Glecirasib Induces Promising Efficacy in Patients With Advanced Lung Cancer

Lung Cancer: Lung CancerGlecirasib, a KRASG12C inhibitor, showed promising efficacy in previously treated KRASG12C-mutated non-small cell lung cancer (NSCLC). According to a pivotal Phase II trial, the covalent, highly selective, and orally bioavailable KRASG12C inhibitor led to promising overall response rate (ORR), progression-free survival (PFS), and clinical activity. Confirmed ORR was 47.9 percent (the primary endpoint), median PFS was 8.2 months, and median overall survival (OS) was 13.6 months. Median duration of response (DOR) has not been reached, and the 12-month DOR rate was 56.6 percent. “This Phase II study of glecirasib monotherapy has met the study's primary endpoint demonstrating promising efficacy in previously treated KRASG12C-mutated NSCLC patients,” said lead author Yuankai Shi, MD, PhD, of the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, speaking at the April 2024 American Society of Clinical Oncology (ASCO) Plenary Series. The KRASG12C mutation occurs in approximately 4.3 percent of NSCLC cases in China, and there are currently no approved targeted therapies for this type of mutation in China. This single-arm study conducted across 43 sites in China provides new data on the effectiveness of glecirasib in patients who have progressed after standard treatment with chemotherapy and immunotherapy. Two KRASG12C inhibitors have received FDA approval—sotorasib and adagrasib. Study Details The study enrolled 119 participants with advanced stages of NSCLC who previously received platinum-based and immune checkpoint inhibitor therapies. Patients were treated with single-agent glecirasib at 800 mg daily. Median age was 62 years, 79 percent were male, and 80.7 percent had ECOG Performance Status 1. The majority were past smokers (59.7%), had adenocarcinoma (95%), did not have brain metastases (83.2%), and had tumor, nodes, and metastases (TNM) Stage IV disease (95%). More than half (51.3%) of patients received one prior line of therapy, 42 percent had two prior lines of therapy, and 6.7 percent had three prior lines of therapy. Nearly all (94.1%) patients were previously treated with platinum-based chemotherapy and a PD-1/PD-L1 inhibitor. After a median follow-up of 10.4 months, the confirmed ORR was 47.9 percent and the confirmed disease control rate was 86.3 percent assessed by IRC. One-third (34.2%) of patients were still on study treatment. The median time to response was 1.41 months. A deep response was observed in 30.8 percent of patients with more than 50 percent tumor reduction. Shi noted that ORR was consistent across specified subgroups of patients. However, the ORR appeared to be higher in patients with an ECOG performance status of 0 (65.2%), those who received only one line of prior treatment (52.5%), and those without central nervous system metastases (50.5%). “Most patient responses are ongoing in the trial,” said Shi. Responses were ongoing in 73.6 percent of patients at 6 months and 56.6 percent at 12 months. The use of glecirasib showed a median PFS of 8.2 months. The 6-month PFS rate was 56.6 percent and 12-month PFS rate was 40 percent. The median OS was 13.6 months, and the 6-month and 12-month OS rates were 83 percent and 54.6 percent, respectively. Safety Findings Glecirasib has a manageable safety profile, Shi noted. Grade 3 or higher treatment-related adverse effects (TRAEs) occurred in 38.7 percent of patients, and serious adverse events occurred in 19.3 percent. A total of 97.5 percent of patients experienced at least one any-grade adverse event. Only 5 percent of patients discontinued the treatment due to TRAEs. The most common TRAES were anemia (56.3%), blood bilirubin increase (48.7%), alanine aminotransferase increase (35.3%), and aspartate aminotransferase increase (35.3%). No Grade 5 TRAEs were seen. TRAEs leading to dose interruption were observed in 37.8 percent of patients. Dose reduction following TRAEs occurred in 18.5 percent of patients. “Glecirasib has a favorable GI profile compared to other KRAS G12C inhibitors,” Shi said. Gastrointestinal toxicity included Grade 1/2 nausea (6.7%), vomiting (7.6%), and diarrhea (3.4%). Grade 3 nausea occurred in only one patient (0.8%). “Glecisarib may offer efficacy and safety tolerability advantages over current FDA-approved KRASG12C inhibitors. However, randomized studies are needed. Low rates of GI toxicity were seen with glecirasib treatment,” noted ASCO discussant Julia Rotow, MD, Clinical Director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute and Assistant Professor of Medicine at Harvard Medical School. “Rates of Grade 3 or higher hepatotoxicity will require monitoring in subsequent studies. The role of glecirasib in combination therapy and for CNS control remains to be established.” Emerging RAS-targeted therapies continue to offer hope for improved outcomes of patients with KRAS-mutated NSCLC, she added. Mark L. Fuerst is a contributing writer.