A phase I study of binimetinib (MEK 162), a MEK inhibitor, plus carboplatin and pemetrexed chemotherapy in non-squamous non-small cell lung cancer
Mené sur 13 patients atteints d'un cancer du poumon non épidermoïde non à petites cellules, cet essai de phase I évalue la dose maximale tolérée du bibimétinib (un inhibiteur de MEK 162) en combinaison avec une chimiothérapie à base de carboplatine et pémétrexed, et analyse les caractéristiques pharmacocinétiques de cette combinaison
Introduction : MEK inhibition is a potential therapeutic strategy in non-small cell lung cancer (NSCLC).This phase I study evaluates the MEK inhibitor binimetinib plus carboplatin and pemetrexedin stage IV non-squamous NSCLC patients (NCT02185690). Methods : A standard 3 + 3 dose-escalation design was used. Binimetinib 30 mg BID (dose level1 [DL1]) or 45 mg BID (dose level 2 [DL2]) was given with standard doses of carboplatinand pemetrexed using an intermittent dosing schedule. The primary outcome was determinationof the recommended phase II dose (RP2D) and safety of binimetinib. Secondary outcomesincluded efficacy, pharmacokinetics, and an exploratory analysis of response basedon mutation subtype. Results : Thirteen patients (6 DL1, 7 DL2) were enrolled: 7KRAS, 5 EGFR, and 1 NRAS mutation. The RP2D was binimetinib 30 mg BID. Eight patients (61.5%) had grade 3/4adverse events, with dose limiting toxicities in 2 patients at DL2. Twelve patientswere evaluated for response, with an investigator-assessed objective response rate(ORR) of 50% (95% CI 21.1%-78.9%; ORR 33.3% by independent-review, IR), and diseasecontrol rate 83.3% (95% CI 51.6%-97.9%). Median progression free survival (PFS) was4.5 months (95% CI 2.6 months–NA), with a 6-month and 12-month PFS rate of 38.5% (95%CI 19.3%-76.5%) and 25.6% (95% CI 8.9%-73.6%), respectively. In an exploratory analysis, KRAS/NRAS-mutated patients had an ORR of 62.5% (ORR 37.5% by IR) vs. 25% in KRAS/NRAS wild-type patients. In MAP2K1–mutated patients, the ORR was 42.8%. Conclusion : The addition of binimetinib to carboplatin and pemetrexed appears to have manageabletoxicity with evidence of activity in advanced non-squamous NSCLC.
Lung Cancer 2021