Maria Gion Cortes (Madrid, Spain)
Hospital Universitario Ramon y CajalAuthor Of 2 Presentations
14P - Gut and oral microbiota profiling in patients (pts) with hormone receptor-positive (HR+) metastatic breast cancer (MBC) receiving pembrolizumab (P) plus eribulin (E): CALADRIO (ID 32)
- Nancy Teng (Norwich, United Kingdom)
- Matthew J. Dalby (Norwich, United Kingdom)
- Raymond Kiu (Norwich, United Kingdom)
- Tim Robinson (Bristol, United Kingdom)
- Maria Gion Cortes (Madrid, Spain)
- Begona Bermejo De Las Heras (Valencia, Spain)
- Jose Manuel Perez Garcia (Barcelona, Spain)
- Lourdes Calvo-Martinez (A Coruña, Spain)
- Aleix Prat (Barcelona, Spain)
- Raul Marquez Vazquez (Madrid, Spain)
- Manuel Ruiz Borrego (Seville, Spain)
- Susana De la Cruz (Pamplona, Spain)
- Antonio Llombart Cussac (Valencia, Spain)
- Giuseppe Curigliano (Milan, Italy)
- Peter Schmid (London, United Kingdom)
- Mario Mancino (Valencia, Spain)
- Lindsay Hall (Norwich, United Kingdom)
- Stephen Robinson (Norwich, United Kingdom)
- Javier Cortes (Madrid and Barcelona, Spain)
- Andrea Malfettone (Barcelona, Spain)
Abstract
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.
205TiP - ATRACTIB: A Phase 2 Trial of First-Line (1L) Atezolizumab (A) in Combination with Paclitaxel (P) and Bevacizumab (B) in Metastatic Triple-Negative Breast Cancer (mTNBC) (ID 213)
- Antonio Llombart Cussac (Valencia, Spain)
- Alfonso Cortes Salgado (Madrid, Spain)
- Jose Manuel Perez Garcia (Barcelona, Spain)
- Silvia Patricia Cortez Castedo (Madrid, Spain)
- Maria Gion Cortes (Madrid, Spain)
- Serafin Morales Murillo (Alpicat, Spain)
- Isabel Blancas López-Barajas (Granada, Spain)
- Salvador Blanch (Valencia, Spain)
- Isabel Calvo Plaza (Madrid, Spain)
- Nieves Diaz Fernandez (Alicante, Spain)
- Frederik Marmé (Mannheim, Germany)
- Alejandro Martinez Bueno (Barcelona, Spain)
- Maria Teresa Taberner Bonastre (Valencia, Spain)
- Michelino De Laurentiis (Napoli, Italy)
- Manuel Ruiz Borrego (Seville, Spain)
- Peter Schmid (London, United Kingdom)
- Valentina Guarneri (Padova, Italy)
- Joseph Gligorov (Paris, France)
- Miguel Sampayo-Cordero (Barcelona, Spain)
- Javier Cortes (Madrid and Barcelona, Spain)
Abstract
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.