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Intermittent Dosing Schedules of RAF/MEK Inhibitor in RAS/RAF-Mutant Solid Tumors and Multiple Myeloma


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In a single-center phase I dose-escalation and basket dose-expansion study reported in The Lancet Oncology, Guo et al identified the phase II dose and schedule for the oral RAF/MEK inhibitor CH5126766 in patients with RAS/RAF-mutant cancers. The agent also showed antitumor activity across various malignancies.

As stated by the investigators, “CH5126766…a novel MEK-pan-RAF inhibitor, has shown antitumor activity across various solid tumours; however, its initial development was limited by toxicity. We aimed to investigate the safety and toxicity profile of intermittent dosing schedules of CH5126766, and the antitumor activity of this drug in patients with solid tumors and multiple myeloma harboring RAS-RAF-MEK pathway mutations.”

Study Details

The study, performed at the Royal Marsden National Health Service Foundation Trust, included 29 patients with solid tumors in a dose-escalation cohort, who received CH5126766 in three different intermittent (two or three times weekly) dosing schedules given in 28-day cycles. A basket dose-expansion cohort included 29 patients with advanced or metastatic solid tumors or multiple myeloma with RAS/RAF mutations who received the recommended phase II dose identified in the dose-escalation phase. Patients in the expansion cohort included 12 with non–small cell lung cancer (NSCLC), 5 with gynecologic cacner, 4 with colorectal cancer, 1 with melanoma, and 7 with multiple myeloma. All patients had cancers refractory to conventional treatment, or for which no conventional therapy existed.

Key Findings

Median follow-up at data cutoff was 2.3 months.  

KEY POINTS

  • No dose-limiting toxicities were observed at a dose of 4.0 mg twice per week, establishing it as the recommended phase II dose.
  • Among 26 evaluable patients in the expansion cohort, objective response was observed in 7 patients (27%), including 6 (30%) of 20 patients with solid tumors and 1 of 6 with multiple myeloma. Responses were observed in three patients with NSCLC and three with gynecologic cancer.

Dose-limiting toxicities in the dose-escalation phase included grade 3 bilateral retinal pigment epithelial detachment in one patient receiving 4.0 mg of CH5126766 three times per week, and grade 3 rash in two patients and grade 3 creatinine phosphokinase elevation in one patient who received 3.2 mg three times per week.

No dose-limiting toxicities were observed at a dose of 4.0 mg twice per week, establishing it as the recommended phase II dose.

In the expansion cohort, patients with solid tumors received the recommended phase II dose. Those with multiple myeloma received this dose for 3 weeks on followed by 1 week off and were permitted to continue on dexamethasone (up to 20 mg per week) at physician’s discretion.

Among 26 evaluable patients in the expansion cohort, objective response was observed in 7 patients (27%), including 6 (30%) of 20 patients with solid tumors and 1 of 6 with multiple myeloma. Responses were observed in three patients with NSCLC and three with gynecologic cancer.

Among 57 patients evaluable for toxicity, the most common treatment-related adverse events of any grade were skin toxicity (88%), creatinine phosphokinase elevation (74%), visual disturbance (44%), diarrhea (40%), fatigue (37%), and peripheral edema (32%). The most common grade 3 or 4 adverse events were rash (19%), creatinine phosphokinase elevation (11%), hypoalbuminemia (11%), and fatigue (7%). Serious treatment-related adverse events occurred in 9%. No treatment-related deaths were observed.

The investigators concluded: “To our knowledge, this is the first study to show that highly intermittent schedules of a RAF-MEK inhibitor has antitumor activity across various cancers with RAF-RAS-MEK pathway mutations, and that this inhibitor is tolerable. CH5126766 used as a monotherapy and in combination regimens warrants further evaluation.”

Udai Banerji, FRCP, of the Drug Development Unit, The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was supported by Chugai Pharmaceutical. For full disclosures of the study authors, visit thelancet.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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