KRAS mutations are seen most frequently in pancreatic cancer, followed by colorectal cancer and then NSCLC. The most frequent KRAS variant observed in NSCLC is G12C. In the US, KRASG12C is present in ~37% of KRAS NSCLC cases. Since the majority of treatments for NSCLC now target the G12C variant, this variant type is likely to become crowded and competitive. Future opportunities in G12C may be found in R/R patient’s pool of approved KRAS drugs and in the first-line setting. 

Merck has been evaluating MK-1084, a next-generation oral inhibitor targeting KRAS G12C mutations. In NSCLC, MK-1084 was evaluated both as a monotherapy and in combination with KEYTRUDA, with or without chemotherapy (carboplatin and pemetrexed). Among previously treated NSCLC patients receiving MK-1084 monotherapy, the Objective Response Rate (ORR) was 38%, with a median follow-up of 18.9 months. In untreated metastatic NSCLC patients whose tumors had a PD-L1 Tumor Proportion Score (TPS) ≥1%, the combination of MK-1084 and KEYTRUDA achieved an ORR of 77%, with a median follow-up of 12.1 months. For another group of untreated metastatic NSCLC patients receiving MK-1084 in combination with KEYTRUDA and chemotherapy, the ORR was 53%, with a median follow-up of 8.5 months.

MK-1084 was generally well tolerated across all regimens. The combination therapies showed higher rates of Treatment-related Adverse Events (TRAEs) but maintained manageable safety profiles.

KOL insights

“We are encouraged by the promising early data from the KANDLELIT-001 study and look forward to further researching the potential for MK-1084, as monotherapy or in combinations, including with KEYTRUDA in certain settings in patients with KRAS mutations, which are among the most prevalent mutations in cancer. We are committed to evaluating the potential for innovative approaches to help even more patients with cancer and these results further demonstrate the potential of our robust and differentiated pipeline.” – Expert Opinion.

Conclusion

Amgen’s LUMAKRAS and Bristol Myers Squibb’s KRAZATI, the two FDA-approved KRAS G12C inhibitors, have thus far underperformed commercially, falling short of initial sales expectations. Their market position may soon be challenged by next-generation KRAS-targeting therapies currently in development.

Based on early evidence showing MK-1084 in combination with KEYTRUDA had a manageable safety profile and promising anti-tumor activity, the company is now proceeding to a larger Phase III trial to evaluate this combination in certain patients with metastatic NSCLC. MK-1084 stands out in the NSCLC treatment landscape as a targeted KRAS G12C inhibitor with potential for enhanced efficacy and a manageable safety profile. 

MK-1084 use in combination with KEYTRUDA in 1L treatment settings represents a strategic effort to enhance therapeutic efficacy. Merck anticipates releasing additional data from the ongoing Phase III randomized trial evaluating the combination of MK-1084 and KEYTRUDA by 2028 and beyond. The results of these clinical trials are expected to offer deeper insights into the therapeutic potential of MK-1084 and its role in the evolving landscape of targeted treatments for KRAS G12C-mutant cancers. Emerging key players in the pipeline include Eli Lilly, Genfleet Therapeutics/Merck, Merck/Otsuka Pharmaceutical, BioAtla, Roche, Verastem Oncology, and others.