Avelumab Plus Talazoparib in Patients With BRCA1/2- or ATM-Altered Advanced Solid Tumors: Results From JAVELIN BRCA/ATM, an Open-Label, Multicenter, Phase 2b, Tumor-Agnostic Trial

Abstract

Importance: Nonclinical studies suggest that the combination of poly(ADP-ribose) polymerase and programmed cell death 1/programmed cell death-ligand 1 inhibitors has enhanced antitumor activity; however, the patient populations that may benefit from this combination have not been identified.

Objective: To evaluate whether the combination of avelumab and talazoparib is effective in patients with pathogenic BRCA1/2 or ATM alterations, regardless of tumor type.

Design, setting, and participants: In this pan-cancer tumor-agnostic phase 2b nonrandomized controlled trial, patients with advanced BRCA1/2-altered or ATM-altered solid tumors were enrolled into 2 respective parallel cohorts. The study was conducted from July 2, 2018, to April 12, 2020, at 42 institutions in 9 countries.

Interventions: Patients received 800 mg of avelumab every 2 weeks and 1 mg of talazoparib once daily.

Main outcomes and measures: The primary end point was confirmed objective response (OR) per RECIST 1.1 by blinded independent central review.

Results: A total of 200 patients (median [range] age, 59.0 [26.0-89.0] years; 132 [66.0%] women; 15 [7.5%] Asian, 11 [5.5%] African American, and 154 [77.0%] White participants) were enrolled: 159 (79.5%) in the BRCA1/2 cohort and 41 (20.5%) in the ATM cohort. The confirmed OR rate was 26.4% (42 patients, including 9 complete responses [5.7%]) in the BRCA1/2 cohort and 4.9% (2 patients) in the ATM cohort. In the BRCA1/2 cohort, responses were more frequent (OR rate, 30.3%; 95% CI, 22.2%-39.3%, including 8 complete responses [6.7%]) and more durable (median duration of response: 10.9 months [95% CI, 6.2 months to not estimable]) in tumor types associated with increased heritable cancer risk (ie, BRCA1/2-associated cancer types, such as ovarian, breast, prostate, and pancreatic cancers) and in uterine leiomyosarcoma (objective response in 3 of 3 patients and with ongoing responses greater than 24 months) compared with non-BRCA-associated cancer types. Responses in the BRCA1/2 cohort were numerically higher for patients with tumor mutational burden of 10 or more mutations per megabase (mut/Mb) vs less than 10 mut/Mb. The combination was well tolerated, with no new safety signals identified.

Conclusions and relevance: In this phase 2b nonrandomized controlled trial, neither the BRCA1/2 nor ATM cohort met the prespecified OR rate of 40%. Antitumor activity for the combination of avelumab and talazoparib in patients with BRCA1/2 alterations was observed in some patients with BRCA1/2-associated tumor types and uterine leiomyosarcoma; benefit was minimal in non-BRCA-associated cancer types.

Trial registration: ClinicalTrials.gov Identifier: NCT03565991.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Schram reported receiving trial funding from Pfizer during the conduct of the study; receiving trial funding to her institution from AstraZeneca, ArQule, BeiGene/Springworks, Black Diamond Therapeutics, Elevation Oncology, Kura, Eli Lilly and Co, Merus, Northern Biologics, Pfizer, PMV Pharma, Relay Therapeutics, Repare Therapeutics, Revolution Medicines, and Surface Oncology and having a consulting or advisory role with Roche; PharmaMar, AstraZeneca, Merck and Co (Kenilworth, New Jersey), Clovis Oncology, Tesaro; GlaxoSmithKline, Novartis, Pfizer, Takeda, BIOCAD, Immunogen, Mersana, Eisai, and Oncxerna outside the submitted work. Dr Colombo reported receiving personal fees from Pfizer during the conduct of the study and receiving personal fees from AstraZeneca, Clovis, Roche, Merck Sharpe & Dohme, GlaxoSmithKline, Immunogen, Mersana, Eisai, Oncxerna, Novartis, and Nuvation Bio outside the submitted work. Dr Arrowsmith reported that their institution, Tennessee Oncology, has a research relationship with Sarah Cannon Research Institute, which is compensated for research by study sponsors including the sponsor of this study. Dr Narayan reported receiving grants from Pfizer during the conduct of the study and receiving grants and personal fees from Pfizer, Janssen Pharmaceuticals, and Merck; receiving personal fees from Regenergon, Amgen, Myovant Sciences, and Exelixis; receiving grants from Bristol Myers Squibb and Tmunity Therapeutics outside the submitted work. Dr Yonemori reported receiving grants from Pfizer during the conduct of the study and receiving honoraria from Pfizer, Eisai, Takeda, Eli Lilly and Co, Chugai, Fuji Film Pharma, Merck Sharp & Dohme, Ono, Boeringer Ingerlheim, AstraZeneca, Daiichi Sankyo, OncXerna, Genmab, and Novartis; having a consulting or advisory role with Novartis, Eisai, AstraZeneca, Chugai, Takeda, Genmab, and OncXerna; and receiving research support to institution from Merck Sharpe & Dohme, Daiichi-Sankyo, AstraZeneca, Taiho, Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seattle Genetics, Eisai, Eli Lilly and Co, Genmab, Boeringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, and Haihe outside the submitted work. Dr Scambia reported receiving research support from Merck & Co; having a consulting or advisory role with Tesaro, Johnson & Johnson, and Clovis Oncology Italy outside the submitted work. Dr Zelnak reported receiving personal fees from AstraZeneca, Gilead, Seattle Genetics, Puma Biotechnology, Novartis, and Pfizer outside the submitted work. Dr Bauer reported receiving personal fees for consulting from Guadrant Health, Loxo, Exelixis, Blueprint Medicines, Foundation Medicine, AstraZeneca, Pfizer, Eli Lilly and Co, Bayer, and Bristol Myers Squibb; receiving personal fees for consulting to the institution from Ignyta, Moderna Therapeutics, and Pfizer; being on the speakers’ bureau for Bayer, Bristol Myers Squibb, and Eli Lilly and Co; receiving research support to the institution from Mirati Therapeutics, MedImmune, AbbVie, AstraZeneca, Leap Therapeutics, MabVax, Stemline Therapeutics, Merck, Eli Lilly and Co, GlaxoSmithKline, Novartis, Pfizer, Genentech/Roche, Deciphera, Merrimack, Immunogen, Millennium, Ignyta, Calithera Biosciences, Kolltan Pharmaceuticals, Principa Biopharma, Peleton, Immunocore, Aileron Therapeutics, Bristol Myers Squibb, Amgen, Moderna Therapeutics, Sanofi, Boehringer Ingelheim, Astellas Pharma, Five Prime Therapeutics, Jacobio, Top Alliance BioScience, Loxo, Janssen Pharmaceuticals, Clovis Oncology, Takeda, Karyopharm Therapeutics, Onyx, Phosplatin Therapeutics, Foundation Medicine, and ARMO BioSciences; and receiving travel grants from Astellas Pharma, AstraZeneca, Celgene, Clovis Oncology, Genentech, Eli Lilly and Co, Merck (Darmstadt, Germany), Novartis, Pharmacyclics, Sysmex, and Pfizer outside the submitted work. Dr Ulahannan reported receiving research support to the institution from Pfizer during the conduct of the study; having a consulting or advisory role with Array, Incyte, Bayer, Syros, and Eisai and receiving research support to the institution from AbbVie, ArQule, AstraZeneca, Atreca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Ciclomed, Evelo Biosciences, G1 Therapeutics, GlaxoSmithKline, IGM Biosciences, Incyte, Isofol, Klus Pharma, Macrogenics, Merck & Co (Kenilworth, New Jersey), Mersana Therapeutics, OncoMed Pharmaceuticals, Regeneron, Revolution Medicines, Synermore Biologics, Takeda, Tarveda, Tesaro, Tempest, and Vigeo outside the submitted work. Dr Colleoni reported receiving grants from Roche outside the submitted work. Dr Aftimos reported receiving travel grants from Amgen, Merck and Co (Kenilworth, New Jersey), Daiichi Sankyo, Pfizer, Merck Sharpe & Dohme, and Roche; receiving honoraria from Synthon, Amgen, Novartis, and Gilead; receiving grants from Roche; receiving personal fees from Roche, Novartis, Macrogenics, Gilead, Amcure, Radius, Menarini, Servier, G1 Therapeutics, Boehringer Ingelheim, Deloitte, and Synthon outside the submitted work. Dr Telli reported receiving personal fees from Pfizer during the conduct of the study and receiving grants from AstraZeneca, Bayer, Pfizer, Genentech, Merck (Darmstadt, Germany), OncoSec, Tesaro, EMD Serrono, Vertex, Biothera, Calithera, Hummingbird Biosciences, and AbbVie; receiving personal fees from OncoSec, Gilead, Guardant, Natera, Genentech, RefleXion, Sanofi, G1 Therapeutics, Immunomedics, Novartis, Blueprint Medicines, Eli Lilly and Co, AbbVie, Merck, and Daiichi Sankyo outside the submitted work. Dr Domchek reported receiving personal fees from AstraZeneca and GlaxoSmithKline during the conduct of the study and research support to the institution from AstraZeneca and Pfizer and having a consulting or advisory role with AstraZeneca and Clovis outside the submitted work. Dr Galsky reported receiving personal fees from Pfizer during the conduct of the study and receiving research support to the institution from Janssen Oncology; Dendreon; Novartis; Bristol Myers Squibb; Merck (Darmstadt, Germany); AstraZeneca; and Genentech/Roche; receiving fees for consulting or advisory roles to the institution from BioMotiv, Janssen Pharmaceuticals, Dendreon, Merck (Darmstadt, Germany), GlaxoSmithKline, Eli Lilly and Co, Astellas Pharma, Genentech, Bristol Myers Squibb, Novartis, Pfizer, AstraZeneca, Seattle Genetics, Incyte, Aileron Therapeutics, Dracen, Inovio Pharmaceuticals, NuMab, Dragonfly Therapeutics, Basilea, Urogen Pharmaceuticals, and Gilead; and receiving personal fees from Incyte, Bristol Myers Squibb, Merck, Genentech, AstraZeneca, EMD Serono, Seattle Genetics, Janssen Pharmaceuticals, Numab, Dragonfly, GlaxoSmithKline, Basilea, Urogen, Rappta, and Alligator; and owning stock in Rappta outside the submitted work; in addition, Dr Galsky has a patent for Compositions and Methods for Treating Cancer, Overcoming PD-1/PD-L1 Blockade Resistance, and Determining Resistance to Checkpoint Inhibitor Treatment pending. Ms Hoyle and Dr Chappey reported being employed by and owning stock in Pfizer during the conduct of the study and outside the submitted work. Dr Stewart reported being employed by Pfizer during the conduct of the study and owning shares in Pfizer and AstraZeneca outside the submitted work. Dr Blake-Haskins reported being employed by and owning stock in Pfizer during the conduct of the study and outside the submitted work. Dr Yap reported serving as medical director of the Institute for Applied Cancer Science, which has a commercial interest in DNA damage repair response and other inhibitors; receiving research support from and serving as a consultant or advisor to Merck (Darmstadt, Germany) and Pfizer; receiving research support to the institution from Artios, AstraZeneca, Bayer, Clovis, Constellation, Cyteir, Eli Lilly and Co, Forbius, F-Star, GlaxoSmithKline, Genentech, ImmuneSensor, Ipsen, Jounce, Karyopharm, Kyowa, Novartis, Ribon Therapeutics, Regeneron, Repare, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, and Vertex; having a consulting or advisory role with Almac, Aduro, AstraZeneca, Atrin, Axiom, Axiom, Bayer, Bristol Myers Squibb, Calithera, Clovis, Cybrexa, F-Star, Guidepoint, Ignyta, I-Mab, Janssen, Repare, Roche, Rubius, Schrodinger, Seagen, Varian, and Zai Lab outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Study Flow Diagram

Q2W indicates every 2 weeks; QD, once daily.

Figure 2.. Efficacy Summary in the BRCA1/2 Cohort

Time to and duration of response in the full analysis set per blinded independent central review, for all patients in the BRCA1/2 cohort and in BRCA-associated and non–BRCA-associated tumor types. Molecular analysis was based on results from central laboratories and supplemented by local laboratories when central results were not available. Patients with alterations in non-BRCA DNA damage response genes are indicated accordingly. CA-125 indicates cancer antigen 125; CR, complete response; HR, hormone receptor; LOH, loss of heterozygosity; mCRPC, metastatic castration-resistant prostate cancer; mut/MB, mutations per megabase; PD-L1, programmed cell death–ligand 1; PR, partial response; PSA, prostate-specific antigen; TMB, tumor mutational burden; TNBC, triple-negative breast cancer; uLMS, uterine leiomyosarcoma.