Background: Fulzerasib (GFH925), a KRAS G12C inhibitor, showed substantial efficacy in previously treated NSCLC patients (pts) as monotherapy. Activation of epidermal growth factor receptor (EGFR) is identified to be one of the dominant mechanisms for KRAS inhibition resistance. Preclinical evidence showed synergistic activity in KRAS G12C mutant NSCLC modeling using fulzerasib in combination with cetuximab. Here we report the first results for a KRAS G12C inhibitor combined with an anti-EGFR antibody in NSCLC pts as front-line treatment. Methods: KROCUS (NCT05756153) was an open-label, single-arm, multi-center, Phase II study with the primary objective to evaluate the efficacy of fulzerasib in combination with cetuximab in pts with previously untreated advanced NSCLC harboring KRAS G12C mutation. Secondary objectives included safety/tolerability, pharmacokinetics and biomarkers. Pts were enrolled to receive fulzerasib (oral, 600 mg BID) and cetuximab (intravenous, 500 mg/m², every two weeks [Q2W]) combination treatment in a 28-day cycle. Results: As of Jan. 30, 2024, a total of 27 pts (median age: 68 yrs old; 55.6% female) were treated, 11 (40.7%) with baseline brain metastases. Of 20 pts who had at least one post-treatment tumor assessment, ORR was 80.0% (95% CI: 56.3, 94.3, including one CR), of whom eight pts had ≥ 50% tumor shrinkages in the target lesions. Disease control rate (DCR) was 100% (95% CI: 83.2, 100.0). Five out of seven pts (71.4%) with brain metastases achieved PRs. Nine pts with baseline PD-L1 expression tested (six TPS≥1% and three TPS <1%) all achieved PRs. The overall safety profile of the combination was favorable. Treatment-related adverse events (TRAEs) of any grade occurred in 21 (77.8%) pts. 5 pts (18.5%) experienced G3 TRAEs and no G4 or 5 TRAEs. Three pts (11.1%) had dose reduction/interruption with fulzerasib due to TRAEs but no pts discontinued treatment while one pt (3.7%) had dose reduction/interruption and three (11.1%) discontinued cetuximab due to TRAEs. Table 1 shows the most common TRAEs or G3 TRAEs. Conclusions: The preliminary data from ongoing KROCUS study has demonstrated very promising efficacy and favorable safety profile of fulzerasib + cetuximab in the first line setting of KRAS G12C mutated NSCLC. More data will be generated to provide clinical evidence supporting this combination as a potential frontline therapy. Clinical trial information: NCT05756153.

*Grouped Terms: dermatitis acneiform, rash, perioral dermatitis, and rash pustular.