KRAS mutations are seen most frequently in pancreatic cancer, followed by Colorectal Cancer and NSCLC. The most frequent KRAS variant observed in NSCLC is G12C. In the US, KRASG12C is present in ~40% of KRAS NSCLC cases. Many companies are focusing on developing their candidates for the treatment of KRAS mutated NSCLC, like Eli Lilly (olomorasib), Genfleet Therapeutics (DUPERT), Merck (MK-1084), Verastem oncology (avutometinib), and others.

ASCO 2025 brought olomorasib in combination with immunotherapy (KEYTRUDA) in first-line treatment of patients with KRAS G12C-mutant advanced NSCLC. The study demonstrated robust antitumor activity, with a confirmed Overall Response Rate (ORR) of 74% in all patients and an impressive 90% ORR in patients with high PD-L1 expression. The Disease Control Rate (DCR) was 91% overall and 89.5% in the PD-L1 ≥50% subgroup. Median Duration of Response (DoR) was not estimable, with a median follow-up of 9.6 months and 12-month DoR rate of 62.7%; 6-month DoR rate stood at 94.7%. Progression-free survival (PFS) also showed sustained benefit, with median PFS not yet reached and 12-month PFS rate of 62.7% overall and 66.7% in high PD-L1 patients. At 6 months, PFS rates were 82.2% (all) and 87.5% (PD-L1 ≥50%). 

The waterfall plot revealed consistent and deep tumor shrinkage in the majority of patients. In terms of safety, the treatment was manageable: elevated liver function tests were mainly Grade 3 or lower, had a median onset of 32 days and median duration of 6 days, with no bilirubin elevation or clinical symptoms. These were effectively managed through dose adjustments or corticosteroids, and no patients discontinued both agents due to liver toxicity. 

KOL insights

“Prognosis for patients with KRAS G12C-mutant NSCLC remains poor, despite the approval of first-generation KRAS inhibitors, which are currently limited to second or later line use. Further progress may be achieved with the addition of targeted therapy to immunotherapy in NSCLC.” – Expert Opinion

Conclusion

KRAS mutations, once deemed undruggable, have seen progress with selective inhibitors like Amgen’s LUMAKRAS and Mirati’s KRAZATI, both targeting the KRAS G12C variant in NSCLC. While LUMAKRAS was the first approved, its full approval was delayed by an FDA CRL in 2023, and it faced setbacks due to liver toxicity in combination trials. KRAZATI showed promise with a 43% ORR but had a slow commercial uptake and regulatory hurdles in Europe. Both drugs highlight the need for broader KRAS-targeted therapies, prompting companies like Eli Lilly, Merck, and Verastem to develop next-generation inhibitors. 

As a second-generation KRAS G12C inhibitor, olomorasib was specifically designed to offer a differentiated profile that could potentially overcome limitations of currently available treatment options. The obtained results of LOXO-RAS-20001 were promising making Eli Lilly and Company initiate two global Phase III trials, one in first-line metastatic NSCLC (NCT06119581 [SUNRAY-01]) and the other in early-stage NSCLC (NCT06890598 [SUNRAY-02]), to further evaluate this promising combination.