Intellectual Property: PCT/US2019/059598 for Expansion of TILs Utilizing AKT Pathway Inhibitors. PCT/US2019/012729 for Processes for Generating TIL Products Enriched for Tumor Antigen-specific T-cells. PCT/US2019/029286 for Gene Editing of Tumor Infiltrating Lymphocytes and Uses of Same in Immunotherapy. PCT/US2019/065892 for Methods of Expanding Tumor Infiltrating Lymphocytes Using Engineered Cytokine Receptor Pairs and Uses Thereof. PCT/US2019/012733 for Processes for Generating TIL Products Enriched for Tumor Antigen-Specific T-Cells. PCT/US2020/013095 for System and Methods for Monitoring Adoptive Cell Therapy Clonality and Persistence. PCT/US2020/063767 for Processes for the Production of Tumor Infiltrating Lymphocytes (TILs) and Methods of Using the Same. PCT/US2020/057135 for Gene Editing of Tumor Infiltrating Lymphocytes and Uses of Same in Immunotherapy. One patent application is nonpublic, for which Iovance declines to furnish any informationTravel, Accommodations, Expenses: Iovance Biotherapeutics Friedrich Graf FinckensteinEmployment: Adverum, Iovance Biotherapeutics, Roche/GenentechLeadership: Iovance BiotherapeuticsStock and Other Ownership Interests: Roche/Genentech, Bristol Myers Squibb, Johnson & Johnson, Iovance Biotherapeutics, AdverumTravel, Accommodations, Expenses: Iovance Biotherapeutics, Roche/Genentech Maria FardisEmployment: Iovance Biotherapeutics, Acerta PharmaLeadership: Iovance Biotherapeutics, Acerta PharmaStock and Other Ownership Interests: Iovance Biotherapeutics, Acerta Pharma, Gilead Sciences, AbbVie, Kartos TherapeuticsPatents, Royalties, Other Intellectual Property: Iovance Biotherapeutics, Acerta PharmaTravel, Accommodations, Expenses: Iovance Biotherapeutics, Acerta Pharma John M. KirkwoodConsulting or Advisory Role: Bristol Myers Squibb, Novartis, Iovance Biotherapeutics, Elsevier, Amgen, Checkmate Pharmaceuticals, Harbour BioMed, Istari Oncology, OncoSec, Scopus BioPharma, PfizerSpeakers' Bureau: Bristol Myers SquibbResearch Funding: Amgen, Bristol Myers Squibb, Castle Biosciences, Checkmate Pharmaceuticals, Immunocore, Iovance Biotherapeutics, Novartis, Merck Jason A. ChesneyResearch Funding: Amgen, Replimune, Iovance Biotherapeutics, Bristol Myers SquibbPatents, Royalties, Other Intellectual Property: University of Louisville US PatentsNo other potential conflicts of interest were reported.

Purpose: Combination of antiprogrammed cell death protein-1 (PD-1) plus anti-cytotoxic T-cell lymphocyte-4 (anti-CTLA-4) immunotherapy shows greater response rates (RRs) than anti-PD-1 antibody alone in melanoma, but RR after initial anti-PD-1 and programmed death ligand-1 (PD-L1) antibody progression awaits robust investigation. Anti-CTLA-4 antibody alone after anti-PD-1/L1 antibody progression has a historical RR of 13%. We report the results of the first prospective clinical trial evaluating ipilimumab 1 mg/kg plus pembrolizumab following progression on anti-PD-1 immunotherapy., Methods: Patients with advanced melanoma who had progressed on anti-PD-1/L1 antibody as immediate prior therapy (including non-anti-CTLA-4 antibody combinations) were eligible. Patients received pembrolizumab 200 mg plus ipilimumab 1 mg/kg once every 3 weeks for four doses, followed by pembrolizumab monotherapy. The primary end point was RR by irRECIST. After 35 patients, the trial met the primary end point and was expanded to enroll a total of 70 patients to better estimate the RR., Results: Prior treatments included 60 on anti-PD-1 antibody alone and 10 on anti-PD-1/L1 antibody-based combinations. Thirteen patients had progressed in the adjuvant setting. The median length of prior treatment with anti-PD-1/L1 antibody was 4.8 months. Response assessments included five complete and 15 partial responses, making the irRECIST RR 29% among the entire trial population. The median progression-free survival was 5.0 months, and the median overall survival was 24.7 months. The median duration of response was 16.6 months. There was no difference in median time on prior anti-PD1/L1 or time to PD1 + CTLA4 initiation between responders and nonresponders. Grade 3-4 drug-related adverse events occurred in 27% of patients. Responses occurred in PD-L1-negative, non-T-cell-inflamed, and intermediate tumor phenotypes., Conclusion: To our knowledge, this is the first prospective study in melanoma of pembrolizumab plus low-dose ipilimumab after anti-PD-1/L1 immunotherapy failure, demonstrating significant antitumor activity and tolerability., Competing Interests: Zeynep ErogluConsulting or Advisory Role: Regeneron, Sun Pharma, Genentech/Roche, Novartis, OncoSec, Natera, ElsevierResearch Funding: Novartis, Pfizer Bruce BrocksteinConsulting or Advisory Role: Exelixis/IpsenResearch Funding: AstraZenecaPatents, Royalties, Other Intellectual Property: UpToDate. Author and Editorial duties Andrew S. PoklepovicConsulting or Advisory Role: NovartisSpeakers' Bureau: Bristol Myers Squibb Sunil BabuEmployment: Fort Wayne Medical Oncology & HematologyStock and Other Ownership Interests: Fort Wayne Medical Oncology & Hematology, Lutheran HospitalHonoraria: Bristol Myers Squibb, Alexion Pharmaceuticals, Lilly, Bayer, AstraZenecaConsulting or Advisory Role: Bristol Myers Squibb, Alexion Pharmaceuticals, AstraZeneca, argenx, Boehringer Ingelheim, Bayer, Kite, a Gilead company, Janssen Oncology, AmgenSpeakers' Bureau: Alexion PharmaceuticalsResearch Funding: Bristol Myers Squibb, Novartis, Genentech/Roche, AstraZeneca/MedImmune, Janssen Oncology, Amgen, TG Therapeutics, Abbvie, Lilly, Alexion Pharmaceuticals, Merck, Novartis, Syndax, Nektar, Sanofi, argenxTravel, Accommodations, Expenses: Bristol Myers Squibb, Alexion Pharmaceuticals, Lilly, Janssen Oncology, Genentech/Roche Sigrun HallmeyerLeadership: Association of Community Cancer Centers (ACCC)Honoraria: Cardinal HealthConsulting or Advisory Role: Bristol Myers Squibb, Cardinal Health, Array PharamceuticalSpeakers' Bureau: Bristol Myers SquibbTravel, Accommodations, Expenses: Cardinal Health, Bristol Myers SquibbUncompensated Relationships: Society for Immunotherapy of Cancer Mario VelascoEmployment: Cancer Care Specialists of IL Jose LutzkyConsulting or Advisory Role: Castle Biosciences, Iovance Biotherapeutics, Replimune, RegeneronResearch Funding: Bristol Myers Squibb, Novartis, Iovance Biotherapeutics, Immunocore, Regeneron, Replimune, Vyriad Emily HiggsEmployment: LillyStock and Other Ownership Interests: LillyResearch Funding: LillyPatents, Royalties, Other Intellectual Property: Jeffrey D. Helterbrand, Richard E. Higgs, Phillip W. Iversen, Automatic Contextual Segmentation for Imaging Bones for Osteoporosis Therapies (Granted February 1, 2000, US Patent 6,021,213). Raymond E. Kaiser, Richard E. Higgs, Randall K. Julian Jr, System and Methods for Quantitatively Comparing Complex Mixtures Using Single Ion Chromatograms Derived From Spectroscopic Analysis of Such Admixtures (Granted March 23, 1999, US Patent 5,885,841)Travel, Accommodations, Expenses: Lilly Vernon K. SondakConsulting or Advisory Role: Merck/Schering Plough, Novartis, Bristol Myers Squibb, Regeneron, Replimune, EisaiTravel, Accommodations, Expenses: Polynoma, Merck, Bristol Myers Squibb, Replimune Thomas F. GajewskiStock and Other Ownership Interests: Jounce Therapeutics, Evelo Therapeutics, Five Prime Therapeutics, PyxisConsulting or Advisory Role: Merck, Jounce Therapeutics, Adaptimmune, FOGPharma, Allogene Therapeutics, Pyxis, Trillium Therapeutics, Janssen Oncology, Gilead SciencesResearch Funding: Bristol Myers Squibb, Merck, Roche/Genentech, Incyte, Seattle Genetics, Ono Pharmaceutical, Aduro Biotech, Pyxis, BayerPatents, Royalties, Other Intellectual Property: Licensing to Evelo, Licensing to Aduro, Licensing to BMS, Licensing to Pyxis Nikhil I. KhushalaniStock and Other Ownership Interests: Bellicum Pharmaceuticals, Mazor Robotics, Amarin Corporation, Asensus SurgicalHonoraria: SanofiConsulting or Advisory Role: Bristol Myers Squibb, AstraZeneca, Regeneron, Array BioPharma, Immunocore, Merck, Incyte, Jounce Therapeutics, Iovance Biotherapeutics, NCCN/PfizerResearch Funding: Bristol Myers Squibb, Merck, Novartis, GlaxoSmithKline, HUYA Bioscience International, Amgen, Regeneron, Celgene, Replimune Jason J. LukeStock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch OncologyConsulting or Advisory Role: Array BioPharma, Bristol Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, TTC Oncology, Alphamab, Compugen, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf Therapeutics, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius Therapeutics, Tesaro, Xilio Therapeutics, XencorResearch Funding: Merck, Bristol Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Checkmate Pharmaceuticals, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma, EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring Bank, Trishula TherapeuticsPatents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)Travel, Accommodations, Expenses: Bristol Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio TherapeuticsNo other potential conflicts of interest were reported.

Background: Several therapeutic options are now available in the adjuvant melanoma setting, mandating an understanding of their benefit‒risk profiles in order to make informed treatment decisions. Herein we characterize adjuvant nivolumab select (immune-related) treatment-related adverse events (TRAEs) and evaluate possible associations between safety and recurrence-free survival (RFS) in the phase III CheckMate 238 trial., Methods: Patients with resected stage IIIB-C or IV melanoma received nivolumab 3 mg/kg every 2 weeks (n=452) or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks (n=453) for up to 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. First-occurrence and all-occurrence select TRAEs were analyzed within discrete time intervals: from 0 to 3 months of treatment, from >3-12 months of treatment, and from the last dose (regardless of early or per-protocol treatment discontinuation) to 100 days after the last dose. Possible associations between select TRAEs and RFS were investigated post randomization in 3-month landmark analyses and in Cox model analyses (including a time-varying covariate of select TRAE), within and between treatment groups., Results: From the first nivolumab dose to 100 days after the last dose, first-occurrence select TRAEs were reported in 67.7% (306/452) of patients. First-occurrence select TRAEs were reported most frequently from 0 to 3 months (48.0%), during which the most common were pruritus (15.5%) and diarrhea (15.3%). Most select TRAEs resolved within 6 months. There was no clear association between the occurrence (or not) of select TRAEs and RFS by landmark analysis or by Cox model analysis within treatment arms or comparing nivolumab to the ipilimumab comparator arm., Conclusion: Results of this safety analysis of nivolumab in adjuvant melanoma were consistent with its established safety profile. In the discrete time intervals evaluated, most first-occurrence TRAEs occurred early during treatment and resolved. No association between RFS and select TRAEs was evident., Trial Registration Number: NCT02388906., Competing Interests: Competing interests: MM: Consulting or Advisory Role: Bristol Myers Squibb, Novartis, MSD Oncology, Pierre Fabre, Roche/Genentech; Honoraria: Bristol Myers Squibb, MSD Oncology, Novartis, Pierre Fabre, Roche/Genentech; Research Funding: Novartis, Roche/Genentech; JL: Grants: Achilles Therapeutics, Aveo, Bristol Myers Squibb, MSD, Nektar, Novartis, Pierre Fabre, Pfizer, Pharmacyclics, Roche/Genentech, Secarna, Vitaccess, Covance, Immunocore; Personal Fees: Achilles Therapeutics, AstraZeneca, Boston Biomedical, Bristol Myers Squibb, Eisai, EUSA Pharma, Imugen, Incyte, Ipsen, iOnctura, Kymab, Merck Serono, MSD, Nektar, Novartis, Pierre Fabre, Pfizer, Pharmacyclics, Roche/Genentech, Secarna, Vitaccess; PAA: Grant: Array, Bristol Myers Squibb, Roche/Genentech; Personal Fees: 4SC, Array, AstraZeneca, Bristol Myers Squibb, Idera, Immunocore, Incyte, Genmab, Medimmune, MSD, NewLink Genetics, Novartis, Merck Serono, Pierre Fabre, Roche/Genentech, Sandoz, Sanofi, Syndax, Sun Pharma, Ultimovacs; Advisory/consultant role and travel support: MSD; MDV: Consultant/Advisory Boards: Bristol Myers Squibb, Merck, Novartis, Pierre Fabre, Sanofi; HG: Consulting or Advisory Role: Amgen, Bristol Myers Squibb, MSD Oncology, Novartis, Roche, Pierre Fabre; Travel, Accommodations, Expenses: Bristol Myers Squibb, Roche; Honoraria: Amgen, Bristol Myers Squibb, MSD Oncology, Novartis, Roche; Research Funding: Bristol Myers Squibb, MSD Oncology, Roche, Novartis; CLC: Nothing to disclose; AA: Personal Fees: Bristol Myers Squibb, MSD, Novartis, Merck, Roche; Travel Grant: Bristol Myers Squibb, MSD, Novartis, Merck, Roche; SD: Consulting or Advisory Role: MSD; Research Funding: AstraZeneca, Bristol Myers Squibb, MSD, Roche; Travel, Accommodations, Expenses: Bristol Myers Squibb; Stock Ownership/Employment: Sanofi Pasteur (immediate family member); MS Grant: AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Gilead, Merck Serono, MSD, Mylan, Novartis, Pfizer, Regeneron, Roche, Samsung; J-JG: Personal Fees: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche, Sanofi, SunPharma; VC-S: Advisory Board: Incyte, Merck-Sorono, MSD; Meeting Expenses: Bristol Myers Squibb, Pierre Fabre; Speaker Fee: Novartis; IM: Grant: Amgen, BionCoTech, Bristol Myers Squibb, Incyte, MSD, Roche; Personal Fees: Amgen, BionCoTech, Bristol Myers Squibb, Incyte, MSD, Regeneron, Roche, Sanofi; Non-financial Support: BionCoTech, Bristol Myers Squibb, MSD, Roche; MOB: Consulting or Advisory Role: Adaptimmune, Bristol Myers Squibb, EMD Serono, GlaxoSmithKline, Genzyme, Immunocore, Immunovaccine, Merck, Novartis; Expert Testimony: Merck; Honoraria: Bristol Myers Squibb, Merck, Novartis, Roche; Research Funding: Takara Bio, Merck; AMDG: Consulting or Advisory Role: Bristol Myers Squibb, Incyte, MSD, Pierre Fabre; JL: Consulting or Advisory Role: Array BioPharm, Bristol Myers Squibb, Novartis; Speakers’ Bureau: Array BioPharm, Novartis, Regeneron; Travel, Accommodations, and Expenses: Bristol Myers Squibb, Novartis, Pfizer; Research Funding: Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, Elios Pharmaceutical, Genentech/Roche, Incyte, Merck Seronon, Merck, Novartis, Pfizer, Viralytics; LDLC-M: Nothing to disclose; VA: Personal Fees: Bristol Myers Squibb, Merck Serono, MSD, Novartis, Pierre Fabre, Roche, Oncosec; PA: Nothing to disclose; AH: Nothing to disclose; LF: Grant: Bristol Myers Squibb, EMD Serono, Incyte, Kartos, Merck, Pfizer, Array; Consulting or Advisory Role: Elsevier/Via Oncology, Hoosier Cancer Research Network; MM: Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, MSD, Novartis, Pfizer, Roche; Travel, Accommodations, and Expenses: AstraZeneca, Bristol Myers Squibb, MSD, Roche; NIK: Consulting or Advisory Role: Array BioPharma, AstraZeneca, Bristol Myers Squibb, EMD Serono, Immunocore, HUYA Bioscience International, Genentech, Merck, Regeneron; Research Funding: Amgen, HUYA Bioscience International, GlaxoSmithKline, Merck, Novartis, Regeneron; Stock/Other Ownership Interests: Amarin Corporation, Bellicum Pharmaceuticals, Mazor Robotics, TransEnterix; VdP: Employee: Bristol Myers Squibb; Stock Ownership: Bristol Myers Squibb; ML: Employee: Bristol Myers Squibb; Stock Ownership: Advaxis Immunotherapies, Bristol Myers Squibb; JW: Consulting or Advisory Role: AbbVie Inc, Altor Bioscience, Amgen, AstraZeneca, Bristol Myers Squibb, CytomX Therapeutics, Daiichi Sankyo, Eisai, Genentech, GlaxoSmithKline, Medivation, Merck, Nektar Therapeutics, Novartis, Pieris Pharmaceuticals, Inc, Roche, SELLAS Life Sciences Group, Inc, WindMIL Therapeutics; Research Funding: Astellas Pharma, Bristol Myers Squibb, Genentech, Incyte Corporation, Merck, Novartis, Roche; Travel, Accommodations, and Expenses: Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Genentech, GlaxoSmithKline, Merck, Novartis, Pieris Pharmaceuticals, Inc, Roche; Honoraria: AbbVie Inc, Altor Bioscience, Amgen, AstraZeneca, Bristol Myers Squibb, CytomX Therapeutics, Daiichi Sankyo, Eisai, Genentech, GlaxoSmithKline, Medivation, Merck, Nektar Therapeutics, Novartis, Pieris Pharmaceuticals, Inc, Roche, SELLAS Life Sciences Group, Inc, WindMIL Therapeutics; Stock/Ownership Interests: Biond; Patents: Named on a patent submitted by Moffitt Cancer Center for an ipilimumab biomarker; named on a patent submitted from Biodesix for a PD-1 antibody biomarker., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A diagnosis of melanoma requires multidisciplinary specialized care across all stages of disease. Although many important advances have been made for the treatment of melanoma for local and advanced disease, barriers to optimal care remain for many patients who live in areas without ready access to the expertise of a specialized melanoma center. In this article, we review some of the recent advances in the treatment of melanoma and the persistent challenges around the world that prevent the delivery of the best standard of care to patients living in the community. With the therapeutic landscape continuing to evolve and newer more complex drug therapies soon to be approved, it is important to recognize the many challenges that patients face and attempt to identify tools and policies that will help to improve treatment outcomes for their melanoma.

Background: IL-2 inducible kinase (ITK) is highly expressed in metastatic melanomas and its inhibition suppresses melanoma cell proliferation. We hypothesize that ibrutinib has a direct antitumor effect in melanoma cell lines and that treatment of metastatic melanomas with ibrutinib induces antitumor responses., Methods: We assessed the ibrutinib effect on melanoma cell proliferation, apoptosis, and motility. Patients with metastatic melanoma refractory to PD-1 and MAPK inhibitors (if BRAFV600-mutant) were treated with ibrutinib, 840 mg PO QD, as part of a phase II clinical trial (clinicaltrials.gov NCT02581930)., Results: Melanoma cell lines frequently express ITK, YES1, and EGFR. Ibrutinib suppressed cell motility and proliferation in most cell lines. Eighteen patients (13 male; median age 63.5 years, range 37-82; 12 with ipilimumab resistance) were enrolled. The most frequent side effects were fatigue (61%), anorexia (50%), hyponatremia (28%), nausea, and vomiting (22% each). No antitumor responses were seen. At a median follow-up of 6 months (0.3-35.8 months), the median progression-free survival was 1.3 months (range 0.2-5.5 months). Fifteen patients were discontinued from the study due to progression, and 14 patients had died from metastatic melanoma. All archived tumors expressed ITK, 41% had no expression of p16 and PTEN, and 61% had absent tumor-infiltrating lymphocytes (TILs). Ibrutinib significantly suppressed proliferating (Ki67+) CD19+ peripheral blood mononuclear cells and had no significant effect on other lymphocyte subsets., Conclusion: Ibrutinib did not induce any meaningful clinical benefit. ITK expression may not be clinically relevant. Treatment-refractory metastatic melanomas have other fundamental defects (i.e. absent PTEN and p16 expression, absent TILs) that may contribute to an adverse prognosis., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

CheckMate 218, a North American expanded access program (EAP), investigated nivolumab plus ipilimumab in patients with advanced melanoma. Safety and efficacy, including 2-year survival in clinically relevant patient subgroups, are reported. Eligible patients were aged ≥18 years with unresectable stage III/IV melanoma, an Eastern Cooperative Oncology Group performance status of 0/1, and no prior checkpoint inhibitors. Patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 cycles (induction) followed by nivolumab 3 mg/kg every 2 weeks (maintenance) until progression or unacceptable toxicity or a maximum of 48 weeks. Safety and overall survival (OS) data were collected. This EAP included 754 treated patients from the USA (n = 580) and Canada (n = 174). Median follow-up time was 17.8 months. All-grade and grade 3-4 treatment-related adverse events were reported in 96% and 53% of patients and led to treatment discontinuation in 36% and 26% of patients, respectively. OS rates at 12 and 24 months were 82% [95% confidence interval (CI) 79-84] and 70% (95% CI 66-74), respectively. Twenty-four-month OS rates were 63% in patients aged ≥75 years, 56% in patients with elevated lactate dehydrogenase levels, 73% in patients with BRAF wild-type tumors, 70% in patients with BRAF mutant tumors, and 56% in patients with mucosal melanoma. In this EAP, nivolumab plus ipilimumab demonstrated high survival rates and safety outcomes consistent with those from randomized clinical trials, further supporting the use of this combination for advanced melanoma across multiple subgroups., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: To provide guidance to clinicians regarding the use of systemic therapy for melanoma., Methods: ASCO convened an Expert Panel and conducted a systematic review of the literature., Results: A systematic review, one meta-analysis, and 34 additional randomized trials were identified. The published studies included a wide range of systemic therapies in cutaneous and noncutaneous melanoma., Recommendations: In the adjuvant setting, nivolumab or pembrolizumab should be offered to patients with resected stage IIIA/B/C/D BRAF wild-type cutaneous melanoma, while either of those two agents or the combination of dabrafenib and trametinib should be offered in BRAF -mutant disease. No recommendation could be made for or against the use of neoadjuvant therapy in cutaneous melanoma. In the unresectable/metastatic setting, ipilimumab plus nivolumab, nivolumab alone, or pembrolizumab alone should be offered to patients with BRAF wild-type cutaneous melanoma, while those three regimens or combination BRAF/MEK inhibitor therapy with dabrafenib/trametinib, encorafenib/binimetinib, or vemurafenib/cobimetinib should be offered in BRAF -mutant disease. Patients with mucosal melanoma may be offered the same therapies recommended for cutaneous melanoma. No recommendation could be made for or against specific therapy for uveal melanoma. Additional information is available at www.asco.org/melanoma-guidelines.

Background: Previously, findings from CheckMate 238, a double-blind, phase 3 adjuvant trial in patients with resected stage IIIB-C or stage IV melanoma, showed significant improvements in recurrence-free survival and distant metastasis-free survival with nivolumab versus ipilimumab. This report provides updated 4-year efficacy, initial overall survival, and late-emergent safety results., Methods: This multicentre, double-blind, randomised, controlled, phase 3 trial was done in 130 academic centres, community hospitals, and cancer centres across 25 countries. Patients aged 15 years or older with resected stage IIIB-C or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) to receive nivolumab or ipilimumab via an interactive voice response system and stratified according to disease stage and baseline PD-L1 status of tumour cells. Patients received intravenous nivolumab 3 mg/kg every 2 weeks or intravenous ipilimumab 10 mg/kg every 3 weeks for four doses, and then every 12 weeks until 1 year of treatment, disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was recurrence-free survival by investigator assessment, and overall survival was a key secondary endpoint. Efficacy analyses were done in the intention-to-treat population (all randomly assigned patients). All patients who received at least one dose of study treatment were included in the safety analysis. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of Jan 30, 2020. This study is registered with ClinicalTrials.gov, NCT02388906., Findings: Between March 30 and Nov 30, 2015, 906 patients were assigned to nivolumab (n=453) or ipilimumab (n=453). Median follow-up was 51·1 months (IQR 41·6-52·7) with nivolumab and 50·9 months (36·2-52·3) with ipilimumab; 4-year recurrence-free survival was 51·7% (95% CI 46·8-56·3) in the nivolumab group and 41·2% (36·4-45·9) in the ipilimumab group (hazard ratio [HR] 0·71 [95% CI 0·60-0·86]; p=0·0003). With 211 (100 [22%] of 453 patients in the nivolumab group and 111 [25%] of 453 patients in the ipilimumab group) of 302 anticipated deaths observed (about 73% of the originally planned 88% power needed for significance), 4-year overall survival was 77·9% (95% CI 73·7-81·5) with nivolumab and 76·6% (72·2-80·3) with ipilimumab (HR 0·87 [95% CI 0·66-1·14]; p=0·31). Late-emergent grade 3-4 treatment-related adverse events were reported in three (1%) of 452 and seven (2%) of 453 patients. The most common late-emergent treatment-related grade 3 or 4 adverse events reported were diarrhoea, diabetic ketoacidosis, and pneumonitis (one patient each) in the nivolumab group, and colitis (two patients) in the ipilimumab group. Two previously reported treatment-related deaths in the ipilimumab group were attributed to study drug toxicity (marrow aplasia in one patient and colitis in one patient); no further treatment-related deaths were reported., Interpretation: At a minimum of 4 years' follow-up, nivolumab demonstrated sustained recurrence-free survival benefit versus ipilimumab in resected stage IIIB-C or IV melanoma indicating a long-term treatment benefit with nivolumab. With fewer deaths than anticipated, overall survival was similar in both groups. Nivolumab remains an efficacious adjuvant treatment for patients with resected high-risk melanoma, with a safety profile that is more tolerable than that of ipilimumab., Funding: Bristol Myers Squibb and Ono Pharmaceutical., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Nivolumab, a PD-1 inhibitor, has demonstrated prolonged survival benefit in patients with advanced melanoma. Bempegaldesleukin (BEMPEG; NKTR-214), a first-in-class CD122-preferential IL-2 pathway agonist, provides sustained signaling through the IL-2βγ receptor, which activates effector T and natural killer cells. In the Phase I/II PIVOT-02 trial, the combination of bempegaldesleukin plus nivolumab was well-tolerated and demonstrated clinical activity as first-line therapy in metastatic melanoma. Here, we describe the design of and rationale for the Phase III, global, randomized, open-label PIVOT IO 001 trial comparing bempegaldesleukin plus nivolumab with nivolumab alone in patients with previously untreated, unresectable or metastatic melanoma. Primary end points include objective response rate, progression-free survival and overall survival. Key secondary end points include further investigation of safety/tolerability, previously assessed in the PIVOT-02 trial. Clinical Trial Registration: NCT03635983 (ClinicalTrials.gov).

Background: Traditional chemotherapy agents adversely affect wound healing and need to be held prior to or after surgery. Immune checkpoint inhibitors (ICIs) and targeted agents are now standard of care for the several treatment cancers. We hypothesize that ICI and targeted therapy do not have similar adverse effects on perioperative outcomes., Methods: We performed a review of melanoma patients undergoing surgery at an academic hospital between 2011 and 2019. All patients received ICI or targeted therapy ≤ 60 days prior to surgery, including palliative procedures. Preoperative performance status was assessed using Eastern Cooperative Oncology Group score and American Society of Anesthesiologists Classification System. Thirty-day complications were classified by Clavien-Dindo grade. No statistical comparisons were performed., Results: Of 63 patients included in the analysis, 29 (46%) patients received ICI and 34 (54%) received targeted therapy with median of 14 days (IQR 5-27 days) between the last preoperative dose and day of surgery (ICI, median 18 days [IQR 13-34.5]; targeted therapy, median 7 days [IQR 3-22.25]). There were no perioperative mortalities. Among patients treated with ICI, 22 patients (76%) had no complications. Four patients had wound infections (2 readmitted), 1 had reoperation (hematoma) and 2 readmitted for other reasons (fever; volvulus). Among patients treated with targeted therapy, 25 patients (74%) had no complications. Seven patients had wound infections (none readmitted), 1 had reoperation (flap failure) and 1 had dehiscence (not treated)., Conclusions: Patients undergoing treatment with ICI or targeted therapies can safely undergo surgery without substantially increased risk of serious intraoperative and postoperative complications.

Targeted BRAF and MEK inhibition has become an appropriate first-line treatment of BRAF-mutant advanced cutaneous melanoma. The authors present an overview of the MAPK pathway as well as the other major pathways implicated in melanoma development. Melanoma brain metastases are a devastating complication of melanoma that can be traced to derangements in cell signaling pathways, and the current evidence for targeted therapy is reviewed. Finally, activating KIT mutations are rarely found to cause melanomas and may provide an actionable target for therapy. The authors review the current evidence for targeted KIT therapy and summarize the ongoing clinical trials., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Current management of locoregional and oligometastatic melanoma is typically with surgery; however, some patients are unable to undergo resection due to location/size of their tumors and/or the anticipated morbidity of the surgery. While there are currently no established guidelines for neoadjuvant therapy in melanoma, neoadjuvant BRAF-targeted therapy may make resection more feasible. A retrospective analysis was conducted of 23 patients with BRAFV600-mutant, stage III/IV melanoma treated with BRAF-targeted therapy prior to surgery, with no adjuvant treatment. Surgical specimens, preoperative imaging, and clinical outcomes were evaluated. Results: Ten of 23 patients (44%) attained a pathologic complete response (pCR), with no correlation between RECIST response based on preoperative imaging and pathologic response. After a median of 43-month follow-up, only 1 patient (10%) with a pCR recurred, while 8 of 13 (62%) patients without a pCR recurred. Patients with a pCR had significantly improved relapse-free (RFS) and overall survival (OS) compared to patients with residual tumor. Neoadjuvant BRAF-targeted therapy is associated with a high pCR rate in patients with stage III-IV melanoma, which may correlate with improved RFS and OS., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

New effective therapies are greatly needed for metastatic uveal melanoma, which has a very poor prognosis with a median survival of less than 1 y. The melanocortin 1 receptor (MC1R) is expressed in 94% of uveal melanoma metastases, and a MC1R-specific ligand (MC1RL) with high affinity and selectivity for MC1R was previously developed. Methods: The 225 Ac-DOTA-MC1RL conjugate was synthesized in high radiochemical yield and purity and was tested in vitro for biostability and for MC1R-specific cytotoxicity in uveal melanoma cells, and the lanthanum-DOTA-MC1RL analog was tested for binding affinity. Non-tumor-bearing BALB/c mice were tested for maximum tolerated dose and biodistribution. Severe combined immunodeficient mice bearing uveal melanoma tumors or engineered MC1R-positive and -negative tumors were studied for biodistribution and efficacy. Radiation dosimetry was calculated using mouse biodistribution data and blood clearance kinetics from Sprague-Dawley rat data. Results: High biostability, MC1R-specific cytotoxicity, and high binding affinity were observed. Limiting toxicities were not observed at even the highest administered activities. Pharmacokinetics and biodistribution studies revealed rapid blood clearance (<15 min), renal and hepatobillary excretion, MC1R-specific tumor uptake, and minimal retention in other normal tissues. Radiation dosimetry calculations determined pharmacokinetics parameters and absorbed α-emission dosages from 225 Ac and its daughters. Efficacy studies demonstrated significantly prolonged survival and decreased metastasis burden after a single administration of 225 Ac-DOTA-MC1RL in treated mice relative to controls. Conclusion: These results suggest significant potential for the clinical translation of 225 Ac-DOTA-MC1RL as a novel therapy for metastatic uveal melanoma., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Immunotherapy has revolutionized the treatment of melanoma, with implications for the surgical management of this disease. Surgeons must be aware of the impact of various immunotherapies on patients with resectable and unresectable disease, and how surgical decision-making should progress as a result. We expect that current and developing immunotherapies will increase surgeon involvement for resection of metastatic melanoma, whether for tumor harvests to generate autologous lymphocytes or for consolidating control of disease beyond what immunotherapies alone can achieve. Despite remarkable advancements in the field, significant work is needed to optimize the immuno-modulation that targets cancers while minimizing toxicity for patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Increased cross-sectional imaging for surveillance of metastatic melanoma has led to more diagnoses of asymptomatic intussusception., Methods: We performed a multi-institutional retrospective review of patient records with a history of metastatic melanoma and a diagnosis of intussusception. Patients were divided into three groups: 1) asymptomatic patients without current evidence of melanoma (no evidence of disease [NED]); 2) asymptomatic intussusception and known active metastatic melanoma; 3) symptomatic intussusception and known active metastatic melanoma; the number of patients requiring surgery and intraoperative findings were recorded., Results: We reviewed 73 patients diagnosed with intussusception from 2004 to 2017. Among asymptomatic patients with NED (n = 16), 14 spontaneously resolved and 2 underwent pre-emptive surgery without abnormal intraoperative findings. Of asymptomatic patients with active metastatic disease (n = 32), 25 were initially observed and 7 underwent pre-emptive surgery and 9 of the 25 initially observed patients required surgery for development of symptoms. In this group, all 16 patients undergoing surgery (50% of the group) had intraoperative findings of intussusception and/or metastatic intestinal melanoma.. All symptomatic patients with metastatic melanoma (n = 25) underwent surgery; all had intraoperative findings of intussusception and/or metastatic melanoma except 1 (Meckel's diverticulum)., Conclusion: Asymptomatic patients with NED do not require surgery and intussusception will likely resolve spontaneously. Asymptomatic patients with known metastatic melanoma may be initially observed, but a low threshold for surgery should be maintained. Symptomatic patients with known metastases should undergo surgery., (© 2019 Wiley Periodicals, Inc.)

In February 2018, the Melanoma Research Foundation and the Moffitt Cancer Center hosted the Second Summit on Melanoma Central Nervous System (CNS) Metastases in Tampa, Florida. In this white paper, we outline the current status of basic science, translational, and clinical research into melanoma brain metastasis development and therapeutic management. We further outline the important challenges that remain for the field and the critical barriers that need to be overcome for continued progress to be made in this clinically difficult area., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: BRAF inhibitors are clinically active in patients with advanced BRAF V600 -mutant melanoma, although acquired resistance remains common. Preclinical studies demonstrated that resistance could be overcome using concurrent treatment with the HSP90 inhibitor XL888. Patients and Methods: Vemurafenib (960 mg p.o. b.i.d.) combined with escalating doses of XL888 (30, 45, 90, or 135 mg p.o. twice weekly) was investigated in 21 patients with advanced BRAF V600 -mutant melanoma. Primary endpoints were safety and determination of a maximum tolerated dose. Correlative proteomic studies were performed to confirm HSP inhibitor activity. Results: Objective responses were observed in 15 of 20 evaluable patients [75%; 95% confidence interval (CI), 51%-91%], with 3 complete and 12 partial responses. Median progression-free survival and overall survival were 9.2 months (95% CI, 3.8-not reached) and 34.6 months (6.2-not reached), respectively. The most common grade 3/4 toxicities were skin toxicities, such as rash ( n = 4, 19%) and cutaneous squamous cell carcinomas ( n = 3, 14%), along with diarrhea ( n = 3, 14%). Pharmacodynamic analysis of patients' peripheral blood mononuclear cells (PBMC) showed increased day 8 HSP70 expression compared with baseline in the three cohorts with XL888 doses ≥45 mg. Diverse effects of vemurafenib-XL888 upon intratumoral HSP client protein expression were noted, with the expression of multiple proteins (including ERBB3 and BAD) modulated on therapy. Conclusions: XL888 in combination with vemurafenib has clinical activity in patients with advanced BRAF V600 -mutant melanoma, with a tolerable side-effect profile. HSP90 inhibitors warrant further evaluation in combination with current standard-of-care BRAF plus MEK inhibitors in BRAF V600 -mutant melanoma. Clin Cancer Res; 24(22); 5516-24. ©2018 AACR See related commentary by Sullivan, p. 5496 ., (©2018 American Association for Cancer Research.)

Background: Interleukin 2 (IL-2) is a growth factor for T and natural killer cells, promotes proinflammatory cytokines, and can lead to durable responses in patients with melanoma. Vascular endothelial growth factor (VEGF) promotes angiogenesis and modulates host innate and adaptive immunity. High VEGF levels were found to be associated with nonresponse to IL-2. Ziv-aflibercept may deplete VEGF and thereby enhance antitumor T-cell responses, thus supporting a combination immunotherapeutic strategy with IL-2., Methods: NCI 8628 was a phase 2 trial of ziv-aflibercept and IL-2 (arm A) versus IL-2 alone (arm B) randomized at 2:1, respectively. Eligible patients had inoperable American Joint Committee on Cancer stage III or stage IV melanoma. The primary endpoint was progression-free survival (PFS)., Results: A total of 89 patients were enrolled and 84 patients were treated. The median follow-up was 41.4 months. Among treated patients (55 patients in arm A and 29 patients in arm B), PFS was significantly improved in favor of arm A, with a median of 6.9 months (95% confidence interval [95% CI], 4.1-8.7 months) versus 2.3 months (95% CI, 1.6-3.5 months) (P<.001). No significant difference was noted with regard to overall survival, with a median of 26.9 months (95% CI, 14.4-63.6 months) for arm A and 24.2 months (95% CI, 11.3-36.4 months) for arm B. The response rate (according to Response Evaluation Criteria In Solid Tumors [RECIST]) was 22% in arm A (4 complete responses [CRs] and 8 partial responses [PRs]) and 17% in arm B (1 CR and 4 PRs). Stable disease or PR or CR was noted in 65% of patients in arm A and 48% of patients in arm B. The combination was found to be superior to monotherapy in patients with high and low levels of serum VEGF and VEGF receptor 2. Adverse events were consistent with the expected profiles of monotherapy with IL-2 and ziv-aflibercept., Conclusions: Ziv-aflibercept and IL-2 were found to significantly improve PFS compared with IL-2 alone, thereby meeting the primary endpoint of the current study. These findings support further study of immunotherapeutic combination strategies involving VEGF inhibitors., (© 2018 American Cancer Society.)

Background: Brain metastases are a common cause of disabling neurologic complications and death in patients with metastatic melanoma. Previous studies of nivolumab combined with ipilimumab in metastatic melanoma have excluded patients with untreated brain metastases. We evaluated the efficacy and safety of nivolumab plus ipilimumab in patients with melanoma who had untreated brain metastases., Methods: In this open-label, multicenter, phase 2 study, patients with metastatic melanoma and at least one measurable, nonirradiated brain metastasis (tumor diameter, 0.5 to 3 cm) and no neurologic symptoms received nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for up to four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks until progression or unacceptable toxic effects. The primary end point was the rate of intracranial clinical benefit, defined as the percentage of patients who had stable disease for at least 6 months, complete response, or partial response., Results: Among 94 patients with a median follow-up of 14.0 months, the rate of intracranial clinical benefit was 57% (95% confidence interval [CI], 47 to 68); the rate of complete response was 26%, the rate of partial response was 30%, and the rate of stable disease for at least 6 months was 2%. The rate of extracranial clinical benefit was 56% (95% CI, 46 to 67). Treatment-related grade 3 or 4 adverse events were reported in 55% of patients, including events involving the central nervous system in 7%. One patient died from immune-related myocarditis. The safety profile of the regimen was similar to that reported in patients with melanoma who do not have brain metastases., Conclusions: Nivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases. (Funded by Bristol-Myers Squibb and the National Cancer Institute; CheckMate 204 ClinicalTrials.gov number, NCT02320058 .).