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

Claire F Friedman, Christine Spencer, Christopher R Cabanski, Katherine S Panageas, Daniel K Wells, Antoni Ribas, Hussein Tawbi, Katy Tsai, Michael Postow, Alexander Shoushtari, Paul Chapman, Joyson Karakunnel, Samantha Bucktrout, Pier Gherardini, Travis J Hollmann, Richard O Chen, Margaret Callahan, Theresa LaVallee, Ramy Ibrahim, Jedd Wolchok, Claire F Friedman, Christine Spencer, Christopher R Cabanski, Katherine S Panageas, Daniel K Wells, Antoni Ribas, Hussein Tawbi, Katy Tsai, Michael Postow, Alexander Shoushtari, Paul Chapman, Joyson Karakunnel, Samantha Bucktrout, Pier Gherardini, Travis J Hollmann, Richard O Chen, Margaret Callahan, Theresa LaVallee, Ramy Ibrahim, Jedd Wolchok

Abstract

Background: There 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.

Methods: We 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.

Results: Objective 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.

Conclusions: In 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 number: NCT02731729.

Keywords: immunotherapy; melanoma; tumor microenvironment.

Conflict of interest statement

Competing interests: CFF reports personal/consultancy fees from AstraZeneca, as well as participation in steering committees (compensation waived) for Merck and Genentech; these are outside the scope of the submitted work. She also reports institutional research funding from Genentech, Merck, Bristol Myers Squibb, Daiichi, and AstraZeneca. AR reports personal/consultancy fees from Amgen, Chugai, Genentech, Jounce, Merck, Novartis, Nurix, Sanofi, and Vedanta; stock from prior consulting with Advaxis, CytomX, Five Prime, RAPT, IsoPlexis, and Kite-Gilead; being a member of the scientific advisory board and stockholder in 4C Biomed, Apricity, Arcus, Highlight, Compugen, ImaginAb, MapKure, Merus, Rgenix, Lutris, PACT Pharma, and Tango; and receiving research funding to the institution from Agilent and Bristol-Myers Squibb through a Stand Up to Cancer Catalyst grant. KKT reports institutional research funding from Array/Pfizer, Bristol Myers Squibb. Oncosec, Regeneron, and Replimune. HT reports personal/consultancy fees from Genentech, Merck, BMS, Novartis, Iovance, and Eisai and research funding to institution from Genentech, Merck, BMS, Novartis, Celgene, and GSK. TL discloses the following: LISCure Biosciences Scientific Advisory Board, June 2020 up to the present and stock ownership in AstraZeneca; consulting: TRex Bio, Grey Wolf Therapeutics, Exosis, and BiOne Cure; these are outside the scope of the submitted work. MP reports personal/consultancy fees from Array BioPharma, Aduro Biotech, Bristol Myers Squibb, Incyte, Merck, Newlink Genetics, Novartis, and Eisai; honoraria from Bristol Myers Squibb and Merck; research funding from Array BioPharma, AstraZeneca/Medimmune, Bristol Myers Squibb, Infinity Pharmaceuticals, Merck, Novartis, and RgenixA. NS reports personal/consultancy fees from Bristol-Myers Squibb, Immunocore, and Castle Biosciences; research funding to institution from BMS, Immunocore, Xcovery, and Novartis. MC reports institutional research support and employment of a family member by Bristol-Myers Squibb, and consulting, advisory, or speaking compensation for AstraZeneca/MedImmune, Incyte, Moderna, Immunocore and Merck. PC reports consulting/advisory/or speaking compensation from Immunocore, Merck, Cell Medica, Takeda Millenium, and Astra Zeneca; stock ownership in Rgenix; and research funding from Pfizer. DKW is a scientific founder of, holds equity in, and receives consulting fees from Immunai. RI discloses the following: scientific advisory board membership at Harpoon, BitBio, and Arcus; board of directors at Surface Oncology; non-compensated board membership at Lyell; non-compensated scientific advisory board membership at ImaginAb; advisor: IMV and Georgiamune. JK discloses the following: either scientific advisory board membership, stock ownership, or receiving consulting fees from AstraZeneca, Arcus Biosciences, Tizona Therapeutics, Trishula Therapeutics, Primevax, and Elucida Oncology. JW is a consultant for Amgen, Apricity, Ascentage Pharma, Arsenal IO, Astellas, AstraZeneca, Bayer, Bicara Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Dragonfly, Eli Lilly, F Star, Georgiamune, Idera, Imvaq, Kyowa Hakko Kirin, Maverick Therapeutics, Merck, Neon Therapeutics, Psioxus, Recepta, Tizona, Trieza, Truvax, Trishula, Sellas, Surface Oncology, Syndax, Syntalogic, and Werewolf Therapeutics. JDW reports receiving grant/research support from Bristol Myers Squibb and Sephora; having equity in Tizona Pharmaceuticals, Adaptive Biotechnologies, Imvaq, Beigene, Linneaus, Apricity, Arsenal IO, Georgiamune, Trieza, Maverick, and Ascentage.

© 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.

Figures

Figure 1
Figure 1
Change in tumor burden, TTF, and overall survival. (A) Percentage change from baseline in the sum of the diameters of the target lesions in patients receiving ipilimumab (gold) or ipilimumab plus nivolumab (teal). Triangles denote the presence of a new lesion. Two patients in the ipilimumab plus nivolumab arm did not have postbaseline target lesion measurements and are not displayed on the plot (clinical progression, presence of a new lesion (counted as radiographic progressive disease) but no measurement of the target lesions). (B) Maximum percentage change from baseline in the sum of the diameters of the target lesions at week 18. Asterisks denote that the response (complete or partial) was confirmed by a second scan by week 18. Two patients, one in each arm, had a maximum change in the sum of target lesion diameters of less than 20% but had a best overall response of progressive disease due to the presence of a new lesion. (C) Kaplan-Meier curves for TTF. (D) Kaplan-Meier curves for overall survival. TTF, time-to-treatment failure.
Figure 2
Figure 2
Trends in peripheral immune characteristics and CB over the course of therapy. (A) Trends in CD4+ and CD8+ T cells by CB (pink denotes no CB, n=6; green denotes CB, n=10). Thick lines represent mean fold change±95% CI of group cell population over time as percent of total leukocytes; light-colored lines represent measurements of individual patients. (B) Trends in CD4+ T cells by CB. Thick lines represent mean fold change±95% CI of group cell population over time as percent of total leukocytes; light-colored lines represent measurements of individual patients. (C) Comparison of fold change from baseline in CD4+ and CD8+ T-cell populations by CB prior to cycle 2 of therapy. (D) Trends in CD4+ T-cell cytokine PSI and effector PSI by CB (pink denotes no CB, n=7; green denotes CB, n=11). Thick lines represent mean fold change±95% CI of group cell population over time as percent of total leukocytes; light-colored lines represent measurements of individual patients. (E) Trends in IFN-γ secretion frequency and signal intensity from CD4+ T cells by CB. Thick lines represent mean fold change±95% CI of group cell population over time as percent of total leukocytes; light-colored lines represent measurements of individual patients. (F) Differences in regulatory PSI and IL-10 secretion frequency and from CD4+ T cells at baseline by CB (pink denotes no CB; n=6; green denotes CB, n=11). *P

Figure 3

Features of the tumor microenvironment…

Figure 3

Features of the tumor microenvironment in patients with melanoma treated with ipilimumab or…

Figure 3
Features of the tumor microenvironment in patients with melanoma treated with ipilimumab or ipilimumab plus nivolumab. (A) Mutational landscape indicating melanoma and immunotherapy-related genes with alterations in patients (n=10) at all timepoints. (B) Heatmap of expression profiling of patient tumors (n=10) by RNA sequencing at the on-treatment timepoint. The list of genes comprising each signature (heatmap columns) is detailed in online supplemental table S2. (C) Heatmap showing immune population scores calculated by EPIC deconvolution of the gene expression data for all patients with on-treatment samples sent for RNA sequencing (n=10). BOR, best overall response; CAFs, cancer associated fibroblasts; PD, progressive disease; PR, partial response; SD, stable disease.
Figure 3
Figure 3
Features of the tumor microenvironment in patients with melanoma treated with ipilimumab or ipilimumab plus nivolumab. (A) Mutational landscape indicating melanoma and immunotherapy-related genes with alterations in patients (n=10) at all timepoints. (B) Heatmap of expression profiling of patient tumors (n=10) by RNA sequencing at the on-treatment timepoint. The list of genes comprising each signature (heatmap columns) is detailed in online supplemental table S2. (C) Heatmap showing immune population scores calculated by EPIC deconvolution of the gene expression data for all patients with on-treatment samples sent for RNA sequencing (n=10). BOR, best overall response; CAFs, cancer associated fibroblasts; PD, progressive disease; PR, partial response; SD, stable disease.

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