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ObjectivePatients with melanoma and early stable disease (SD) with pembrolizumab have unclear prognosis. We present post hoc analyses of long-term outcomes for patients with early SD, partial response (PR)or complete response (CR) with pembrolizumab.Patients and methodsPatients who received pembrolizumab in the KEYNOTE-001 and KEYNOTE-006 studies and had SD, PRor CR at weeks 12 or 24 were included.ResultsOf 294 patients in the week 12 analysis, 107 (36.4%) had SD at week 12, of whom 7 (6.5%) had a best overall response of CR, 43 (40.2%) had PRand 57 (53.3%) had SD. Forty-eight-month overall survival (OS) rates were 95.2%, 73.0%and 47.7%, respectively, for patients with CR, PRand SD at week 12. Similar results were observed in the 241 patients in the week 24 analysis. Forty-eight-month OS rates were 72.1% for patients with SD at week 12 followed by subsequent responseand 75.0% for patients with PR at week 12 followed by no change in response or progression. Thirty-six-month and 48-month OS rates were 11.6% and not reached, respectively, for patients with SD at week 12 followed by progression before week 24.ConclusionsA substantial proportion of patients (46.7%) with early (week 12) SD with pembrolizumab achieved subsequent PR or CR. Patients with SD at week 12 and subsequent CR/PR had similar survival to those who maintained PR. In contrast, patients with SD at week 12 and subsequent progression had poor survival outcomes. These findings may guide treatment decisions for patients achieving early SD.Trial registrationClinicaltrials.gov: NCT01295827 (KEYNOTE-001); NCT01866319 (KEYNOTE-006).

Additional file 1: Supplemental figures and tables are available within the “Additional file 1.docx” file which contains 16S rRNA OTU ASV variant analysis (Fig S1), differential clustering based on RNAseq expression levels (Fig S2), correlation between metagenome and metatranscriptome data (Fig S3), temporal stability of GMB PCoAs (Fig S4) and temporal stability PERMANOVA results (Table S1).

BackgroundThe programmed death 1 (PD-1) receptor is a negative regulator of T-cell effector mechanisms that limits immune responses against cancer. We tested the anti-PD-1 antibody lambrolizumab (previously known as MK-3475) in patients with advanced melanoma.MethodsWe administered lambrolizumab intravenously at a dose of 10 mg per kilogram of body weight every 2 or 3 weeks or 2 mg per kilogram every 3 weeks in patients with advanced melanoma, both those who had received prior treatment with the immune checkpoint inhibitor ipilimumab and those who had not. Tumor responses were assessed every 12 weeks.ResultsA total of 135 patients with advanced melanoma were treated. Common adverse events attributed to treatment were fatigue, rash, pruritus, and diarrhea; most of the adverse events were low grade. The confirmed response rate across all dose cohorts, evaluated by central radiologic review according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was 38% (95% confidence interval [CI], 25 to 44), with the highest confirmed response rate observed in the cohort that received 10 mg per kilogram every 2 weeks (52%; 95% CI, 38 to 66). The response rate did not differ significantly between patients who had received prior ipilimumab treatment and those who had not (confirmed response rate, 38% [95% CI, 23 to 55] and 37% [95% CI, 26 to 49], respectively). Responses were durable in the majority of patients (median follow-up, 11 months among patients who had a response); 81% of the patients who had a response (42 of 52) were still receiving treatment at the time of analysis in March 2013. The overall median progression-free survival among the 135 patients was longer than 7 months.ConclusionsIn patients with advanced melanoma, including those who had had disease progression while they had been receiving ipilimumab, treatment with lambrolizumab resulted in a high rate of sustained tumor regression, with mainly grade 1 or 2 toxic effects. (Funded by Merck Sharp and Dohme; ClinicalTrials.gov number, NCT01295827.).

As we enter the era of targeted therapy for melanoma, attempts are being made to sub-group tumors on the basis of their driving oncogenic mutations, with the hope of developing truly personalized therapeutic regimens. c-KIT is a receptor tyrosine kinase whose aberrant activation is implicated in the progression of gastrointestinal stromal tumors and some acute myeloid leukemias. The role of c-KIT signaling in melanoma has been controversial; although c-KIT activity is critical to melanocyte development, its expression tends to be lost in most melanomas. Some reports have even shown that the re-expression of c-KIT induces apoptosis in melanoma cell lines. The recent publication of work showing the presence of activating c-KIT mutations in acral and mucosal melanomas, as well as melanomas arising on skin with chronic sun damage, has renewed interest in c-KIT signaling in melanoma. Recent work from our own laboratory has further identified melanomas with constitutive c-KIT signaling activity resulting from c- KIT receptor overexpression. Although the initial clinical trials of the c-KIT inhibitor imatinib mesylate in melanoma were negative, some dramatic responses have been seen in patients with very high c-KIT expression and/or documented activating mutations, fostering the belief that focused studies in patients selected on the basis of c-KIT mutational status will yield more encouraging results. The current review discusses the role of c-KIT signaling in melanoma progression and how this new information can be applied to the targeted therapy of melanoma.

TPS9609 Background: Despite improved outcomes for melanoma patients with the introduction of checkpoint inhibitors (CPIs), ̃50% of patients do not respond. A subset of responders ultimately progress and have limited treatment options, underscoring a high unmet need for novel treatments with durable benefit. Patients with mucosal melanoma exhibit response rates and progression-free survival times ̃2 times lower than those with cutaneous melanoma. Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds the intermediate-affinity interleukin-2 receptor complex to preferentially activate CD8+ T and NK cells with minimal expansion of regulatory T cells. Nemvaleukin has been granted Orphan Drug designation for the treatment of mucosal melanoma by the FDA. In ARTISTRY-1, the intravenous (IV) recommended phase 2 dose (RP2D) of 6 µg/kg nemvaleukin monotherapy demonstrated durable antitumor activity in patients with advanced melanoma, including mucosal melanoma, previously treated with a CPI. In ARTISTRY-2, the subcutaneous (SC) RP2D of 3 mg q7d was identified demonstrating pharmacodynamic effects consistent with IV delivery. Data support further evaluation of nemvaleukin monotherapy among patients with advanced mucosal and cutaneous melanoma. Methods: ARTISTRY-6 is a phase 2, global, multicenter, open-label study. Eligible patients have had prior treatment with an anti–PD-(L)1 therapy with or without anti–CTLA-4 therapy and have an ECOG performance status of 0 or 1 and adequate hematologic reserve and hepatic and renal function. Patients with advanced cutaneous (Cohort 1) and mucosal (Cohort 2) melanoma will receive nemvaleukin at the SC and IV RP2D, respectively. Patients will receive nemvaleukin until progression or intolerable toxicity. The primary objective is to evaluate the antitumor activity of nemvaleukin monotherapy defined by overall response rate. Additional objectives include the evaluation of safety, health-related quality of life, predictive biomarkers, pharmacokinetics, immunogenicity, and pharmacodynamic effects. Clinical trial information: NCT04830124.

BACKGROUND: Ipilimumab 3 mg/kg was the first agent to demonstrate improved survival in previously treated patients with metastatic melanoma in a phase 3 trial (MDX010-20). Ipilimumab produced a characteristic spectrum of immune-related adverse events (irAEs) of special interest, consistent with its immune-based mechanism of action. METHODS: In MDX010-20, 676 previously treated patients were randomized 3:1:1 to receive ipilimumab 3 mg/kg plus the glycoprotein 100 melanoma antigen vaccine (gp100), ipilimumab 3 mg/kg + placebo, or gp100 vaccine + placebo. For the current report, the authors conducted a detailed analysis of the time to onset and resolution of irAEs associated with ipilimumab therapy. RESULTS: Grade 2 through 5 irAEs generally developed during the induction phase of treatment (0-12 weeks). Most, including grade 3/4 irAEs, were reversible when managed with treatment guidelines using vigilant monitoring and corticosteroids. The median time to resolution (to grade 1 or 0 or to the grade at baseline) of irAEs that had an onset during the induction phase was approximately 6 weeks for grade 2 through 4 irAEs and 8 weeks for grade 3 and 4 irAEs. Across the entire study duration, most grade 2 through 4 irAEs resolved within 12 weeks. CONCLUSIONS: Most ipilimumab-associated irAEs, including grade 3/4 symptoms, developed within 12 weeks of initial dosing and resolved within 12 weeks of onset. IrAEs were well characterized in their evolution and could be managed using published algorithms. Cancer 2013. © 2013 American Cancer Society.