Relapsed/refractory patients

2017 ASCO Annual Meeting: Results from the biomarker-driven basket trial of RO51267 (CH5126766), a potent RAF/MEK inhibitor, in RAS- or RAF- mutated malignancies, including multiple myeloma (Abstract 2506)

The results of this trial were presented by Maxime Chénard-Poirier from the Royal Marsden Hospital in London in an oral abstract session at ASCO 2017 Annual Meeting in Chicago, Illinois. This presentation was part of the ‘Developmental Therapeutics - Clinical Pharmacology and Experimental Therapeutics’ session on Saturday June 4th, 2017.

CH5126766 is a first-in-class MEK inhibitor, with a long half-life (an average of 60 hours). Based on this extended half-life, dosing frequencies of two or three times weekly were studied in a dose escalation trial of 22 patients. However, the maximum tolerated dose and frequency was 4 mg two times per week.  The most commonly reported adverse events (AEs) included rash, CK elevation, blurred vision, diarrhea, mucositis, fatigue and nausea. The most common grade 3 or higher toxicity was skin rash, which was managed with topical treatment.

This agent shows much promise for treatment of many malignancies, including myeloma, since approximately 20% of myeloma patients are positive for KRAS and NRAS mutations. In-vitro, MEK inhibitors are active against myeloma cell lines regardless of RAS status. 

Preliminary results:
  • Study included 4 myeloma patients (pts)
  • All pts had received prior therapy with proteasome inhibitors and immunomodulatory drugs
  • Total 75% of pts had a history of autologous stem cell transplant (ASCT)
  • n = 1 pt with KRAS- and NRAS- mutation demonstrated a partial response; therapy is ongoing
  • n = 2 pts with KRAS-only mutation demonstrated stable disease
  • n = 1 pt NRAS-only mutation demonstrated clinical relapse
  • The patient with partial response (PR) had no high-risk cytogenetic features, had received three prior lines of therapy and two ASCTs
  • PR was achieved with single agent CH5126766, without concomitant dexamethasone therapy

In summary, twice weekly scheduling is well-tolerated.  Preliminary results suggest single agent MEK inhibition may have activity in relapsed/refractory multiple myeloma.

References
  1. Maxime Chénard-Poirier. Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics. American Society of Clinical Oncology (ASCO®) Annual Meeting; 2017 June 2–6; Chicago, IL, USA. Abstract 2506.
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