Genomic and molecular considerations for sotorasib treatment in KRAS G12C-mutant non-small cell lung cancer

Targeted therapy can be a standard treatment in oncogene-driven non-small cell lung cancer (NSCLC). Alterations in the KRAS oncogene are the most common mutations detected in NSCLC and may represent approximately 30% of cases (1). Currently, there are two Food and Drug Administration (FDA)-approved targeted therapies in KRAS G12C-mutant lung cancer, sotorasib and adagrasib. Sotorasib was granted accelerated approval by the FDA in 2021 based on the CodeBreak100 trial demonstrating efficacy and safety in this patient population (2). In this report, we further comment on additional endpoints from the CodeBreak100 trial including molecular correlates of response to sotorasib for KRAS G12C-mutant NSCLC (3).

Mutant KRAS has been historically described as “undruggable” until the discovery of a drug-binding pocket at the switch II region (4). Current KRAS inhibitors including sotorasib and adagrasib bind to this pocket locking the protein into an inactive guanosine diphosphate (GDP) conformation (5). CodeBreak200 is a phase III clinical trial comparing sotorasib versus docetaxel in advanced KRAS G12C-mutant NSCLC after progression on chemoimmunotherapy (6). A progression-free survival (PFS) advantage in the sotorasib group was observed [5.6 vs. 4.5 months; hazard ratio (HR) 0.66, P=0.0017] without significant overall survival (OS) difference (10.6 vs. 11.3 months; HR 1.01, P=0.53). Rates of treatment interruption and discontinuation were 36% and 10% in the sotorasib arm respectively, comparing favorably to the docetaxel subgroup (6).

The pooled 2-year analysis of the CodeBreak100 trial is the most mature published dataset of any KRAS inhibitor in NSCLC. In this analysis of 174 patients, a median PFS of 6.3 months and a median OS of 12.5 months were observed (3). Patients were stratified as long-term responders and early-progressors (23% and 36% of the cohort respectively). Also, it is notable that 11/45 patients on sotorasib beyond 1 year had new onset treatment-related effects. This highlights the importance of continued follow-up for delayed toxicity on sotorasib.

Genomic biomarkers may provide an opportunity to identify subgroup populations with molecular features suggesting a favorable response to sotorasib. Predictive biomarkers for response to KRAS inhibitors may include TP53, STK11, and KEAP1. In a pooled analysis of genomic datasets, the incidence of TP53, STK11, and KEAP1 co-alterations in KRAS G12C-mutant NSCLC was 35%, 31%, and 23% respectively (5). In the long-term analysis of CodeBreak100, Dy et al. reported clinical outcomes of the co-mutation subgroups. Co-alteration of KEAP1 appears to be a negative prognosticator as 16 patients had early progression versus 3 patients who had long-term responses. In the STK11 co-mutated population, sotorasib yielded 8 patients with long-term responses versus 17 patients with early progression. STK11 alteration has been seen across studies as a negative predictive biomarker to immunotherapy response. A subset analysis of the POSEIDON trial evaluating the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibody tremelimumab and the anti-programmed cell death ligand 1 (PDL1) antibody durvalumab with chemotherapy in front-line metastatic STK11-mutant NSCLC demonstrated improved PFS in the immunotherapy cohort versus the chemotherapy-alone arm (6.4 vs. 4.6 months respectively; HR 0.47) (7). The KRAS mutated cohort showed an improved PFS in the immunotherapy cohort versus the chemotherapy-alone arm (8.5 vs. 5.7 months respectively; HR 0.57) (7). The effect of STK11 and KEAP1 in the context of KRAS mutations are further being explored in the ongoing prospective phase II trial LUNGMAP S1900E investigating the efficacy of sotorasib in KRAS G12C-mutant NSCLC with co-alterations including TP53, STK11, and KEAP1 (8).

In addition, the authors also describe the utility of liquid biopsies to stratify responses. They report that there was no significant difference between median variable allele frequency and tumor mutation burden in long-term responders versus early progressors. Those in the long-term responder group had lower baseline ctDNA which speaks to the likelihood of a lower tumor burden. Their data suggest that liquid biopsies may be utilized to estimate sotorasib efficacy based on clearance of ctDNA and molecular response. An abstract presented at AARC23 demonstrated that lower baseline ctDNA and clearance of ctDNA after treatment initiation corresponded with sotorasib response (9). The time points evaluated include plasma analyses at treatment initiation, cycle 2 day 1 (C2D1), and the end of treatment. Patients with non-detectable ctDNA at C2D1 had a superior median PFS compared to those patients with detectable ctDNA after treatment initiation (8.3 vs. 4.4 months respectively; P=0.007).

Precision therapy in KRAS-mutant NSCLC has historically been an unmet need. Additional options are needed to combat acquired and innate mutational resistance. The recent publication of the 2-year data from the CodeBreak100 trial has shown the possibility of assessing biomarker-directed approaches in identifying subset populations who would derive benefit from a selective KRAS inhibitor. Current clinical investigations are evaluating G12C inhibitors with combination immunotherapy and other pathway inhibitors such as SHP2 (5,10). In the CodeBreaK 100/101 phase 1b trial, sotorasib in combination with either pembrolizumab or atezolizumab demonstrated that a “lead in” treatment strategy had less grade 3 or 4 hepatotoxicity compared to combination concurrent therapy. In refractory metastatic colorectal cancer, sotorasib in combination with epidermal growth factor receptor (EGFR) inhibitor panitumumab was well tolerated and demonstrated clinical activity (11). Further studies are required to characterize the safest and most efficacious pairing of selective G12C inhibitors.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-52/coif). H.H. reports grants or contracts from BMS, Lilly Oncology, Roche Diagnostics, BillionToOne; consulting fees from Mirati, Janssen, Astrazeneca, Regeneron; and payment or honoraria from Amgen, Mirati, Foundation Medicine, Janssen, Astrazeneca, EMD Serono, Merck, Regeneron. The other author has no conflicts of interest to declare.

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