LBA45 - Early switch from targeted to immunotherapy in advanced BRAFV600-positive melanoma: Long-term OS and final PFS results of the randomized phase II ImmunoCobiVem trial

Background

Knowledge about the optimal sequencing of immune checkpoint inhibitors (ICI) and targeted therapies (TT) in BRAF^V600-positive advanced melanoma remains limited. While first-line ICI is superior to TT in terms of overall survival (OS), it is still uncertain whether a short run-in with TT and switch to ICI before progression may improve benefit.

Methods

The 1:1 randomised phase 2 ImmunoCobiVem trial compared – after a 3-month run-in phase with vemurafenib (V, 960 mg twice daily) and cobimetinib (C, 60 mg daily d 21-28, Q4W) – in Arm A continuous V+C until progressive disease (PD1) and second-line (2L) atezolizumab (ATEZO, 1200 mg Q3W) versus (Arm B) early switch to ATEZO after the run-in phase and then crossover to V+C at PD1. PFS from start of run-in phase until PD1 was the primary study endpoint (PFS1); secondary efficacy endpoints were OS, overall PFS (PFS2) and PFS3, i.e., the time from PD1 to PD2 (PD after crossover), best overall response rates (BORR) and safety.

Results

The final analysis at a median follow-up of 57.0 months (IQR 22.7-63.0) confirmed higher initial tumor control (PFS1) for continuous TT treatment (Arm A [69 patients] vs. Arm B [66 patients]; HR=0.61, 95% CI 0.41-0.91, p=0.006), but early switch to ICI (Arm B) resulted in better long-term OS (3-, 4- and 5-year landmark OS 55% [95% CI 41-66], 42% [29-55] and 40% [27-53] for Arm A, and 55% [41-67], 53% [38-65] and 45% [31-58] for Arm B; descriptive hazard ratio [A vs. B] 1.17, 95% CI 0.71-1.91). Absolute BORR in arms A and B were 81% and 89%, respectively, with 15 (22%) respectively 19 (29%) patients achieving a complete response (CR, as per RECIST) at least once along each treatment sequence. At crossover, retreatment with TT after progression on ICI (Arm B) resulted in higher PFS3 than treatment with ICI after TT failure (Arm A).

Conclusions

The early switch to ICI after TT run-in led to an improved landmark OS at 4- and at 5-years compared to Arm A, although not statistically significant. The better early tumor control (PFS1) in Arm A and treatment options outside the trial diluted the overall effect size for early switch to ICI, so that it remained small. No subgroups were identified for which a TT run-in (Arm B) provided clinical benefit.

Clinical trial identification

EudraCT 2015-005097-37; NCT02902029.

Editorial acknowledgement

Editorial and medical writing assistance was provided by Dr. Markus Hartmann (Ecc-Oncology, Trier, Germany).

Legal entity responsible for the study

University Hospital, Essen.

Funding

F. Hoffmann-La Roche Ltd.

Disclosure

D. Schadendorf: Financial Interests, Personal, Invited Speaker: BMS, MSD, Merck Serono, Sanofi, Neracare, SunPharma; Financial Interests, Personal, Advisory Board: BMS, Novartis, MSD, Immunocore, Pierre Fabre, Sanofi/Regeneron, Pfizer, Philogen, Neracare, InFlarX, BioAlta, Daiichi Sanyko, NoviGenix, Anaveon, AstraZeneca, PamGene, BioNTech, Immatics, CureVac, Erasca, Formycon, Replimune, Seagen, SunPharma, Ultimovacs; Financial Interests, Personal, Steering Committee Member: Novartis, BMS, MSD; Financial Interests, Institutional, Coordinating PI: Novartis, BMS, MSD, Pierre Fabre; Financial Interests, Institutional, Research Grant: BMS, MSD; Financial Interests, Institutional, Local PI: Sanofi, Philogen; Non-Financial Interests, Member of Board of Directors: EORTC-MG; Non-Financial Interests, Leadership Role, Founding member and SC chair: European Melanoma Registry (EuMelaReg). L. Kandolf Sekulovic: Financial Interests, Personal, Invited Speaker: Janssen, MSD, BMS, Roche, Novartis, Medison; Financial Interests, Personal, Advisory Board: MSD, BMS, Novartis, Medison. F. Meier: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Novartis, MSD, Sanofi, Philogen, Immunocore; Financial Interests, Personal, Invited Speaker: Sanofi, Immunocore. T.K. Eigentler: Financial Interests, Personal and Institutional, Advisory Role: Pharma. M. Ziemer: Financial Interests, Personal, Invited Speaker: BMS, Sanofi-Aventis, Sun Pharma, Pierre Fabre Pharma; Financial Interests, Institutional, Local PI: BMS, MSD, Regeneron/Biontecho, Pierre Fabre Pharma, Regeneron, HUYA Biosceines international, Pfizer, Philogen, Iovance Biotherapeutics. P. Terheyden: Financial Interests, Personal, Advisory Board: Almirall, Biotest, BMS, Sanofi; Financial Interests, Personal, Invited Speaker: Almirall, Bristol Myers Squibb, Sanofi, Kyowa Kirin, Biofrontera, 4SC; Financial Interests, Personal, Other, Travel support: BMS, Pierre-Fabre. A. Gesierich: Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Invited Speaker, Travel costs, congress fee: Novartis, BMS; Financial Interests, Personal, Advisory Board, Congress fee: MSD; Financial Interests, Personal, Advisory Board, Travel costs, congress fee: Pierre Fabre, Sanofi; Financial Interests, Personal, Advisory Board: BMS, Roche, Amgen; Financial Interests, Personal, Invited Speaker: Immunocore, Amgen. K.C. Kähler: Financial Interests, Personal, Advisory Role: BMS, MSD, Pierre Fabre, Roche, Immunocore, Regeneron, Sanofi-Aventis. D.C. Ziogas: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, BMS, Ipsen, Pierre Fabre, Gilead, Amgen; Financial Interests, Personal, Advisory Board: Roche. Ž. Mijušković: Financial Interests, Personal, Speaker’s Bureau: Novartis, Eli Lilly, Janssen, AbbVie, Loreal, Eucerin; Other, Personal, Officer: Serbian Association of Dermatovenereologists; Other, Personal, Member: soriasis Committee of the National Health Insurance Fund. M. Garzarolli: Financial Interests, Personal and Institutional, Advisory Role: Pharma. C. Garbe: Financial Interests, Personal, Advisory Board: CeCaVa, MSD, NeraCare, Philogen; Non-Financial Interests, Leadership Role, President: European Association of Dermatooncology (EADO). A. Roesch: Financial Interests, Personal, Writing Engagement: BMS; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal and Institutional, Funding: BMS, Novartis. S. Ugurel-Becker: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck Sharp and Dohme, Merck Serono, Novartis; Financial Interests, Institutional, Coordinating PI: Bristol Myers Squibb, Merck Serono; Non-Financial Interests, Leadership Role: Dermatologic Cooperative Oncology Group (DeCOG). R. Gutzmer: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, PierreFabre, Novartis, Merck Sharp Dohme, MerckSerono, Almirall, Immunocore, Delcath, KyowaKirin, Sanofi/Regeneron, SUN Pharma; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, PierreFabre, Novartis, Merck Sharp Dohme, Merck Serono, Almirall, Sanofi/Regeneron, Sun Pharma; Financial Interests, Institutional, Research Grant: KyowaKirin, Almirall, Sun Pharma, Amgen, Sanofi/Regeneron, MerckSerono; Non-Financial Interests, Member of Board of Directors: DeCOG; Other, Travel and meeting support: PierreFabre, Sun Pharma. J.J. Grob: Financial Interests, Personal, Advisory Board: BMS, MSD, Novartis, Roche, Pierre fabre, Novartis, Pfizer, Sanofi, Philogen, Iteos Therapeutics, Sun Pharma; Financial Interests, Personal, Invited Speaker: BMS, Novartis, Pierre Fabre, Sanofi; Financial Interests, Personal, Steering Committee Member: Novartis; Financial Interests, Institutional, Research Grant: Pierre fabre. L. Zimmer: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Novartis, MSD, Sun Pharma, Pierre Fabre, Sanofi; Financial Interests, Personal, Other, Travel Support: Bristol Myers Squibb, MSD, Sun Pharma, Pierre Fabre, Sanofi, Novartis, Amgen; Financial Interests, Personal, Invited Speaker: Novartis, MSD, Pierre Fabre, Roche; Financial Interests, Personal and Institutional, Research Grant: Novartis; Non-Financial Interests, Member: German Cancer Society, Dermatologic Cooperative Oncology Group. E. Livingstone: Financial Interests, Personal, Advisory Board: Novartis, BMS, Sanofi, Sun Pharma, Recordati, MSD; Financial Interests, Personal, Invited Speaker: Novartis, BMS; Financial Interests, Personal, Other, Innvator´s Circle: Pierre Fabre; Non-Financial Interests, Principal Investigator: BMS, Novartis, Regeneron, MSD, Philogen, 4SC, Biontech, Immatics, Immunocore; Non-Financial Interests, Member: DeCOG, DKG; Other, Travel expenses: Pierre Fabre, Sun Pharma. All other authors have declared no conflicts of interest.