Glecirasib may deliver ‘efficacy and tolerability advantages’ for KRAS-mutant lung cancer
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Key takeaways:
- Patients with NSCLC receiving glecirasib had promising response and survival outcomes.
- Glecirasib produced elevated hepatoxicity data that should be examined.
Nearly 50% of patients with pretreated, locally advanced non-small cell lung cancer harboring a KRAS G12C mutation responded to treatment with glecirasib, findings from a phase 2 study conducted in China showed.
The results, presented by Yuankai Shi, MD, PhD, of the Cancer Hospital, Chinese Academy of Medical Sciences in Beijing, during an ASCO Plenary Series session, compared favorably with current FDA-approved KRAS G12C inhibitors in terms of overall response rate, PFS and OS, although glecirasib (Jacobio Pharmaceuticals) had a higher hepatotoxicity rate and needs further evaluation.
“Glecirasib may offer efficacy and tolerability advantages over current FDA-approved KRAS G12C inhibitors; however, randomized studies are needed,” Julia K. Rotow, MD, clinical director at the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, said as a discussant during the session.
Background and methodology
Roughly 30% of individuals with NSCLC harbor a KRAS mutation in the U.S., and about 12% have a KRAS G12C mutation, according to background presented during the session.
The FDA has previously approved two drugs targeting KRAS G12C in advanced NSCLC — sotorasib (Lumakras, Amgen) and adagrasib (Krazati, Bristol Myers Squibb).
Researchers tested glecirasib in a single-arm study at 43 different sites in China.
Study criteria required participants have locally advanced or metastatic NSCLC with a KRAS G12C mutation and been previously treated with platinum-based therapy and immune checkpoint inhibitors to be included.
ORR served as the study’s primary efficacy endpoint, with duration of response, PFS, OS, disease control rate and safety as secondary endpoints.
The 119 participants (median age, 62 years; 79% men; 94.1% had prior PD-L1 and platinum-based chemotherapy) received 800 mg of glecirasib daily.
Response and survival
An independent review committee confirmed an ORR of 47.9% (95% CI, 38.5-57.3), which included a complete response rate of 3.4% and 38.5% having stable disease.
Glecirasib also conferred an 86.3% disease control rate (95% CI, 78.7-92).
At a median follow-up of 10.4 months, study participants had a median PFS of 8.2 months (95% CI, 5.5-13.1) and median OS of 13.6 months (95% CI, 10.9 to not reached). Study investigators reported that median duration of response had not been reached.
According to Rotow, adagrasib had a 42.9% ORR, 79.5% disease control rate, PFS of 6.5 months and OS of 12.6 months in its phase 1/phase 2 trial.
Sotorasib, in a phase 2 trial, had a 37.1% ORR, 80.6% disease control rate, PFS of 6.8 months and OS of 12.5 months. Rotow said the phase 2 data of sotorasib offered a fairer comparison to glecirasib than the phase 3 data, which had lower numbers across the board.
“There is no head-to-head study here, this is cross-trial comparison,” she said. “You do see what appears to be a trend toward a better response rate and better progression free survival of glecirasib.”
Adverse events
For glecirasib, treatment-related adverse events (TRAEs) occurred in 97.5% of patients, the most common being anemia (56.3%), increased blood bilirubin (48.7%), increased alanine aminotransferase (35.3%), increased aspartate aminotransferase (35.3%), hypertriglyceridemia (28.6%) and increased gamma-glutamyl transferase (15.1%).
Grade 3 or worse TRAEs occurred in 39.5% of patients, although researchers observed no grade 5 events, and 5% of participants stopped treatment due to TRAEs.
Glecirasib had significantly more hepatotoxic TRAEs than both sotorasib and adagrasib. Neither of those drugs had rates eclipsing 10%.
Conversely, glecirasib had minimal gastrointestinal TRAEs including nausea (5.9%), vomiting (7.6%) and diarrhea (3.4%).
Sotorasib had rates above 7.9% for all three, including 27.8% for diarrhea, and adagrasib had percentages higher than 50% for each of those TRAEs, including 69.8% for diarrhea.
Next steps
Rotow had four unanswered questions after examining results of glecirasib, the first being, “Will improved tolerability facilitate use as part of combination therapy strategies with RAS pathway inhibitors? With chemotherapy? With Immunotherapy?” she asked.
She briefly discussed the topic, stressing the need for more information on hepatotoxicity based on prior therapy.
However, due to the trial parameters, she guessed researchers accumulated at least half of the data after immune checkpoint inhibitor therapy.
“It does give some reassurance regarding tolerability, but if that prior therapy is enriching for toxicity, that might help us use this agent in a safer fashion or change our monitoring parameters,” Rotow said.
Other questions included, “Will prior immune checkpoint inhibitor therapy impact tolerability? Will this agent have central nervous system activity? Where does this drug fall compared with other KRAS inhibitors in development?”
Rotow concluded that “emerging RAS-targeted therapies continue to offer hope for improved outcomes for patients with KRAS-mutated NSCLC.”
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Shi Y, et al. Abstract 468214. Presented at: ASCO Plenary Series; April 30, 2024.
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