Anti–PD-(L)1 agents have limited activity in relapsed/refractory (r/r) TNBC. Blockade of immune suppression by antagonism of the adenosine pathway may increase the antitumor activity of PD-1 inhibitors in r/r TNBC. Here, we present data on the A2AR antagonist TAM + the anti–PD-1 antibody spartalizumab in TNBC.
In part 1 of this phase II study (NCT03207867), pts with relapsed TNBC were given 160 mg oral TAM twice daily, continuously, plus 400 mg intravenous spartalizumab every 4 weeks. The primary objective was to evaluate the overall response rate (ORR) per RECIST v1.1. Secondary objectives were to assess the safety and tolerability of the combination treatment, and to characterize changes in the immune infiltrates in tumors upon treatment. Tumor biopsies were taken prior to and on treatment for biomarker analyses.
As of Dec 3, 2021, 30 pts with PD-(L)1–naive TNBC were enrolled in part 1. The majority of pts had received ≥2 lines of therapy for their disease and had an ECOG status ≤1 at study entry. Based on data from 27 pts with ≥1 post-baseline scan, the ORR was 11%, the disease control rate was 37%, and median progression-free survival was 1.8 months. In all 30 pts, common, all-grade, treatment-related adverse events (TRAEs) were observed in 23 pts (77%); Grade ≥3 TRAEs were reported in seven pts (including fatigue [n=2]; increased aspartate aminotransferase [n=2]; increased alanine aminotransferase [n=2]; dyspnea [n=1]; interstitial lung disease [n=1]; and duodenal ulcer [n=1]). There was evidence of a robust induction of CD8 infiltration in the tumors upon treatment (n=13), unlike the changes observed during a phase I trial of spartalizumab in a similar TNBC population. In addition, a trend was seen between CD8 percent marker area change and TAM exposure. Pharmacokinetics data will be presented.
TAM + spartalizumab showed clinical benefit in a fraction of pts with relapsed TNBC. Biomarker data support the role of TAM in shifting the immune microenvironment toward a “T-cell–inflamed” tumor, and possibly in increasing the efficacy of anti–PD-1 agents.
NCT03207867.
Editorial assistance was provided by Manoshi Nath, MSc of Articulate Science Ltd, and was funded by Novartis Pharmaceuticals Corporation.
Novartis Pharmaceuticals Corporation.
Novartis Pharmaceuticals Corporation.
G. Jerusalem: Financial Interests, Personal, Advisory Board: Novartis, Roche, Pfizer, BMS, Lilly, AstraZeneca, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, BMS, Lilly, AstraZeneca, Seagen, Novartis, AZ/Daiichi Sankyo, BMS; Financial Interests, Institutional, Invited Speaker: Novartis, Roche, Syneos Health, Iqvia, TRIO, Bayer, MSD, IBCSG, PRA, Eli Lilly, PPD, Theradex, ABCSG, Modra, AstraZeneca, Odonate Therapeutics, BMS, ICON, Boehringer Ingelheim, Quintiles, Pfizer, Lilly, Daiichi Sankyo, Seagen, MedImmune; Non-Financial Interests, Personal, Member: ASCO, BSMO; Other, Personal, Other, Medical writer support: MedImmune, Novartis, Roche, Lilly, Amgen, BMS, AstraZeneca, Merck, Pfizer; Other, Personal, Other, Support for attending meetings and/or travel: Novartis, Lilly, BMS, Roche, Amgen, AstraZeneca, Pfizer. F.G.M. De Braud: Financial Interests, Personal, Invited Speaker: BMS, Healthcare Research & Pharmacoepidemiology, Merck Group, MSD, Pfizer, Servier, Sanofi, Roche, Amgen, Incyte, Dephaforum, Seagen, Novartis, F.Hoffmann-LaRoche Ltd., BMS, Ignyta Operating Inc., Merck Sharp & Dohme Spa, Kymab, Pfizer, Tesaro, MSD, MedImmune LCC, Exelixis Inc., Loxo Oncology Incorporated, Daiichi Sankyo Dev. Limited, Basilea Pharmaceutica International AG, Janssen-Cilag International NV, Merck KGAA; Financial Interests, Personal, Other, Consultant Advisory Board: Roche, EMD Serono, NMS Nerviano Medical Science, Sanofi, MSD, Novartis, Incyte, BMS, Menarini, AstraZeneca, Pierre Fabre. P. Grell: Financial Interests, Personal, Invited Speaker: Servier; Financial Interests, Personal, Advisory Board: Roche. A. Gonçalves: Financial Interests, Institutional, Invited Speaker: Novartis, Roche, MSD, AstraZeneca, Daiichy Sankyo. T.J.Y. Tan: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Everest Medicines (Singapore) Pte Ltd., DKSH, Pfizer; Financial Interests, Personal, Invited Speaker: DKSH, AstraZeneca, Novartis, Roche, Pfizer, MSD, DHPL Malaysia SDN BHD; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Roche, Novartis, AstraZeneca, Odonate, Daiichi Sankyo, Genentech, Sanofi; Non-Financial Interests, Personal, Member: ASCO. R. Greil: Financial Interests, Personal, Advisory Role: Celgene, Novartis, Amgen, Bristol Myers Squibb, Takeda, AbbVie, AstraZeneca, Janssen, Gilead, Merck, Daiichi Sankyo, Sanofi, Sandoz; Financial Interests, Personal, Sponsor/Funding: Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, Merck, Sandoz, AbbVie, Gilead, Daiichi Sankyo; Financial Interests, Personal, Other, Travel, Accomodations, Expenses: Roche, Amgen, Janssen, AstraZeneca, Novartis, Merck, Celgene, Gilead, Bristol Myers Squibb, AbbVie, Daiichi Sankyo. T.A. Yap: Financial Interests, Personal, Other, Consultant: Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Bristol Myers Squibb, Clovis, Cybrexa, EMD Serono, Guidepoint, Ignyta, I-Mab, Jansen, Merck, Pfizer, Repare, Roche, Schrodinger, Varian, Zai Labs, AbbVie, Acrivon, Adagene, Amphista, Artios, Athena, Avoro, Baptist Health Systems, Beigene, Boxer, C4 Therapeutics, Calithera, Cancer Research UK, Diffusion, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Idience, ImmuneSensor, Institut Gustave Roussy, Intellisphere, Kyn, MEI Pharma, Mereo, Natera, Nexys, Novocure, OHSU, OncoSec, Ono Pharma, Pegascy, PER, Piper-Sandler, Prolynx, resTORbio, Theragnostics, Versant, Vibliome, Xinthera, ZielBio; Financial Interests, Personal, Other, University of Texas MD Anderson Cancer Center, where I am Medical Director of the Institute for Applied Cancer Science, which has a commercial interest in DDR and other inhibitors (IACS30380/ART0380 was licensed to Artios): MD Anderson Cancer Center, Institute for Applied Cancer Sciences; Financial Interests, Personal, Stocks/Shares: Seagan; Financial Interests, Institutional, Other, Grant/Research support: Bayer, Cyteir, EMD Serono, GlaxoSmithKline, Karyopharm, Pfizer, Repare, Sanofi, Artios, AstraZeneca, Beigene, BioNTech, Blueprint, BMS, Clovis, Constellation, Eli Lilly, Forbius, F-Star, Genentech, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, KSQ, Kyowa, Merck, Mirati, Novartis, Ribon Therapeutics, Regeneron, Rubius, Scholar Rock, Seattle Genetics, Tesaro, Vivace, Acrivon, Zenith. C. Lin: Financial Interests, Personal, Other, Travel support: BeiGene, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Blueprint Medicines, Bristol Myers Squibb, Daiichi Sankyo, Novartis, AbbVie, PharmaEngine, Merck KGaA; Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Roche. K.A. Kornbluth: Financial Interests, Personal, Full or part-time Employment, I work full-time as a Clinical Trial Leader at Novartis: Novartis Institutes for BioMedical Research. J. Mataraza: Financial Interests, Institutional, Full or part-time Employment: Novartis; Financial Interests, Personal, Stocks/Shares: Novartis. L.H. Lee: Financial Interests, Personal, Full or part-time Employment: Novartis. J.A. Otero: Financial Interests, Personal, Full or part-time Employment, I am a full time employee (Senior Clinical Program Leader) in the translational clinical oncology group: Novartis; Financial Interests, Personal, Stocks/Shares: Novartis; Non-Financial Interests, Personal, Member: AACR, ASCO, ASHPO, ASH, American Academy of Pediatrics (AAP). E. Garralda: Financial Interests, Personal, Advisory Board: Genentech, F.Hoffmann/La Roche, Neomed Therapeutics1 Inc, Boehringer Ingelheim, Janssen Global Services, Alkermes, Thermo Fisher, MabDiscovery, Anaveon, Lilly, Hengrui; Financial Interests, Personal, Invited Speaker: Ellipses Pharma, Seattle Genetics, Bristol Mayers Squibb, MSD, F-Star Therapeutics; Financial Interests, Institutional, Funding: Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho. All other authors have declared no conflicts of interest.