Background

Changes occurring in host-associated microbial communities (i.e. microbiota) may modulate responses to checkpoint blockade immunotherapy. We previously showed that anti-programmed cell death 1 protein P added to microtubule-targeting chemotherapy E has an encouraging antitumor activity in HR+ MBC pts regardless of programmed death-ligand 1 status. The CALADRIO study assessed the impact of gut and oral microbiota on clinical outcome of pts from the KELLY trial.

Methods

The phase 2 KELLY trial investigated the efficacy and safety of P plus E in 44 pts with pre-treated, HR+, HER2-negative, locally recurrent inoperable or MBC (NCT03222856). Fecal and saliva samples were prospectively collected at baseline (BL), after 3 cycles, and end of treatment from a subset of pts. Tumor response was grouped into clinical benefit (CB; complete or partial responses, or stable disease [SD] ≥24 weeks) and no CB (SD <24 weeks or progressive disease) as per RECIST 1.1. Shotgun metagenomic and 16S rRNA gene sequencing were used to characterize fecal and saliva microbiota profiles, respectively. Microbiota data were analyzed using MEGAHIT, LEfSe, Wilcoxon ranked sum, and PERMANOVA methods.

Results

A total of 58 fecal and 68 saliva samples were collected. Overall P+E did not cause significant gut or oral microbiota perturbations, indicating any drug-related microbial toxicity. Across all pts, dominant gut microbiota genera included Bacteroides and Faecalibacterium, with a common oral microbe, Prevotella, also present. LeFSe analysis suggested CB was driven in part by gut-associated Bacteroides fragilis and oral-associated Streptococcus with an abundance ≥50%. Pts experiencing CB had gut and oral microbiota richness at BL and a decrease over treatment potentially related to the antibiotic usage. Several typical oral microbes in both saliva and fecal samples were also observed, suggesting a potential translocation along the oral-gut axis.

Conclusions

These preliminary findings suggest potential avenues for downstream microbiota pts stratification before commencement of treatment. Further investigation is required in larger cohorts.

Clinical trial identification

NCT03222856.

Legal entity responsible for the study

MEDSIR.

Funding

MEDSIR.

Disclosure

M. Gion Cortes: Financial Interests, Personal, Sponsor/Funding: Roche; Financial Interests, Personal, Sponsor/Funding: Pfizer. J.M. Perez Garcia: Non-Financial Interests, Personal, Advisory Role: Roche; Non-Financial Interests, Personal, Advisory Role: Lilly; Non-Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Financial Interests, Personal, Sponsor/Funding: Roche. A. Prat: Non-Financial Interests, Personal, Full or part-time Employment: Novoartis; Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Personal, Sponsor/Funding: Pfizer, Novartis, Roche, MSD Oncology, Lilly, Daiichi Sankyo, Amgen, Guardant Health; Non-Financial Interests, Personal, Advisory Role: Amgen, Roche, Novartis, Pfizer, Bristol Myers Squibb, Boehringer, Puma, Oncolytics Biotech, Daiichi Sankyo, AbbVie, AstraZeneca, NanoString Technologies (to the Institution); Financial Interests, Institutional, Funding: Roche, Novartis, Incyte, Puma Biotechnology; Financial Interests, Personal, Ownership Interest: Patents:- PCT/EP2016/080056, - WO/2018/096191, US 63/023785, HER2DX (filing); Financial Interests, Personal, Sponsor/Funding: Daiichi Sankyo; Other, Personal, Other: Oncolytics, Peptomyc S.L. A. Llombart Cussac: Non-Financial Interests, Personal, Leadership Role: Eisai, Celgene, Lilly, Pfizer, Roche, Novartis, MSD;; Financial Interests, Personal, Stocks/Shares: MEDSIR, Initia-Research; Non-Financial Interests, Institutional, Advisory Role: Lilly, Roche, Pfizer, Novartis, Pierre Fabre, GenomicHealth, GSK; Non-Financial Interests, Personal, Speaker’s Bureau: Lilly, AstraZeneca, MSD; Financial Interests, Personal, Funding: Roche, Foundation Medicine, Pierre Fabre, Agendia; Financial Interests, Personal, Sponsor/Funding: Roche, Lilly, Novartis, Pfizer, AstraZeneca. M. Mancino: Financial Interests, Personal and Institutional, Full or part-time Employment: MEDSIR. J. Cortés: Non-Financial Interests, Personal, Advisory Role: Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology.; Financial Interests, Personal, Sponsor/Funding: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, Daiichi Sankyo.; Financial Interests, Personal and Institutional, Funding: Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London.; Financial Interests, Personal, Stocks/Shares: MEDSIR. A. Malfettone: Financial Interests, Personal and Institutional, Full or part-time Employment: MEDSIR. All other authors have declared no conflicts of interest.

Background

KEYNOTE-355 (NCT02819518) evaluated pembro + chemo vs pbo + chemo in previously untreated patients (pts) with locally recurrent inoperable or metastatic TNBC. Pembro + chemo improved the PFS and OS in pts with PD-L1 combined positive score (CPS) ≥10 disease. We present results for patient-reported outcome (PRO) measures among pts with PD-L1 CPS ≥10.

Methods

Pts were randomized 2:1 to pembro 200 mg or pbo Q3W for up to 35 cycles + chemo (investigator’s choice of nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin). QLQ-C30 (including global health status/quality of life [GHS/QoL]) and physical and emotional functioning scales), QLQ-BR23, and EQ-5D visual analogue scale (VAS) were prespecified. PROs were assessed at baseline, during treatment, and the 30-day safety follow-up visit and analyzed for pts who received ≥1 dose of study treatment and completed ≥1 PRO assessment. Change in PRO scores from baseline were assessed at wk 15 (latest timepoint at which completion/compliance rates were ≥60%/≥80%; negative values favor the pembrolizumab group). Time to deterioration (TTD) in PROs was defined as time to first onset of ≥10-point worsening in score from baseline.

Results

These PRO analyses included 317 pts with PD-L1 CPS ≥10 (pembro + chemo; n = 217; pbo + chemo, n = 100). Completion/compliance at wk 15 was 77.0%/87.0% with pembro + chemo and 70.0%/81.4% with pbo + chemo. There were no between-group differences in change from baseline to wk 15 in the QLQ-C30 GHS/QoL, emotional functioning, physical functioning, or the EQ-5D VAS scale scores, and no between-group difference in TTD in QLQ-C30 GHS/QoL, emotional functioning, or physical functioning (Table). Analyses by QLQ-BR23 showed no decrease in HRQoL with pembro + chemo vs pbo + chemo. Table: 164O

Conclusions

Addition of pembro to chemo did not result in a decrease in HRQoL in pts with previously untreated, PD-L1–positive (CPS ≥10) advanced, TNBC.

Clinical trial identification

NCT02819518, EudraCT 2016-001432-35.

Editorial acknowledgement

Additional support was provided by Wilbur Panof Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Medical writing assistance was provided by Kara Nyberg, PhD, of ICON plc (Blue Bell, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp.

Funding

Merck Sharp & Dohme Corp.

Disclosure

D.W. Cescon: Financial Interests, Personal, Consultancy/Advisory role: AstraZeneca, Exact Sciences, Eisai, Gilead, GlaxoSmithKline, Merck, Novartis, Pfizer Roche; Financial Interests, Institutional, Research Funding: GlaxoSmithKline, Inivata, Merck, Pfizer, Roche; Other: is a member of a trial steering committee for AstraZeneca, Merck and GlaxoSmithKline; Other: holds a holds a patent (US62/675,228) for methods of treating cancers characterized by a high expression level of spindle and kinetochore associated complex subunit 3 (ska3) gene. P. Schmid: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Puma, Roche, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Genentech, Novartis, Oncogenex, Roche; Other, Spouse - Employee: Roche. H.S. Rugo: Financial Interests, Personal, Invited Speaker: Puma; Financial Interests, Personal, Advisory Board: Samsung; Financial Interests, Personal, Invited Speaker: Mylan; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: Lilly; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: OBI Pharma; Financial Interests, Institutional, Invited Speaker: Immunomedics; Financial Interests, Institutional, Invited Speaker: Macrogenics; Financial Interests, Institutional, Invited Speaker: Daiichi; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: Merck; Financial Interests, Institutional, Invited Speaker: Odonate; Financial Interests, Institutional, Invited Speaker: Sermonix; Financial Interests, Institutional, Invited Speaker: Seattle Genetics; Financial Interests, Institutional, Invited Speaker: Polyphor; Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim; Non-Financial Interests, Advisory Role, I advise a number of companies without compensation: various. S-A. Im: Financial Interests, Personal, Consulting/Advisory role: Amgen, AstraZeneca, Eisai, Hanmi, Lilly, Medpacto, Inc., Novartis, Pfizer, Roche/Genentech; Financial Interests, Personal, Research Funding: AstraZeneca, Pfizer, Roche/Genentech; Financial Interests, Personal, Other, Travel, accommodations, expenses: Novartis; Roche/Genentech; Financial Interests, Personal, Other: Roche. M. Md Yusof: Financial Interests, Personal, Honoraria: AstraZeneca, Bayer, Boehringer Ingelheim, Merck, MSD, Specialised Therapeutics, Zuellig Pharma, Novartis, Pfizer, Roche, Eisai, Celgene; Financial Interests, Institutional, Research grant: Astellas, AstraZeneca, Arcus, Genentech, Mundi Pharma, Novartis, Pfizer, Roche. C.E. Gallardo: Financial Interests, Personal, Consulting/Advisory role: Lilly, MSD, Roche; Financial Interests, Personal, Speakers Bureau: Bristol Myers Squibb; Financial Interests, Personal, Research Funding: Novartis Pharma SAS, Roche; Financial Interests, Personal, Other, Travel, accommodations, expenses: MSD, Roche. C.H. Barrios: Financial Interests, Personal, Consulting/Advisory role: Boehringer Ingelheim, Eisai Europe Ltd., GlaxoSmithKline, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche/Genentech; Financial Interests, Personal, Research Funding: AB Science, Abraxis BioScience, Amgen, Asana Biosciences, Astellas Pharma, AstraZeneca, Biomarin, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Exelixis, GlaxoSmithKline, ImClone Systems, Investigator in AbbVie-sponsored cl. Trials, LEO Pharma, Lilly, Medivation, Merck, Merrimack, Millennium, Mylan, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche/Genentech, Sanofi, Taiho Pharmaceutical. J.M. Perez Garcia: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Expert Testimony: Eisai. H. Iwata: Financial Interests, Personal, Advisory Board: Chugai; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Chugai; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Invited Speaker: Taiho; Financial Interests, Personal and Institutional, Invited Speaker: Chugai; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker: MSD; Financial Interests, Personal and Institutional, Invited Speaker: Amgen; Financial Interests, Personal and Institutional, Invited Speaker: Sanofi; Financial Interests, Personal and Institutional, Invited Speaker: Lilly; Financial Interests, Personal and Institutional, Invited Speaker: Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Bayer; Financial Interests, Personal and Institutional, Invited Speaker: Pfizer; Financial Interests, Personal and Institutional, Invited Speaker: Kyowa Hakko Kirin; Financial Interests, Personal and Institutional, Invited Speaker: Behringer; Financial Interests, Personal and Institutional, Invited Speaker: Nihon Kayaku. N. Masuda: Financial Interests, Other, Leadership: Japan Breast Cancer Research Group Association (JBCRG); Financial Interests, Personal, Honoraria: AstraZeneca, Chugai Pharma, Eisai, Lilly Japan, Pfizer; Financial Interests, Institutional, Research Funding: AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eisai, Eli Lilly, Kyowa-Kirin, MSD, Novartis, Pfizer, Sanofi. E. Gokmen: Financial Interests, Other: Eli Lilly, Janssen Oncology, Novartis, Pfizer, Roche; Financial Interests, Personal, Consulting/Advisory Role: Lilly, Novartis, Pfizer, Roche; Financial Interests, Personal, Speaker Bureau: Lilly, Novartis, Pfizer, Roche; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: BMS, MSD Oncology, Novartis, Pfizer, Roche. S. Loi: Financial Interests, Institutional, Expert Testimony, Consultant: Aduro Biotech; Financial Interests, Institutional, Advisory Board, Consultant: Novartis; Financial Interests, Institutional, Advisory Board, Consultant: GlaxoSmithKline; Financial Interests, Institutional, Advisory Board, Consultant: Roche Genentech; Financial Interests, Institutional, Advisory Board, Consultant: AstraZeneca; Financial Interests, Institutional, Advisory Board, Consultant: Silverback Therapeutics; Financial Interests, Institutional, Advisory Board, Consultant: G1 Therapeutics; Financial Interests, Institutional, Expert Testimony, Consultant: Puma Biotechnologies; Financial Interests, Institutional, Expert Testimony, Consultant: Pfizer; Financial Interests, Institutional, Expert Testimony, Consultant: Seattle Genetics; Financial Interests, Institutional, Expert Testimony, Consultant: BMS; Financial Interests, Institutional, Funding, Research: Novartis; Financial Interests, Institutional, Funding, Research: BMS; Financial Interests, Institutional, Funding, Research: Merck; Financial Interests, Institutional, Funding, Research: Puma Biotechnology; Financial Interests, Institutional, Funding, Research: Eli Lilly; Financial Interests, Institutional, Funding, Research: Nektar Therapeutics; Financial Interests, Institutional, Funding, Research: AstraZeneca; Financial Interests, Institutional, Funding, Research: Seattle Genetics; Financial Interests, Institutional, Funding, Research: Roche - Genentech; Non-Financial Interests, Advisory Role, Consultant (Non remunerated): Seattle Genetics; Non-Financial Interests, Advisory Role, Consultant (Non remunerated): Novartis; Non-Financial Interests, Advisory Role, Consultant (Non remunerated): Bristol Myers Squibb; Non-Financial Interests, Advisory Role, Consultant (Non remunerated): Merck; Non-Financial Interests, Advisory Role, Consultant (Non remunerated): AstraZeneca; Non-Financial Interests, Advisory Role, Consultant (Non remunerated): Roche Genentech. A. Haiderali, Z. Guo, A. Martin Nguyen: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.; Financial Interests, Personal, Ownership Interest, Stock and Other Ownership Interests: Merck & Co., Inc. X. Zhou: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. J. Cortés: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Advisory Board: Cellestia; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Erytech; Financial Interests, Personal, Advisory Board: Athenex; Financial Interests, Personal, Advisory Board: Polyphor; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Advisory Board: LEUKO; Financial Interests, Personal, Advisory Board: Bioasis; Financial Interests, Personal, Advisory Board: Clovis oncology; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Celgene; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Samsung Bioepis; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Invited Speaker: Merck Sharp & Dohme; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Ellipses; Financial Interests, Personal, Advisory Board: Hibercell; Financial Interests, Personal, Advisory Board: BioInvent; Financial Interests, Personal, Advisory Board: Zymeworks; Financial Interests, Personal, Advisory Board: Gemoab; Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Advisory Board: Menarini; Financial Interests, Personal, Advisory Board: Reveal Genomics; Financial Interests, Personal, Stocks/Shares: MedSIR; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Stocks/Shares: Nektar Therapeutics; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Ariad Pharmaceuticals; Financial Interests, Institutional, Research Grant: Baxalta GMBH/Servier Affaires; Financial Interests, Institutional, Research Grant: Bayer healthcare; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: Guardanth Health; Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Piqur Therapeutics; Financial Interests, Institutional, Research Grant: Puma B; Financial Interests, Institutional, Research Grant: Queen Mary University of London; Other, Other, Travel cost and expenses: Roche; Other, Travel cost and expenses: Novartis; Other, Travel cost and expenses: Eisai; Other, Travel cost and expenses: Daiichi Sankyo. All other authors have declared no conflicts of interest.

Background

Patients (pts) with a/mTNBC have limited treatment options and poor prognosis. Combining checkpoint inhibitors with 1L chemotherapy improves outcomes but only in PD-L1+ve a/mTNBC, emphasizing a critical need. Dato-DXd, a TROP2 antibody-drug conjugate (ADC) with potent topoisomerase (TOPO) I inhibitor payload, elicited a 34% objective response rate (ORR) in heavily pretreated a/mTNBC and 52% ORR in a subset naïve to TOPO I-based ADCs. In BEGONIA, an ongoing 2-part, open-label platform study, D (an anti-PD-L1 antibody) combined with other therapies, including ADCs, is being evaluated in 1L a/mTNBC (NCT03742102). Here, we report preliminary results of Dato-DXd + D.

Methods

Unresectable a/mTNBC pts eligible for 1L treatment, regardless of PD-L1/TROP2 status, received intravenous Dato-DXd 6 mg/kg + D 1120 mg every 3 weeks until progression or unacceptable toxicity. Primary endpoints are safety and tolerability. Secondary endpoints include investigator-assessed ORR (RECIST v1.1) and response duration. Data cutoff was Nov 2021.

Results

29 pts received Dato-DXd + D (24 ongoing), 27 had the opportunity to have 2 postbaseline scans. Median (range) follow-up was 3.9 (2–6) months. Confirmed ORR was 20/27 (74%; 95% CI, 54–89); 2 (7%) pts had complete and 18 (67%) had partial responses, all were in response at data cutoff. No dose-limiting toxicities were observed. 4 pts (14%) underwent 1 Dato-DXd dose reduction due to stomatitis, 4 (14%) had 1 Dato-DXd dose delay, and 4 (14%) had 1 D dose delay. No dose modifications were required due to diarrhea. Table: 166MO

Summary of adverse events (AEs), n (%)

Conclusions

Combination of Dato-DXd + D in 1L a/mTNBC demonstrated robust response rates with a manageable safety profile in this preliminary analysis, warranting further investigation. Additional enrollment and analysis of translational data is ongoing. Funding: AstraZeneca/Daiichi Sankyo.

Clinical trial identification

NCT03742102.

Editorial acknowledgement

Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Nicole Seneca, PhD, of Parexel (Hackensack, NJ) and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca/Daiichi Sankyo.

Funding

AstraZeneca/Daiichi Sankyo.

Disclosure

P. Schmid: Financial Interests, Personal and Institutional, Other, Employment, consulting or advisory role and research funding: Genentech; Financial Interests, Personal and Institutional, Other, Employment, Honoraria, consulting or advisory role and research funding: Roche; Financial Interests, Personal and Institutional, Other, Honoraria, consulting or advisory role and research funding: AstraZeneca; Financial Interests, Personal and Institutional, Other, Honoraria, consulting or advisory role and research funding: Novartis; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: Pfizer; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Bayer; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Celgene; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Eisai; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Merck; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Puma Biotechnology; Financial Interests, Institutional, Funding, Research Funding: Astellas Pharma; Financial Interests, Institutional, Funding, Research funding: OncoGenex. K.H. Jung: Financial Interests, Personal, Advisory Role, Consulting or advisory role: AstraZeneca; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Celgene; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Eisai; Financial Interests, Personal, Advisory Role, Consulting or advisory role: MSD; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Novartis; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Roche; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Takeda. P.J. Wysocki: Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: AstraZeneca; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: Astellas; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: Amgen; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: BMS; Financial Interests, Institutional, Other, Honoraria: Gilead; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: IPSEN; Financial Interests, Personal and Institutional, Other, Honoraria, consulting or advisory role and research funding: Immunicom; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: Janssen; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: MSD; Financial Interests, Personal and Institutional, Other, Honoraria, consulting or advisory role and research funding: Merck; Financial Interests, Personal and Institutional, Other, Honoraria, consulting or advisory role and research funding: Pierre Fabre; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: Pfizer; Financial Interests, Personal and Institutional, Other, Honoraria, consulting or advisory role and research funding: Roche; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: Sanofi. J. Jassem: Financial Interests, Personal, Other, Personal fees: AstraZeneca; Financial Interests, Personal, Other, Personal fees: Pfizer; Financial Interests, Personal, Other, Personal fees: Roche; Financial Interests, Personal, Advisory Role, Consulting or Advisory role: AstraZeneca; Financial Interests, Personal, Advisory Role, Consulting or Advisory role: Pfizer; Financial Interests, Personal, Advisory Role, Consulting or Advisory role: Exact Sciences; Financial Interests, Personal, Other, Conference registration fee: Boehringer Ingelheim. C.X. Ma: Financial Interests, Personal and Institutional, Funding, Funding: Puma; Financial Interests, Personal and Institutional, Funding, Funding: Pfizer; Financial Interests, Personal, Advisory Role, Consulting Fees: Gilead; Financial Interests, Personal, Advisory Role, Consulting Fees: AstraZeneca; Financial Interests, Personal, Advisory Role, Consulting Fees: Athenex; Financial Interests, Personal, Advisory Role, Consulting Fees: Jacobio; Financial Interests, Personal, Advisory Role, Consulting Fees: Natera; Financial Interests, Personal, Advisory Role, Consulting Fees: Bayer Healthcare; Financial Interests, Personal, Advisory Role, Consulting Fees: Biovica; Financial Interests, Personal, Advisory Role, Consulting Fees: Eisai; Financial Interests, Personal, Advisory Role, Consulting Fees: Eli Lilly; Financial Interests, Personal, Advisory Role, Consulting Fees: Novartis; Financial Interests, Personal, Advisory Role, Consulting Fees: Phillips Electronics; Financial Interests, Personal, Advisory Role, Consulting Fees: Sanofi; Financial Interests, Personal, Advisory Role, Consulting Fees: Seattle Genetics; Financial Interests, Personal, Advisory Role, Consulting Fees: Pfizer. R. Fernandes: Financial Interests, Personal, Advisory Role, Consulting fees: Canadian Agency for Drugs and Technologies in Health (CADTH); Financial Interests, Institutional, Other, Honoraria: Bayer; Financial Interests, Institutional, Other, Honoraria: Pfizer; Financial Interests, Institutional, Other, Honoraria: Ipsen; Financial Interests, Institutional, Other, Honoraria: BMS; Financial Interests, Institutional, Other, Honoraria: Merck; Financial Interests, Institutional, Other, Honoraria: Novartis; Financial Interests, Institutional, Other, Honoraria: Janssen. R. Huisden: Financial Interests, Personal, Full or part-time Employment, Personal fees from AstraZeneca during the conduct of the study and outside the submitted work: AstraZeneca. R. Stewart: Financial Interests, Personal, Full or part-time Employment, Personal fees from AstraZeneca, during the conduct of the study and outside the submitted work: AstraZeneca; Financial Interests, Personal, Other, Personal fees from Pfizer, outside the submitted work: Pfizer. P. Vukovic: Financial Interests, Personal, Full or part-time Employment, Personal fees from AstraZeneca during the conduct of the study and outside the submitted work: AstraZeneca. A. Tablante Nunes: Financial Interests, Personal, Full or part-time Employment, Personal fees from AstraZeneca during the conduct of the study and outside the submitted work: AstraZeneca. Z. Nowecki: Financial Interests, Institutional, Other, Honoraria: AstraZeneca; Financial Interests, Institutional, Other, Honoraria: Sanofi Aventis; Financial Interests, Institutional, Other, Honoraria: MSD; Financial Interests, Institutional, Other, Honoraria: Roche.

Background

The IMpassion130 and KEYNOTE-355 trials have established a substantial benefit from adding an immune checkpoint inhibitor (ICI) to 1L chemotherapy (CT) for mTNBC with programmed death-ligand 1 (PD-L1)–positive tumors. However, many patients (pts) still have a poor outcome with a high unmet medical need. Preclinical and small ongoing clinical studies in TNBC provided encouraging results on the synergism between ICIs, vascular endothelial growth factor (VEGF)-targeted agents, and standard CT without adding significant toxicity. ATRACTIB is evaluating the safety and efficacy of A (anti-PD-L1 antibody) combined with P and B (a VEGF-targeted drug) as 1L regimen for mTNBC pts irrespective of PD-L1 status.

Trial design

ATRACTIB is an international, investigator-initiated, open-label, single-arm, phase 2 trial (NCT04408118). Pts aged ≥18 years, with unresectable locally advanced or mTNBC, Eastern Cooperative Oncology Group performance status of 0–1, who had received no prior systemic therapy or ≥12 months since (neo)adjuvant taxane-based CT are eligible. Pts receive A (840 mg IV, days 1, 15) with P (90 mg/m² IV, days 1, 8, 15), and B (10 mg/kg IV, days 1, 15) on each 28-day cycle until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint is investigator-assessed progression-free survival (PFS) as per RECIST v.1.1. Secondary efficacy endpoints include objective response rate (ORR), clinical benefit rate, time until response, response duration, overall survival, and best percentage change in the sum of the diameters of measurable tumors; safety and tolerability as per NCI-CTCAE v.5.0. Exploratory endpoints are PFS and ORR as per immune-related RECIST, and analysis of predictive biomarkers. The primary analysis consists of median PFS estimation (H₀: ≤7 months; H₁: ≥9.5 months) based on the exponential maximum likelihood estimation test. A sample size of 100 pts is needed to attain 80% power at a nominal one-sided α level of 5%. An interim analysis is planned for assessing the safety and feasibility in the first 20 pts who have completed a 3-month follow-up or reached the end of study. This trial was opened to accrual in October 2020.

Clinical trial identification

NCT04408118.

Legal entity responsible for the study

MEDSIR S.L.

Funding

F. Hoffmann-La Roche Ltd.

Disclosure

A. Cortés Salgado: Financial Interests, Personal, Research Grant: Pfizer; Financial Interests, Personal, Advisory Role: Clovis, Pfizer, GSK, Roche; Financial Interests, Personal, Speaker’s Bureau: GSK, AstraZeneca, MSD; Financial Interests, Personal, Other, Travel: Daiichi; Financial Interests, Personal, Ownership Interest: Co-Founder: ONCARE. J.M. Perez Garcia: Financial Interests, Personal, Advisory Board: Lilly, Roche, Eisai, Daiichi Sankyo, AstraZeneca, Seattle Genetics; Financial Interests, Personal, Other, Travel: Roche. I. Blancas López-Barajas: Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Lilly; Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Novartis, Eisai, Celgene, Pfizer, Lilly, Pierre, Fabre, Bristol Myers Squibb, Kiowa-kirin, Veracyte. P. Schmid: Financial Interests, Personal, Advisory Role: AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Puma, Roche, Eisai, Celgene; Financial Interests, Institutional, Research Grant: Astellas AstraZeneca, Genentech, Novartis, Oncogenex, Roche, Medivation; Financial Interests, Personal, Other, Employee/ Spouse: Roche. V. Guarneri: Financial Interests, Personal, Advisory Role: Eli Lilly, Novartis, Roche, MSD, Gilead; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly, Novartis, GSK; Financial Interests, Institutional, Research Grant: BMS, AstraZeneca, Roche, Nerviano, Eli Lilly, Merck, Novartis; Financial Interests, Personal, Royalties: Pending (HER2 DX), Reveal Genomics. J. Gligorov: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Daiichi, Eisai, Genomic Health, Immunomedics, Ipsen, Macrogenics, MSD, Novartis, Onxeo, Pfizer, Roche Genentech, Seagen; Financial Interests, Personal, Advisory Role: AstraZeneca, Daiichi, Eisai, Genomic Health, Immunomedics, Ipsen, Macrogenics, MSD, Novartis, Onxeo, Pfizer, Roche Genentech, Seagen; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Daiichi, Eisai, Genomic Health, Immunomedics, Ipsen, Macrogenics, MSD, Novartis, Onxeo, Pfizer, Roche Genentech, Seagen; Financial Interests, Institutional, Research Grant: AstraZeneca, Daiichi, Eisai, Genomic Health, MSD, Novartis, Pfizer, Roche Genentech; Financial Interests, Personal, Expert Testimony: AstraZeneca, Daiichi, Eisai, Genomic Health, Immunomedics, Ipsen, Macrogenics, MSD, Novartis, Onxeo, Pfizer, Roche Genentech, Seagen; Financial Interests, Personal, Other, Travel: AstraZeneca, Daiichi, Eisai, Genomic Health, MSD, Novartis, Pfizer, Roche Genentech, Seagen. M. Sampayo-Cordero: Financial Interests, Personal, Other, Honoraria: MEDSIR, Syntax for Science, Optimapharm, Ability Pharma; Financial Interests, Personal, Research Grant: MEDSIR; Financial Interests, Personal, Other, Travel: MEDSIR, Syntax for Science, Optimapharm, and Roche; Financial Interests, Personal, Other, Consultant: MEDSIR, Syntax for Science, and Optimapharm; Financial Interests, Personal, Speaker’s Bureau: MEDSIR; Financial Interests, Personal, Full or part-time Employment: MEDSIR. A. Llombart Cussac: Financial Interests, Personal, Project Lead: Eisai, Celgene, Lilly, Pfizer, Roche, Novartis, MSD; Financial Interests, Personal, Stocks/Shares: MedSIR, Initia-Research; Financial Interests, Personal, Advisory Role: Lilly, Roche, Pfizer, Novartis, Pierre Fabre, GenomicHealth, GSK; Financial Interests, Personal, Speaker’s Bureau: Lilly, AstraZeneca, MSD; Financial Interests, Personal, Research Grant: Roche, Foundation Medicine, Pierre Fabre, Agendia; Financial Interests, Personal, Other, Travel: Roche, Lilly, Novartis, Pfizer, AstraZeneca. J. Cortés: Financial Interests, Personal, Advisory Role: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks; Financial Interests, Personal, Other, honoraria: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London; Financial Interests, Personal, Stocks/Shares: MedSIR, Nektar Pharmaceuticals, Leuko (relative); Financial Interests, Personal, Other, travel: Roche, Novartis, Eisai, pfizer, Daiichi Sankyo, AstraZeneca. All other authors have declared no conflicts of interest.

Background

Patients (pts) with a/mTNBC have limited treatment options and poor prognosis. Combining checkpoint inhibitors with 1L chemotherapy improves outcomes but only in PD-L1+ve a/mTNBC, emphasizing a critical need. Dato-DXd, a TROP2 antibody-drug conjugate (ADC) with potent topoisomerase (TOPO) I inhibitor payload, elicited a 34% objective response rate (ORR) in heavily pretreated a/mTNBC and 52% ORR in a subset naïve to TOPO I-based ADCs. In BEGONIA, an ongoing 2-part, open-label platform study, D (an anti-PD-L1 antibody) combined with other therapies, including ADCs, is being evaluated in 1L a/mTNBC (NCT03742102). Here, we report preliminary results of Dato-DXd + D.

Methods

Unresectable a/mTNBC pts eligible for 1L treatment, regardless of PD-L1/TROP2 status, received intravenous Dato-DXd 6 mg/kg + D 1120 mg every 3 weeks until progression or unacceptable toxicity. Primary endpoints are safety and tolerability. Secondary endpoints include investigator-assessed ORR (RECIST v1.1) and response duration. Data cutoff was Nov 2021.

Results

29 pts received Dato-DXd + D (24 ongoing), 27 had the opportunity to have 2 postbaseline scans. Median (range) follow-up was 3.9 (2–6) months. Confirmed ORR was 20/27 (74%; 95% CI, 54–89); 2 (7%) pts had complete and 18 (67%) had partial responses, all were in response at data cutoff. No dose-limiting toxicities were observed. 4 pts (14%) underwent 1 Dato-DXd dose reduction due to stomatitis, 4 (14%) had 1 Dato-DXd dose delay, and 4 (14%) had 1 D dose delay. No dose modifications were required due to diarrhea. Table: 166MO

Summary of adverse events (AEs), n (%)

Conclusions

Combination of Dato-DXd + D in 1L a/mTNBC demonstrated robust response rates with a manageable safety profile in this preliminary analysis, warranting further investigation. Additional enrollment and analysis of translational data is ongoing. Funding: AstraZeneca/Daiichi Sankyo.

Clinical trial identification

NCT03742102.

Editorial acknowledgement

Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Nicole Seneca, PhD, of Parexel (Hackensack, NJ) and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca/Daiichi Sankyo.

Funding

AstraZeneca/Daiichi Sankyo.

Disclosure

P. Schmid: Financial Interests, Personal and Institutional, Other, Employment, consulting or advisory role and research funding: Genentech; Financial Interests, Personal and Institutional, Other, Employment, Honoraria, consulting or advisory role and research funding: Roche; Financial Interests, Personal and Institutional, Other, Honoraria, consulting or advisory role and research funding: AstraZeneca; Financial Interests, Personal and Institutional, Other, Honoraria, consulting or advisory role and research funding: Novartis; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: Pfizer; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Bayer; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Celgene; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Eisai; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Merck; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Puma Biotechnology; Financial Interests, Institutional, Funding, Research Funding: Astellas Pharma; Financial Interests, Institutional, Funding, Research funding: OncoGenex. K.H. Jung: Financial Interests, Personal, Advisory Role, Consulting or advisory role: AstraZeneca; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Celgene; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Eisai; Financial Interests, Personal, Advisory Role, Consulting or advisory role: MSD; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Novartis; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Roche; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Takeda. P.J. Wysocki: Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: AstraZeneca; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: Astellas; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: Amgen; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: BMS; Financial Interests, Institutional, Other, Honoraria: Gilead; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: IPSEN; Financial Interests, Personal and Institutional, Other, Honoraria, consulting or advisory role and research funding: Immunicom; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: Janssen; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: MSD; Financial Interests, Personal and Institutional, Other, Honoraria, consulting or advisory role and research funding: Merck; Financial Interests, Personal and Institutional, Other, Honoraria, consulting or advisory role and research funding: Pierre Fabre; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: Pfizer; Financial Interests, Personal and Institutional, Other, Honoraria, consulting or advisory role and research funding: Roche; Financial Interests, Personal and Institutional, Other, Honoraria and consulting or advisory role: Sanofi. J. Jassem: Financial Interests, Personal, Other, Personal fees: AstraZeneca; Financial Interests, Personal, Other, Personal fees: Pfizer; Financial Interests, Personal, Other, Personal fees: Roche; Financial Interests, Personal, Advisory Role, Consulting or Advisory role: AstraZeneca; Financial Interests, Personal, Advisory Role, Consulting or Advisory role: Pfizer; Financial Interests, Personal, Advisory Role, Consulting or Advisory role: Exact Sciences; Financial Interests, Personal, Other, Conference registration fee: Boehringer Ingelheim. C.X. Ma: Financial Interests, Personal and Institutional, Funding, Funding: Puma; Financial Interests, Personal and Institutional, Funding, Funding: Pfizer; Financial Interests, Personal, Advisory Role, Consulting Fees: Gilead; Financial Interests, Personal, Advisory Role, Consulting Fees: AstraZeneca; Financial Interests, Personal, Advisory Role, Consulting Fees: Athenex; Financial Interests, Personal, Advisory Role, Consulting Fees: Jacobio; Financial Interests, Personal, Advisory Role, Consulting Fees: Natera; Financial Interests, Personal, Advisory Role, Consulting Fees: Bayer Healthcare; Financial Interests, Personal, Advisory Role, Consulting Fees: Biovica; Financial Interests, Personal, Advisory Role, Consulting Fees: Eisai; Financial Interests, Personal, Advisory Role, Consulting Fees: Eli Lilly; Financial Interests, Personal, Advisory Role, Consulting Fees: Novartis; Financial Interests, Personal, Advisory Role, Consulting Fees: Phillips Electronics; Financial Interests, Personal, Advisory Role, Consulting Fees: Sanofi; Financial Interests, Personal, Advisory Role, Consulting Fees: Seattle Genetics; Financial Interests, Personal, Advisory Role, Consulting Fees: Pfizer. R. Fernandes: Financial Interests, Personal, Advisory Role, Consulting fees: Canadian Agency for Drugs and Technologies in Health (CADTH); Financial Interests, Institutional, Other, Honoraria: Bayer; Financial Interests, Institutional, Other, Honoraria: Pfizer; Financial Interests, Institutional, Other, Honoraria: Ipsen; Financial Interests, Institutional, Other, Honoraria: BMS; Financial Interests, Institutional, Other, Honoraria: Merck; Financial Interests, Institutional, Other, Honoraria: Novartis; Financial Interests, Institutional, Other, Honoraria: Janssen. R. Huisden: Financial Interests, Personal, Full or part-time Employment, Personal fees from AstraZeneca during the conduct of the study and outside the submitted work: AstraZeneca. R. Stewart: Financial Interests, Personal, Full or part-time Employment, Personal fees from AstraZeneca, during the conduct of the study and outside the submitted work: AstraZeneca; Financial Interests, Personal, Other, Personal fees from Pfizer, outside the submitted work: Pfizer. P. Vukovic: Financial Interests, Personal, Full or part-time Employment, Personal fees from AstraZeneca during the conduct of the study and outside the submitted work: AstraZeneca. A. Tablante Nunes: Financial Interests, Personal, Full or part-time Employment, Personal fees from AstraZeneca during the conduct of the study and outside the submitted work: AstraZeneca. Z. Nowecki: Financial Interests, Institutional, Other, Honoraria: AstraZeneca; Financial Interests, Institutional, Other, Honoraria: Sanofi Aventis; Financial Interests, Institutional, Other, Honoraria: MSD; Financial Interests, Institutional, Other, Honoraria: Roche.