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Saroosh Arif



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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-54 - A Phase I/Ib Study of Binimetinib (MEK162), a MEK Inhibitor Plus Carboplatin/Pemetrexed in Non-Squamous NSCLC (ID 14205)

      16:45 - 18:00  |  Author(s): Saroosh Arif

      • Abstract

      Background

      MEK remains an important potential target in RAS/RAF dependent tumours. Binimetinib (MEK16) is a highly selective oral inhibitor of MEK1/2, which has shown activity in melanoma and other cancers. Data from preclinical models suggest greater activity with intermittent versus continuous dosing of MEK inhibitors when added to chemotherapy. This dose escalation study combines intermittent binimetinib with pemetrexed plus carboplatin in chemotherapy naive patients with advanced non-squamous NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A standard 3+3 dose-escalation design was used with planned dose expansion at RP2D (N=30) in genotypically defined cohorts (KRAS G12C mutant (mt), non-G12C mt and wild type). The primary endpoint was to define the RP2D of binimetinib using an intermittent dosing schedule in combination with standard doses of pemetrexed and carboplatin. Secondary objectives included safety, pharmacokinetics (PK), response and exploring potential biomarkers of response or toxicity. Binimetinib (30-45 mg BID) was commenced on day 1 cycle 1 for 5 days followed by a 48-hour washout period. If well tolerated, pemetrexed/carboplatin (500 mg/m2/AUC 5 mg*min/mL) were added on day 8 cycle 1 and binimetinib resumed from days 8-26 with a 48 hour drug washout before cycle 2. For subsequent cycles, pemetrexed/carboplatin were administered on day 1, binimetinib on days 1-19 every 21 days. Key eligibility criteria included ECOG performance status 0-1, adequate organ function, measureable disease by RECIST and no active CNS metastasis. Patients with EGFR/ALK mt lung cancer were permitted in the dose escalation phase after progression on standard TKI therapy.

      4c3880bb027f159e801041b1021e88e8 Result

      Between 03/2017 and 04/2018, 11 patients have been enrolled in 2 dose escalation cohorts (4 KRAS mt, 4 EGFR mt including 1 ex20ins). Six patients were treatment-naive, 3 received prior EGFR TKI and 2 prior pembrolizumab. To date, 7 have experienced grade 3 adverse events (AEs) deemed at least possibly related to binimetinib (anemia, neutropenia, abdominal pain, diarrhea, nausea, vomiting, fatigue, transaminitis). No grade 4/5 AEs have been seen. Related AEs seen in >20% of patients include: rash, mucositis, diarrhea, fatigue, transient visual changes, nausea, edema, neutropenia and vomiting. Antitumour activity was seen at each dose level of binimetinib. Final data on toxicity, response, PK and confirmation of RP2D will be presented at the meeting.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The addition of binimetinib to pemetrexed/carboplatin appears to have manageable toxicity with evidence of activity in non-squamous NSCLC. Dose expansion in genotypically defined cohorts will continue and a cohort combining binimetinib with pembrolizumab is planned.

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