The oral KRAS G12C inhibitor glecirasib has emerged as a therapeutic option for previously treated KRAS G12C–mutated non–small cell lung cancer (NSCLC). It may potentially improve efficacy and tolerability compared with current U.S. Food and Drug Administration–approved agents, according to data presented during the ASCO Plenary Series: April 2024 Session.¹

Results of the phase II study of glecirasib (JAB-21822) 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 5% of patients discontinuing treatment and no deaths as a result of treatment-related adverse events.

“Glecirasib shows superior overall response and progression-free survival when compared with traditional docetaxel or chemotherapy in the second-line and later settings, 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 in China. “However, clinical trials are needed to understand the role of glecirasib as a single agent or in combination with immunotherapy in the first-line setting.”

As Dr. Shi reported, KRAS G12C mutation is 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.

Study Details

The single-arm study enrolled 119 patients with advanced or metastatic NSCLC with KRAS G12C mutation, who were refractory or intolerant to previous treatments, including immunotherapy and platinum-based regimens. The recommended phase II dose of 800 mg daily was based on a previously conducted phase I/II study.

The primary endpoint was objective response rate per independent review committee. Secondary endpoints included objective response rate per investigator, duration of response, disease control rate, time to response, progression-free survival, overall survival, and safety.

Key Results

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

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 57% and 40%, respectively. The median overall survival was 13.6 months, with 6-month and 12-month overall survival rates of 83% and 55%, respectively. With a median follow-up of 10.4 months, 74.4% of patients were still undergoing treatment at the time of data cutoff.

Toxicity

Results also showed a manageable safety profile in the 119 patients who received 800 mg once daily of glecirasib monotherapy, according to the study authors.

Treatment-related adverse events of any grade were reported 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 observed, said Dr. Shi, who noted six patients (5%) discontinued treatment as a result of treatment-related adverse events.

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

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

Next Steps

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

Expert Point of View

Julia K. Rotow, MD

The invited discussant of the phase II study by Shi et al was Julia K. Rotow, MD, Clinical Director, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, and Assistant Professor of Medicine, Harvard Medical School, Boston. She compared the efficacy and safety data of glecirasib, a covalent KRAS G12C inhibitor, with the currently approved KRAS G12C inhibitors sotorasib and adagrasib, for previously treated KRAS G12C–mutated non–small cell lung cancer (NSCLC).

Although glecirasib appeared to trend toward better efficacy than sotorasib and adagrasib, Dr. Rotow cautioned that the differences were “modest and could be from a range of cross-trial variations, so ongoing confirmation will be needed.”

Dr. Rotow also highlighted the distinct side-effect profile of glecirasib, particularly the low rates of gastrointestinal toxicity, noting “only 5.9% of patients experienced nausea, and the majority of events were grade 1 or 2.” In addition, she added, 3.4% of patients had diarrhea, which makes glecirasib “very distinct from some of the other toxicity profiles in this space.” According to Dr. Rotow, this favorable gastrointestinal toxicity profile may potentially lead to better patient tolerability and compliance.

However, Dr. Rotow also noted the higher rates of hepatotoxicity observed with glecirasib compared with sotorasib and adagrasib. She emphasized that “rates of grade 3 and higher hepatotoxicity will require monitoring in subsequent studies” to ensure patient safety and to determine the optimal management strategies for these adverse events.

More to Learn

Dr. Rotow raised several important questions that remain unanswered and require further investigation. They include the impact of prior immune checkpoint inhibitor therapy on the tolerability of glecirasib, the potential for combination therapy with other agents, and the efficacy of glecirasib against central nervous system disease. Addressing these questions will be crucial in determining the optimal role of glecirasib in the treatment landscape of KRAS G12C–mutated NSCLC.

“Glecirasib may offer efficacy and tolerability advantages over current FDA-approved KRAS G12C inhibitors, but further randomized and prospective studies are needed,” Dr. Rotow concluded. She also highlighted the rapidly evolving field of RAS-targeted therapies, noting “they continue to offer hope for improved outcomes for patients with KRAS-mutated NSCLC.” As more data become available, the role of glecirasib and other novel agents in the treatment of KRAS-mutated NSCLC will become clearer, she added, potentially leading to improved patient outcomes and quality of life.

DISCLOSURE: Dr. Shi reported no conflicts of interest. Dr. Rotow reported financial relationships with AstraZeneca, Gritstone Oncology, AbbVie, Eli Lilly, Takeda, Guardant Health, Sanofi/Regeneron, Genentech, Janssen, BioAtla, G1 Therapeutics, Jazz Pharmaceuticals, Amgen, Summit Therapeutics, Daiichi Sankyo, BMS, Pfizer, and Black Diamond Therapeutics.

REFERENCE

1. Shi Y, Fang J, Xing L, et al: A pivotal phase 2 single-arm study of glecirasib (JAB-21822) in patients with NSCLC harboring KRAS G12C mutation. ASCO Plenary Series: April 2024 Session. Abstract 468214. Presented April 30, 2024.