A phase II study of stereotactic body radiotherapy and focal adhesion kinase inhibitor in advanced pancreatic adenocarcinoma.

740 Background: There are limited treatment options for pts with borderline resectable (BRPC) and locally advanced (LAPC) pancreatic ductal adenocarcinoma (PDAC). Stereotactic body radiation therapy (SBRT) permits ablative radiation dosing in fewer treatments, which may spare radiation depletion of immune cells. Focal adhesion kinase (FAK) is implicated in cancer cell proliferation, survival and pathologic fibrosis. FAK inhibition may mitigate the fibrotic and immunosuppressive tumor microenvironment of PDAC, and combined with ablative radiation, improve oncologic outcomes. Methods: BRPC and LAPC pts with stable or responding disease after at least 3 months of induction chemotherapy were treated on a prospective, single-arm, phase II trial, with SBRT plus concurrent and adjuvant defactinib (FAK inhibitor, Verastem). Treatment entailed online adaptive SBRT 50 Gy in 5 fractions with concurrent and adjuvant defactinib starting on day 2 of SBRT, for up to 12 months or progression. Defactinib was prescribed 400 mg PO BID in 21-day cycles. The primary endpoint was progression-free survival (PFS). Secondary endpoints included toxicity, local control (LC), distant metastasis (DM)-PFS, and overall survival (OS). Exploratory endpoints included tumor immune cell infiltration and fibrosis in tumor microenvironment. Pts were randomized 6:1 to include a control cohort of 6 pts treated with SBRT alone and included in the toxicity and correlatives analysis. Results: Induction chemotherapy prior to enrollment included FOLFIRINOX (75%), gemcitabine/nab-paclitaxel (22%) and NALIRIFOX (3%). Of the 42 treated pts, 36 received SBRT plus defactinib (experimental arm evaluable for primary endpoint) and 6 received SBRT only. Most of the experimental arm was male (58%), with LAPC (78%) and a median age of 69 (range 55-83). At a median follow-up of 18 months, the 1-year PFS, LC, DM-PFS and OS was 71% 57-88, 80% 67-94, 76% 63-92, and 94% 85-100, respectively. Pts that received SBRT and defactinib without surgery (86%) had improved OS compared to those treated with SBRT, defactinib and surgical resection (p=0.02). Acute grade 3 toxicity included lymphopenia (6%) and hepatic enzyme elevation (6%). Late grade 3 effects included abdominal cramping (3%), hematemesis (3%) while on anticoagulation, lymphopenia (6%), hepatic enzyme elevation (6%), anemia (9%), and fatigue (3%). There were no grade 4+ toxicities. Analysis of pre- and post-treatment tumor biopsy tissues by single cell RNA sequencing showed on-target repression of the FAK pathway and induction of several signatures indicative of immune activation in both PDAC and tumor infiltrating immune cells. Conclusions: SBRT plus concurrent and adjuvant FAK-inhibition with defactinib is well tolerated and may improve oncologic outcomes in BRPC and LAPC pts, with or without surgical resection. Clinical trial information: NCT04331041 .