Spartalizumab or placebo in combination with dabrafenib and trametinib in patients with BRAF V600-mutant melanoma: exploratory biomarker analyses from a randomized phase 3 trial (COMBI-i)

Abstract

Background: The randomized phase 3 COMBI-i trial did not meet its primary endpoint of improved progression-free survival (PFS) with spartalizumab plus dabrafenib and trametinib (sparta-DabTram) vs placebo plus dabrafenib and trametinib (placebo-DabTram) in the overall population of patients with unresectable/metastatic BRAF V600-mutant melanoma. This prespecified exploratory biomarker analysis was performed to identify subgroups that may derive greater treatment benefit from sparta-DabTram.

Methods: In COMBI-i (ClinicalTrials.gov, NCT02967692), 532 patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally two times daily and trametinib 2 mg orally one time daily or placebo-DabTram. Baseline/on-treatment pharmacodynamic markers were assessed via flow cytometry-based immunophenotyping and plasma cytokine profiling. Baseline programmed death ligand 1 (PD-L1) status and T-cell phenotype were assessed via immunohistochemistry; BRAF V600 mutation type, tumor mutational burden (TMB), and circulating tumor DNA (ctDNA) via DNA sequencing; gene expression signatures via RNA sequencing; and CD4+/CD8+ T-cell ratio via immunophenotyping.

Results: Extensive biomarker analyses were possible in approximately 64% to 90% of the intention-to-treat population, depending on sample availability and assay. Subgroups based on PD-L1 status/TMB or T-cell inflammation did not show significant differences in PFS benefit with sparta-DabTram vs placebo-DabTram, although T-cell inflammation was prognostic across treatment arms. Subgroups defined by BRAF V600K mutation (HR 0.45 (95% CI 0.21 to 0.99)), detectable ctDNA shedding (HR 0.75 (95% CI 0.58 to 0.96)), or CD4+/CD8+ ratio above median (HR 0.58 (95% CI 0.40 to 0.84)) derived greater PFS benefit with sparta-DabTram vs placebo-DabTram. In a multivariate analysis, ctDNA emerged as strongly prognostic (p=0.007), while its predictive trend did not reach significance; in contrast, CD4+/CD8+ ratio was strongly predictive (interaction p=0.0131).

Conclusions: These results support the feasibility of large-scale comprehensive biomarker analyses in the context of a global phase 3 study. T-cell inflammation was prognostic but not predictive of sparta-DabTram benefit, as patients with high T-cell inflammation already benefit from targeted therapy alone. Baseline ctDNA shedding also emerged as a strong independent prognostic variable, with predictive trends consistent with established measures of disease burden such as lactate dehydrogenase levels. CD4+/CD8+ T-cell ratio was significantly predictive of PFS benefit with sparta-DabTram but requires further validation as a biomarker in melanoma. Taken together with previous observations, further study of checkpoint inhibitor plus targeted therapy combination in patients with higher disease burden may be warranted.

Trial registration number: NCT02967692.

Keywords: Drug Therapy, Combination; Melanoma; Tumor Biomarkers.

Conflict of interest statement

Competing interests: HAT reports personal consulting fees and institutional research support from Novartis; institutional research support and personal consulting fees from Merck, Bristol Myers Squibb, and Genentech; institutional research support from GSK and Celgene; and consulting fees from Eisai and Iovance. CR reports consulting fees from and advisory board participation with Bristol Myers Squibb, Roche, Pierre Fabre, Novartis, Amgen, Sanofi, Merck, Merck Sharp & Dohme, and AstraZeneca. JCB reports stock ownership of and employment with Novartis; also, he is a coinventor on a patent application related to reported biomarker subgroups of interest. DG reports employment with Novartis and that they are a coinventor on a patent application related to reported biomarker subgroups of interest. EG reports stock ownership of and employment with Novartis. JG, AS, and GG report employment with Novartis. KTF reports grants or contracts from Novartis and Sanofi; consulting fees from, advisory board participation with, stock ownership of, and a leadership or fiduciary role with Clovis Oncology and Strata Oncology; consulting fees from and a leadership or fiduciary role with Vivid Biosciences and Checkmate Pharmaceuticals; consulting fees from, advisory board participation with, and stock ownership of X4 Pharmaceuticals, PIC Therapeutics, Sanofi, Amgen, Asana, Adaptimmune, Fount, Aeglea, Shattuck Labs, Tolero, Apricity, Oncoceutics, FogPharma, Neon, Tvardi, xCures, Monopteros, and Vibliome; stock ownership of and a leadership or fiduciary role with Loxo Oncology; and consulting fees from Lilly, Novartis, Genentech, Bristol Myers Squibb, Merck, Takeda, Verastem, Boston Biomedical, Pierre Fabre, and Debiopharm. AR reports clinical trial funding and consulting fees from and advisory board participation with Novartis; consulting fees from Amgen, Bristol Myers Squibb, Chugai, Genentech, Merck, Roche, Sanofi, and Vedanta; advisory board participation with and stock ownership of Advaxis, Apricity, Arcus, Compugen, CytomX, Five Prime, Highlight Therapeutics, ImaginAb, IsoPlexis, Kalthera, Kite-Gilead, Merus, PACT Pharma, RAPT, Rgenix, and Tango; and research funding from Agilent and Bristol Myers Squibb through Stand Up To Cancer (SU2C). RD reports intermittent, project-focused consulting fees from and advisory relationships with Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, CatalYm, Second Genome, Regeneron, Alligator, MaxiVAX SA, and touchlME. DS reports clinical trial funding to their institution from Novartis; institutional research grants and personal consulting fees, payments or honoraria, and support for attending meetings/travel from and advisory board participation with Novartis and Bristol Myers Squibb; institutional research grants and personal consulting fees and support for attending meetings/travel from and advisory board participation with Amgen; consulting fees, payments or honoraria, and support for attending meetings/travel from and advisory board participation with Pierre Fabre, Sanofi-Genzyme, and Merck Serono; consulting fees and support for attending meetings/travel from and advisory board participation with Merck Sharp & Dohme, Roche, Incyte, Array BioPharma, Pfizer, Regeneron, 4SC, InflaRx, NeraCare, Ultimovacs, Sun Pharma, Philogen, Immunocore, and Sandoz-Hexal; and leadership or fiduciary roles in the Dermatologic Cooperative Oncology Group, German Cancer Society, Hilfe-Stiftung, Deutsche Hautkrebsstiftung, NVKH eV, and EUMelaReg. GVL reports consulting fees from and advisory board participation with Aduro Biotech, Amgen, Array BioPharma, Boehringer Ingelheim, Bristol Myers Squibb, Hexel AG, Highlight Therapeutics, Merck Sharp & Dohme, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group, Regeneron, SkylineDx BV, and Specialised Therapeutics Australia Pty Ltd; and personal payments or honoraria from Bristol Myers Squibb and Pierre Fabre. PDN reports consulting fees from AstraZeneca, Bristol Myers Squibb, Immunocore, Ipsen, Merck Sharp & Dohme, Merck, Novartis, Pfizer, and 4SC; personal payments or honoraria from Novartis, Merck, and Pfizer; and support for meeting attendance/travel from Bristol Myers Squibb. PAA reports research funding from, consulting fees from, and advisory board participation with Bristol Myers Squibb, Roche Genentech, Array BioPharma, and Sanofi; consulting fees from and advisory board participation with Novartis, Merck Serono, MedImmune, Sun Pharma, Idera, Sandoz, and 4SC; consulting fees from Italfarmaco, Pfizer, OncoSec, Takis, and Lunaphore; advisory board participation with Pierre Fabre, Incyte, AstraZeneca, Syndax, Ultimovacs, Immunocore, Alkermes, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Nouscom, and Seagen; consulting fees from, advisory board participation with, and support for meeting attendance/travel from Merck Sharp & Dohme; and leadership or fiduciary roles with the Society for Immunotherapy of Cancer, Society for Melanoma Research, Melanoma Foundation, and the Campania Society of Immunotherapy of Cancer. All authors acknowledge funding for medical writing support by ArticulateScience from Novartis, related to the present study.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1

Characterization (A) and prognostic impact (B and C) of T-cell phenotypes. Representative samples of the inflamed, excluded, and desert T-cell phenotypes derived from digital pathology immunohistochemistry of tumor-infiltrating and stroma-infiltrating lymphocytes are shown in (A). Based on average CD8 density values, the top third of tumors were defined as inflamed; the bottom third of stroma and other samples were defined as desert; and samples between these thresholds were defined as excluded. Shown in (B and C) are Kaplan-Meier estimates of progression-free survival based on these phenotypes in the placebo-DabTram (B; inflamed, n=73; excluded, n=72; desert, n=62) and sparta-DabTram (C; inflamed, n=66; excluded, n=91; desert, n=52) treatment arms. CD, cluster of differentiation; placebo-DabTram, placebo plus dabrafenib and trametinib; sparta-DabTram, spartalizumab plus dabrafenib and trametinib.

Figure 2

Immunophenotyping of peripheral blood mononuclear cells using markers for T-cell activation and proliferation (N=323) and cytokine profiling (N=468) of plasma samples taken at baseline and after 4 weeks of treatment. Shown are proliferating CD8+/PD-1+ T cells (A), activated cytotoxic CD8+ T cells (B), and plasma IFN-γ (C). CD, cluster of differentiation; HLA, human leukocyte antigen; IFN, interferon; PD-1, programmed death receptor 1; placebo-DabTram, placebo plus dabrafenib and trametinib; sparta-DabTram, spartalizumab plus dabrafenib and trametinib.

Figure 3

Progression-free survival based on baseline peripheral CD4+/CD8+ T cell ratios. Shown are Kaplan-Meier estimates of progression-free survival in patients randomized to either the sparta-DabTram or placebo-DabTram arm with peripheral blood mononuclear cell samples reflecting baseline CD4+/CD8+ T-cell ratios at or above the median (N=204) (A) or below the median (N=204) (B) value of 2.9 at baseline. CD, cluster of differentiation; placebo-DabTram, placebo plus dabrafenib and trametinib; sparta-DabTram, spartalizumab plus dabrafenib and trametinib.

Figure 4

Predictive and prognostic value of baseline and on-treatment ctDNA shedding. (A) Kaplan-Meier estimates of progression-free survival (left) and overall survival (right) based on baseline and on-treatment ctDNA shedding in either the placebo-DabTram (top) or sparta-DabTram (bottom) arm. ‘No Shed’ indicates no ctDNA shedding observed at baseline or week 8 (placebo-DabTram, n=53; sparta-DabTram, n=56), ‘Loss at W8’ indicates shedding observed at baseline but not at week 8 (placebo-DabTram, n=122; sparta-DabTram, n=136), and ‘Shed at W8’ indicates shedding observed at both baseline and week 8 (placebo-DabTram, n=27; sparta-DabTram, n=16). (B) Kaplan-Meier estimates of progression-free survival (left) and overall survival (right) based on treatment with placebo-DabTram or sparta-DabTram in patients without (top; N=138) or with (bottom; N=342) baseline ctDNA shedding. ctDNA, circulating tumor DNA; placebo-DabTram, placebo plus dabrafenib and trametinib; sparta-DabTram, spartalizumab plus dabrafenib and trametinib.