C Robert1, K D Lewis2, R Gutzmer3, D Stroyakovskiy4, H Gogas5, S Protsenko6, R P Pereira7, T Eigentler8, P Rutkowski9, L Demidov10, I Caro11, H Forbes12, K Shah11, Y Yan11, H Li12, G A McArthur13, P A Ascierto14. 1. Gustave Roussy and Université Paris-Saclay, Villejuif, France. Electronic address: caroline.robert@gustaveroussy.fr. 2. University of Colorado Comprehensive Cancer Center, Aurora, USA. 3. Haut-Tumour-Centrum Minden (HTCM), Klinik für Dermatologie, Allergologie, Venerologie und Phebologie, Johannes Wesling Klinikum Minden, Ruhr Universität Bochum, Minden, Germany. 4. Moscow City Oncology Hospital No. 62 of Moscow Healthcare Department, Moscow, Russia. 5. First Department of Medicine, Laiko General Hospital, National and Kapodistrian University of Athens, Athens, Greece. 6. Department of Chemotherapy and Innovative Technologies, N. N. Petrov National Medical Research Center of Oncology, St. Petersburg, Russia. 7. Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. 8. Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. 9. Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland. 10. N. N. Blokhin Russian Cancer Research Center, Ministry of Health, Moscow, Russia. 11. Genentech, Inc., South San Francisco, USA. 12. Hoffmann-La Roche Limited, Mississauga, Canada. 13. Melanoma and Skin Service and Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, Australia. 14. Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale," Naples, Italy.
Abstract
BACKGROUND: The phase III IMspire150 study (NCT02908672) demonstrated significantly improved progression-free survival (PFS) with atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAFV600-mutated advanced melanoma. We report exploratory biomarker analyses to optimize targeting of patients who are more likely to benefit from triplet combination therapy. PATIENTS AND METHODS: Five hundred fourteen patients were randomized to atezolizumab (n = 256) or control (n = 258). Outcomes were evaluated in subgroups defined by key biomarkers, including programmed death-ligand 1 (PD-L1) expression, lactate dehydrogenase (LDH) level, tumor mutational burden (TMB), and interferon-γ (IFN-γ) gene signature. Exploratory recursive partitioning analysis was then used to model associations between PFS and baseline covariates, including key biomarkers. RESULTS: PFS benefit for atezolizumab versus control was greater in patients with high TMB [≥10 mutations/Mb; hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.52-1.02; P = 0.067] versus low TMB (<10 mutations/Mb; HR 0.92; 95% CI 0.65-1.30; P = 0.64) and similar between patients with strong IFN-γ (≥median; HR 0.76; 95% CI 0.54-1.06) versus weak IFN-γ (<median; HR 0.79; 95% CI 0.58-1.08). In patients with elevated LDH, PFS benefit for atezolizumab versus control was greater in the PD-L1- subgroup (HR 0.53; 95% CI 0.29-0.95; P = 0.032) than in the PD-L1+ subgroup (HR 1.16; 95% CI 0.75-1.80; P = 0.51). Recursive partitioning analysis showed that IFN-γ discriminated PFS outcomes in patients with normal LDH, whereas TMB discriminated outcomes in patients with elevated LDH in the atezolizumab group. Neither IFN-γ nor TMB discriminated PFS outcomes in the control group. CONCLUSIONS: Treatment benefits in the atezolizumab group seemed to be most evident in patients with elevated LDH and PD-L1- tumors. LDH remains the primary predictor of outcomes regardless of treatment. IFN-γ and TMB further differentiate outcomes for patients treated with atezolizumab, vemurafenib, and cobimetinib.
BACKGROUND: The phase III IMspire150 study (NCT02908672) demonstrated significantly improved progression-free survival (PFS) with atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAFV600-mutated advanced melanoma. We report exploratory biomarker analyses to optimize targeting of patients who are more likely to benefit from triplet combination therapy. PATIENTS AND METHODS: Five hundred fourteen patients were randomized to atezolizumab (n = 256) or control (n = 258). Outcomes were evaluated in subgroups defined by key biomarkers, including programmed death-ligand 1 (PD-L1) expression, lactate dehydrogenase (LDH) level, tumor mutational burden (TMB), and interferon-γ (IFN-γ) gene signature. Exploratory recursive partitioning analysis was then used to model associations between PFS and baseline covariates, including key biomarkers. RESULTS: PFS benefit for atezolizumab versus control was greater in patients with high TMB [≥10 mutations/Mb; hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.52-1.02; P = 0.067] versus low TMB (<10 mutations/Mb; HR 0.92; 95% CI 0.65-1.30; P = 0.64) and similar between patients with strong IFN-γ (≥median; HR 0.76; 95% CI 0.54-1.06) versus weak IFN-γ (<median; HR 0.79; 95% CI 0.58-1.08). In patients with elevated LDH, PFS benefit for atezolizumab versus control was greater in the PD-L1- subgroup (HR 0.53; 95% CI 0.29-0.95; P = 0.032) than in the PD-L1+ subgroup (HR 1.16; 95% CI 0.75-1.80; P = 0.51). Recursive partitioning analysis showed that IFN-γ discriminated PFS outcomes in patients with normal LDH, whereas TMB discriminated outcomes in patients with elevated LDH in the atezolizumab group. Neither IFN-γ nor TMB discriminated PFS outcomes in the control group. CONCLUSIONS: Treatment benefits in the atezolizumab group seemed to be most evident in patients with elevated LDH and PD-L1- tumors. LDH remains the primary predictor of outcomes regardless of treatment. IFN-γ and TMB further differentiate outcomes for patients treated with atezolizumab, vemurafenib, and cobimetinib.
Authors: Hussein A Tawbi; Caroline Robert; Jan C Brase; Paul D Nathan; Paolo A Ascierto; Daniel Gusenleitner; Eduard Gasal; James Garrett; Alexander Savchenko; Güllü Görgün; Keith T Flaherty; Antoni Ribas; Reinhard Dummer; Dirk Schadendorf; Georgina V Long Journal: J Immunother Cancer Date: 2022-06 Impact factor: 12.469