Elironrasib May Overcome Resistance to Prior KRAS G12C Inhibition in Non-small Cell Lung Cancer
The small molecule KRAS inhibitor elironrasib targets the active GTP-bound form of KRAS G12C and led to encouraging responses in certain patients with heavily pretreated lung cancer
BOSTON – Elironrasib led to meaningful and durable responses in patients with metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC), including after prior treatment with KRAS G12C inhibitors and in the presence of features linked to KRAS inhibitor resistance, according to data from a phase I trial presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held October 22-26.
There are currently two FDA-approved therapies for KRAS G12C-mutated lung cancer: sotorasib (Lumakras) and adagrasib (Krazati). Both benefit some patients with KRAS G12C mutations, the most common KRAS-related driver of NSCLC, but too few responses are sustained for long periods of time due to preexisting or acquired resistance mechanisms, especially alterations affecting KRAS and other RAS-related pathways.
“Available KRAS G12C inhibitors target the inactive form of the KRAS protein, its GDP-bound ‘OFF’ state,” explained Bruna Pellini, MD, an assistant member of the Department of Thoracic Oncology at the Moffitt Cancer Center and Research Institute, and the presenter of the study.
“Our team wanted to see whether targeting the active, GTP-bound form of KRAS G12C—it’s ‘ON’ state—would help patients overcome resistance to the first-generation KRAS G12C inhibitors,” she said.
In the phase I trial, 24 patients with metastatic, KRAS G12C-mutated NSCLC were treated with elironrasib. All patients had undergone at least two prior lines of therapy, half at least three prior therapies, and 92% (22/24) experienced disease progression after prior treatment with a KRAS G12C inhibitor. At baseline, 88% (21/24) of tumors had KRAS G12C alterations detectable via circulating tumor DNA.
After treatment with elironrasib, 42% (10/24) of patients experienced partial responses with at least 30% tumor shrinkage, and many were durable with half being sustained for at least 11.2 months. Among all patients, the median follow-up time was 17.6 months, with half of the patients remaining progression-free for at least six months, and 62% still alive at 12 months.
“While this study is too small and it is too early to draw any definitive conclusions, these results provide excellent signals,” said Pellini, who called the response rate and durations “very striking” given the low response rates often seen in those who have already progressed after multiple rounds of therapy.
Notably, clinical benefit was observed in all seven patients whose tumors, at baseline, harbored alterations in receptor tyrosine kinase and MAPK pathways, which are associated with resistance to KRAS G12C inhibitors. Five of the seven experienced partial responses, and the remaining two saw their disease stabilize.
“Responses in these patients, whose tumors had co-alterations of significance that are known to reactivate RAS signaling despite prior KRAS G12C inhibition, suggest elironrasib could potentially remain active even in the presence of these unique mechanisms that drive high levels of GTP-bound KRAS G12C,” Pellini stated.
The therapy demonstrated a favorable safety profile, according to Pellini. Grade 3 treatment-related adverse events (TRAEs) were observed in 8% (2/24) of patients, and no grade 4 or 5 TRAEs occurred. None of the patients stopped treatment because of drug intolerability.
“This study illustrates how mechanism-driven drug design can overcome resistance. If the findings are borne out in larger trials, this approach could offer a new therapeutic paradigm for patients with a KRAS G12C mutation, not only in lung cancer but potentially across a range of solid tumors with the same alteration,” Pellini said.
Moving forward, Pellini emphasized the importance of ongoing follow-up and translational work, including serial ctDNA and tissue profiling, designed to answer questions regarding resistance. Ultimately, this knowledge could redefine patient selection and help tailor combinational approaches in future studies, she said.
Limitations of the study include its small sample size, single-arm design, and limited follow-up with respect to long-term safety, biomarker identification, and overall survival in this early analysis.
The study was supported by Revolution Medicines.
Pellini has received research support to the institution from Bristol Myers Squibb (BMS), the BMS Foundation/the Robert A. Winn Diversity in Clinical Trials Awards Program, and Merck; speaker honoraria from AstraZeneca, Amgen, Boehringer Ingelheim, Merck, Foundation Medicine, Regeneron, and OncoHost; and travel support from BMS, MSD, Gilead, and Regeneron. Additionally, Pellini has done consulting/advisory board work with AstraZeneca, AbbVie, Bayer, BMS, Catalyst Pharmaceuticals, Gilead, Guardant Health, Foundation Medicine, Illumina, Regeneron, Merus, and OncoHost, and is a steering committee member for BMS.
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