Assessment of the Fanconi anemia repair pathway as a predictor of clinical activity of pembrolizumab (PEM)

Abstract only 2555 Background: Given the activity of immune checkpoint inhibitors (ICI) in mismatch repair deficient tumors, we evaluated if homologous recombination repair deficiency associates with solid tumor response to ICI. Methods: We conducted a phase 2 trial (NCT03274661) of PEM in metastati...

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Published in:	Journal of clinical oncology Vol. 37; no. 15_suppl; p. 2555
Main Authors:	Villalona-Calero, Miguel Angel, Diaz, John Paul, Diaz, Zuanel, Duan, Wenrui, Schroeder, Eric Douglas, Aparo, Santiago, Gatcliffe, Troy Antony, Alonso, Alfredo Pedro, Cuitiva, Sebastian, Albrecht, Federico, Venkatappa, Siddhartha A., Guardiola, Victor, Troner, Michael B., Garrido, Sara M., Walker, Gail, Rubens, Muni, De Zarraga, Fernando I., Vuong, Hao
Format:	Journal Article
Language:	English
Published:	20-05-2019
Online Access:	Get full text
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Summary:	Abstract only 2555 Background: Given the activity of immune checkpoint inhibitors (ICI) in mismatch repair deficient tumors, we evaluated if homologous recombination repair deficiency associates with solid tumor response to ICI. Methods: We conducted a phase 2 trial (NCT03274661) of PEM in metastatic solid tumor patients progressing on standard of care and for whom PEM had no FDA approved indication. We evaluated a triple stain (FANCD2foci/DAPI/Ki67) immunofluorescence functional assay of the Fanconi Anemia pathway (FATSI) in treated patients’ archived tumors as a correlative biomarker. Patients with microsatellite unstable tumors were not eligible. The primary objective was objective response rate (iORR, CR+PR) by Immune Response Criteria, with the hypothesis that patients with FATSI negative tumors will have better clinical outcome. Secondary objectives were progression free survival (PFS), 6 months PFS and survival. PEM 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 tested vs. the null hypothesis that the true iORR ≤5%. If ≥ 2 of the first 20 evaluable patients had an objective response the trial proceeded to full accrual of 39 evaluable patients. Outcomes were evaluated according to FATSI staining. Results: 42 patients (40 evaluable) (35F,7M; median age 62[36-83]) enrolled. Median # of prior regimens was 2[1-7]. Primary Dx included ovarian/fallopian (13), endometrial (10), colorectal (3), cervix (2), pancreatic(2), vaginal (2) and 1 each of various others. No unexpected toxicities occurred. Response evaluation showed 2 CR, 5 PR, 11 SD, 22 PD and 2 NE (iORR 18%). FATSI tumor analyses results are available in 34 patients; 25 FATSI positive, 9 negative. 2 PR, 8 SD, 14 PD, 1 NE occurred among the FATSI (+) (iORR 8%) and 2 CR, 2 PR, 2 SD, 3 PD among the FATSI (-) patients (iORR 44%). mPFS and 6m-PFS were 54 days and 12% (3/25) in FATSI (+), versus 248 days and 56% (5/9) in FATSI (-) patients; p = 0.017. Conclusions: PEM has meaningful antitumor activity in non MSI-high malignancies with no current FDA approved indications. Evaluation of FATSI as a biomarker supports a biomarker selected population approach. Clinical trial information: NCT03274661.
ISSN:	0732-183X 1527-7755
DOI:	10.1200/JCO.2019.37.15_suppl.2555