Biomarker Research (Jun 2022)

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

  • Miguel A. Villalona-Calero,
  • John P. Diaz,
  • Wenrui Duan,
  • Zuanel Diaz,
  • Eric D. Schroeder,
  • Santiago Aparo,
  • Troy Gatcliffe,
  • Federico Albrecht,
  • Siddhartha Venkatappa,
  • Victor Guardiola,
  • Sara Garrido,
  • Muni Rubens,
  • Fernando DeZarraga,
  • Hao Vuong

DOI
https://doi.org/10.1186/s40364-022-00386-0
Journal volume & issue
Vol. 10, no. 1
pp. 1 – 11

Abstract

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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.

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