Update on Clinical Safety and Efficacy of the Novel Oral Dual RAF/MEK Inhibitor RO5126766 (CH5127566) in RAS-mutant Multiple Myeloma
Authors: Sriskandarajah Priya , Boyd Kevin , Xu Wen , Moreno Candilejo Irene , Ellis Sidra , Price Amy , Sherborne Amy L , Croft James , Shah Vallari , Dawes Joanna , Parmar Mona , Turner Alison , Hall Emma , Tunariu Nina , Lopez Juanita S , de Bono Johann S. , Banerji Udai , Kaiser Martin 
Published: October 2019

Abstract
Background
Mutations of RAF/RAS genes are one of the most common oncogenic events in multiple myeloma. Therapeutic targeting of RAF/RAS/MAPK signalling using small molecule inhibitors has led to significant responses in solid cancers. Recently, combined inhibition of key pathway kinases has demonstrated increased efficacy and decrease toxicity, leading to development of second-generation small molecules with dual inhibitory function.
RO5126766 is a potent dual RAF-MEK inhibitor that has demonstrated significant clinical activity with minor toxicities in various solid cancers carrying RAS mutations in a currently ongoing phase I basket study (Trial number NCT204007509; Chenard-Poirier et al. ASCO 2017). Based on the drug's promising efficacy, the trial has been expanded to include myeloma patients with RAF/RAS tumour mutations to provide information on safety and preliminary efficacy in this patient population. We report updated results for RAF/RAS-mutant relapsed and refractory MM patients treated with RO5126766.
Methods
MM patients with relapsed or relapsed and refractory myeloma whose disease had progressed after at least 3 prior therapies were recruited to the study. All patients had been treated with an IMiD and a proteasome inhibitor and their tumours were confirmed to carry a RAS mutation by sequencing. Patients were treated with RO5126766 4mg twice weekly for 3 out of 4 weeks, in 28 day cycles, with the addition of optional weekly dexamethasone as per investigator's discretion. Response assessment was completed using IMWG criteria and toxicities were reported according to CTCAE version 4.0. Whole body diffusion-weighted MRI every 3 cycles was used for functional imaging disease assessment.
Results
At the time of analysis, a total of five patients were recruited; one was still receiving cycle 1 of therapy, with the four remaining patients being evaluable at the point of abstract submission. The median age of evaluable patients at initiation of treatment was 74 years (range 70-76). Patients had received median 4 (range 3-5) lines of prior therapy, including autologous stem cell transplant (75%). Three tumours had a KRAS mutation whilst in one tumour, synchronous KRAS and NRAS mutations were found.
Three patients received RO5126766 alone, while 1 patient also received weekly concomitant dexamethasone. One patient (KRAS and NRAS mutations) achieved a partial response after 1 cycle of therapy but progressed after 7 months. A second patient achieved stable disease (confirmed biochemically and by functional MRI imaging) with single agent RO5126766 treatment and currently continues on trial having completed 8 cycles of therapy. The two remaining patients progressed after 2 and 1.5 cycles, with the latter patient receiving dexamethasone in combination with RO5126766.
The two patients who received 7 and 8 cycles of RO5126766 experienced no clinically significant adverse events (AE), with commonly reported toxicities including grade 1 rash (2/2), grade 1 diarrhoea and grade 1 thrombocytopenia. This is in line with tolerability profile observed in the solid tumour cohorts (n=28 solid tumour patients recruited to date) of this basket trial. One patient developed worsening kidney impairment attributable to disease progression with rising serum free light chains and came off study. Interestingly, ocular toxicities, commonly associated with RAF-MEK inhibitors, were not observed in this patient cohort, which may be related to their dosing schedule.
Conclusion
In this basket study across RAS mutated tumours, the novel, dual RAF-MEK inhibitor RO5126766 as monotherapy in myeloma patients has shown promising single agent activity. In line with observations in the in parallel recruiting solid tumour cohorts, the dual RAF-MEK inhibitor RO5126766 is generally well tolerated and can be administered as an ongoing therapy. This has been observed in a solid tumour patient who has been receiving RO5126766 for 3.5 years with little and manageable toxicities.
Longitudinal patient bone marrow trephine material has been collected and analysis of phospho-protein markers of RAS/MAPK pathway activation for PD biomarker evaluation will be performed. Recruitment to this study continues and data will be updated prior to the conference. Potential single-agent activity of RO5126766 with manageable toxicity grants further evaluation of its use as a molecularly targeted therapy in myeloma.

Disclosures
Sriskandarajah: Celgene: Other: Travel, Accommodation expenses, Speakers Bureau. Boyd:Celgene: Consultancy, Honoraria, Other: Advisory role; Janssen: Honoraria, Other: Travel and Accommodation expenses; Novartis: Consultancy, Honoraria. Shah:Sanofi: Other: Travel and Accommodation expenses; Celgene: Other: Travel, Accommodation expenses. Hall:Sanofi (Inst): Research Funding; Cambridge Major Laboratories (Inst): Research Funding; Accuray (Inst): Research Funding; Kyowa Hakko Karin (Inst): Research Funding; Astrazeneca (Inst): Research Funding; Bayer (Inst): Research Funding. Tunariu:Janssen: Speakers Bureau; Sanofi: Speakers Bureau. de Bono:Sanofi (Inst): Research Funding; AstraZeneca (Inst): Research Funding; GlaxoSmithKline: Other: Travel, Accomodation expenses; AstraZeneca: Consultancy, Honoraria, Other; Astellas Pharma: Consultancy, Honoraria, Other: Travel, Accommodation expenses; Sanofi: Consultancy, Honoraria, Other: Travel, Accommodation expenses; Genentech/Roche: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Orion Pharma GmBH: Other: Travel, Accommodation expenses; Qiagen: Other: Travel, Accommodation expenses; Taiho Pharmaceutical: Other: Travel, Accommodation expenses; Vertex: Other: Travel, Accommodation expenses; Genentech (Inst): Research Funding; Abiraterone Rewards to Investors (Inst): Patents & Royalties: Abiraterone; PARP inhibitors and DNA repair defects (Inst): Patents & Royalties: PARP inhibitors; Genmab: Other: Travel, Accommodation expenses. Banerji:Institute of Cancer research: Employment; Novartis: Consultancy; Onyx (Inst): Research Funding; Chugai Pharma (Inst): Research Funding; AstraZenca (Inst): Research Funding; Astex Pharmaceuticals: Consultancy. Kaiser:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Other: Travel Support; Bristol-Myers Squibb: Consultancy, Other: Travel support; Chugai: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding.