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Background: Merkel cell carcinoma is a rare skin cancer associated with poor survival. Based on a previous Phase II trial of adults with advanced Merkel cell carcinoma by Kim and colleagues (2022), there is now a strong rationale for combination therapy (i.e., nivolumab and ipilimumab) to become a treatment option for patients with advanced Merkel cell carcinoma. The goal of this paper was to report on the secondary outcome of quality of life (QOL) among patients on this trial., Methods: Patients receiving combined nivolumab and ipilimumab, with or without stereotactic body radiation therapy (SBRT), completed the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 prior to starting treatment and every 2 weeks thereafter. Changes in QOL during treatment and post-treatment were evaluated using piecewise random-effects mixed models. Exploratory analyses compared changes in QOL between study arms. The original trial was registered with ClinicalTrials.gov (NCT03071406)., Results: Study participants (n = 50) reported no changes in overall QOL (ps > 0.05), but emotional functioning improved during treatment (p = 0.01). Cognitive and social functioning worsened post-treatment (ps < 0.01). In general, patients treated with combination therapy only (n = 25) reported no change in QOL over time, whereas patients also treated with SBRT (n = 25) consistently demonstrated worsening QOL post-treatment., Conclusion: QOL is generally preserved in patients treated with combination therapy, but the addition of SBRT may worsen QOL. Combined with clinical efficacy data published previously, results support the use of combination therapy with nivolumab and ipilimumab as a treatment option for patients with advanced Merkel cell carcinoma., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

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.)

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.

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).

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: 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 .).

Background: The anti-programmed cell death-1 (PD-1) inhibitors pembrolizumab and nivolumab alone or in combination with ipilimumab have shown improved objective response rates and progression-free survival compared to ipilimumab only in advanced melanoma patients. Anti-PD-1 therapy demonstrated nearly equal clinical efficacy in patients who had progressed after ipilimumab or were treatment-naïve. However, only limited evidence exists regarding the efficacy of ipilimumab alone or in combination with nivolumab after treatment failure to anti-PD-therapy., Patients and Methods: A multicenter retrospective study in advanced melanoma patients who were treated with nivolumab (1 or 3 mg/kg) and ipilimumab (1 mg or 3 mg/kg) or ipilimumab (3 mg/kg) alone after treatment failure to anti-PD-1 therapy was performed. Patient, tumour, pre- and post-treatment characteristics were analysed., Results: In total, 47 patients were treated with ipilimumab (ipi-group) and 37 patients with ipilimumab and nivolumab (combination-group) after treatment failure to anti-PD-1 therapy. Overall response rates for the ipi- and the combination-group were 16% and 21%, respectively. Disease control rate was 42% for the ipi-group and 33% for the combination-group. One-year overall survival rates for the ipi- and the combination-group were 54% and 55%, respectively., Conclusions: Ipilimumab should be considered as a viable treatment option for patients with failure to prior anti-PD-1 therapy, including those with progressive disease as best response to prior anti-PD-1. In contrast, the combination of ipilimumab and nivolumab appears significantly less effective in this setting compared to treatment-naïve patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: Treatment of locally advanced unresectable or metastatic cutaneous squamous cell carcinoma (mCSCC) is suboptimal with a paucity of robust data on systemic therapy. This retrospective study aimed to evaluate the efficacy and outcomes of patients with locally advanced unresectable or mCSCC treated with systemic therapy., Methods: Records of patients with CSCC treated with systemic therapy from January 2001 to January 2011 were reviewed. Response was assessed using WHO criteria. Descriptive results were assessed using Wilcoxon rank-sum test for ordinal responses and Pearson χ test for categorical responses. Survival was calculated by the Kaplan-Meier method., Results: Of 28 patients identified, 25 patients (M:F=18:7), median age 66 years (range, 39 to 85 y), had the required data for final analysis. Partial response was 44% and stable disease (SD) was 24%. The median progression-free survival (PFS) and overall survival (OS) were 5.5 months (2.3, 13.2) and 10.9 months (5.3, 21.3) respectively; 3-year OS was 22%. Patients with WHO response had improved PFS (20.8 mo; 4.4, NR) and OS (37.5 mo; 10.3, NR) compared with patients with SD/PD (PFS 2.7 mo; OS 5.9 mo). Use of platinum-based therapy significantly improved PFS and OS, whereas taxanes and cetuximab had no impact in this small cohort. There was no difference in PFS or OS with multiagent versus single-agent therapy., Conclusions: Platinum-based therapy remains as one of the standard options in advanced CSCC management. Agents to improve response rates are needed and future trials should address the use of novel targeted and new chemotherapy combinations in CSCC.

Background: Given the propensity for hematogenous metastases, neoadjuvant chemotherapy (NAC) could treat occult metastatic disease early, potentially improving survival and better defining which primary angiosarcomas (AS) benefit from surgical resection., Methods: A retrospective comparison was performed of 23 patients with resectable, localized cutaneous/soft tissue primary AS treated with surgery alone (S, n = 13) or NAC followed by surgery (NAC-S, n = 12)., Results: Primary sites included breast/chest (n = 9), head/neck (n = 9), extremity (n = 3), and other (n = 2). 23% S versus 40% NAC-S had prior radiation (RT). NAC regimens were paclitaxel (n = 6) or gemcitabine/docetaxel (n = 4). Seventy percent were high grade. Distant metastases were found in 17% after NAC. Non-primary wound closure was required in 54 %S versus 30%NAC-S (P = 0.4). R0 resections were achieved in 85% S versus 80% NAC-S (30% had a complete pathologic response). Two-year local recurrence (LR)-free, disease-free, and overall survivals were 67.1, 38.5, and 61.5% for S versus 68.6, 54.9, and 68.6% for NAC-S (P = 0.52, 0.67, and 0.58). The mean number of surgical resections/patient to maintain local control was 1.8 S versus 1.3 NAC-S (P = 0.06)., Conclusions: NAC for primary AS was well tolerated. Although there was no statistically significant survival benefit, NAC helped define who would benefit from surgical resection., (© 2015 Wiley Periodicals, Inc.)

Background: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma., Methods: In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries. Eligible patients were 18 years or older, had unresectable or metastatic melanoma, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAF(V 600) mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m(2) every 3 weeks or paclitaxel 175 mg/m(2) combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used permuted blocks (block size of six) within each stratum. Primary endpoints were the proportion of patients who had an objective response and overall survival. Treatment was given open-label, but those doing tumour assessments were masked to treatment assignment. We assessed objective responses per-protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. The trial is closed and this is the first interim analysis, reporting the objective response primary endpoint. This study is registered with ClinicalTrials.gov, number NCT01721746., Findings: Between Dec 21, 2012, and Jan 10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab and 133 to ICC. Confirmed objective responses were reported in 38 (31·7%, 95% CI 23·5-40·8) of the first 120 patients in the nivolumab group versus five (10·6%, 3·5-23·1) of 47 patients in the ICC group. Grade 3-4 adverse events related to nivolumab included increased lipase (three [1%] of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two [1%] each); for ICC, these included neutropenia (14 [14%] of 102), thrombocytopenia (six [6%]), and anaemia (five [5%]). We noted grade 3-4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths occurred., Interpretation: Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need., Funding: Bristol-Myers Squibb., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Gastric cancer remains a global public health problem with considerable heterogeneity in pathogenesis and clinical presentation across geographic regions. Improved understanding of the molecular biology of this disease has opened avenues for targeted intervention. An individualized treatment approach is required for optimal management of this cancer. Overcoming resistance to therapy requires combining targeted agents with the traditional options of chemotherapy/radiation therapy, and also targeting more than 1 pathway of carcinogenesis at a time. Encouraging molecular hypothesis and biomarker-driven trials will lead to improved patient outcomes and may eventually enable the therapeutic nihilism associated with gastric cancer to be overcome., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We had previously demonstrated that low dose irinotecan (CPT-11) leads to increased accumulation of cells in S-phase and shows a therapeutic synergy with S-phase specific chemotherapy such as gemcitabine and 5-fluorouracil. In this phase II study, our objectives were to evaluate the tolerability and activity of low dose CPT-11 followed 24 h later by gemcitabine as second line therapy in patients with metastatic non-small cell lung cancer (NSCLC). CPT-11 (60 mg/m) was administered 24 h before gemcitabine (1000 mg/m) on days 1, 2, 8, and 9 every 3 weeks. Twenty-nine patients were evaluable for response. The median follow-up was 7.4 months. Partial response (PR) was seen in two (6.9, 95% confidence interval (CI): 0.009-0.228). PR and stable disease were seen in 22 patients (75.9, 95% CI: 0.564-0.897). The median survival time was 13.8 months (95% CI: 8.1-19.3). The median time to progression was 4.6 months (95% CI: 2.6-6.2). Thirty-eight patients were evaluable for toxicity. Neutropenia (grade 3 or 4) was observed in 27 patients (71%). Eight patients did not receive cycle 2 of therapy owing to prolonged neutropenia. No treatment-related deaths occurred. Scheduled administration of low dose CPT-11, 24 h before gemcitabine in the second line therapy of NSCLC yielded comparable disease control rates (PR and stable disease) when compared with other studies using the two chemotherapy drugs in the traditional sequence. However, this approach was associated with higher grade 3/4 neutropenia and is not recommended for further study in metastatic NSCLC.

Surgical resection for selected patients with hepatic metastases from colorectal cancer can cure approximately one-fourth of these patients. The addition of regional chemotherapy as an attempt to improve this statistic has been extensively investigated in clinical trials. As part of a multidisciplinary educational program, a series of debates on various topics in oncology are held at the Roswell Park Cancer Institute, Buffalo, New York, involving the medical, surgical, and radiation oncology departments. One such debate focused on the use of regional chemotherapy after potentially curative resection of hepatic metastases from colorectal cancer. The representative medical and surgical oncology fellows (N.I.K. and B.P.M.), with guidance from their respective mentors (C.G.L., J.F.G., and N.J.P.), presented concise reviews from the literature arguing for and against the use of regional chemotherapy in this setting. They appear as Parts 1 and 2 in this article. This exercise is purely educational and does not in any way reflect the opinion or the clinical practice of the authors. ., (Copyright 2002 Wiley-Liss, Inc.)

Purpose: To identify a dose and schedule of oxaliplatin (OXP) to be safely administered in combination with protracted-infusion (PI) fluorouracil (5-FU) and external-beam radiation therapy (XRT) for patients with primary esophageal carcinoma (EC)., Patients and Methods: Eligibility included therapeutically naïve EC patients with clinical disease stages II, III, or IV. Initial doses and schedules for cycle 1 consisted of OXP 85 mg/m(2) on days 1, 15, and 29; PI 5-FU 180 mg/m(2) for 24 hours for 35 days; and XRT 1.8 Gy in 28 fractions starting on day 8. At completion of cycle 1, eligible patients could undergo an operation or begin cycle 2 without XRT. Postoperative patients were eligible for cycle 2. Stage IV patients were allowed three cycles in the absence of disease progression. OXP and 5-FU increases were based on dose-limiting toxicity (DLT) encountered in cohorts of three consecutive patients., Results: Thirty-eight eligible patients received therapy: 22 noninvasively staged as IV and 16 noninvasively staged as II and III. Thirty-six patients completed cycle 1, 29 patients started cycle 2, and 24 patients completed cycle 2. The combined-modality therapy was well tolerated, but DLT prevented OXP and 5-FU escalation. No grade 4 hematologic toxicity was noted. Eleven grade 3 and two grade 4 clinical toxicities were noted in eight patients. After cycle 1, 29 patients (81%) had no cancer in the esophageal mucosa. Thirteen patients underwent an operation with intent to resect the esophagus; five patients (38%) exhibited pathologic complete responses., Conclusion: OXP 85 mg/m(2) on days 1, 15, and 29 administered with PI 5-FU and XRT is safe, tolerable, and seems effective against primary EC. The role of OXP in multimodality regimens against EC deserves further evaluation.

BackgroundIn 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.MethodsPatients 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).ResultsSymptomatic 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.ConclusionsNivolumab 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.