D‐1553 is a small molecule inhibitor selectively targeting KRAS G12C and currently in Phase II clinical trials. It is an inhibitor of the RAS-MEK signaling system. D1553 shows anticancer efficacy in vitro and in vivo in KRAS G12C mutant animals. The drug has antitumor activity in vitro and in in vivo models with KRAS G12C mutation. 

The efficacy and safety results of Phase II study (NCT04585035) were reported at ESMO 2023. The Phase IA and IB were dose-escalation studies whereas the Phase II study evaluated the combination of garsorasib and cetuximab. The key endpoints of the Phase II trial were Objective Response Rate (ORR), Disease Control Rate (DCR), Progression Free Survival (PFS) and Duration of Response (DOR) and Overall Survival (OS).

In the study, as of August 2023, 40 patients were evaluated out of which 21 patients remained on treatment. An ORR of 45% and DCR of 95% were reported. Reduction in target lesions was observed in 92.5% of the patients. The median time to response was found to be 5.9 weeks whereas, the median DOR was 8.6 months. The median PFS in the study was found to be 7.6 months. Due to limited follow-up period, the median OS was not reached but the 9-month OS rate was 82.4%. 

Most treatment related adverse events (TRAEs) observed were mild or moderate. Garsorasib related adverse events were observed in 2.5% of the patients whereas, 12.5% patients experienced cetuximab related adverse events. Grade III TRAEs included rash, dermatitis, acneiform, etc.

KOL insights

“What we are excited to see is this wave of new therapies targeting RAS mutations. There are a lot of clinical trials and new approaches for targeting RAS. The biggest unmet need in CRC is how to treat patients who have RAS mutations. With ongoing research, we may be on to something.” -Chief of Hematology and Oncology 

Conclusion

KRAS mutations are seen most frequently in pancreatic cancer, followed by Colorectal Cancer (CRC) and Non-small cell lung cancer (NSCLC). Roughly 40%-45% of CRC cases have KRAS mutations in the United States. In addition, the most common KRAS variation in CRC is G12D.  At present, the majority of companies are targeting G12C variants, however the most frequent KRAS variant observed in NSCLC is G12C. 

In extensively pretreated patients with KRAS G12C mutant CRC, the combination of garsorasib  with cetuximab demonstrated an acceptable safety profile, a greater response rate than garsorasib monotherapy, and a promising PFS. The efficacy results show a robust improvement over garsorasib monotherapy and the SoC. Thus, combination of garsorasib and cetuximab may provide a new therapeutic option for heavily pretreated patients with KRAS G12C mutation.

 

For more insight into the patient's burden/epidemiology, treatment, and changing market landscape-related advancements, refer to the KRAS Inhibitors Competitive Landscape and Market Forecast Report and Colorectal Cancer Market Insight and Forecast Report