Glecirasib monotherapy demonstrated efficacy in previously treated patients with KRAS G12C–mutated non–small cell lung cancer (NSCLC) according to data presented during the ASCO Plenary Series: April 2024 Session (Abstract 468214).

Results of the pivotal Chinese phase II study of glecirasib (JAB-21822), an oral inhibitor of KRAS G12C, showed a confirmed objective response rate of 47.9% in patients with KRAS G12C–mutated advanced NSCLC. Patients who received glecirasib had a median progression-free survival of 8.2 months and a median overall survival of 13.6 months at the time of data cutoff. Median duration of response has not been reached. Glecirasib also demonstrated a manageable safety profile, with only 5% of patients discontinuing treatment and no deaths due to treatment-related adverse events reported.

“Glecirasib shows superior overall response and progression-free survival when compared to traditional docetaxel or chemotherapy in the second line and later, and the KRAS G12C inhibitor is associated with better quality of life with regard to side effects,” said lead study author Yuankai Shi, MD, PhD, Professor of Medical Oncology at the National Cancer Center and Cancer Hospital and the Chinese Academy of Medical Sciences and Peking Union Medical College.  “However, for the first line, clinical trials are needed to understand the role of glecirasib as a single agent or in combination with immunotherapy.”

As Dr. Shi reported, KRAS G12C mutations are found in approximately 13% of patients with NSCLC in the United States and 4% in China. Glecirasib is a covalent, highly selective, and orally bioavailable KRAS G12C inhibitor. The recommended phase II dose of 800 mg daily was based on a previously conducted phase I/II study.

The single-arm phase II study enrolled 119 patients with advanced or metastatic NSCLC and a KRAS G12C mutation who were refractory or intolerant to previous treatments, including immunotherapy and platinum-based regimens. The primary endpoint of the trial was objective response rate per independent review committee, with secondary endpoints including objective response rate per investigator, duration of response, disease control rate, time to response, progression-free survival, overall survival, and safety.

Favorable Results Support Ongoing Development

Of 117 evaluable patients, 3.4% achieved a confirmed complete response, 44.4% achieved a confirmed partial response, and 38.5% maintained stable disease. Glecirasib resulted in a confirmed objective response rate of 47.9% and a disease control rate of 86.3%.

The median time to response was 1.4 months, and the median duration of response has not been reached. The 6-month and 12-month duration of response rates were 73.6% and 56.6%, respectively.

The median progression-free survival was 8.2 months, with 6-month and 12-month progression-free survival rates of 56.6% and 40%, respectively. The median overall survival was 13.6 months, with 6-month and 12-month overall survival rates of 83% and 54.6%, respectively.

Results also showed a manageable safety profile in the 119 patients who received 800 mg of glecirasib monotherapy once daily. Treatment-related adverse events of any grade occurred in 97.5% of patients, with 38.7% experiencing at least one grade 3 or 4 treatment-related adverse event. No fatal treatment-related adverse events were reported, said Dr. Shi, who noted that only six patients (5%) discontinued treatment due to treatment-related adverse events.

Common treatment-related adverse events (occurring in ≥ 10% of patients) included anemia (56.3%), increased blood bilirubin, increased alanine aminotransferase and aspartate aminotransferase, hypertriglyceridemia, and increased gamma-glutamyl transferase. Grade 3 or 4 treatment-related adverse events were primarily related to liver toxicity and hypertriglyceridemia. Glecirasib resulted in minimal gastrointestinal toxicities, with only one patient experiencing grade 3 nausea.

“The favorable gastrointestinal toxicity profile of glecirasib is noteworthy, with most patients experiencing only grade 1 or 2 events of nausea (5.9%), vomiting (7.6%), and diarrhea (3.4%),” said Dr. Shi.

According to Dr. Shi, these results support the ongoing development of glecirasib as a potential treatment option for KRAS G12C–mutated NSCLC. Pivotal trials evaluating glecirasib as a second-line therapy and beyond in both NSCLC and pancreatic ductal adenocarcinoma are ongoing in China, said Dr. Shi, with multiple glecirasib-based combination therapies also under clinical development.

Disclosure: For full disclosures of the study authors, visit coi.asco.org.