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307 Atezolizumab plus vemurafenib and cobimetinib provides favorable survival outcomes in patients with high tumor mutation burden and proinflammatory gene signature in the phase 3 IMspire150 study
  1. Karl Lewis1,
  2. Paolo Ascierto2,
  3. Caroline Robert3,
  4. Rodrigo Munhoz4,
  5. Gabriella Liszkay5,
  6. Luis De La Cruz Marino6,
  7. Judit Olah7,
  8. Paola Queirolo8,
  9. Jacek Mackiewicz9,
  10. Kalpit Shah10,
  11. Harper Forbes11,
  12. Christian Hertig11,
  13. Yibing Yan10,
  14. Ralf Gutzmer12 and
  15. Grant McArthur13
  1. 1University of Colorado Comp. Cancer Ctr, Aurora, CO, USA
  2. 2Istituto Nazionale Tumori IRCCS, Napoli, Italy
  3. 3Gustave Roussy and Université Paris-Sacl, Villejuif-Paris, France
  4. 4Instituto do Câncer do Estado, São Paulo, Brazil
  5. 5Országos Onkológiai Intézet, Budapest, Hungary
  6. 6Hospital Universitario Virgen Macarena, Seville, Spain
  7. 7University of Szeged Szent-Györgyi, Szeged, Hungary
  8. 8IRCCS Istituto Europeo di Oncologia, Milan, Italy
  9. 9Greater Poland Cancer Centre, Poznan, Poland
  10. 10Genentech, Inc., South San Francisco, CA, USA
  11. 11F. Hoffmann-La Roche Ltd., Mississauga, Canada
  12. 12Haut-Tumour-Zentrum Hannover (HTZH), Hannover, Germany
  13. 13Peter MacCallum Cancer Centre, Melbourne, Australia


Background The phase 3 IMspire150 study (NCT02908672) showed that first-line atezolizumab (A) combined with vemurafenib (V) + cobimetinib (C) improved progression-free survival (PFS) vs placebo (P) + V + C in patients with BRAFV600 mutation–positive advanced melanoma (15.1 vs 10.6 months; hazard ratio [HR] 0.78; 95% CI 0.63–0.97; P=0.0249). Insights into the clinical benefit of the A+V+C triple combination in prognostic molecular subgroups of patients can inform treatment selection and future clinical research.

Methods 514 patients were randomized 1:1 to A+V+C (n=256) or P+V+C (n=258). The efficacy endpoints analyzed included PFS and duration of response (DOR) estimated using the Kaplan-Meier method. Outcomes were based on investigator-assessed best overall response per Response Evaluation Criteria in Solid Tumors v1.1. Patients were primarily categorized into binary subgroups defined by tumor mutation burden (TMB; low or high: <10 or ≥10 mutations/Mb, respectively) or by the < or ≥ median values of interferon (IFN)-gamma or CD8+ tumor cells. In addition, these subgroups were further broken down based on the proportion of programmed death-ligand 1 (PD-L1)-expressing tumor-infiltrating cells as PD-L1+ (≥1%) or PD-L1– (<1%).

Results Patients treated with P+V+C with high and low TMB had similar PFS outcomes. However, the magnitude of the PFS benefit with A+V+C vs P+V+C was markedly higher in patients with high TMB (≥10 mutations/Mb) compared with patients with low TMB (<10 mutations/Mb) in whom the benefit between treatment arms was comparable (figure 1A). The magnitude of the PFS benefit with A+V+C was further enhanced in patients with high TMB and PD-L1– compared with patients with high TMB and PD-L1+. Overall, patients with potential for increased antitumor immunity (IFN-gamma ≥ median or CD8+ ≥ median) who received A+V+C had more favorable outcomes compared with their counterparts with IFN-gamma < median or CD8+ < median. In general, the PFS benefit with A+V+C vs P+V+C was more readily apparent in PD-L1– subgroups. Similar trends were seen with DOR (figure 1B).

Abstract 307 Figure 1

Forest plot of PFS (A) and DOR (B). mo, months; NE, not evaluable; Neg, negative; NE, not estimable; Pos, positive.

Conclusions There was a trend of larger magnitude of PFS benefit with A+V+C vs P+V+C in PD-L1– patient subgroups, who benefit less with single-agent immunotherapy. The PFS and DOR benefits were more evident in patients with high IFN-gamma or TMB >10 mutations/Mb. Additional multivariate analyses are ongoing to delineate the PFS trends observed.

Trial Registration ClinicalTrials. gov, identifier NCT02908672

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