PMID- 36252998 OWN - NLM STAT- MEDLINE DCOM- 20221019 LR - 20221108 IS - 2051-1426 (Electronic) IS - 2051-1426 (Linking) VI - 10 IP - 10 DP - 2022 Oct TI - Phase Ib study of pembrolizumab in combination with trastuzumab emtansine for metastatic HER2-positive breast cancer. LID - 10.1136/jitc-2022-005119 [doi] LID - e005119 AB - BACKGROUND: Preclinical and clinical data support potential synergy between anti-HER2 therapy plus immune checkpoint blockade. The safety and tolerability of trastuzumab emtansine (T-DM1) combined with pembrolizumab is unknown. METHODS: This was a single-arm phase Ib trial (registration date January 26, 2017) of T-DM1 plus pembrolizumab in metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Eligible patients had HER2-positive, metastatic breast cancer previously treated with taxane, trastuzumab, and pertuzumab, and were T-DM1-naive. A dose de-escalation design was used, with a dose-finding cohort followed by an expansion cohort at the recommended phase 2 dose (RP2D), with mandatory baseline biopsies. The primary endpoint was safety and tolerability. Secondary endpoints included objective response rate (ORR) and progression-free survival (PFS). Immune biomarkers were assessed using histology, protein/RNA expression, and whole exome sequencing. Associations between immune biomarkers and treatment response, and biomarker changes before and during treatment, were explored. RESULTS: 20 patients received protocol therapy. There were no dose-limiting toxicities. The RP2D was 3.6 mg/kg T-DM1 every 21 days plus 200 mg pembrolizumab every 21 days. 85% of patients experienced treatment-related adverse events (AEs) >/=grade 2, 20% of patients experienced grade 3 AEs, and no patients experienced grade >4 AEs. Four patients (20%) experienced pneumonitis (three grade 2 events; one grade 3 event). ORR was 20% (95% CI 5.7% to 43.7%), and median PFS was 9.6 months (95% CI 2.8 to 16.0 months). Programmed cell death ligand-1 and tumor infiltrating lymphocytes did not correlate with response in this small cohort. CONCLUSIONS: T-DM1 plus pembrolizumab was a safe and tolerable regimen. Ongoing trials will define if there is a role for checkpoint inhibition in the management of HER2-positive metastatic breast cancer. TRIAL REGISTRATION NUMBER: NCT03032107. CI - (c) Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Waks, Adrienne G AU - Waks AG AD - Harvard Medical School, Boston, Massachusetts, USA. AD - Dana-Farber Cancer Institute, Boston, Massachusetts, USA. FAU - Keenan, Tanya E AU - Keenan TE AD - Dana-Farber Cancer Institute, Boston, Massachusetts, USA. FAU - Li, Tianyu AU - Li T AD - Dana-Farber Cancer Institute, Boston, Massachusetts, USA. FAU - Tayob, Nabihah AU - Tayob N AD - Dana-Farber Cancer Institute, Boston, Massachusetts, USA. FAU - Wulf, Gerburg M AU - Wulf GM AD - Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. AD - Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. FAU - Richardson, Edward T 3rd AU - Richardson ET 3rd AD - Harvard Medical School, Boston, Massachusetts, USA. AD - Brigham and Women's Hospital, Boston, Massachusetts, USA. FAU - Attaya, Victoria AU - Attaya V AD - Dana-Farber Cancer Institute, Boston, Massachusetts, USA. FAU - Anderson, Leilani AU - Anderson L AD - Dana-Farber Cancer Institute, Boston, Massachusetts, USA. FAU - Mittendorf, Elizabeth A AU - Mittendorf EA AD - Harvard Medical School, Boston, Massachusetts, USA. AD - Dana-Farber Cancer Institute, Boston, Massachusetts, USA. AD - Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA. FAU - Overmoyer, Beth AU - Overmoyer B AD - Harvard Medical School, Boston, Massachusetts, USA. AD - Dana-Farber Cancer Institute, Boston, Massachusetts, USA. FAU - Winer, Eric P AU - Winer EP AD - Harvard Medical School, Boston, Massachusetts, USA. AD - Dana-Farber Cancer Institute, Boston, Massachusetts, USA. AD - Yale Cancer Center, New Haven, Connecticut, USA. FAU - Krop, Ian E AU - Krop IE AD - Harvard Medical School, Boston, Massachusetts, USA. AD - Dana-Farber Cancer Institute, Boston, Massachusetts, USA. AD - Yale Cancer Center, New Haven, Connecticut, USA. FAU - Agudo, Judith AU - Agudo J AD - Harvard Medical School, Boston, Massachusetts, USA. AD - Dana-Farber Cancer Institute, Boston, Massachusetts, USA. FAU - Van Allen, Eliezer M AU - Van Allen EM AUID- ORCID: 0000-0002-0201-4444 AD - Harvard Medical School, Boston, Massachusetts, USA. AD - Dana-Farber Cancer Institute, Boston, Massachusetts, USA. FAU - Tolaney, Sara M AU - Tolaney SM AUID- ORCID: 0000-0002-5940-8671 AD - Harvard Medical School, Boston, Massachusetts, USA sara_tolaney@dfci.harvard.edu. AD - Dana-Farber Cancer Institute, Boston, Massachusetts, USA. LA - eng SI - ClinicalTrials.gov/NCT03032107 PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - J Immunother Cancer JT - Journal for immunotherapy of cancer JID - 101620585 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Immune Checkpoint Inhibitors) RN - 0 (Ligands) RN - 0 (Taxoids) RN - 63231-63-0 (RNA) RN - DPT0O3T46P (pembrolizumab) RN - P188ANX8CK (Trastuzumab) RN - SE2KH7T06F (Ado-Trastuzumab Emtansine) SB - IM MH - Ado-Trastuzumab Emtansine MH - Antibodies, Monoclonal, Humanized MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects MH - *Breast Neoplasms/pathology MH - Female MH - Humans MH - Immune Checkpoint Inhibitors MH - Ligands MH - RNA/therapeutic use MH - Taxoids MH - Trastuzumab/adverse effects PMC - PMC9577940 OTO - NOTNLM OT - Breast Neoplasms COIS- Competing interests: AGW: Receives institutional research funding from Genentech/Roche, MacroGenics and Merck. TEK: Became an employee at Merck, after her contributions to this manuscript. GMW: Reports grants during the conduct of the study from SU2C-AACR-DT0209, the Mary Kay Ash Foundation, the Ovarian Cancer Research Foundation, the Breast Cancer Alliance, the Breast Cancer Research Foundation, and NIH RO1 1R01CA226776; reports grants outside the submitted work from Merck and GlaxoSmithKline; and holds patent US 20090258352 A1 Pin1 as a marker for abnormal cell growth licensed to Cell Signaling and R&D Systems. ETR: Reports institutional research support from AstraZeneca and an honorarium for a seminar at MJH Life Sciences. EAM: Reports compensated service on scientific advisory boards for AstraZeneca, Exact Sciences, Merck, and Roche/Genentech; uncompensated service on steering committees for Bristol Myers Squibb, Lilly, and Roche/Genentech; institutional research support from Roche/Genentech (via SU2C grant) and Gilead; and the following non-financial interests and non-remunerated activities: Board of Directors for the American Society of Clinical Oncology and Scientific Advisor for Susan G. Komen for the Cure Foundation. BO: Receives institutional research funding from Genentech, Incyte, and Eisai. EPW: Reports institutional research funding from Genentech/Roche; serving as a consultant for Athenex, Carrick Therapeutics, G1 Therapeutics, Genentech/Roche, Genomic Health, Gilead, GlaxoSmithKline, GSK, Jounce, Lilly, St. Lucia, Syros, and Zymeworks; a non-paid scientific advisory board membership at Leap Therapeutics; and serving as President-Elect of the American Society of Clinical Oncology (ASCO). IEK: Receives institutional research support from Merck, Genentech/Roche, Macrogenics, and Pfizer; receives fees from Novartis and Merck for Data Monitoring Board participation; receives honoraria from AstraZeneca; and receives consulting fees from Bristol Myers Squibb, Daiichi Sankyo, Macrogenics, Taiho Oncology, Genentech/Roche, Seattle Genetics, and AstraZeneca. In addition, his spouse holds a leadership or fiduciary role, and owns stock in, PureTech. EMVA: Receives advisory/consulting fees from Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Janssen, Manifold Bio, and Monte Rosa; receives research support from Novartis and BMS; holds equity in Tango Therapeutics, Genome Medical, Genomic Life, Syapse, Enara Bio, Manifold Bio, Microsoft, and Monte Rosa; has filed institutional patents on chromatin mutations and immunotherapy response, and methods for clinical interpretation; performs intermittent legal consulting on patents for Foley Hoag; and is on the editorial board of JCO Precision Oncology, Science Advances. SMT: Reports a consulting or advisory board role for Novartis, Pfizer, Merck, Lilly, Nektar, NanoString Technologies, AstraZeneca, Puma Biotechnology, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, Odonate Therapeutics, OncoPep, Kyowa Hakko Kirin, Samsung Bioepis, CytomX Therapeutics, Daiichi Sankyo, Athenex, Gilead, Mersana, Certara, Chugai Pharma, Ellipses Pharma, Infinity, 4D Pharma, OncoSec Medical, BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, and Myovant; and reports institutional research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Cyclacel, Nektar, Gilead, Odonate Therapeutics, Sanofi, and Seattle Genetics.The other authors declare no potential conflicts of interest. EDAT- 2022/10/18 06:00 MHDA- 2022/10/20 06:00 PMCR- 2022/10/17 CRDT- 2022/10/17 20:42 PHST- 2022/09/17 00:00 [accepted] PHST- 2022/10/17 20:42 [entrez] PHST- 2022/10/18 06:00 [pubmed] PHST- 2022/10/20 06:00 [medline] PHST- 2022/10/17 00:00 [pmc-release] AID - jitc-2022-005119 [pii] AID - 10.1136/jitc-2022-005119 [doi] PST - ppublish SO - J Immunother Cancer. 2022 Oct;10(10):e005119. doi: 10.1136/jitc-2022-005119.