Abstract 557P
Background
KRAS mutations are found in 20-25% of non-squamous NSCLC and effective therapies targeting the RAS/MEK/ERK pathway are needed. Binimetinib an oral selective MEK Inhibitor plus platinum-based chemotherapy is promising. We design a multicenter open-label phase IB trial to define the recommended phase II dose and early efficacy of Binimetinib in combination with Pem and Cis.
Methods
Eligible patients (pts) had: stage III-IV NSCLC unsuitable for curative treatment, performance status (PS) 0-1, KRAS exons 2 or 3 (codon 12, 13 or 61) mutations, no prior systemic therapy. Pts were enrolled into part 1: 3+3 design with dose escalation in 2 dose levels (DL) of Binimetinib and part 2: expansion cohort at the maximum tolerated DL. Treatment consisted of 4 cycles of Cis 75 mg/m2, Pem 500 mg/m2 and Binimetinib 30 (DL1)/45 mg (DL2) BID d1-14 (d3-14 in cycle 1) q3w followed by Pem and Binimetinib until progressive disease (PD) or unacceptable toxicity.
Results
From May 2017 to Dec 2019, 18 pts (13 in part 1, 5 in part 2) were enrolled. Median age was 56 years (48–73), 56% were male, 65% had PS 1. KRAS mutations were 83% at codon 12, 6% at codon 13 and 6% at codon 61. In part 1, 9 pts (3 in DL1, 6 in DL2) were evaluable for DLT and no DLT occurred. Median number of cycles was 2 (1-17, range). All pts are off treatment mainly due to PD (30%) or pts/physicians decision (30%). Together with part 2, 10 pts received 45 mg Binimetinib, one of which was excluded from efficacy due to eligibility violation. Overall response rate was 33% (7 – 70%, 95% CI). Median progression-free survival and overall survival were 5.7 months (1.1 - 14.0, 95% CI) and 6.5 months (1.8 – NR, 95% CI), respectively. No grade 4/5 adverse events (AEs) were observed. Most common treatment-related grade 3 AEs were fatigue (30%), nausea, anemia, hypertension and lung infection (20% each). One patient experienced a grade 3 thromboembolic event. No grade 3 ocular or cardiac AE occurred.
Conclusions
The combination of Cis, Pem and Binimetinib at 45mg BID was safe. No early signal of increased efficacy of the addition of Binimetinib to chemotherapy was observed in KRAS-mutant NSCLC.
Clinical trial identification
NCT02964689.
Editorial acknowledgement
Legal entity responsible for the study
Swiss Group for Clinical Cancer Research (SAKK).
Funding
Array BioPharma Inc.
Disclosure
P.R. Froesch: Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Takeda; Honoraria (self), Advisory/Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy: BMS. M.T. Mark: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AstraZenca; Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Takeda. S.I. Rothschild: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): AstraZenca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): BMS; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Merck Serono; Honoraria (self), Advisory/Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy: Eli Lilly; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Takeda. S. Schmid: Research grant/Funding (self): AstraZenca; Research grant/Funding (self): BMS; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Boehringer Ingelheim; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Travel/Accommodation/Expenses: Takeda. O. Gautschi: Honoraria (self), Advisory/Consultancy: Amgen; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): AbbVie. M. Früh: Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): BMS; Honoraria (institution), Advisory/Consultancy: MSD; Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): AstraZenca; Honoraria (institution), Advisory/Consultancy: Boehringer Ingelheim; Honoraria (institution), Advisory/Consultancy: Roche; Honoraria (institution), Advisory/Consultancy: Takeda. All other authors have declared no conflicts of interest.