KRAS mutations occur in as many as 30% of non-small cell lung cancers (NSCLC) and were once considered “undruggable.” However, updated results from the phase 2 KROCUS trial suggest that a first-line combination consisting of the investigational KRAS G12c inhibitor fulzerasib (Dupert) plus the EGFR-targeting antibody cetuximab (Erbitux) is associated with a high and durable objective response rate (ORR) and is well-tolerated.
The updated efficacy and safety analysis from KROCUS was presented on March 27 at the 2025 European Lung Cancer Congress (ELCC), held in Paris, France (Abstract LBA1). “The combination shows the potential to provide a chemo-free treatment option for our patients,” reported Margarita Majem, MD, PhD, from the Hospital de la Santa Creu i Sant Pau in Barcelona, Spain.
80% Objective Response Rate, 100% Disease Control Rate
The single-group, phase 2, open-label trial enrolled patients with pathologically confirmed KRAS G12C–mutated advanced NSCLC who had not previously received systemic therapy for advanced or metastatic disease and had no other known driver mutations. Patients with stable and asymptomatic brain metastases were included.
The patients received oral fulzerasib at 600 mg twice daily, plus intravenous cetuximab at 500 mg/m2 every 2 weeks, until disease progression or intolerable adverse effects.
Initial results from the KROCUS trial were reported at the 2024 American Society of Clinical Oncology annual meeting. Those data showed that as of Jan. 30, 2024, among 27 patients who received the combination (11 of whom had brain metastases), the objective response rate (ORR) was 80% and the disease control rate (including complete and partial responses, as well as stable disease) was 100%. Five of seven patients with brain metastases who were available for posttreatment assessment had a partial response to the fulzerasib/cetuximab combination. Biomarker analyses suggested that responses were similar among patients with either STK11 or KEAP1 comutations.
At ELCC, updated data reported by Dr. Majem showed that after a median follow-up of 12.8 months for 45 evaluable patients treated with the combination, of whom 16 (34%) had brain metastases, the primary endpoint of ORR was 80%, with 26 patients (57.8%) having a 50% or greater tumor shrinkage. The disease control rate remained 100%.
As of mid-January 2025, 24 patients were still receiving treatment, with a median treatment duration of 10.1 months (range, 0.2–18.4 months). Among 20 patients with responses who were followed for at least 12 months, the median duration of response was not reached, the median progression-free survival (PFS) was 12.5 months, and the median overall survival had not been reached.
Updated biomarker analyses showed similar response rates across PD-L1 expression levels, and the investigators reported no significant correlation between responses and EGFR expression levels. Responses were seen in tumors with KEAP1 or STK11 comutations, and response rates were similar between the comutation types.
Although 41 of 47 patients (87.2%) who received at least one dose of the combination had a treatment-related adverse event, only 7 (14.9%) had grade 3 events, with none related to fulzerasib. Three patients (6.4%) had treatment-related adverse events that required discontinuation, and five (10.6) had events that led to dose reductions; four of these five events were related to the KRAS G12c inhibitor.
The most common treatment-related adverse events were rash, asthenia, pruritus, nausea, dyspnea, peripheral edema, diarrhea, acneiform dermatitis, anemia, and pyrexia.
Expert Applauds “Very Impressive” Efficacy With Low Toxicity
Invited discussant Joop de Langen, MD, from The Netherlands Cancer Institute in Amsterdam, called the objective response rate of 80% “very impressive” and noted that the PFS was superior to that seen with the standard of care established by the KEYNOTE-189 trial, which compared pemetrexed and platinum-based chemotherapy with or without pembrolizumab (Keytruda).
“Also outstanding is the low level of grade 3 or higher toxicity,” he said.
