Clinical Response to Sotorasib May Vary By Genomic Profile in NSCLC

The clinical response to sotorasib could vary in patients with KRAS G12C–mutated non–small cell lung cancer depending on their co-mutational status.

The clinical response to sotorasib (Lumakras) could vary in patients with KRAS G12C–mutated non–small cell lung cancer (NSCLC) depending on their co-mutational status, according to preliminary findings from an exploratory analysis of the phase 2 CodeBreak100 trial (NCT03600883) presented during the International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer.

Sotorasib is a KRAS inhibitor that was first approved in May 2021 for heavily pretreated KRAS p.G12C-mutant NSCLC based on findings from CodeBreaK100 trial, which showed that the first-in-class small molecule elicited an objective response rate of 37.1%, median progression-free survival of 6.8 months and median overall survival of 12.5 months.

“Recently, diverse and frequently coexisting mechanisms of acquired resistance to KRAS inhibitors were reported, including secondary alterations in KRAS itself, as well as other components of the RT kinase MAP kinase pathways,” said Ferdinandos Skoulidis, MD, PHD, department of Thoracic and Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center.

Skoulidis presented his team’s findings at the 2021 World Congress on Lung Cancer.2

Researchers conducted tissue analysis and looked at the following genomic profiles in 65 patients, who had baseline tissue samples and at least 3 months follow-up: KEAP1 (n=11); STRK11 (n=13); cell cycle genes (n=27); DNA damage response (DDR) genes (n=50); RAS/MAPK pathway (n=23), PI3K/AKT/mTOR pathway genes (n=24), RTK genes (n=39), WNT pathway genes (n=24).

A total of 33.8% (n=22) patients were early progressors, meaning that their disease progressed before 3 months; 35.4% (n=23) were late progressors (event of progressive disease at or after 3 months; and 30.8% (n=20) had ongoing disease control. However, the results varied by co-mutational subgroups.

Notably, KEAP1 mutational status was associated with early progression (63.6%; n=7), which is consistent with the poor prognosis often seen for these patients. Conversely, the majority of patients with cell cycle (51.9%; n=14) and WNT pathway 50%; n=12) experienced late progression, highlighting an opportunity for combination therapy in this subgroup.

“In view of these results, we hypothesize that baseline tumor genomic profiles may affect clinical response in patterns of resistance to sotorasib,” Skoulidis said.

Further investigation into co-mutational status and sotorasib response is needed, Skoulidis added, emphasizing that the results should be interpreted with caution and should be considered hypothesis-generating.

“RTK genes still [had] no association with either early or late progression, and this warrants further investigation, in larger studies, of course,” he said. “The small sample size of each of the subgroups represents a limitation of the study nonetheless, groupings of permutations into functional pathways may help determine patters of response and resistance.”


  1. A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of AMG 510 in Subjects With Solid Tumors With a Specific KRAS Mutation (CodeBreaK 100). Updated September 2, 2021. Accessed September 14, 2021.
  2. Skoulidis F, Schuler M, Wolf J, et. Al. Genomic profiles and potential determinants of response and resistance in KRAS p/G12C-mutated NSCLC treated with sotorasib. Presented at: 2021 World Conference on Lung Cancer. Sept. 8-14, 2021; virtual. Abstract MA14.03.