A Randomized Phase 2 Study of Pembrolizumab With or Without Radiation in Patients With Recurrent or Metastatic Adenoid Cystic Carcinoma

Abstract

Purpose: We evaluated the safety and efficacy of pembrolizumab (pembro) ± radiation therapy (RT) in a phase 2 study among patients with progressive, metastatic adenoid cystic carcinoma (ACC).

Methods and materials: Eligible patients had metastatic ACC with progression within the last year and ≥1 measurable lesion. Patients were randomized to pembro alone or with RT to 30 Gy in 5 fractions (pembroRT). The primary endpoint was objective response rate outside the RT field. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and local RT responses.

Results: We randomized 20 patients (10 per arm) from 2017 to 2018. We did not observe objective response outside of the radiation treatment field; stable disease (SD) was the best response in 12 (60%) patients and was not different per arm (7 pembro, 5 pembroRT, P = .65). A tumor growth rate decrease (TGR) of >25% was noted among 7 of 12 patients and >75% in 4 patients. There were local responses in the irradiated field among all evaluable pembroRT patients. Median PFS and OS were 4.5/not reached for pembroRT and 6.6 / 27.2 months for pembro patients. One patient developed grade 3 liver enzyme elevation after 27 cycles of therapy. Correlative analyses confirm low levels of programmed death-ligand 1 expression (PD-L1), and CD8 infiltrating T-cells. We identified associations between local response and both MYB/NFIB translocation and PD-L1 expression and between changes in systemic immune populations and RT.

Conclusions: Pembrolizumab and pembroRT were well tolerated. We observed no objective responses, but 60% of patients with PD before the study achieved SD, the majority with decreased TGR and half (n = 10) with clinical benefit (SD >6 months). We observed favorable local responses within the RT field. Additional strategies are needed to further delay progression and effect response.

Trial registration: ClinicalTrials.gov NCT03087019.

Conflict of interest statement

Disclosures: A.B. reports honoraria from AstraZeneca. N.G.C. reports research support paid to the institution: Merck, Pfizer, and GSK; consulting/honoraria: Bayer, Eisai, and Roche. R.H.M. reports research support paid to the institution: ViewRay Inc. J.H.L. reports consulting (advisory board): Genentech, Bayer, and Novartis; research support to institution: Novartis, Bayer, Takeda, and BMS. G.J.H. receives research support to institution from: BMS, Exicure, GSK, NantKwest, Kite, Regeneron, Sanofi Genzyme, Kartos, and the ASCO Conquer Cancer and V Foundations; consulting/honoraria: Regeneron, Sanofi Genzyme, Maverick, Merck, Kura, Bio-Rads, and Prelude. M.N. reports consultant to Daiichi Sankyo and AstraZeneca; research grant from Merck, Canon Medical Systems, AstraZeneca, and Daiichi Sankyo; honorarium from Roche. V.S. reports consulting fees from: Tango Therapeutics and Slate Path Capital. S.I.P. reports consulting/scientific advisory board: Abbvie, AstraZeneca, Cue Biopharma, Fusion Pharmaceuticals Inc., Merck Serono, Newlink Genetics, Oncolys BioPharma, Replimmune, and Sensei Bio; grant/research support: Abbvie, AstraZeneca, Cue Biopharma, and Tesaro. L.J.W. reports data safety monitoring board member: PDS Biotechnology; consultant for: Bayer Healthcare, Blueprint Medicines, Eisai Inc, Eli Lilly and Company, Exelixis, Genentech Inc, Merck & Co Inc, Ayala Pharmaceuticals, CUE Biopharma, Loxo Oncology, and Rakuten Medical. J.D.S. reports research support paid to the institution: Merck, BMS, and Regeneron; consulting/scientific advisory board/travel fees from: Debiopharm, BMS, Nanobiotix, Tilos, AstraZeneca, LEK, Catenion, ACI Clinical, and Immunitas; expert witness fees. R.I.H. reports consulting fees from BMS, Merck, Pfizer, Kura, Eisai, Celgene, Genentech, Astra Zeneca, GSK during the conduct of the study as well as research grants to the institution from BMS, Merck, Pfizer, Genentech, Astra Zeneca and GSK.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Fig. 1.

Decrease in tumor measurements from baseline (RECIST criteria). Patients treated with pembrolizumab and radiation are shown in blue and pembrolizumab-only patients are shown in red. (A color version of this figure is available at https://doi.org/10.1016/j.ijrobp.2020.08.018.)

Fig. 2.

(A) Progression-free survival (radiation/pembrolizumab arm is denoted by the solid line, pembrolizumab only the dotted line). (B) Overall survival (radiation/pembrolizumab arm is denoted by the solid line, pembrolizumab only by the dotted line).

Fig. 3.

(A) Percent change in tumor growth rate (TGR) on protocol compared with prior protocol treatment. (B) Best local response in irradiated lesions in patients treated with pembrolizumab/radiation (dotted line represents 50% best overall response).

Fig. 4.

Case of likely pseudoprogression within irradiated liver metastases. Baseline scan from July 5, 2017, demonstrates 2 liver metastases with bidirectional measurement of 11.4 cm2. After radiation and pembrolizumab, initial restaging demonstrates an increase to 43.5 cm2 (283% baseline measurement). Subsequent scans demonstrate continued decrease to 10.9 cm2 at which point the patient was removed from trial for distant progression.