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Evaluation of acquired resistance to sotorasib in KRAS p.G12C-mutated colorectal cancer: Exploratory plasma biomarker analysis of CodeBreaK 100
Background
Sotorasib, a specific, irreversible KRAS G12C inhibitor, is approved in multiple countries for adults with KRAS p.G12C-mutated locally advanced or metastatic NSCLC who have received prior systemic therapy. Approval was based on the global phase 1/2 CodeBreaK 100 trial, which also investigated sotorasib in other solid tumours, including colorectal cancer (CRC). Here we describe putative mechanisms of acquired resistance to sotorasib in patients with CRC.
Methods
Patients with advanced KRAS p.G12C-mutated CRC from the CodeBreaK100 phase 1/2 trial who received sotorasib monotherapy at 960 mg once daily were analysed for efficacy. The primary endpoint was objective response rate (ORR) assessed by central review. To investigate biomarkers of resistance to sotorasib, an exploratory endpoint was defined to examine acquired genomic alterations at disease progression. Plasma samples collected at baseline and progression were analysed for genomic alterations with the 74-gene Guardant 360 ® ctDNA test for CRC. Acquired genomic alterations were defined by their absence at baseline and presence at progression.
Results
In 91 patients with CRC treated with sotorasib, the ORR was 12%. At a median follow-up of 12.5 months, median progression-free survival was 4.2 months and median overall survival was 13.4 months. A total of 45 patients with CRC had a plasma sample sequenced both at baseline and at progression. At least one new acquired genomic alteration at progression was detected in 33 (73%) patients. The acquired genomic alterations were heterogeneous, with variants detected across multiple genes and pathways. The most prevalent putative pathway of resistance was found in a set of receptor tyrosine kinases (RTKs) (12 patients [27%]; including 7 patients [16%] with EGFR alterations), followed by alterations in the cell cycle pathway in 10 patients (22%) and in the DNA damage response pathway in 10 patients (22%). Secondary RAS alterations occurred in 7 patients (16%), while 27 patients (60%) had >1 alteration.
Conclusions
Diverse mechanisms of acquired resistance occur in patients with advanced KRAS p.G12C-mutated CRC treated with sotorasib. New RTK alterations frequently emerged at progression, highlighting the potential role for combining sotorasib with upstream inhibitors of RTK, such as SHP2 or EGFR inhibitors. Serial plasma DNA analysis revealed acquired resistance patterns that support the development of KRAS G12C inhibitor combination therapies.
Clinical trial identification
NCT03600883.
Editorial acknowledgement
Editorial support was provided by David Cutler, PhD at Aspire Scientific Ltd (Bollington, UK).
Legal entity responsible for the study
The authors.
Funding
Amgen Inc.
Disclosures
M. Fakih: Honoraria (self): Guardant Health, Incyte; Advisory / Consultancy: Incyte, Seattle Genetic, GSK; Research grant / Funding (institution): Verastem, Amgen, BMS. G. Falchook: Research grant / Funding (institution): Amgen. J. Strickler: Advisory / Consultancy: Seagen, Bayer, Pfizer; Research grant / Funding (institution): Amgen, Roche/Genentech, Seagen. A. Hindoyan: Shareholder / Stockholder / Stock options: Amgen Inc; Full / Part-time employment: Amgen Inc. A. Anderson: Shareholder / Stockholder / Stock options: Amgen Inc.; Full / Part-time employment: Amgen Inc. A. Ang: Shareholder / Stockholder / Stock options: Amgen; Full / Part-time employment: Amgen. T. Kurata: Honoraria (self): Bristol-Myers Squibb, Ono, Eli Lilly, AstraZeneca, MSD, Pfizer, Nipponkayaku, Chugai; Research grant / Funding (self): Amgen, MSD, AstraZeneca, Takeda, Bristol-Myers Squibb; Research grant / Funding (institution): Novartis, Chugai, Delta-Fly Pharma, Janssen Pharma, Sanofi. T. Price: Honoraria (self): Servier, Merck. The author has declared no conflicts of interest.
