Abstract 1018P
Background
Rigosertib is a panRAS signaling inhibitor that competitively binds to RAS binding domains of downstream effector proteins, resulting in disruption of multiple RAS-mediated pathways (MAPK, PI3K, RalGDS) and tumor suppression in preclinical models. Inhibition of RAS pathways by rigosertib has also been shown to increase tumor immunogenicity. Here we report safety and interim efficacy of the first clinical trial of rigosertib in combination with the immune checkpoint inhibitor (ICI) nivolumab, in advanced KRAS mutated NSCLC patients who progressed on first line ICI-containing treatment.
Methods
Phase I dose escalation used an accelerated titration design with single patient cohorts and converted to 3+3 design to determine the maximally tolerated dose (MTD), followed by a Phase 2a dose-expansion. Rigosertib escalation occurred with three dose levels (D1: 280mg twice daily; D2: 560mg/280mg daily; D3: 560mg twice daily) taken by mouth for 21 consecutive days of the 28-day cycle. Nivolumab was fixed at 240mg every 2 weeks given intravenously. Primary endpoint of the Phase I was MTD and for the Phase 2a was overall response rate. Secondary endpoints include median progression free survival and overall survival.
Results
18 patients have currently been enrolled. 94% of patients had non-G12C mutations and 82% had at least 2 prior lines of treatment (all progressed on prior ICI). One dose limiting toxicity of grade 3 hyponatremia occurred at D3 level, previously described with rigosertib. All other toxicities were grade 1-2, with the most common being dysuria/hematuria (65%), proteinuria (35%), fatigue (24%) and nausea (24%). Of 13 patients evaluable for treatment response, 1 achieved a complete response (CR; KRAS G12V), 2 experienced partial response (PR; KRAS G12C and G12D) and 1 had stable disease (KRAS G12V), for a total disease control rate of 31%. The durability of response for the CR and 2 PRs were 7, 8 and 6 months, respectively, with the latter PR continuing to respond on treatment. Two of the responders had STK11 co-mutations and low PD-L1 expression at diagnosis.
Conclusions
Combination of Rigosertib and Nivolumab is safe, well tolerated and has shown early efficacy for the treatment of KRAS mutated NSCLC patients with prior progression on ICI.
Clinical trial identification
NCT04263090.
Editorial acknowledgement
Legal entity responsible for the study
Rajwanth Veluswamy MD MSCR (Investigator Initiated Trial).
Funding
Bristol Myers Squibb and Onconova Therapeutics.
Disclosure
R. Veluswamy: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, AstraZeneca, Merck, Novocure; Financial Interests, Personal, Invited Speaker, Unbranded: AstraZeneca; Financial Interests, Personal, Advisory Role: BeiGene; Financial Interests, Personal, Invited Speaker: Onconova Therapeutics; Financial Interests, Personal, Research Grant: Bristol Myers Squibb, Onconova, AstraZeneca. R. Samstein: Financial Interests, Personal, Proprietary Information, inventor on intellectual property held by MSKCC on using tumor mutation burden to predict immunotherapy response which has been licensed to PGDx: Memorial Sloan Kettering. J.E. Gomez: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb. D.B. Doroshow: Financial Interests, Personal, Advisory Role: Mirati Therapeutics. E. Shum: Financial Interests, Personal, Advisory Board: AstraZeneca, Janssen, Genentech, Boehringer-Ingleheim; Financial Interests, Personal, Research Grant: Delfi Diagnostics. A. Saxena: Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca, Blueprint Medicine, Jazz Pharmaceuticals; Financial Interests, Personal, Advisory Role: Genentech. N. Bhardwaj: Financial Interests, Personal, Advisory Board: Apricity, BioNTech, Boehringer Ingelheim, BreakBio, Carisma Therapeutics, CureVac, Genentech, Genotwin, Gilead, Novartis, Primevax, Rome Therapeutics, Tempest Therapeutics, Rubius Therapeutics; Financial Interests, Personal, Research Grant: DC Prime, Dragonfly Therapeutics, Harbour Biomed Sciences, Regeneron Pharmaceuticals. F.R. Hirsch: Financial Interests, Personal, Advisory Board: Genentech, AstraZeneca, Sanofi, Regeneron, Daiichi, Novartis, OncoCyte, Novocure, Nectin Therapeutics, NextCure. M. Merad: Financial Interests, Personal, Advisory Board: Compugen Inc, Myeloid Therapeutics Inc, Morphic Therapeutic Inc, Asher Bio Inc, Dren Bio Inc, Nirogy Inc, Oncoresponse Inc, Owkin, Pionyr, Larkspur, Innate Pharma Inc, DBV Inc, Genenta Inc; Financial Interests, Personal, Research Grant: Genentech Inc, Regeneron Inc, Boehringer Ingelheim Inc, Takeda Inc. All other authors have declared no conflicts of interest.