Binimetinib, pemetrexed and cisplatin, followed by maintenance of binimetinib and pemetrexed in patients with advanced non-small cell lung cancer (NSCLC) and KRAS mutations. The phase 1B SAKK 19/16 trial
Mené sur des patients atteints d'un cancer du poumon non à petites cellules de stade avancé (âge médian : 60 ans), cet essai de phase IB évalue la dose maximale tolérée du binimétinib (un inhibiteur de MEK) en combinaison avec le pémétrexed et le cisplatine
Background : KRAS mutations are found in 20-25% of non-squamous non-small cell lung cancer (NSCLC) and therapies targeting the RAS/MEK/ERK pathway are in development. We performed amulticenter open-label phase 1B trial to determine the recommended phase 2 dose andearly antitumor activity of the MEK-inhibitor binimetinib combined with cisplatin and pemetrexed. Methods : Eligible patients (pts) had stage III-IV NSCLC unsuitable for curative treatment, KRAS exon 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 dose (MTD). Pts received 4 cyclesof cisplatin 75 mg/m2, pemetrexed 500 mg/m2and binimetinib 30 (DL1)/45 mg (DL2) orally twice a day (bid) d1-14 q3w followed bypemetrexed and binimetinib until progressive disease (PD) or unacceptable toxicity. Results : From May 2017 to Dec 2019, 18 pts (13 dose escalation, 5 expansion cohort) were enrolled. Median age was 60 (48-73, range). KRAS mutations were 87.5% at codon 12. No DLT occurredin the dose escalation cohort. Median number of cycles was 2 (1-17, range). Treatment discontinuation was mainly due to PD (33%) or pts/physicians’ decision (27%). Togetherwith the expansion cohort, 16 pts were evaluable for safety. Most frequent treatment-related grade 3 AEs were lung infection (25%), fatigue (19%), anemia (19%). Overall responserate among 9 evaluable pts receiving binimetinib at MTD (45 mg bid) was 33% (7-70%,95% CI). Median progression-free survival was 5.7 months (1.1-14.0, 95% CI) and overallsurvival 6.5 months (1.8-NR, 95% CI). Conclusions : Pts treated with combination of cisplatin, pemetrexed and binimetinib presented noun expected toxicity. No early signal of increased antitumor activity of binimetinib added to chemotherapy was observed in our pts population.