Background: KRAS mutations have been associated with poor prognosis in NSCLC and resistance to epidermal growth factor (EGFR) tyrosine kinase inhibitors. FAK represents a therapeutic target in KRAS mutant NSCLC. The RHOA-FAK axis is a critical downstream mediator of RAS signal transduction and FAK inhibition results in growth suppression in KRAS mutant but not KRAS wild type (wt) cancers both in vitro and in vivo. Interestingly, loss of function of the tumor suppressors CDKN2A/INK4a/ARF (p16) and/or p53 appears requisite for efficacy of FAK inhibition in KRAS-driven cancers. Specifically, in vitro and in vivo studies in xenograft and transgenic KRAS mutant NSCLC adenocarcinoma models carrying INK4a/Arf and/or p53 mutant genotypes demonstrated susceptibility to FAK inhibition evidenced by tumor inhibition and prolonged survival. Furthermore, treatment with FAK inhibitors reduces the proportion of cancer stem cells (CSCs) compared to treatment with standard chemotherapy which enriches for CSCs. Defactinib is an oral inhibitor of FAK and proline-rich tyrosine-kinase-2 currently in clinical development in a number of indications including mesothelioma and ovarian cancer. Methods: Pts with KRAS mutant advanced NSCLC (> 1 prior platinum based doublet) are enrolled into 1 of 4 cohorts (A-D): wt INK4a/Arf, wt p53 (A); INK4a/Arf mutation, wt p53 (B); wt INK4a/Arf, p53 mutation (C), or INK4a/Arf mutation, p53 mutation (D). Defactinib is administered continuously at 400 mg PO BID in 21 day cycles until disease progression. The primary endpoint is the Progression Free Survival (PFS) rate at week 12. In the Simon 2 stage design, if ≥ 4 of 11 pts have PFS at week 12, enrollment in that cohort will be expanded to a total of 34 pts. PFS at 12 weeks of ≥ 50% will be deemed clinically important and ≤ 25% will be deemed not clinically valuable. Response rate (RR), PFS, overall survival (OS), and comparisons between Cohort A to B, C, and D will also be measured. Associations between pharmacodynamic biomarkers (including pFAK) and clinical outcomes (RR, PFS, OS) will be evaluated. The study is currently enrolling at 8 US centers. Clinical trial information: NCT 01951690.