Ipilimumab alone or in combination with nivolumab in patients with advanced melanoma who have progressed or relapsed on PD-1 blockade: clinical outcomes and translational biomarker analyses

Abstract

BackgroundThere are no validated biomarkers that can aid clinicians in selecting who would best benefit from anticytotoxic T lymphocyte-associated antigen 4 monotherapy versus combination checkpoint blockade in patients with advanced melanoma who have progressive disease after programmed death 1 (PD-1) blockade.MethodsWe conducted a randomized multicenter phase II trial in patients with advanced melanoma. Patients were randomly assigned to receive either 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab or 3 mg/kg of ipilimumab every 3 weeks for up to four doses. Patients were stratified by histological subtype and prior response to PD-1 therapy. The primary clinical objective was overall response rate by week 18. Translational biomarker analyses were conducted in patients with blood and tissue samples.ResultsObjective responses were seen in 5 of 9 patients in the ipilimumab arm and 2 of 10 patients in the ipilimumab+nivolumab arm; disease control rates (DCRs) (66.7% vs 60.0%) and rates of grade 3–4 adverse events (56% vs 50%) were comparable between arms. In a pooled analysis, patients with clinical benefit (CB), defined as Response Evaluation Criteria in Solid Tumors response or progression-free for 6 months, showed increased circulating CD4+ T cells with higher polyfunctionality and interferon gamma production following treatment. Tumor profiling revealed enrichment of NRAS mutations and activation of transcriptional programs associated with innate and adaptive immunity in patients with CB.ConclusionsIn patients with advanced melanoma that previously progressed on PD-1 blockade, objective responses were seen in both arms, with comparable DCRs. Findings from biomarker analyses provided hypothesis-generating signals for validation in future studies of larger patient cohorts.Trial registration numberNCT02731729.

Real world evidence of Lenvatinib + anti PD-1 as an advanced line for metastatic melanoma

“…The median dose of Lenvatinib used was 10 mg ( 8 – 20 ), with 14 patients (33%) staying at the starting dose of 20 mg with no dose interruptions and the other 28 (67%) having dose reductions. The most common cause for dose reduction was toxicity in 19 patients (45%) with 3 of them stopping treatment due to toxicity (one patient experienced perforation requiring emergency surgery, one developing grade 4 skin toxicity and one who stopped both agents due to severe neurological toxicity and continued only Lenvatinib with a reduced dose of 10 mg).…”

Applying single‐cell highly multiplexed secretome proteomics to characterize immunotherapeutic products and predict clinical responses

“…Moreover, Friedman et al. carried out a phase II study on ipilimumab (CTLA‐4 inhibitor) alone or in combination with nivolumab treatment of patients with advanced melanoma who have progressed or relapsed on PD‐1 blockade [93]. During this study, patients were randomly assigned to receive either ipilimumab alone or nivolumab plus ipilimumab.…”

“…Therefore, single-cell polyfunctional secretome assays were able to predict R/R AML patient response and can be used as a potential biomarker in various immune-based therapies for precision medicine. Moreover, Friedman et al carried out a phase II study on ipilimumab (CTLA-4 inhibitor) alone or in combination with nivolumab treatment of patients with advanced melanoma who have progressed or relapsed on PD-1 blockade[93]. During this study, patients were randomly assigned to receive either ipilimumab alone or nivolumab plus ipilimumab.…”

Up-front Nivolumab With or Without Salvage Ipilimumab Across International Metastatic Database Consortium Risk Groups in Metastatic Clear Cell Renal Cell Carcinoma

“…Retrospective reports gave support to the notion that patients could safely be treated with sequential CPI, possibly achieving added benefit. 8,9 In malignant melanoma where approval of CPI monotherapy preceded the successful development of the ipilimumab/nivolumab doublet, 10 CTLA-4-directed salvage strategies have been studied prospectively with a clear efficacy signal 11,12 All this motivated the design of the HCRN GU16-260 study presented by Atkins et al 13 This phase II response-adaptive trial offered up-front nivolumab to patients with treatment-naive metastatic ccRCC, irrespective of International Metastatic Database Consortium (IMDC) risk category (Part A). Patients who achieved an objective response were treated up to 96 weeks.…”

“…Retrospective reports gave support to the notion that patients could safely be treated with sequential CPI, possibly achieving added benefit. 8,9 In malignant melanoma where approval of CPI monotherapy preceded the successful development of the ipilimumab/nivolumab doublet, 10 CTLA-4–directed salvage strategies have been studied prospectively with a clear efficacy signal 11,12…”