Background: KRAS mutations (mt) occur in ~30% of lung adenocarcinomas, among which G12C is most common (40%), followed by G12V (22%) and G12D (16%). Approved treatments for advanced KRAS mt NSCLC (excluding G12C) are limited to chemotherapy and immune checkpoint inhibitors (ICIs). Avutometinib is a novel small molecule RAF/MEK clamp. Focal adhesion kinase (FAK) activation is a resistance mechanism to RAF/MEK inhibition. Defactinib, a small molecule FAK inhibitor, has shown synergistic antitumor activity with avutometinib in preclinical models. In prior studies, avutometinib ± defactinib has shown responses in patients (pts) with KRAS mt NSCLC, including KRAS G12V. Methods: RAMP 202 is a randomized, phase 2, adaptive, multicenter, open-label study evaluating the efficacy and safety of avutometinib ± defactinib in previously-treated KRAS mt NSCLC (NCT04620330). Key inclusion criteria include histologically confirmed NSCLC with known KRAS mt and ≥1 prior systemic therapy (platinum-based and immune checkpoint inhibitor or appropriate therapy for activating mutation). Part A evaluated the optimal regimen, either 4.0 mg avutometinib orally (PO), twice weekly, 3 weeks on, 1 week off (mono) or 3.2 mg avutometinib PO twice weekly + 200 mg defactinib PO twice per day, 3 weeks on, 1 week off (combo) in pts with KRAS G12V mt NSCLC. Primary endpoint was confirmed objective response rate (ORR) by blinded independent central review. The optimal regimen determined in Part A would subsequently be assessed for efficacy in Part B. Exploratory assessment of ORR is also planned in KRAS-other (non-G12V) NSCLC. Results: Of 35 pts with KRAS G12V enrolled to Part A, 16 pts received mono, and 19 received combo. Patients received up to 5 lines of prior systemic therapy (median 2), including prior platinum-based chemotherapy, ICIs, and bevacizumab. No confirmed responses were seen in the mono group. In the combo group, 2 pts (11%) experienced a confirmed partial response. The duration of each response was 7.9 and 8.5 months, with both ongoing at data cut. The majority of treatment-related adverse events (TRAEs, any grade) (N = 72) were mild to moderate. The most common Grade ≥3 TRAEs included blood CPK increase (11.1%), diarrhea (5.6%), anemia (5.6%), and rash (1.4%). Most AEs were manageable/reversible. Conclusions: In this heavily pretreated population of patients with KRAS G12V mt NSCLC, limited clinical activity was observed with combination therapy. While no new safety signals were identified, criteria to proceed to part B were not met, and further evaluation of avutometinib ± defactinib in KRAS G12V mt NSCLC will not be pursued. Additional trials evaluating rational avutometinib combinations (sotorasib, adagrasib, everolimus) are ongoing in patients with KRAS mt NSCLC. Clinical trial information: NCT04620330.