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BackgroundThere are limited therapeutic options for patients with progressive disease (PD) on or after PD-1–blocking antibody therapy. Vidutolimod (CMP-001) is a first-in-class, immunostimulatory virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist. This phase 1b study evaluated the safety and clinical activity of intratumoral vidutolimod with and without pembrolizumab in patients with refractory melanoma.MethodsThis two-part, open-label, multicenter, phase 1b study (NCT02680184) enrolled adults with histologically confirmed metastatic or unresectable cutaneous melanoma who had stable disease after ≥12 weeks or PD on anti−PD-1 treatment, measurable disease per RECIST v1.1, ECOG PS 0/1, and ≥1 lesion accessible for intratumoral injection. Part 1 evaluated vidutolimod + pembrolizumab and Part 2 evaluated vidutolimod monotherapy. Key objectives included assessment of safety and clinical activity, and exploratory analyses were performed on available tumor biopsies using immunohistochemistry and RNAseq.ResultsAt data cutoff (August 17, 2021), 159 patients had enrolled in Part 1 and 40 patients in Part 2. The median age was 64 years in Part 1 (range, 30-90) and 68 years in Part 2 (range, 30-89). Most patients had PD as their last response to prior anti–PD-1 therapy (Part 1, 93.1%; Part 2, 80.0%). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 37.1% of patients treated with vidutolimod + pembrolizumab and in 22.5% of patients treated with vidutolimod monotherapy. No treatment-related deaths occurred. Based on the efficacy data presented in Table 1, vidutolimod polysorbate 20 (PS20) A was selected for further development as this formulation in combination with pembrolizumab had a best objective response rate (ORR; RECIST v1.1) of 23.5%, with a median duration of response (DOR) of 25.2 months. Vidutolimod monotherapy had an ORR of 20.0%, with a median DOR of 5.6 months. Exploratory translational analyses identified association of unique biomarkers with response among patients with T cell–inflamed versus non-T cell–inflamed tumors at baseline.Abstract 950 Table 1Safety and clinical activity of vidutolomod ± pembrolizumabConclusionsPromising clinical activity was observed with vidutolimod + pembrolizumab and vidutolimod monotherapy in patients with PD-1 blockade–refractory melanoma. A manageable safety profile was observed. The DOR with vidutolimod + pembrolizumab was substantially longer than with vidutolimod monotherapy. Clinical studies to confirm the efficacy of vidutolimod + PD-1 blockade in patients with previously untreated unresectable/metastatic melanoma (phase 2/3, NCT04695977) or PD-1 blockade–refractory melanoma (phase 2, NCT04698187) are ongoing.AcknowledgementsThis work was supported by Checkmate Pharmaceuticals. Medical writing assistance was provided by Steffen Biechele, PhD (ApotheCom, San Francisco, CA, USA), and funded by Checkmate Pharmaceuticals.Trial RegistrationNCT02680184Ethics ApprovalThis study was approved by the WCG-WIRB; WIRB approval tracking number: 20152597.

Background Therapeutic options are limited for patients with advanced melanoma that is refractory to PD-1 blockade. This study was performed in this patient population to assess the safety and antitumor activity of CMP-001, a CpG-A TLR9 agonist packaged within a virus-like particle. Methods Patients were eligible for this 2-part, open-label, multicenter, phase 1b study if they had metastatic/unresectable melanoma and stable disease after =12 weeks or progressive disease (PD) on/after anti-PD-1 therapy. Part 1 evaluated CMP-001 plus pembrolizumab dose-escalation and dose-expansion. Part 2 evaluated CMP-001 monotherapy. Accessible lesion(s) were injected intratumorally with CMP-001, at a polysorbate 20 (PS20) concentration of either 0.01% or 0.00167%. The Part 1 primary objective was to identify the recommended phase 2 dose (RP2D) and schedule of CMP-001 plus pembrolizumab, while the Part 2 primary objective was to assess the safety of CMP-001 monotherapy. Secondary objectives for both parts were a preliminary assessment of antitumor activity of CMP-001 plus pembrolizumab and CMP-001 monotherapy, and the overall safety profile and pharmacodynamics of the combination. Results In Part 1 (N=159) and Part 2 (N=40), 93.1% and 80.0% of patients had PD as their last response to prior anti–PD-1 therapy, respectively. The most common treatment-related adverse events (TRAEs; >25%) were flu-like symptoms (Parts 1 and 2) and injection-site reactions (Part 1). Grade 3/4 TRAEs were reported in 36.5% (Part 1) and 22.5% (Part 2) of patients, the most common being hypotension (Part 1: 6.9%; Part 2: 5.0%). No Grade 5 TRAEs were observed. In Part 1, the best objective response rate (ORR; RECIST v1.1) in patients treated with pembrolizumab and CMP-001 (PS20 0.01%) was 23.5% (23/98), while CMP-001 PS20 (0.00167%) resulted in a lower ORR of 11.5% (7/61). Seven additional patients had a delayed response after initial PD (table 1). The median duration of response was >1 year. In the 37 RECIST v1.1 and post-progression responders, the mean regression in injected and noninjected target lesions was 54.7% and 52.7%, respectively. In Part 2, the best ORR with CMP-001 monotherapy was 17.5% (7/40 patients); the response duration was shorter than in Part 1. Intratumoral CMP-001 PS20 0.01% 10 mg was selected as the RP2D. Conclusions Intratumoral CMP-001 was well-tolerated and provided both local and distant responses in patients with advanced melanoma with disease progression on prior PD-1 blockade. CMP-001 monotherapy induced systemic tumor regression in some patients, but duration of response was substantially increased by the addition of pembrolizumab. Acknowledgements This work was supported by Checkmate Pharmaceuticals. Medical writing assistance was provided by Cindy Rigby, PhD, of ApotheCom (San Francisco, CA) and was funded by Checkmate Pharmaceuticals. Trial Registration NCT02680184 Ethics Approval This study was approved by the WCG-WIRB, WIRB approval tracking number 20152597. Consent N/A References N/A

Background The use of immune checkpoint inhibitors is increasing in cancer therapy today. It is critical that treatment teams become familiar with the organ systems potentially impacted by immune-related adverse events associated with these drugs. Here, we report adverse skeletal effects of immunotherapy, a phenomenon not previously described. Case presentations In this retrospective case series, clinical, laboratory and imaging data were obtained in patients referred to endocrinology or rheumatology with new fractures (n = 3) or resorptive bone lesions (n = 3) that developed while on agents targeting PD-1, CTLA-4 or both. The average age of patients was 59.3 (SD 8.6), and five were male. Cancer types included melanoma, renal cell carcinoma and non-small cell lung cancer. All fracture patients had vertebral compression, and two of the three had multiple fracture sites involved. Sites of resorptive lesions included the shoulder, hand and clavicle. Biochemically, elevated or high-normal markers of bone resorption were seen in five of the six patients. Erythrocyte sedimentation rate was elevated in three of the four patients where checked. Conclusions This case series represents the first description of potential skeletal adverse effects related to immune checkpoint inhibitors. These findings are important for providers caring for patients who experience musculoskeletal symptoms and may merit additional evaluation.

BackgroundPatients with advanced cutaneous melanoma and persistent disease after checkpoint inhibitor therapy have poor outcomes and limited treatment options, highlighting a significant unmet medical need.1 Autologous TIL cell therapies have shown promise in this population attributable, in part, to their intrinsic and patient-specific antitumor activity2; however, no such therapies are approved. Made from each patient‘s digested and cryopreserved tumor, ITIL-168 is an autologous TIL cell therapy manufactured to offer an unrestricted T-cell receptor repertoire. A single-center compassionate use clinical series demonstrated the feasibility and clinical utility of an earlier version of ITIL-168.3 DELTA-1 is a global, multicenter phase 2 study to evaluate efficacy and safety of ITIL-168. DELTA-1 will enroll patients with melanoma relapsed after or refractory to PD-1 inhibitors (PD-1i), patients intolerant to PD-1i, and patients whose best response to PD-1i was stable disease.MethodsPatients aged ≥18 years with histologically confirmed advanced cutaneous melanoma, ECOG performance status 0–1, and adequate organ function will be enrolled in 1 of 3 cohorts. Cohort 1 (n≈80) will include patients who relapsed after or were refractory to ≥1 prior line of systemic therapy, including a PD-1i and, if BRAF-mutated, a BRAFi ± MEKi. Cohorts 2 and 3 (n≈25 each) will include patients intolerant to PD-1i and those with stable disease after ≥4 doses of PD-1i, respectively. After tumor resection for TIL harvest, patients must have ≥1 remaining measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patients with uveal, acral, or mucosal melanoma, prior allogeneic transplant or cell therapy, and with central nervous system (CNS) disorder or symptomatic and/or untreated CNS metastases are ineligible. Patients will receive 5 days of lymphodepleting chemotherapy (cyclophosphamide ×2 days overlapping with fludarabine ×5 days) followed by a single ITIL-168 infusion (≥5×109 cells) and supportive short course high-dose IL-2. The primary endpoint is objective response rate (ORR) per central review. Key secondary endpoints include duration of response, progression-free survival, overall survival, disease control rate, TIL persistence, and safety. Hypothesis testing of ORR will be performed for cohort 1. Two interim analyses will occur after 20 patients in cohort 1 have been followed for ≥28 days (safety) and evaluated for response ≥3 months after ITIL-168 infusion (futility). The primary analysis will occur when all patients in the cohort 1 modified intent-to-treat population have been followed for ≥6 months after the first posttreatment disease assessment.AcknowledgementsMedical writing support was provided by Christopher Waldapfel, PharmD, of Instil Bio, Inc, and Phylicia Aaron, PhD, of Nexus GG Science, with funding from Instil Bio, Inc.ReferencesSchadendorf D, van Akkoi ACJ, Berking C, et al. Melanoma. Lancet 2018;392(10151):971–984.Borch TH, Anderson R, Ellebaek E, et al. Future role for adoptive T-cell therapy in checkpoint inhibitor-resistant metastatic melanoma. J Immunother Cancer 2020;8(2):e000668.Hawkins RE, Jiang Y, Lorigan PC, et al. Clinical feasibility and treatment outcomes with unselected autologous tumor infiltrating lymphocyte therapy in patients with advanced cutaneous melanoma. Cancer Res 2021;81(13):LB150.Ethics ApprovalAll patients will provide written informed consent. The study will be approved by the Institutional Review Board/Independent Ethics Committee at each site and conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation.ConsentN/A; the abstract does not contain sensitive or identifiable patient information.

BackgroundLimited data exist on safe discontinuation of antiprogrammed cell death protein 1 (PD-1) therapy in responding patients with advanced melanoma. The use of 18fluorodeoxyglucose (18FDG)-PET/CT scan and tumor biopsy for assessment of active disease may be an effective predictive biomarker to guide such treatment decisions.MethodsA retrospective study of 122 patients with advanced melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anticytotoxic T-lymphocyte-associated protein 4 combination therapy at Georgetown Lombardi Comprehensive Cancer Center was conducted. Uveal melanoma patients and those receiving concurrent experimental therapy were excluded. Baseline characteristics, treatment outcomes, and survival were analyzed. Patients who decided to come off treatment typically after 12 months using CT scan radiographic complete response (CR), 18FDG-PET/CT scan complete metabolic response (CMR) or tumor biopsy of a non-CR/CMR tumor site negative for active disease (possible pathological CR) were identified and compared with patients who discontinued treatment due to toxicity while their disease was in control. Event-free survival (EFS) was assessed from the last dose of anti-PD-1 therapy to progression requiring subsequent treatment (surgery, radiation, and/or systemic therapy) or referral to hospice/death due to melanoma.Results24 (20%) patients discontinued treatment by choice with no active disease and 28 (23%) patients discontinued treatment due to toxicity with disease control after 12-month and 4-month median treatment durations, respectively. Similar baseline characteristics were observed between cohorts except higher prior receipt of ipilimumab (29% vs 7%; p=0.036) and fewer BRAF mutant positive disease (17% vs 41%; p=0.064) in patients off treatment by choice. Three-year EFS rates were 95% and 71%, respectively. No significant associations between EFS and sex, disease stage, lactate dehydrogenase elevation, BRAF status, prior systemic therapy, ECOG performance status, presence of brain metastases, or combination versus monotherapy were observed. Tumor biopsies led to alternative management in 3/10 patients due to active metastatic melanoma or second malignancy.ConclusionsAnti-PD-1 therapy discontinuation after 12 months when no active disease is observed on CT scan, PET/CT scan or tumor biopsy may have low rates of disease relapse in patients with advanced melanoma. Biopsy of residual disease may frequently lead to a change in management. These findings are undergoing validation in the EA6192 trial.

s Background Patients with chronic viral infections including human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV) are at increased risk of developing malignancies. The safety and efficacy of ICI therapy in patients with both cancer and chronic viral infections is not well established as most clinical trials of ICIs excluded these patient populations. Methods We performed a retrospective analysis of patients with advanced-stage cancers and HIV, HBV, or HCV infection treated with ICI therapy at 5 MedStar Health hospitals from January 2011 to April 2018. Results We identified 50 patients including 16 HIV, 29 HBV/HCV, and 5 with concurrent HIV and either HBV or HCV. In the HIV cohort (n = 21), any grade immune-related adverse events (irAEs) were 24% with grade ≥ 3 irAEs 14%. Among 5 patients with matched pre/post-treatment results, no significant changes in HIV viral load and CD4+ T-cell counts were observed. RECIST confirmed (n = 18) overall response rate (ORR) was 28% with 2 complete responses (CR) and 3 partial responses (PR). Responders included 2 patients with low baseline CD4+ T-cell counts (40 and 77 cells/ul, respectively). In the HBV/HCV cohort (n = 34), any grade irAEs were 44% with grade ≥ 3 irAEs 29%. RECIST confirmed ORR was 21% (6 PR). Among the 6 patients with known pre/post-treatment viral titers (2 HCV and 4 HBV), there was no evidence of viral reactivation. Conclusions Our retrospective series is one of the largest case series to report clinical outcomes among HIV, HBV and HCV patients treated with ICI therapy. Toxicity and efficacy rates were similar to those observed in patients without chronic viral infections. Viral reactivation was not observed. Tumor responses occurred in HIV patients with low CD4 T-cell counts. While prospective studies are needed to validate above findings, these data support not excluding such patients from ICI–based clinical trials or treatment.

Background Epacadostat is a potent inhibitor of the immunosuppressive indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. We present phase 1 results from a phase 1/2 clinical study of epacadostat in combination with ipilimumab, an anti-cytotoxic T-lymphocyte-associated protein 4 antibody, in advanced melanoma (NCT01604889). Methods Only the phase 1, open-label portion of the study was conducted, per the sponsor’s decision to terminate the study early based on the changing melanoma treatment landscape favoring exploration of programmed cell death protein 1 (PD-1)/PD-ligand 1 inhibitor-based combination strategies. Such decision was not related to the safety of epacadostat plus ipilimumab. Patients received oral epacadostat (25, 50, 100, or 300 mg twice daily [BID]; 75 mg daily [50 mg am, 25 mg pm]; or 50 mg BID intermittent [2 weeks on/1 week off]) plus intravenous ipilimumab 3 mg/kg every 3 weeks. Results Fifty patients received ≥1 dose of epacadostat. As of January 20, 2017, 2 patients completed treatment and 48 discontinued, primarily because of adverse events (AEs) and disease progression (n = 20 each). Dose-limiting toxicities occurred in 11 patients (n = 1 each with epacadostat 25 mg BID, 50 mg BID intermittent, 75 mg daily; n = 4 each with epacadostat 50 mg BID, 300 mg BID). The most common immune-related treatment-emergent AEs included rash (50%), alanine aminotransferase elevation (28%), pruritus (28%), aspartate aminotransferase elevation (24%), and hypothyroidism (10%). Among immunotherapy-naive patients (n = 39), the objective response rate was 26% by immune-related response criteria and 23% by Response Evaluation Criteria in Solid Tumors version 1.1. No objective response was seen in the 11 patients who received prior immunotherapy. Epacadostat exposure was dose proportional, with clinically significant IDO1 inhibition at doses ≥25 mg BID. Conclusions When combined with ipilimumab, epacadostat ≤50 mg BID demonstrated clinical and pharmacologic activity and was generally well tolerated in patients with advanced melanoma. Trial registration ClinicalTrials.gov identifier, NCT01604889. Registration date, May 9, 2012, retrospectively registered. Electronic supplementary material The online version of this article (10.1186/s40425-019-0562-8) contains supplementary material, which is available to authorized users.