Combination of anti–PD-1 agents with BRAF/MEK inhibitors (i) may provide synergistic antitumor effects in BRAF-mutant melanoma. The ph 1/2 KEYNOTE-022 study (NCT02130466) is assessing safety and antitumor activity of recommended doses of pembro + BRAFi D + MEKi T; updated and additional ph 1 results are reported.
Treatment-naive pts with BRAFV600E/K-mutant stage III/IV melanoma received pembro 2 mg/kg Q3W + D 150 mg BID + T 2 mg QD. Primary end point was safety; AEs were graded per CTCAE v4.0. Efficacy end points were ORR, PFS, and OS. Data cutoff: Mar 1, 2017.
Of the 15 pts enrolled, 10 (66.7%) had PD-L1+ tumors (≥1% staining), 13 (86.7%)/2 (13.3%) had ECOG PS 0/1, and 1 (6.7%) had stable brain metastases. Median follow-up was 19.7 mo (range, 15.9-31.1). 3/15 (20.0%) pts had DLTs (pt 1 had gr 4 neutropenia; pt 2 had gr 4 ALT increase; and pt 3 had gr 4 ALT, gr 3 AST, and gr 3 GGT increase); all resolved. Thus, this dose was the MTD and recommended ph 2 regimen. 11 (73%) pts had gr 3-4 TRAEs; ALT increase, AST increase, and pyrexia occurred in ≥ 20% of pts. 7 (46.7%) pts had immune-mediated AEs, most commonly hyperthyroidism in 3 pts (2 gr 1 and 1 gr 2) and hypothyroidism in 4 pts (all gr 1). Treatment was discontinued (d/c) for 2 events (1 gr 2 pneumonitis and 1 gr 3 autoimmune hepatitis) and was interrupted for 3 events (1 gr 1 hyperthyroidism, 1 gr 2 anterior uveitis, and 1 gr 3 erythematous rash); all resolved. ORR (RECIST v.1.1, investigator; confirmed + unconfirmed) was 67%; 1 pt had CR, 9 had PR; an additional 2 pts had SD and 3 had PD. ORR (RECIST v.1.1, investigator; confirmed only) was 53%; 8 pts had PR; an additional 3 pts had SD and 4 had PD. Median time to response was 2.8 mo (range, 2.2-3.0); median DOR was not reached (range, 2.8-26.5 mo). Among the 8 pts with confirmed ORR, 6 had ongoing responses and 2 had progression at data cutoff. 2 pts remained on triplet therapy, 2 d/c D + T, and 4 d/c pembro + D + T as of last follow-up.
Updated results show that approved doses of pembro + D + T continue to demonstrate promising antitumor activity for BRAF-mutant melanoma. A randomized ph 2 study is currently evaluating this triplet regimen as first-line therapy for BRAF-mutant melanoma.
Clinical trial identification
NCT02130466, May 1, 2014
Legal entity responsible for the study
Merck & Co., Inc., Kenilworth, NJ, USA
Merck & Co., Inc., Kenilworth, NJ, USA
A. Ribas: Stock ownership with Kite Pharma; honoraria with Amgen, Pfizer, Roche, and Merck F.S. Hodi: Advisory board member with Merck, Genentech, Novartis, EMD Serono, and Amgen; research funding from Bristol-Myers Squibb. V. Atkinson: Advisory board member with MSD, Novartis, and Pierre Fabre; speakers\' bureau involvement with MSD, Bristol-Myers Squibb, and Novartis; honoraria with MSD, Bristol-Myers Squibb, and Novartis; travel expenses from MSD, Bristol-Myers Squibb, and Novartis. M.S. Carlino: Advisory board member with Bristol-Myers Squibb, Merck, Amgen, and Novartis; honoraria from Merck and Bristol-Myers Squibb. G.V. Long: Advisory board member with Amgen, Bristol-Myers Squibb, Array, Merck MSD, Novartis, Pierre-Fabre, and Roche; honoraria from Bristol-Myers Squibb, Roche, and Merck MSD. W.H. Miller: Consultant fees from Bristol-Myers Squibb, Roche, Novartis, Merck, GSK, and Amgen. Y. Huang: Employment with Novartis. B. Homet Moreno: Employment with Merck; stock ownership with Merck. N. Ibrahim: Employment with Merck; stock ownership with Merck and GSK. O. Hamid: Advisory board member Amgen, Novartis, Roche, Bristol-Myers Squib, Merck; speakers\' bureau Bristol-Myers Squibb, Genentech, Novartis, Amgen; research funding AstraZeneca, Bristol-Myers Squibb, Celldex, Genentech, Immunocore, Incyte, Merck, Merck Serono, MedImmune, Novartis, Pfizer, Rinat, Roche. All other authors have declared no conflicts of interest.