Biomarkers of acquired resistance to sotorasib (soto) plus panitumumab (pani) in chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC)

Abstract Introduction: New RTK alterations emerge at progression when patients (pts) with KRAS G12C-mutated mCRC are treated with soto monotherapy, suggesting addition of an EGFR inhibitor may help counter soto resistance and inhibit further tumor growth. Soto plus pani has shown a 3-fold higher objective response rate than monotherapy but may give rise to new patterns of resistance. We report emerging mutations after treatment with the doublet in the dose exploration/expansion cohorts of CodeBreaK 101 Subprotocol H. Methods: We evaluated pts who had KRAS G12C-mutated mCRC, were KRASG12C inhibitor-naïve, and had paired plasma samples at baseline and progression after treatment with soto (960 mg PO daily) plus pani (6 mg/kg IV Q2W). Samples were analyzed using the 74-gene Guardant 360® ctDNA test. Acquired genomic alterations were defined as absent at baseline and present at progression. We also studied the association between acquired mutations and time to progression (TTP). Results: Of 21 pts with paired plasma samples, 17 (81%) had ≥1 acquired genomic alteration. RTK alterations and secondary (2°) RAS alterations were most common; each occurred in 57% of pts (Table). KRAS amplification was the most common single alteration (43%). Of the 74 acquired alterations observed, 23 (32%) were potentially actionable per OncoKB™, including BRAF V600E, METex14, and ERBB2 S310F. EGFR alterations and RAS single nucleotide variants (SNVs) were not seen in pts with TTP <3 months. Discussion: A higher rate of acquired 2° RAS and RTK mutations at progression was observed after treatment with the doublet compared to prior analysis of soto monotherapy. Many detected EGFR mutations and RAS SNVs are functionally oncogenic and not seen in pts with early progression, suggesting clonal evolution mediating 2° resistance. Our results reinforce the dependence of continued tumor growth on RAS and EGFR signaling in mCRC and may suggest the need for triplet therapy. Table. Acquired genomic alterations observed ALTERATION PATIENTS, n (%) RTK alteration 12 (57) EGFR 7 (33) EGFR amplification 3 (14) EGFR G465R 1 (5) EGFR G465D 1 (5) EGFR G465E 1 (5) EGFR S464L 1 (5) EGFR L704V 1 (5) EGFR G87R 1 (5) 2° RAS genomic alterations 12 (57) KRAS amplification 9 (43) KRAS Q61H 1 (5) NRAS Q61R 1 (5) NRAS Q61L 1 (5) NRAS Q61H 1 (5) NRAS Q61K 1 (5) NRAS G60E 1 (5) Citation Format: David S. Hong, Yasutoshi Kuboki, Rona Yaeger, John H. Strickler, Toshiki Masuishi, Corey Langer, Ardaman Shergill, Edward Kim, Antreas Hindoyan, Qui Tran, Lata Mukundan, Emily Chan, Abraham Anderson, Marwan G. Fakih. Biomarkers of acquired resistance to sotorasib (soto) plus panitumumab (pani) in chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2308.