Background: Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequent mutated oncogene in non-small cell lung cancer (NSCLC). KRASG12C is the most common KRAS variant, present in ~13% of patients (pts) with non-squamous NSCLC. KRASG12C mutations cause the accumulation of active, GTP-bound KRAS, which leads to activation of downstream pathways involved in cell proliferation and invasiveness. JDQ443 is a potent, structurally novel, selective KRAS^G12C inhibitor that irreversibly traps KRAS^G12C in its inactive, GDP-bound form. Data from the JDQ443 monotherapy arm of the first-in-human KontRASt-01 study demonstrated encouraging anti-tumor activity and an acceptable safety profile of JDQ443 in pts with previously treated, KRAS G12C-mutated, advanced NSCLC. For pts with advanced NSCLC who progress following first-line immunotherapy or doublet platinum-based chemotherapy, single agent docetaxel remains a standard option, although it presents modest activity and is generally poorly tolerated. In this context, alternative treatment options are needed to improve pt outcomes. Methods: KontRASt-02 (NCT05132075) is a global, Phase III, open-label, randomized, multicenter study evaluating JDQ443 as a monotherapy in comparison to docetaxel in pts with KRAS G12C-mutated, advanced NSCLC previously treated with PD-(L)1 inhibitors and platinum-based chemotherapy (either in combination or as sequential treatments). Approximately 360 pts stratified by ECOG performance status (0 vs 1 and 2) and prior therapy (platinum-based chemotherapy and immunotherapy combined vs sequential) will be randomized at 1:1 to receive 200 mg oral JDQ443 twice daily continuously or 75 mg/m² intravenous docetaxel once every 21 days. The primary endpoint of this study is progression-free survival (PFS) per Blinded Independent Review Committee (BIRC) according to RECIST version 1.1. The key secondary endpoint is overall survival (OS); other secondary endpoints include objective response rate, disease control rate, time to response, duration of response, PFS on subsequent therapy, safety of JDQ443 monotherapy, pt-reported outcomes, pharmacokinetics, time to deterioration of ECOG performance status, and safety in pts who crossover from docetaxel to JDQ443. Exploratory objectives include biomarker analyses aimed at investigating predictors of responsiveness to JDQ443. Pts randomized to docetaxel will be allowed to crossover to JDQ443 following confirmed disease progression per BIRC. To allow more pts to be treated with JDQ443, crossover will also be offered to all patients on docetaxel if the primary endpoint (PFS) is met. Treatment beyond progression will be allowed for pts receiving JDQ443 according to investigator judgement. The KontRASt-02 study is currently enrolling pts. Clinical trial information: NCT05132075.