Another KRAS Inhibitor Scores an Early Win in Advanced Non-Small Cell Lung Cancer

A China-developed KRAS inhibitor led to objective responses in half of patients with previously treated KRAS-mutant non-small cell lung cancer (NSCLC), a prospective non-randomized trial showed.

Overall, 61 of 123 patients responded to garsorasib as confirmed by an independent review committee (IRC), and the median duration of response (DOR) exceeded a year. An additional 39% of patients had stable disease, resulting in a disease control rate of 89%.

Half the patients had grade ≥3 adverse events (AEs), primarily hepatic and gastrointestinal, reported Shun Lu, MD, PhD, of Shanghai Jiao Tong University, and co-authors in Lancet Respiratory Medicine.

“The data show that garsorasib is effective and well tolerated in Asian patients with locally advanced or metastatic KRAS^G12C-mutated NSCLC,” the authors stated in their discussion. “The IRC-assessed ORR [objective response rate] was 50%, meeting the prespecified target ORR.”

“The ORR for garsorasib in this study seems to be lower than that of approved tyrosine kinase inhibitors for other targetable driver mutations,” they added. “Sotorasib [Lumakras] and adagrasib [Krazati] have also shown similar results to ours. This lower activity might be due to the genetic heterogeneity and complex biology of KRAS.”

Toxicity was manageable in most cases with dose modification and supportive medication, and the overall results suggest garsorasib could be a promising option for previously treated KRAS-mutated NSCLC, Lu and co-authors concluded.

The authors of an accompanying commentary agreed that garsorasib has activity and a toxicity profile similar to those of currently approved KRAS inhibitors.

“The results from the D1553-102 study group confirm the activity of [guanosine diphosphate]-bound KRAS^G12C inhibitors as a drug class,” wrote Jia Luo, MD, of Dana-Farber Cancer Institute in Boston, and Liza Villaruz, MD, of the UPMC Hillman Cancer Center in Pittsburgh. “Furthermore, they provide supporting evidence of the modest benefit of garsorasib in KRAS^G12C–mutated NSCLC, similar to that provided by already-approved KRAS^G12C inhibitors. If the drug is ultimately approved, it could provide greater global access to an oral, targeted option for patients with KRAS^G12C-mutated NSCLC.”

Despite promising activity in early clinical trials, a phase III trial of sotorasib versus docetaxel did not show a statistically significant benefit in overall survival, they added.

“Developing effective therapies for KRAS^G12C-mutated NSCLC requires less iteration and more exploration,” Luo and Villaruz continued. “Most inhibitors under investigation are similar to garsorasib… . Researchers and investigators in this field should focus on better preclinical models or translational studies of therapy resistance, testing rational combinations of KRAS^G12C inhibitors … and developing the next generation of targeted therapies.”

Lu and colleagues reported findings from the phase II component of a phase I/II clinical trial of garsorasib in previously treated KRAS^G12C-mutated NSCLC. The phase I component showed a “well tolerated safety profile and encouraging antitumor activity,” the authors noted. The multicenter phase II trial continued investigation of garsorasib at 43 sites in China.

Eligible patients had previously received platinum-based chemotherapy, immune checkpoint inhibitors, or both. The primary endpoint was IRC-adjudicated ORR.

The results showed that treatment with garsorasib led to one complete response and 60 partial responses, and 48 patients had stable disease. Median progression-free survival was 7.6 months. The authors reported that 55% of patients remained progression-free at 6 months and 35% at 12 months. Median time to response was 1.4 months and median DOR was 12.8 months.

The safety analysis included all 123 patients and showed that 99% of patients had one or more AEs, regardless of source, and 95% had treatment-related adverse events (TRAEs). Grade ≥3 TRAEs occurred in 61 patients, most commonly increased liver enzymes, increased bilirubin, increased alkaline phosphatase, vomiting, and nausea. No patient withdrew because of TRAEs. Two deaths of unknown cause were considered treatment related.

Investigators have planned a randomized, double-blind, phase III trial that will have “more stringent management of patient dropout and crossover and blinded imaging review by an IRC to minimize systemic bias.”

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