Olomorasib Plus Pembrolizumab Shows Promise in KRAS G12C-Mutated NSCLC
核心洞察
Olomorasib combined with pembrolizumab demonstrated a 77% overall response rate in first-line NSCLC (搜索) patients with KRAS G12C (搜索) mutations, regardless of PD-L1 expression.
In previously treated NSCLC (搜索) patients, the combination therapy achieved a 40% overall response rate and an 88% disease control rate.
Common adverse events included diarrhea, fatigue, and increased ALT levels, with manageable safety profiles observed across both cohorts.
The combination of olomorasib (LY3537982) and pembrolizumab (Keytruda) has shown promising antitumor activity in patients with KRAS G12C-mutated metastatic non-small cell lung cancer (NSCLC (搜索)). The phase 1/2 LOXO-RAS-20001 study (NCT04956640), presented at the 2024 ASCO Breakthrough meeting, revealed a 77% overall response rate (ORR) in the first-line setting, regardless of PD-L1 expression.
Yutaka Fujiwara, MD, PhD, primary director at the Aichi Cancer Center in Nagoya and director of Mitsui Memorial Hospital in Tokyo, Japan, highlighted the favorable safety profile and efficacy of olomorasib, a second-generation KRAS G12C (搜索) inhibitor, across multiple tumor types.
The LOXO-RAS-20001 study included dose-escalation and dose-expansion phases, evaluating olomorasib as a monotherapy and in combination with other treatments. The presentation focused on two cohorts receiving olomorasib plus pembrolizumab: Part B4 (n = 43), for patients previously treated with chemotherapy, immunotherapy, or other KRAS G12C (搜索) inhibitors, and Part G (n = 17), for treatment-naive patients. Two dose levels of olomorasib (50 mg and 100 mg twice daily) were examined.
Efficacy Data
At the data cutoff of March 18, 2024, the ORR in previously treated patients (Part B4) was 40%. Partial responses were observed in 13% of patients in Part G and 17% in Part B4. The median time to response was 1.4 months. The disease control rate was 88% and 81% for Parts G and B4, respectively. The median progression-free survival (PFS) was not estimable (NE; 95% CI, 3.6-NE) in Part G, with a 6- and 12-month PFS rate of 72.8%. The median follow-up was 5.5 months. The median time on treatment for all patients was 3.5 months (range, 0-17).
Patient Characteristics
The median age across both cohorts was 67 years (range, 42-83), with a majority of male patients (53%). The study population included White (47%), Asian (27%), and Black or African American (5%) patients, with 21% unreported.
In Part B4, 81% of patients had prior immunotherapy, and the median number of prior systemic therapies was 2 (range, 0-8). Specifically, 69% were pretreated with platinum-based chemotherapy/anti-PD-L1 therapy (82%), platinum-based chemotherapy alone (18%), and a KRAS G12C (搜索) inhibitor (39%). Progressive disease (76%) was the primary reason for discontinuing prior KRAS G12C inhibitor therapy, followed by toxicity (18%).
Safety and Tolerability
The primary objectives of the trial included assessing safety and tolerability. Eligible patients had an ECOG performance score of 0 or 1, measurable disease per RECIST v1.1, a locally advanced solid tumor, and a KRAS G12C (搜索) mutation. Patients in Part B4 could have received prior chemotherapy, anti-PD-(L)1 therapy, and KRAS G12C inhibitor therapy, while those in Part G were treatment-naive for metastatic disease.
The most common adverse events (AEs) of any grade were diarrhea (28%), fatigue (27%), and increased alanine aminotransferase (ALT) level (25%). Grade 3 AEs included diarrhea (13%), ALT level increase (8%), and pruritus (3%).
Ongoing Research
Fujiwara announced the ongoing global registrational trial, SUNRAY-01 (NCT06119581), which will further evaluate olomorasib and pembrolizumab with or without chemotherapy in first-line patients with KRAS G12C-mutated advanced NSCLC (搜索).