The KRAS oncogene was discovered nearly four decades ago and is the most frequently mutated oncogenic driver in human cancer, occurring in up to 40% of lung adenocarcinomas. The recent approval of two inhibitors—sotorasib and adagrasib—targeting KRAS G12C, the most common KRAS mutation in non-small cell lung cancer (NSCLC), upended the long-held conception of this oncogene as an “undruggable” target.
In the New Horizons in Targeting KRAS G12C session at the 2024 World Conference on Lung Cancer, speakers shared clinical trial data for the new KRAS G12C inhibitors garsorasib, olomorasib, fulzerasib, and divarasib—all covalently binding inhibitors similar to sotorasib and adagrasib.
Ziming Li, MD, Shanghai Chest Hospital and Shanghai Jiao Tong University, China, presented updated data from a pivotal phase II single-arm study of the potent and selective oral KRAS G12C inhibitor garsorasib.
Patients with locally advanced or metastatic NSCLC harboring the KRAS G12C mutation, with disease progression after prior anti-PD-(L)1 therapy and platinum-based chemotherapy or intolerance to these regimens due to toxicity, received garsorasib at different centers in China.
The overall response rate (ORR) was 52% and the disease control rate (DCR) was 89%. The median duration of response was 13 months. Median progression-free survival (PFS) and overall survival (OS) were 9 and 14 months, respectively.
“Garsorasib could become a promising, novel treatment option for KRAS G12C-mutated NSCLC patients who have a high unmet medical need,” Dr. Li said.
Qing Zhou, MD, PhD, Professor and Director of Pulmonary Oncology at the Cancer Hospital of Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, China, shared key news on fulzerasib.
“Just 2 weeks ago, this novel drug was approved by the National Medical Products Administration in China and became the first KRAS G12C therapy approved in China,” Prof. Zhou said. “That is good news for us.”
Fulzerasib was evaluated in its pivotal phase II single-arm study of patients with KRAS G12C-positive advanced NSCLC, with progression after standard treatment (less than three lines) that included an immune checkpoint inhibitor, platinum-based chemotherapy, or both.
Of the 116 enrolled patients, 30% had brain metastases; 59% had received one prior line of therapy, and the remaining patients had received two.
The confirmed ORR was 49% and the DCR was 91%. Biomarker analyses showed that patients with KRASG12C detected in cell-free circulating DNA had worse PFS than those without. KRASG12C-positivity in blood was also significantly associated with baseline tumor burden.
Caicun Zhou, MD, PhD, Director of Oncology at the Shanghai East Hospital, China, put these studies in perspective. “The efficacy of some of the next-generation KRAS G12C inhibitors, including fulzerasib and divarasib, is around 49% to 59%—better than the two other compounds available in the market, sotorasib and adagrasib,” Prof. Zhou said.
“There are several KRAS G12C inhibitors under clinical development. Three of these new drugs seem to have better response rates and PFS than sotorasib and adagrasib and a better safety profile,” Dr. Zhou said. “But I think phase III studies are needed to confirm the efficacy. Also, we do not know if these compounds have efficacy in patients with brain metastases.”
The session also included a presentation by Adrian Sacher, MD, Assistant Professor at the University of Toronto, Toronto, who shared long-term follow-up clinical results for divarasib as a monotherapy and in combination with atezolizumab. Finally, Yutaka Fujiwara, MD, PhD, Head of Thoracic Oncology at the Aichi Cancer Center Hospital, Aichi, Japan, discussed clinical data for olomorasib with pembrolizumab and chemotherapy as first-line treatment in patients with KRAS G12C-mutant advanced NSCLC.
