KRAS-mutant advanced NSCLC responds to fulzerasib–cetuximab combo

First-line treatment with the combination of fulzerasib and cetuximab appears to induce deep and durable responses in patients with advanced nonsmall cell lung cancer (NSCLC) harbouring KRAS G12C mutation, in addition to having a favourable safety profile, according to the results of the phase II, open-label, single-arm KROCUS trial.

Over a median follow-up of 12.8 months, the primary endpoint of objective response rate (ORR) was 80 percent, with a confirmed ORR of 68.9 percent, reported first study author Dr Margarita Majem from the Hospital de la Santa Creu i Sant Pau in Barcelona, Spain. [ELCC 2025, abstract LBA1]

The disease control rate (DCR) was 100 percent, and more than half of the patients (57.8 percent) had at least a 50-percent tumour shrinkage.

Majem noted that 10 out of 14 patients with brain metastases achieved systemic response per RECIST 1.1 (ORR, 71.4 percent). Nontarget lesions either disappeared or were stable, and brain target lesions in all five patients shrank during the treatment.

At data cutoff, 24 out of 47 patients were still on treatment. The median duration of treatment was 10.1 months. Over a median follow-up of 12.8 months, the median duration of response was not reached, while the median progression-free survival was 12.5 months.

Response seen across subgroups

In biomarker analyses, Majem and colleagues saw similar response rates across PD-L1 subgroups and found no correlation between response to treatment with fulzerasib plus cetuximab and EGFR expression.

The confirmed ORRs were 57.1 percent, 62.5 percent, and 75.0 percent in patients with baseline PD-L1 tumor proportion score (TPS) expression of <1 percent (n=14), 1 percent to 49 percent (n=8), of at least 50 percent (n=12), respectively. The confirmed ORRs in those with baseline EGFR H scores of <200 (n=19) or at least 200 (n=13) were 68.4 percent and 76.9 percent, respectively.

Additionally, most patients with STK11 or KEAP1 co-mutations responded to the fulzerasib plus cetuximab combination, Majem noted.

The confirmed ORRs were 62.5 percent in patients with KRAS G12C and STK11 co-mutation (n=8) and 66.7 percent in those with a KRAS G12C and KEAP1 co-mutation (n=3).

Good safety profile

“[Fulzerasib plus cetuximab had a] good safety profile. Most treatment-related (TRAEs) were grade 1 or 2, with no new safety signals,” Majem said.

At least one TRAE occurred in 87.2 percent of the patients, including grade 3 TRAEs in 14.9 percent. Meanwhile, 4.3 percent of patients had at least one serious TRAE, none of which were related to fulzerasib.

The most common TRAEs were rash (53 percent), pruritus, (32 percent), nausea (26 percent), asthenia (26 percent), dermatitis acneiform (19 percent), and diarrhoea (13 percent).

TRAEs led to treatment discontinuation in 6.4 percent of patients, dose reduction in 10.6 percent, and dose interruption in 27.7 percent.

Taken together, the efficacy and safety findings of KROCUS highlight the potential of the combination of a KRAS G12C inhibitor and an anti-EGFR antibody to provide a chemo-free treatment option for NSCLC patients who are treatment-naïve, according to Majem. Planning is underway for a phase III study in patients with PD-L1 expression below 50 percent, she added.

KROCUS population

The trial included 47 patients who had a pathologically confirmed KRAS G12C-mutated advanced NSCLC, had not previously received systemic treatment for advanced or metastatic lesions, and had an Eastern Cooperative Oncology Group performance status of 0-1. Patients with stable and asymptomatic brain metastases were allowed, whereas those with other known actionable driver mutations or alterations were excluded.

All patients received 600 mg of fulzerasib twice daily plus 500 mg/m² of cetuximab every 2 weeks. Treatment lasted until disease progression, intolerable toxicity, or other withdrawal criteria were met. ORR and PFS were evaluated based on RECIST 1.1 criteria.

The median age of the patients at baseline was 68 years, 53.2 percent were male, and 95.7 percent were White. Most patients had stage IVa disease (53.2 percent) and had adenocarcinoma (97.9 percent). A total of 34.0 percent of patients had brain metastasis.