Glecirasib Shows Promising Efficacy in KRAS-Mutated NSCLC

Glecirasib, a highly selective covalent oral inhibitor of KRAS G12C, demonstrated promising efficacy in patients with previously treated KRAS G12C-mutated non-small cell lung cancer (NSCLC), according to a phase II trial from China.

For these patients, the objective response rate (ORR) was 47.9% and median progression-free survival (PFS) was 8.2 months, reported Yuankai Shi, MD, PhD, of the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, during an American Society of Clinical Oncology (ASCO) virtual plenary.

ASCO discussant Julia Rotow, MD, of Dana-Farber Cancer Institute in Boston, said that compared with adagrasib (Krazati) and sotorasib (Lumakras) — which are FDA approved as second-line therapies for patients with KRAS G12C-mutated locally advanced or metastatic NSCLC — “there appears to be a trend towards a better response rate and better progression-free survival with glecirasib.”

A comparison across studies showed that patients treated with adagrasib in KRYSTAL-1 achieved an ORR of 43% and a median PFS of 6.5 months. As for sotorasib, the phase II CodeBreak 100 study showed that patients had an ORR of 37.1% and a median PFS of 6.8 months, while in the phase III randomized CodeBreak 200 trial, the ORR was 28.1% and the median PFS was 5.6 months.

“Efficacy [with glecirasib] appears to be trending in the right direction, but is modest and could be from the range of cross-trial variation,” Rotow said. “So, ongoing confirmation will be needed.”

While plans for FDA approval of glecirasib in NSCLC are unclear, the KRAS inhibitor recently garnered the agency’s orphan drug designation for pancreatic cancer, according to drugmaker Jacobio.

The current study included 119 NSCLC patients (79% men, median age 62 years). About 81% had an Eastern Cooperative Oncology Group (ECOG) performance status score of 1, and 94% had received prior PD-1/L1 inhibitors and platinum-based chemotherapy.

With a median follow-up of 10.4 months, 34.2% of patients were still on treatment.

Of the 119 patients in the study, four achieved a complete response to glecirasib, 52 had a partial response, and 45 had stable disease, resulting in a disease control rate of 86.3%.

Six-month and 12-month PFS rates were 56.6% and 40%, respectively. Median overall survival was 13.6 months, with 6- and 12-month rates of 83% and 54.6%, respectively.

As for safety, KRAS inhibitors “are often more toxic than many of our other targeted agents we use in oncogene-driven lung cancer, and here glecirasib does have a distinct side effect profile that is different from sotorasib and adagrasib,” Rotow said. “Particularly notable are the rates of hepatic toxicities … this is something to watch for if we are treating a patient with this agent.”

Specifically, there were substantially higher rates of treatment-related adverse events with glecirasib involving blood bilirubin increases (all-grade: 48.7%; ≥grade 3: 6.7%) and alanine aminotransferase and aspartate aminotransferase increases (all-grade: 35.3%; ≥grade 3: 10.9%) compared with what was reported with sotorasib and adagrasib in their respective trials.

However, both Shi and Rotow noted that there was very limited gastrointestinal toxicity seen in the study compared with sotorasib and adagrasib, with just 5.9% of patients experiencing any-grade nausea, 7.6% having vomiting, and 3.4% having diarrhea. Just one patient experienced grade 3 nausea.

Discontinuation and dose-reduction rates in the trial were also slightly lower than those seen in CodeBreak 100, and significantly lower than the rates in KRYSTAL-1. “This likely has to do with the different GI toxicity profiles,” Rotow suggested. “This is … something that may be an advantage when selecting among agents.”

Rotow added that there are multiple unanswered questions surrounding glecirasib, such as whether the agent will have central nervous system activity, and what its role will be in combination therapy.

She also wondered how the agent will compare with other KRAS-targeted strategies now under development, such as the KRAS G12C inhibitor divarasib that has demonstrated response rates over 50%, as well as KRAS inhibitors that have different mechanisms of action, such as the KRAS G12C inhibitor RMC-6291.

“Emerging RAS-targeted therapies continue to offer hope for improved outcomes for patients with KRAS-mutated NSCLC,” Rotow said, “hopefully moving response rates from 30%-40% to the over-50% range going forward.”

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