157TiP - Krascendo-170 Lung: a phase Ib/II study of divarasib + pembrolizumab _ platinum-based chemotherapy and pemetrexed in untreated KRAS G12C+ advanced non-small cell lung cancer (NSCLC)

Background

The KRAS G12C mutation, present in ∼12% of NSCLC patients, drives oncogenic signalling and cancer formation and is associated with poor prognosis. The current first-line treatment for advanced KRAS G12C+ NSCLC is checkpoint inhibitor (CPI) ± chemotherapy (CT). Novel combinations using a more targeted, biomarker-directed approach are supported by pre-clinical evidence and may further improve outcomes. Divarasib is an oral KRAS G12C inhibitor with potent pre-clinical and clinical anti-tumour activity. We hypothesize that divarasib + CPI ± CT may improve outcomes for patients with KRAS G12C+ NSCLC.

Trial Design

Krascendo-170 Lung (NCT05789082) is a phase Ib/II, open-label study evaluating the safety and activity of divarasib + pembrolizumab in patients with PD-L1 tumour cell expression ≥1% (Cohort A) and of divarasib + pembrolizumab with platinum-based CT and pemetrexed in patients with any PD-L1 tumour cell expression level (Cohort B). Patients must be ≥18 years old with untreated unresectable/metastatic non-squamous NSCLC (measurable per RECIST v1.1), a confirmed KRAS G12C mutation, and an Eastern Cooperative Oncology Group performance status 0/1. Each cohort will have two stages: divarasib combination dose finding and dose expansion, with two planned dose levels of divarasib (Table). Tumour assessments will be performed at baseline and every 6 weeks for 48 weeks, then every 9 weeks thereafter. Plasma samples will be taken at various timepoints before and after divarasib and pembrolizumab dosing to characterise pharmacokinetics. Patients will be treated until disease progression per RECIST v1.1 or unacceptable toxicity. The co-primary endpoints are adverse events and change from baseline in targeted safety parameters. Key secondary endpoints include objective response rate, progression-free survival and duration of response (all investigator assessed per RECIST v1.1). Table: 157TiP

*Participants will receive one of two doses of divarasib. †Dose expansion will depend on pre-specified safety parameters during the dose-finding stage; ^‡CT: 4 cycles of carboplatin (intravenously, every 3 weeks, AUC5) or cisplatin (intravenously, every 3 weeks, 75 mg/m²) per investigator’s choice. Drug administration schedule: Divarasib: orally once daily; Pemetrexed: 500 mg/m² intravenously every 3 weeks; Pembrolizumab: 200 mg intravenously every 3 weeks.

Clinical trial identification

NCT05789082.

Editorial acknowledgement

Medical writing support for the development of this abstract, under the direction of the authors, was provided by Neave Baldwin, BSc, of Ashfield MedComms, an Inizio company.

Legal entity responsible for the study

F. Hoffmann-La Roche Ltd.

Funding

F. Hoffmann-La Roche Ltd.

Disclosure

F. Skoulidis: Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen Inc, Revolution Medicines, Novartis, BridgeBio, BeiGene, BergenBio, Guardant Health, Tango Therapeutics, Calithera Bioscieces, Hookipa Pharma, Novocure, Merck &Co; Financial Interests, Personal, Invited Speaker: ESMO, Japanese Lung Cancer Society, Medscape LLC, Intellisphere LLC, VSPO McGill Universite de Montreal, RV Mais Promocao Events LTDS, MJH Life Sciences, IDEOlogy Health, MI&T, PER LLC, CURIO LLC, DAVA Oncology, American Association for Cancer Research, IASLC; Financial Interests, Personal and Institutional, Local PI: Amgen Inc, AstraZeneca, Revolution Medicines, Novartis, Merck &Co, Tango Therapeutics, Genentech/Roche ; Financial Interests, Institutional, Research Funding: Revolution Medicines, Mirati Therapeutics, Amgen Inc, Novartis, Merck & Co; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Amgen Inc, Revolution Medicines, Novartis, BridgeBio, BeiGene, BergenBio, Guardant Health, Tango Therapeutics, Calithera Bioscieces, Hookipa Pharma, Novocure, Merch &Co; Financial Interests, Personal, Steering Committee Member: AstraZeneca; Financial Interests, Personal, Stocks or ownership: BioNTech SE, Moderna Inc; Financial Interests, Personal, Trial Chair: Pfizer . K. Cuppens: Financial Interests, Personal, Expert Testimony: AstraZeneca, Merck Sharp Dohme; Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, Merck Sharp Dohme; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, Merck Sharp Dohme, Pfizer. A. Sacher: Financial Interests, Institutional, Coordinating PI: Genentech-Roche, BMS, AstraZeneca; Financial Interests, Institutional, Local PI: Amgen, Iovance, CRISPR Therapeutics, Merck, Pfizer, GSK, Spectrum, Lilly. V. Velcheti: Financial Interests, Personal, Speaker, Consultant, Advisor: BMS, Merck, AstraZeneca, Regeneron. D.H. Lee: Financial Interests, Personal, Speaker, Consultant, Advisor: Abion, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, ChongKeunDang, Janssen, MSD, Novartis, Ono, Pfizer, Roche, ST Cube, AbbVie, Takeda, Blueprint Medicine, BC World Pharm, Yuhan; Non-Financial Interests, Personal, Steering Committee Member: Roche, Abion. M.T. Lin, T.M. Fernando: Financial Interests, Personal, Full or part-time Employment: Genentech, Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd. S. Li, M.S. Mathisen: Financial Interests, Personal, Full or part-time Employment: Genentech, Inc. D. Bradley: Financial Interests, Personal, Full or part-time Employment: Roche Products Ltd. M. Zarak Crnkovic: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.