Results from Garsorasib Expand the Class of KRASG12C Inhibitors in NSCLC

KRASG12C Inhibitors for NSCLC: How Garsorasib Stands Out

Early findings from the use of garsorasib (D-1553), an oral KRASG12C inhibitor, in patients with advanced non–small cell lung cancer (NSCLC) have demonstrated promising potential, leading to the initiation of a Phase II trial. The results were published in the Journal of Thoracic Oncology.

In the Phase I study (NCT05383898), 79 patients with advanced solid tumors were treated with different doses of garsorasib, ranging from 600 mg to 1200 mg once daily and later 400 mg or 600 mg twice daily. The dose expansion phase involved all patients receiving 600 mg of garsorasib twice a day. The primary endpoints of the study were safety and efficacy evaluation.

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Treatment-related adverse events (TRAEs) of any grade were observed in most patients, with 38% experiencing grade 3 or 4 TRAEs. However, only 1.3% of patients had to discontinue treatment due to these adverse events, suggesting the monotherapy with garsorasib was generally well-tolerated. The toxicity profile of garsorasib was found to be similar to other approved KRASG12C inhibitors, such as adagrasib and sotorasib. Moreover, combining KRASG12C inhibitors with immunotherapy showed higher rates of toxicity, particularly hepatotoxicity.

The study also showed that garsorasib had a comparable adverse event profile to sotorasib, indicating that a Phase II trial of garsorasib may yield similar results to those observed in the Phase II CodeBreaK100 trial for sotorasib. The most common treatment-related adverse events included diarrhea, nausea, and alanine aminotransferase increase.

In this research, six patients were identified with stable and assessable brain metastases at the beginning of the study. Among them, the intracranial (IC) overall response rate (ORR) was found to be 17%, and the disease control rate (DCR) was 100%. When comparing these results to the Phase I/II KRYSTAL-1 trial (NCT03785249) that examined the effectiveness of adagrasib in NSCLC patients, the subgroup of patients with brain metastases showed an IC ORR of 33% and a DCR of 85%. It is important to note that the KRYSTAL-1 trial subgroup included 33 patients, which the researchers believed contributed to some of the observed differences in the outcomes.

Among the patients with intracranial (IC) disease and brain metastases at baseline, garsorasib demonstrated an IC overall response rate of 17% and an IC disease control rate of 100%. While the initial response with garsorasib appeared promising with an objective response rate of 40.5% and a disease control rate of 91.9%, further investigation is needed to explore the efficacy and safety in larger patient populations. The median progression-free survival (PFS) in the dose escalation phase was 8.2 months, and the median duration of response (DOR) was 7.1 months after a median follow-up of 8.8 months. In the recommended Phase II dose portion of the study, patients receiving 600 mg of garsorasib twice daily had a median PFS of 7.6 months and a median DOR of 6.9 months.

Related: Advancing Precision Oncology: Targeting KRAS Mutations With LUMAKRAS And KRAZATI

These early results are encouraging and support the progression to a Phase II trial to further explore the potential of garsorasib as a treatment option for patients with advanced non–small cell lung cancer and other solid tumors.

Garsorasib provides an additional treatment option, mainly for patients who have undergone extensive prior treatments. In this study, a significant proportion (69.6%) of patients had either refractory disease or were unable to tolerate previous PD-L1 treatment. Moreover, the majority of patients (93.7%) showed resistance to platinum-containing chemotherapy, with a considerable portion (68.4%) being resistant to both types of treatments. While Phase II trials for garsorasib are still underway, the initial findings suggest that there is currently no clear evidence of superior efficacy or lower toxicity compared to other KRAS G12C inhibitors. Researchers are cautious about drawing definitive conclusions until further data from ongoing trials becomes available.

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