Princess Margaret Hospital, Toronto, ON, Canada
Eric Xueyu Chen , Petr Kavan , Mustapha Tehfe , Jeremy S. Kortmansky , Michael B. Sawyer , E. Gabriela Chiorean , Christopher Hanyoung Lieu , Blase N. Polite , Lucas Wong , Marwan Fakih , Kristen Renee Spencer , Jorge Chaves , Chenxiang Li , David Carpenter , Pierre Leconte , Richard D. Kim
Background: Response to antiPD-1 monotherapy is poor in microsatellite stable (MSS)/mismatch-repair proficient (pMMR) mCRC; the combination of antiPD-1 pembro + anti-MEK bini, with or without chemo, may improve upon this limited response. KEYNOTE-651 (NCT03374254) is an open-label phase 1b multicenter trial of pembro + bini (cohort A) or pembro + bini + chemo (mFOLFOX7 in cohort C, FOLFIRI in cohort E) in MSS/pMMR mCRC. Preliminary results from the dose-finding phase at 2 dose levels (DL) of bini are presented. Methods: Patients (pts) had MSS/pMMR mCRC and must have been previously treated with fluoropyrimidine, irinotecan, and oxaliplatin in cohort A, or with fluoropyrimidine + oxaliplatin-based regimen in cohort E; pts were previously untreated in cohort C. Pts received pembro 200 mg Q3W + bini 30 mg BID (cohort A, DL1), pembro 200 mg Q3W+ bini 30 mg BID + mFOLFOX7 Q2W (cohort C, DL1) or pembro 200 mg Q3W + bini 30 mg BID + FOLFIRI Q2W (cohort E, DL1). Bini dose escalation to 45 mg BID (DL2) was planned in cohorts A, C, and E, with a target dose-limiting toxicity (DLT) of 30%. Primary end point was safety (DLT). Secondary end point was ORR. DCR, PFS, and OS were exploratory. ORR, DCR, and PFS were assessed by investigator per RECIST v1.1. Results: Median study follow-up at data cutoff (Oct 15, 2021) was 36 mo (range, 32-43) for cohort A, 17 mo (2-24) for cohort C, and 11 mo (2-25) for cohort E. In cohort A, 1/6 pts (17%) had DLT at DL1; no DLT occurred in 14 pts (0%) at DL2. In cohort A, gr 3/4 TRAEs occurred in 3/6 pts (50%) at DL1 and 8/14 pts (57%) at DL2. In cohort C, 3/9 evaluable pts (33%) had DLT at DL1; thus, bini dose was not escalated to DL2. In cohort C, gr 3/4 TRAEs occurred in 9/11 total pts (82%). In cohort E, 1/5 evaluable pts (20%) had DLT at DL1 and 5/10 evaluable pts (50%) had DLT at DL2. Enrollment was stopped in cohort E, DL2 and bini dose was de-escalated to DL1; 2/4 additional pts (50%) had DLT at DL1 (total 3/9 pts [33%] had DLT in cohort E, DL1). In cohort E, gr 3/4 TRAEs occurred in 5/9 pts (56%) at DL1 and 10/11 total pts (91%) at DL2. No gr 5 TRAEs occurred in any cohort. ORR was 0% in cohort A; limited efficacy was seen in cohorts C and E (Table). Conclusions: Bini could be safely combined with pembro in cohort A. However, with bini + pembro + chemo, the 45-mg dose of bini was not well tolerated and required dose reduction to 30 mg. Addition of bini to pembro + chemo did not improve efficacy; therefore, enrollment was prematurely closed in cohorts C and E. Efficacy by KRAS mutation status will be shown. Clinical trial information: NCT03374254.
Pts | n | ORR, % (95% CI) | DCR, % | PFS, median (95% CI), moa | OS, median (95% CI), mo |
---|---|---|---|---|---|
Cohort A | 20 | 0 (0-17) | 40 | 2 (2-4) | 7 (5-18) |
Cohort A: bini DL1 | 6 | 0 (0-46) | 50 | 3 (2-NR) | NR (3-NR) |
Cohort A: bini DL2 | 14 | 0 (0-23) | 36 | 2 (2-4) | 7 (3-9) |
Cohort C | 11 | 9 (0-41) | 100 | 12 (4-NR) | NR (12-NR) |
Cohort E | 20 | 15 (3-38) | 70 | 6 (2-NR) | NR (9-NR) |
Cohort E: bini DL1 | 9 | 22 (3-60) | 78 | 6 (1-NR) | 9 (9-NR) |
Cohort E: bini DL2 | 11 | 9 (0-41) | 64 | 5 (2-NR) | NR (5-NR) |
aNR, not reached
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