Background: Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC). KRASG12C, the most frequent KRAS variant, is found in ~13% of patients (pts) with NSCLC. KRAS is a GTPase that regulates cell signaling pathways necessary for proliferation, differentiation, and survival. KRAS mutation reduces the intrinsic GTPase activity of the enzyme, allowing for the accumulation of active, GTP-bound KRAS and hyperactivation of downstream signaling, driving tumorigenesis. JDQ443 is a potent, selective KRAS^G12C inhibitor that irreversibly traps KRAS^G12C in its inactive, GDP bound state and blocks downstream signaling. In preliminary data from the Phase Ib part of the KontRASt-01 study (NCT04699188), JDQ443 showed promising antitumor activity and an acceptable safety profile in previously treated pts with KRAS G12C-mutated advanced NSCLC. Pts with KRAS G12C-mutated NSCLC currently receive the same first-line (1L) treatment as those without driver mutations, consisting of immunotherapy alone or combined with chemotherapy; however, ~30% of pts with NSCLC present with programmed death-ligand 1 (PD-L1) expression <1%, and ~10–20% of pts harbor an STK11 mutation, both indicators of poor response to immunotherapy. Therefore, alternative 1L treatment options are needed for these pts. Of note, PD-L1 expression and STK11 mutation do not affect responsiveness to KRAS^G12C inhibitors, raising interest in the evaluation of these targeted therapies as 1L alternatives to immunotherapy for pts with KRAS G12C-mutated NSCLC. Methods: KontRASt-06 (NCT05445843) is an open-label, Phase II, single-arm, multicenter study evaluating JDQ443 monotherapy (200 mg JDQ443 twice daily in 21-day cycles) as a 1L treatment for 2 cohorts of adult pts with locally advanced or metastatic, KRAS G12C-mutated NSCLC. Cohort A (n=90) includes pts whose tumors have PD-L1 expression <1%, regardless of STK11 mutation status, while Cohort B (n=30) includes pts whose tumors have PD-L1 expression ≥1% and an STK11 co-mutation. Local testing for PD-L1 status and KRAS and STK11 mutations is accepted; KRAS and STK11 mutations may be assessed in blood samples. A tissue sample is required for retrospective biomarker status confirmation and exploratory study. The study is currently enrolling pts into both cohorts. The primary endpoint is the overall response rate (ORR) per RECIST version 1.1, assessed by a blinded independent review committee, in Cohort A. Key secondary endpoints are ORR in Cohort B and duration of response in both cohorts. Other secondary endpoints include progression-free survival, overall survival, safety, pharmacokinetics, and pt-reported outcomes. A comprehensive biomarker strategy aims to investigate predictors of treatment response and resistance in the study population. © 2023 American Association for Cancer Research®. Reused with permission. Clinical trial information: NCT05445843.