Olomorasib Combo Elicits Favorable Efficacy in NSCLC

In the first-line setting, the combination of olomorasib (LY3537982; 50 or 100 mg) plus pembrolizumab (Keytruda) elicited a 77% overall response rate (ORR) and promising antitumor activity, regardless of PD-L1 expression, in patients with KRAS G12C–mutated metastatic non–small cell lung cancer (NSCLC). These data are from the phase 1/2 LOXO-RAS-20001 study (NCT04956640) presented by Yutaka Fujiwara, MD, PhD, at the 2024 American Society of Clinical Oncology (ASCO) Breakthrough meeting held from August 8 to 10, 2024, in Yokohama, Japan.¹

“Olomorasib, a highly selective second-generation KRAS G12C inhibitor, has demonstrated a favorable safety profile and promising efficacy across multiple tumor types. Here we report outcomes of olomorasib plus pembrolizumab in patients with NSCLC,” Fujiwara, primary director at the Aichi Cancer Center in Nagoya and director of Mitsui Memorial Hospital in Tokyo, both in Japan, said during the ASCO Breakthrough meeting presentation.

The LOXO-RAS-20001 study includes dose-escalation and dose-expansion phases for olomorasib, both as a standalone treatment and in combination with other therapies, across various tumor types, including NSCLC. In the presentation, Fujiwara focused on 2 specific cohorts receiving olomorasib in combination with pembrolizumab. Part B4 (n = 43) involved patients with NSCLC who had previously undergone chemotherapy, immunotherapy, or treatment with other KRAS G12C inhibitors, and Part G (n = 17) included patients with NSCLC who had no prior therapy. “In this analysis, we examined 2 dose levels of olomorasib, 50 mg and 100 mg, administered twice daily,” Fujiwara said.

At the data cutoff of March 18, 2024, for those who received prior treatment in part B4, the ORR was 40%. Partial response occurred in 13% of patients in part G and 17% of patients in part B4. The median time to response was 1.4 months; however, the median duration of response was not evaluated. The disease control rate was 88% and 81%, respectively. The median progression-free survival (PFS) was not estimable (NE; 95% CI, 3.6-NE), the PFS rate in Part G at 6 and 12 months was 72.8%, and the median follow-up was 5.5 months. For all patients, the median time on treatment was 3.5 months (range, 0-17).

Across both cohorts, the median age was 67 years (range, 42-83), and the majority of patients were men (53%). Races included were White (47%), Asian (27%), and Black or African American (5%). In addition, there were 21% of patients whose races were unreported.

In part B4, 81% of patients had previously received immunotherapy and the median number of prior systemic therapies was 2 (range, 0-8). Overall, 69% of patients were pretreated: 82% with a platinum-based chemotherapy/anti–PD-L1 therapy, 18% with platinum-based chemotherapy alone, and 39% with a KRAS G12C inhibitor. The reason for discontinuing recent KRAS G12C inhibitor therapy was due to progressive disease (76%), toxicity (18%), or other reason (6%).

The overall key objectives of the trial were safety and tolerability.

Eligible patients in the phase 1a/b portion of the study were 18 years or older and had an ECOG performance score of 0 or 1, measurable disease per RECIST v1.1, a locally advanced solid tumor, and a KRAS G12C mutation. Eligible patients in part B4 could have received prior chemotherapy, anti–PD-(L)1 therapy, and KRAS G12C inhibitor therapy. Eligible patients for part G could have no prior therapy for metastatic disease.

The most common adverse events (AEs) of any grade that emerged during treatment vs those related to treatment were diarrhea (28% vs 23%), fatigue (27% vs 16%), and increased alanine aminotransferase (ALT) level (25% vs 20%). For grade 3, they were diarrhea (13% vs 13%), ALT level increase (8% vs 6%), and pruritus (3% vs 3%).

“Given these promising results, we are currently conducting a global registrational trial called SUNRAY-01 [NCT06119581],” Fujiwara said. In this study, investigators will further assess the combination of olomorasib and pembrolizumab therapy in the first line with the addition of chemotherapy vs no chemotherapy in patients with KRAS G12C–mutated advanced NSCLC.

REFERENCE:

Fujiwara Y, Burns T, Dragnev K, et al. Efficacy and safety of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in combination with pembrolizumab in patients with KRAS G12C-mutant advanced NSCLC. American Society of Clinical Oncology Breakthrough; August 8-10, 2024; Yokohama, Japan.