Results from the biomarker-driven basket trial of RO5126766 (CH5127566), a potent RAF/MEK inhibitor, in RAS- or RAF-mutated malignancies including multiple myeloma.

Abstract

2506 Background: RO5126766 is a potent RAF and MEK inhibitor with activity in xenografts models of RAS and RAF-mutated cancers. We present data from the RAS/RAF-mutated advanced solid tumor cohort and the initial results for the multiple myeloma (MM) cohort. Methods: Patients with KRAS, NRAS or BRAF-mutant tumours were treated with RO5127566 using a novel schedule:4mg twice weekly in 4-week cycles. For MM patients, it was given 3 weeks out of 4 and co-administration of weekly dexamethasone was authorised. Response assessment was completed using RECIST 1.1 criteria for solid tumours and the International Myeloma Working Group (IMWG) criteria were used for MM. Results: A total of 20 patients with solid tumours (10 NSCLC, 5 gynaecological cancers and 5 miscellaneous cancers) and 1 MM patients were evaluable. Among the 10 KRAS-mutant NSCLC patients, tumour regression was seen in 6/10 (60 %), of which 3/10 (30 %) were partial responses. Two of these patients had maintained response for over 1 year and one patient is still on study after 30 cycles. Of the gynaecological cancers, 3/5 patients (60%) achieved a partial response ( KRAS-mutant endometrial and ovarian cancer and BRAF-mutant ovarian). Of these patients, 1 of the KRAS mutants had received 2 previous lines of MEK inhibitors and the BRAF mutant had previously received a BRAF inhibitor. In the miscellaneous group, 4 patients with colorectal cancer (2 BRAF and 2 NRAS) and 1 patient with NRAS-mutant melanoma were treated and none responded. Two patients with MM have been treated so far (1 KRAS, 1 KRAS+NRAS). The one evaluable patient has had an IMWG partial response (PR) after 1 cycle (FLC-λ from 324 mg/L to 161mg/L, ratio 0.03 to 0.08) without concomittant dexamethasone. This patient was previously treated with an immunomodulatory drug, a proteasome inhibitor and two ASCTs. Conclusions: RO5126766 has shown exciting preliminary activity across a wide range of RAS- and RAF-mutated malignancies, with significant response rates in lung and gynaecological cancers. To our knowledge, the PR seen in our MM patient represents one of the first responses to a single-agent RAF/MEK inhibitor in multiple myeloma in a trial context. Clinical trial information: NCT02407509.