Pembrolizumab activity in patients with Fanconi anemia repair pathway competent and deficient tumors

• Main Authors: Miguel A. Villalona-Calero (Author), John P. Diaz (Author), Wenrui Duan (Author), Zuanel Diaz (Author), Eric D. Schroeder (Author), Santiago Aparo (Author), Troy Gatcliffe (Author), Federico Albrecht (Author), Siddhartha Venkatappa (Author), Victor Guardiola (Author), Sara Garrido (Author), Muni Rubens (Author), Fernando DeZarraga (Author), Hao Vuong (Author)
• Format: Book
• Published: BMC, 2022-06-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.1186/s40364-022-00386-0; 2050-7771
• Keywords: FancD2; Homologous recombination; Immune checkpoint inhibitor; Biomarkers; DNA repair; Fanconi; Therapeutics. Pharmacology; RM1-950
• Source: Biomarker Research, Vol 10, Iss 1, Pp 1-11 (2022)

Abstract Background Given the observed antitumor activity of immune-checkpoint-inhibitors in patients with mismatch-repair deficient (MSI-H) tumors, we hypothesized that deficiency in homologous-recombination-repair (HRR) can also influence susceptibility. Methods Patients with disease progression on standard of care and for whom pembrolizumab had no FDA approved indication received pembrolizumab. Patients with MSI-H tumors were excluded. Objectives included immune-related objective response rate (iORR), progression-free survival (PFS) and 20-weeks-PFS. Pembrolizumab was given every 3 weeks and scans performed every six. We evaluated a triple-stain (FANCD2foci/DAPI/Ki67) functional assay of the Fanconi Anemia (FA) pathway: FATSI, in treated patients' archived tumors. The two-stage sample size of 20/39 patients evaluated an expected iORR≥20% in the whole population vs. the null hypothesis of an iORR≤5%, based on an assumed iORR≥40% in patients with functional FA deficiency, and < 10% in patients with intact HRR. An expansion cohort of MSI stable endometrial cancer (MS-EC) followed. Exploratory stool microbiome analyses in selected patients were performed. Results Fifty-two patients (45F,7M;50-evaluable) were enrolled. For the 39 in the two-stage cohort, response evaluation showed 2CR,5PR,11SD,21PD (iORR-18%). FATSI tumor analyses showed 29 competent (+) and 10 deficient (−). 2PR,9SD,17PD,1NE occurred among the FATSI+ (iORR-7%) and 2CR,3PR,2SD,3PD among the FATSI(−) patients (iORR-50%). mPFS and 20w-PFS were 43 days and 21% in FATSI+, versus 202 days and 70% in FATSI(−) patients. One PR occurred in the MS-EC expansion cohort. Conclusions Pembrolizumab has meaningful antitumor activity in malignancies with no current FDA approved indications and FA functional deficiency. The results support further evaluation of FATSI as a discriminatory biomarker for population-selected studies.