A phase II study of talazoparib plus avelumab in patients with stage IV or recurrent nonsquamous non–small cell lung cancer bearing pathogenic STK11 genomic alterations (SWOG S1900C, LUNG-MAP sub-study, NCT04173507).
Authors: Skoulidis Ferdinandos , Redman Mary Weber , Suga Jennifer Marie , Al Baghdadi Tareq , Villano John L. , Goldberg Sarah B. , Villaruz Liza C , Minichiello Katherine , Gandara David R. , Herbst Roy S. , Kelly Karen 
Published: June 2022

9060 Background: Inactivating STK11 genomic alterations are prevalent in non-squamous (nsq) NSCLC and define a patient (pt) subgroup with poor prognosis and inferior response to immune checkpoint inhibitors (CPIs). PARP inhibitors (PARPi) can potentiate response to CPIs in preclinical models. We conducted a single arm Phase II study within Lung-MAP to evaluate the efficacy and safety of talazoparib in combination with avelumab in patients (pts) with previously treated nsq NSCLC harboring pathogenic STK11 genomic alterations. Methods: Eligibility: STK11 pathogenic somatic mutation or bi-allelic loss on tumor identified via LUNGMAP screening; stage IV or recurrent nsq NSCLC, receipt of one prior line of anti-PD-1/anti-PD-L1 therapy and platinum-based chemotherapy for stage IV or recurrent disease (sequentially or in combination) and disease progression > 42 days following treatment initiation, a ECOG PS of 0-1, adequate organ function and no previous PARPi exposure. Pts received talazoparib (1000 mg PO daily) plus avelumab (800 mg IV Q2W). Co-primary objectives were to evaluate the best objective response rate (ORR) and disease control rate at 12 weeks (DCR12) after study registration, assessed by RECISTv1.1. Rejection of an ORR of 10% required ≥ 8 responses or rejection of a DCR12 of 30% required ≥18 w/ disease control at 12 weeks and ≥4 responses. Results: 47 pts enrolled from January 16 - November 16, 2020; 42 pts met eligibility (50% male, 50% female). 54% of pts had PD-L1 TPS < 1%. The median TMB was 8.83 Mut/Mb and 45% of pts had KRAS mutations. 52% of the pts had received ≥2 prior lines of treatment for stage IV disease. As of the November 24, 2021 data cutoff, 3 pts remain on treatment, the ORR was 2% (n = 1) and the DCR12 was 40% (n = 17). 26 pts (62%) had SD as best objective response. One responding pt remained on treatment for > 14 mo. The median progression-free survival (39 events) was 2.7 mo (95% CI, 1.6-3.9 mo) and the median overall survival (30 events) was 7.6 mo (95% CI, 6.3-12.2 mo). There were no reported grade 5 treatment toxicities and most grade 3-4 toxicities were hematologic. Additional biomarker analysis to assess effects of key co-mutations on clinical outcomes will be presented. Conclusions: Treatment with talazoparib and avelumab did not meet the pre-specified threshold for efficacy in previously treated STK11-mutant NSCLC in this biomarker-driven Phase II study, though durable disease stabilization was observed. Further studies are required to determine optimal therapeutic approaches for this challenging subset of NSCLC pts. Funding: NIH/NCI grants U10CA180888, U10CA180819. Talazoparib was provided by Pfizer. Avelumab was provided by Pfizer, as part of an alliance between Pfizer and the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100004755). Clinical trial information: NCT04173507.