Fanconi anemia repair pathway as a predictor of anti-tumor activity of pembrolizumab: interim analysis of open-label, single-arm phase II trial

Objectives: Pembrolizumab, an antibody targeting PD-1, has moderate efficacy in biomarker-unselected gynecologic cancers. We aimed to assess the Fanconi Anemia pathway (FA) homologous recombination repair and solid tumor response to pembrolizumab. Methods: We conducted a phase 2 trial of pembrolizumab in solid tumor patients progressing on standard of care and for whom pembrolizumab had no FDA approved indication. We evaluated a triple-stain (FANCD2foci/DAPI/Ki67) immunofluorescence functional assay of FA (FATSI) that we developed in treated patients’ archived tumors as a correlative biomarker. Patients with microsatellite unstable tumors were not eligible. The primary objective was objective response rate by immune-related Response Evaluation Criteria In Solid Tumors (irRECIST). Secondary objectives were progression-free survival (PFS), and 20-weeks PFS. Pembrolizumab was given every 3 weeks and computed-tomography scans were performed every 6 weeks. We utilized a two-stage phase II trial design to detect an iORR ≥20% in the whole population vs the null hypothesis of an iORR ≤5%. The iORR was expected ≥40% in patients with functional FA deficiency (FATSI negative) and Download : Download high-res image (74KB) Download : Download full-size image Results: A total of 52 patients were enrolled, of which 38 patients had a primary gynecologic malignancy. A total of 20 (53%) patients had endometrial, 13 (34%) had ovarian, 2 (5%) had cervical, 2 (5%) had vaginal, 1 (3%) had vulvar cancer respectively. No unexpected toxicities occurred. Response evaluation showed 3CR, 5PR, 9SD, 21PD with an iORR 21%. FATSI analyses in 36 patients showed 24 FATSI positive and 12 negative. A total of 2CR, 1PR, 5SD, 16PD occurred among the FATSI (+) (iORR 12%) and 1CR, 4PR, 2SD, 5PD among the FATSI (-) patients (iORR 42%). The median PFS for the FATSI negative group was 7.0 months, compared to 3.0 months for the FATSI (+) group, p=0.037). Conclusions: Pembrolizumab demonstrated antitumor activity in advanced recurrent gynecologic malignancies with no current FDA approved indications. The results support evaluation of FATSI as a discriminatory biomarker for population-selected future studies.