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

Chemotherapy (CT) followed by endocrine therapy (ET) is the current standard of care for high-risk hormone receptor (HR)-positive/HER2-negative early breast cancer (EBC). The monarchE, with 27-months follow-up, showed that the addition of abemaciclib for 2 years in combination with ET improves the 3-years invasive relapse rate (IRR) and distant relapse rate (DRR) for patients (pts) with high-risk EBC. Obtaining data on the long-term risk of relapse is needed to put into context the magnitude of abemaciclib benefit.

Methods

We performed a retrospective analysis of 1742 HR-positive/HER2-negative EBC pts fulfilling the high-risk criteria of the monarchE in order to estimate their long-term outcomes. They were selected from El Álamo IV registry with pts diagnosed between 2002 and 2005 and 3 adjuvant GEICAM studies (9906, 2003-10 and 2006-10,) carried out from 1999 to 2010. Pts were divided in 2 cohorts (C), similarly to monarchE: C1) ≥ 4 positive axillary lymph nodes (PALN) or 1–3 PALN with tumor size (T) ≥ 5cm and/or histologic grade (G) 3and C2) 1–3 PALN (with T < 5cm and G < 3) and Ki-67 ≥ 20%. Pts had to have undergone surgery with curative intent and had received adjuvant CT (anthracyclines +/- taxanes) and ET.

Results

El Álamo IV registered 6374 luminal EBC pts from which 16.2% were high-risk and included in the analysis (n=1030; 981 C1, 49 C2). In addition 326 pts from 9906 (311 C1, 15 C2), 225 pts from 2003-10 (C1) and 161 pts from 2006-10 (C1) were included. With a median follow-up of 10.2 years, the IRR and DRR at 5 and 10 years were 22% and 34.8% and 19.7% and 31.0%, respectively. Per-year IRR, DRR, and death rate (DR) are described in the table. IRR and DRR increased from year 2, till year 3 followed by a second peak at years 7-8. DR increased steadily from year 1 (7.8% and 24.8% at 5 and 10 years). Table: 62P

Conclusions

The highest yearly risk of recurrence of high-risk EBC, defined as in monarchE, is at 3 years after diagnosis but remains high in the long-term follow-up.

Legal entity responsible for the study

GEICAM Spanish Breast Cancer Group.

Funding

LILLY.

Disclosure

M. Martin Jimenez: Financial Interests, Personal, Advisory Board: ASTRAZENECA; Financial Interests, Personal, Invited Speaker: PFIZER; Financial Interests, Personal, Invited Speaker: ASTRAZENECA; Financial Interests, Personal, Advisory Board: LILLY; Financial Interests, Personal, Invited Speaker: LILLY; Financial Interests, Personal, Invited Speaker: NOVARTIS; Financial Interests, Personal, Advisory Board: ROCHE/GENENTECH; Financial Interests, Personal, Invited Speaker: ROCHE/GENENTECH; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: NOVARTIS; Financial Interests, Institutional, Research Grant: ROCHE; Financial Interests, Institutional, Research Grant: Puma; Non-Financial Interests, Invited Speaker: TRIO; Non-Financial Interests, Leadership Role: GEICAM. B. Bermejo De Las Heras: Financial Interests, Institutional, Advisory Role: MSD, Roche, Pierre Fabre, Novartis, AstraZeneca, Seagen; Financial Interests, Institutional, Speaker’s Bureau: Pfizer, Roche, MSD, Palex, Eisai, Daiichi, AstraZeneca, Seagen. A. Guerrero: Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Advisory Board: Pfizer, Palex, Novartis, AstraZeneca, Pierre Fabre; Financial Interests, Personal, Other, Travel grant: Pfizer, Novartis; Financial Interests, Institutional, Speaker’s Bureau: Novartis, Pfizer, Lilly, AstraZeneca. A. Santaballa Bertran: Financial Interests, Institutional, Advisory Role: Pfizer. S. Lopez-Tarruella Cobo: Financial Interests, Institutional, Advisory Role: AstraZeneca, Novartis, Roche, Pfizer, Pierre Fabre, Lilly, Seagen, Daiichi Sankyo Europe GmbH, Gilead Sciences,MSD, GalaxoSmithkline, Veracyte; Financial Interests, Personal, Speaker’s Bureau: Lilly. All other authors have declared no conflicts of interest.

Background

Neratinib (N), an irreversible pan-HER TKI, is approved in the EU for extended adjuvant treatment of early-stage HR+ HER2+ breast cancer (BC) after adjuvant trastuzumab (T)-based therapy. The CONTROL trial (NCT02400476) investigated pre-emptive antidiarrheal prophylaxis or dose escalation (DE) for prevention of diarrhea, the most frequent side effect of N.

Methods

CONTROL is an international, multi-cohort, open-label, phase 2 study. Patients (pts) ≥18y with stage I–IIIc HER2+ BC received oral N (240 mg/d for 1y) after T-based adjuvant therapy. Pts were enrolled sequentially into separate cohorts: 1) mandatory loperamide prophylaxis; 2) budesonide + loperamide; 3) colestipol + loperamide; 4) colestipol + loperamide PRN; 5) DE + loperamide PRN (2 cohorts). DE1 schedule: N 120 mg/d x w1, 160 mg/d x w2, then 240 mg/d from w3 to 12m. DE2 schedule: N 160 mg/d x w1&2, 200 mg/d x w3&4, then 240 mg/d from w5 to 12m. Primary endpoint: incidence of grade ≥3 diarrhea.

Results

563 pts were enrolled. All preventive strategies reduced grade 3 diarrhea vs ExteNET (historical control: 39%). Median cumulative duration of grade 3 diarrhea ranged from 2–3.5d in CONTROL (vs 5.0d for ExteNET). The proportion of pts discontinuing N because of diarrhea was decreased in CONTROL vs ExteNET. Key diarrhea outcomes in all CONTROL cohorts are presented in the table and will be fully detailed during the congress. Table: 73P

Patient disposition and diarrhea characteristics: All CONTROL cohorts

Conclusions

These final findings from CONTROL show improved tolerability of N with all diarrhea prophylaxis strategies and suggest that DE1 with loperamide PRN allows pts to stay on treatm.ent longer and receive full benefit from N.

Clinical trial identification

NCT02400476.

Editorial acknowledgement

Editorial/writing assistance for this abstract was provided by Lee Miller (Miller Medical Communications Ltd.). This work was funded by the study sponsor (Puma Biotechnology Inc.).

Legal entity responsible for the study

Puma Biotechnology Inc.

Funding

Puma Biotechnology Inc.

Disclosure

A. Brufsky: Financial Interests, Personal, Advisory Role, Consulting fees: Puma Biotechnology Inc. A.J. Chien, R. Bose: Financial Interests, Institutional, Research Grant: Puma Biotechnology Inc. B. Pistilli: Financial Interests, Personal, Advisory Role, Consulting fees: Puma Biotechnology Inc.; Financial Interests, Personal, Advisory Role, Consulting fees: Pierre Fabre; Financial Interests, Institutional, Research Grant: Puma Biotechnology Inc. D. Diprimeo, N. Foruzan, L.M. McCulloch: Financial Interests, Personal, Full or part-time Employment: Puma Biotechnology Inc.; Financial Interests, Personal, Stocks/Shares: Puma Biotechnology Inc. All other authors have declared no conflicts of interest.

Background

Cyclin-dependent kinase (CDK) 4/6 inhibition + ER signaling blockade is a highly effective treatment option for metastatic ER+/HER2− BC. Preclinical studies show evidence of CDK 4/6 and programmed death-1 (PD-1) blockade synergy. CheckMate 7A8, a non-comparative, phase 2 study, evaluated neoadjuvant NIVO + PALBO + ANA in patients (pts) with ER+/HER2− primary BC. Here, we report safety outcomes from the safety run-in phase.

Methods

Eligible pts were men or postmenopausal women with newly diagnosed, histologically confirmed, untreated ER+/HER2− BC with primary tumor ≥ 2 cm, an ECOG performance status of 0/1, and eligible for post-treatment surgery. Pts received NIVO 480 mg IV every 4 wks (1 cycle), PALBO 125 mg (dose level [DL] 1) or 100 mg (DL 2) PO once daily (QD) for 3 wks per cycle, and ANA 1 mg PO QD, for 5 cycles total/until disease progression. Primary endpoint (safety run-in phase) was the number of pts with occurrence of dose-limiting toxicity (treatment-emergent adverse events [AEs] within 4 wks of treatment start).

Results

As of safety data review on 6 May 2021, 21 pts (DL 1: n = 9; DL 2: n = 12) were treated. Most common grade ≥3 treatment-related AEs (TRAEs) were elevated alanine or aspartate aminotransferase, neutropenia, and decreased white blood cell count in DL 1 (n = 2 each; 22.2%), and decreased neutrophil count (n = 5; 41.7%) in DL 2. 5 pts (DL 1) and 4 pts (DL 2) discontinued treatment due to toxicity, mainly grade ≥3 hepatic TRAEs (Table). The study was closed on 27 July 2021 after safety run-in ended. Additional safety and preliminary efficacy data (database lock: 3 February 2022) will be presented. Table: 92MO

Conclusions

Neoadjuvant NIVO + PALBO + ANA showed a higher incidence of grade ≥3 hepatic TRAEs than historical single-agent safety profiles. These findings show a potential safety risk for the use of endocrine therapy with PD-1 + CDK 4/6 blockade.

Clinical trial identification

NCT04075604.

Editorial acknowledgement

Writing and editorial assistance was provided by Vidya Rajagopalan of Evidence Scientific Solutions, funded by Bristol Myers Squibb.

Legal entity responsible for the study

Bristol Myers Squibb, Princeton, NJ, USA.

Funding

Bristol Myers Squibb, Princeton, NJ, USA.

Disclosure

G. Jerusalem: Financial Interests, Institutional, Research Grant: Novartis, Pfizer; Financial Interests, Institutional, Royalties: Roche; Financial Interests, Personal, Other, Consulting Fees: Novartis, Amgen, Roche, Pfizer, Bristol Myers Squibb, Lilly, AstraZeneca, Daiichi Sankyo, AbbVie; Financial Interests, Personal, Invited Speaker, Honoraria: Novartis, Roche, Amgen, Pfizer, Bristol Myers Squibb, Lilly, AstraZeneca, Seagen; Financial Interests, Personal, Other, Travel/Accommodations/Expenses/Accommodations: Novartis, Roche, Pfizer, Lilly, Amgen; Financial Interests, Personal, Other, Travel/Accommodations/Expense: Bristol Myers Squibb, AstraZeneca; Financial Interests, Personal, Advisory Board: Novartis, Roche, Amgen, Pfizer, Bristol Myers Squibb, Lilly, AstraZeneca, Daiichi Sankyo, AbbVie; Financial Interests, Personal, Other, Medical Writing: Novartis, Roche, Lilly, Amgen, Bristol Myers Squibb, AstraZeneca, MedImmune, Merck. A. Prat: Financial Interests, Personal, Full or part-time Employment: Novartis; Financial Interests, Personal, Other, Honoraria: Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Novartis, Pfizer, Roche, Amgen, Bristol Myers Squibb, Boehringer, Puma, Oncolytics Biotech, Daiichi Sankyo, AbbVie, AstraZeneca, NanoString Technologies; Financial Interests, Institutional, Sponsor/Funding, Research Funding: Novartis, Roche, Incyte, Puma Biotech; Financial Interests, Personal, Invited Speaker, Honoraria: Roche; Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Personal, Other, Honoraria: MSD Oncology, Lilly, Daiichi Sankyo, Amgen, Guardant Health; Financial Interests, Personal, Other, Travel/Accommodations/Expense: Daiichi Sankyo. R.F. Salgado: Financial Interests, Personal, Advisory Board: Roche, Bristol Myers Squibb; Non-Financial Interests, Personal, Other, Travel/Accommodations: Roche, Puma, Merck. M. Reinisch: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Daiichi Sankyo, Roche, Seagen, Somatex, MSD, Lilly, Pfizer; Financial Interests, Personal, Member, Honoraria: Novartis; Financial Interests, Personal, Advisory Board, Consultancy: Somatex; Financial Interests, Personal, Other, Travel: Pfizer, Novartis. C. Saura: Financial Interests, Personal, Advisory Board: AstraZeneca, AX'Consulting, Byondis B.V., Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann, ISSECAM, Medical Statistics Consulting, MediTech, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Pierre Fabre, PintPharma, Puma, Roche Farma, Sanofi-Aventis, Seagen, Zymeworks; Non-Financial Interests, Institutional, Research Grant: Aragon Pharmaceuticals, AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Bristol Myers Squibb, Byondis B.V., Cytomx Therapeutics, Daiichi Sankyo, Eli Lilly and Company, F. Hoffmann-La Roche Ltd., Genentech, German Breast Group Forchungs, GlaxoSmithkline, Immunomedics, Innoup Farma, International Breast Cancer Study Group (IBCSG), Macrogenics, Medica Scientia Innovation Research, Menarini Ricerche, Merck, Merus, Millennium Pharmaceuticals, Novartis, Pfizer, Piqur Therapeutics, Puma, Roche, Sanofi-Aventis, Seattle Genetics, Synthon, Zenith Pharma; Non-Financial Interests, Personal, Member: American Association for Cancer Research (AACR), American Society for Clinical Oncology (ASCO), Geicam (Spanish Breast Cancer Research Group), SOLTI group (Academic research group in breast cancer), Spanish Society of Medical Oncology (SEOM). J. Filian, F. Ades, A. Mazzei-Abba: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. N. Huang: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. S.M. Tolaney: Financial Interests, Personal and Institutional, Other, Ad Board Participant/Consultant; Research Funding (to institution): Bristol Myers Squibb, AstraZeneca, Eli Lilly, Merck, Novartis, Seagen, Sanofi, Eisai, Gilead, Pfizer, Genentech/Roche, Odonate; Financial Interests, Institutional, Research Grant: Nektar, NanoString, Exelixis, Cyclacel; Financial Interests, Personal, Advisory Board: Certara, Mersana Therapeutics, G1 Therapeutics, OncoSec, OncoPep, CytomX, Athenex, Ellipses Pharma, 4D Pharma, Puma, Zymeworks, Zentalis, Reveal Genomics, OncXerna, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Chugai Pharma; Financial Interests, Personal, Other, Consultant: Blueprint Medicines. All other authors have declared no conflicts of interest.

Background

PHERGain trial investigated the potential of metabolic imaging to identify candidates for chemotherapy (CT) de-escalation in HER2-positive, stage I-IIIA, invasive, operable breast cancer with at least one breast lesion evaluable by FDG-PET. Based on data from NeoALTTO study, FDG-PET “responders” were defined as those pts with maximum standardized uptake value (SUV_max) reduction of at least 40% in all their target lesions after two cycles of T and P. Of the 285 patients included in T+P arm, 227 pts were FDG-PET responders and received a total of 8 cycles of T+P. pCR, defined as pT0/isN0, reached 37.9% (86/227 pts). Here we describe secondary preplanned analysis of the best cut-off of SUV_max reduction for pCR prediction.

Methods

ROC analysis was applied to research the most appropriate deltaSUV_max cut-off in HER2+ EBC pts treated exclusively with neoadjuvant T and P (± endocrine therapy).

Results

The delta SUV_max capability of predicting pCR in terms of AUC was 72.1% (95%CI, 65.1-79.2). The optimal SUV_max reduction cut-off was found to be 77.0%, with a 51.2% sensitivity and a 78.7% specificity for prediction of pCR. Yet, using this cut-off, 32.6% (74/227 pts) would be classified as FDG-PET responders increasing the pCR rate from 37.9% (cut-off ≥40%) to 59.5% (44/74 pts) (p<0.01). With this optimized cut-off 19.4% (44/227 pts) would avoid chemotherapy to achieve a pCR. Subgroup analysis in pts with HER2 immunohistochemistry score 3+ will be reported.

Conclusions

Increased deltaSUV_max cut-off (≥77%) after two cycles of exclusive T+P achieves a pCR rate in the range of control arm with CT+TP in PHERGain (59,5% vs. 57,7%, respectively) selecting a subgroup of pts with HER2 addicted tumors. However, the original cut-off (≥40%) maximizes the number of pts who could avoid CT. The definitive value of pCR in the absence of CT should be confirmed by final DDFS results from PHERGain trial.

Legal entity responsible for the study

Medica Scientia Innovation Research (MEDSIR) Barcelona, Spain and Ridgewood, New Jersey.

Funding

Has not received any funding.

Disclosure

G. Gebhart: Financial Interests, Institutional, Advisory Board: Roche; Financial Interests, Institutional, Funding: Roche. M. Keyaerts: Financial Interests, Institutional, Funding, Precirix; Financial Interests, Personal, Stocks/Shares, Abscint. S. Escriva de Romani: Financial interests, Personal, Invited Speaker: Daiichi Sankyo/AstraZeneca, Pfizer, Roche. Financial interests, Personal, Advisory Board: Daiichi Sankyo/AstraZeneca, Roche, Seagen. Financial interests, Insitutional, Other, Local PI: Byondis, Lilly, MedSIR, Roche, Synthon. M.A. Colleoni: Financial Interests, Personal, Other: Novartis; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Role: Pfizer, OBI Pharma, Celldex; AstraZeneca; Financial Interest, Personal, Research Grant: Roche. M. Atienza de Frutos: Financial Interests, Personal, Full or part-time Employment: Lilly; Financial Interests, Personal, Stocks/Shares: Lilly. M. Sampayo-Cordero: Financial Interests, Personal, Other: MEDSIR, Syntax for Science, Nestle; Financial Interests, Personal, Advisory Board: MEDSIR, Syntax for Science, Nestle; Financial Interests, Personal, Speaker’s Bureau: MEDSIR, Syntax for Science, Nestle, Roche; Financial Interests, Personal, Funding: MEDSIR, Syntax for Science, Nestle, Roche. J. Cortés: Financial Interests, Personal, Advisory Board: 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, Zymeworks, Gemoab, Gilead, Menarini, Reveal Genomics; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Baxalta GMBH/Servier Affaires, Roche, Ariad Pharmaceuticals, AstraZeneca, Bayer Healthcare, Eisai, Guardanth Health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, Puma B, Queen Mary University of London; Financial Interests, Personal, Stocks/Shares: MedSIR, Nektar Therapeutics; Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo. J.M. Perez Garcia: Financial Interests, Personal, Advisory Board: Roche, Eli Lilly; Financial Interests, Personal, Expert Testimony: Eisai. A. Llombart Cussac: Financial Interests, Personal, Leadership Role: Eisai, Celgene, Lilly, Pfizer, Roche, Novartis, MSD; Financial Interests, Personal, Stocks/Shares: MEDSIR, Initia-Research; Financial Interests, Personal, Advisory Board: Lilly, Roche, Pfizer, Novartis, Pierre Fabre, Genomic Health, GSK; Financial Interests, Personal, Speaker’s Bureau: Lilly, AstraZeneca, MSD; Financial Interests, Institutional, Funding: Roche, Foundation Medicine, Pierre Fabre, Agendia; Financial Interests, Personal, Other: Roche, Lilly, Novartis, Pfizer, AstraZeneca. All other authors have declared no conflicts of interest.

Background

The phase 2, noncomparative BYLieve study showed efficacy of ALP (PI3K-α inhibitor and degrader) + ET in pts with PIK3CA-mutated, HR+, HER2– ABC progressing on/after (Cohort A) cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI), (Cohort B) CDKi + fulvestrant (FUL), or (Cohort C) AI followed by chemotherapy or ET as immediate prior treatment (Tx). Here we report efficacy for subgroups of interest.

Methods

Pts received ALP + FUL (Cohorts A and C) or ALP + letrozole (Cohort B). Subgroups were pre- (PreM) or postmenopausal (PM; includes surgically sterile) status, and presence of bone lesion-only (BO) or visceral disease (VD) regardless of PreM/PM status for each cohort, and prior Tx for Cohort C (prior CDKi + FUL or AI; used only once in any line/setting). Efficacy endpoints assessed in pts with centrally confirmed PIK3CA mutation were progression-free survival (PFS) and overall survival (OS) for Cohort A (18-mo follow-up [FU]) and PFS for Cohorts B and C (6-mo FU).

Results

A total of 16.5%, 5.2%, and 13.9% of pts were PreM in Cohorts A, B, and C, respectively; 18.2% and 67.8%, 9.6% and 76.5%, and 12.2% and 73.9% had BO and VD in Cohorts A, B, and C, respectively. 19.1% and 40.0% of Cohort C pts had prior CDKI + FUL or CDKi + AI Tx, respectively. Median (m) PFS was numerically higher for PM vs PreM pts, pts with vs without BO, and pts without vs with VD (Cohorts A and B). In Cohort C, mPFS was overall similar across subgroups. In Cohort A, mOS was 5.5-mo longer in PM vs PreM pts; Cohorts B and C OS data were immature by cutoff. Efficacy data are summarized in the table. Table: 175P

Conclusions

Overall, these ad hoc exploratory analyses demonstrate clinical benefit of ALP + ET across subgroups of interest (despite low number of pts in some subgroups) in all cohorts, including PreM pts, and pts with VD who typically have worse prognosis.

Clinical trial identification

NCT03056755; EUDRACT2016-004586-67.

Editorial acknowledgement

We thank Marcelene Yumul, MD, and Casandra M. Monzon, PhD, of Healthcare Consultancy Group, LLC, for their medical editorial assistance with this abstract, which was funded by Novartis.

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation.

Funding

Novartis Pharmaceuticals Corporation.

Disclosure

F. Cardoso: Financial Interests, Personal, Other, Consultancy: Amgen; Financial Interests, Personal, Other, Consultancy: Astellas/Medivation; Financial Interests, Personal, Other, Consultancy: AstraZeneca; Financial Interests, Personal, Other, Consultancy: Celgene; Financial Interests, Personal, Other, Consultancy: Daiichi Sankyo; Financial Interests, Personal, Other, Consultancy: Eisai; Financial Interests, Personal, Other, Consultancy: GE Oncology; Financial Interests, Personal, Other, Consultancy: Genentech; Financial Interests, Personal, Other, Consultancy: GlaxoSmithKline; Financial Interests, Personal, Other, Consultancy: Macrogenics; Financial Interests, Personal, Other, Consultancy: Medscape; Financial Interests, Personal, Other, Consultancy: Merck-Sharp; Financial Interests, Personal, Other, Consultancy: Merus BV; Financial Interests, Personal, Other, Consultancy: Mylan; Financial Interests, Personal, Other, Consultancy: Mundipharma; Financial Interests, Personal, Other, Consultancy: Novartis; Financial Interests, Personal, Other, Consultancy: Pfizer; Financial Interests, Personal, Other, Consultancy: Pierre Fabre; Financial Interests, Personal, Other, Consultancy: prIME Oncology; Financial Interests, Personal, Other, Consultancy: Roche; Financial Interests, Personal, Other, Consultancy: Sanofi; Financial Interests, Personal, Other, Consultancy: Samsung Bioepis; Financial Interests, Personal, Other, Consultancy: Seagen; Financial Interests, Personal, Other, Consultancy: Teva; Financial Interests, Institutional, Invited Speaker: Amgen; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Boehringer-Ingelheim; Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker: Bayer; Financial Interests, Institutional, Invited Speaker: Daiichi; Financial Interests, Institutional, Invited Speaker: Eisai; Financial Interests, Institutional, Invited Speaker: Fresenius GmbH; Financial Interests, Institutional, Invited Speaker: Genentech; Financial Interests, Institutional, Invited Speaker: GlaxoSmithKline; Financial Interests, Institutional, Invited Speaker: Ipsen; Financial Interests, Institutional, Invited Speaker: Incyte; Financial Interests, Institutional, Invited Speaker: Nektar Therapeutics; Financial Interests, Institutional, Invited Speaker: Nerviano; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: Macrogenics; Financial Interests, Institutional, Invited Speaker: Medigene; Financial Interests, Institutional, Invited Speaker: MedImmune; Financial Interests, Institutional, Invited Speaker: Merck; Financial Interests, Institutional, Invited Speaker: Millenium; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Pierre Fabre; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: Sanofi-Aventis; Financial Interests, Institutional, Invited Speaker: Sonus; Financial Interests, Institutional, Invited Speaker: Taiho Oncology; Financial Interests, Institutional, Invited Speaker: Tesaro; Financial Interests, Institutional, Invited Speaker: Tigris; Financial Interests, Institutional, Invited Speaker: Wilex; Financial Interests, Institutional, Invited Speaker: Wyeth; Non-Financial Interests, Leadership Role, President: ABC Global Alliance and ABC Consensus Conference and Guidelines; Non-Financial Interests, Member: ESMO; Non-Financial Interests, Member: ESO; Non-Financial Interests, Member: EORTC; Non-Financial Interests, Member: BCG; Non-Financial Interests, Member: IBCSG; Non-Financial Interests, Member: SOLTI; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Member: AACR; Non-Financial Interests, Member: EACR; Non-Financial Interests, Member: SIS; Non-Financial Interests, Member: ASPIC. D. Juric: Financial Interests, Personal, Other, Consulting fees: Novartis, EMD Serono, Eisai, Genentech, Ipsen, Syros Pharmaceuticals, Vibliome Therapeutics, Mapkure, Petra Pharma, Relay Therapeutics; Silverback Therapeutics, PIC Therapeutics; Financial Interests, Institutional, Other, Research funding: Novartis, Genentech, Takeda, Eisai, EMD Serono, Placon, Amgen, Syros Pharmaceuticals, InventisBio, Infinity Pharmaceuticals, Takeda, Pfizer; Financial Interests, Personal, Other, Ownership interest: Relay Therapeutics, PIC Therapeutics, Vibliome Therapeutics. F. Lerebours: Financial Interests, Personal, Other, Support for attending meetings and travel: Eisai, Mundipharma, Novartis, Pfizer, Roche; Financial Interests, Personal, Other, Participation on a Data Safety Monitoring Board or Advisory Board/Honoraria: AstraZeneca/Daiichi Sankyo, Eisai, Lilly, Novartis, Pierre Fabre, Pfizer, Roche, Seagen. I. Krop: Financial Interests, Personal, Other, Support for the present publication: Novartis; Financial Interests, Personal, Other, Payment or honoraria for lectures: Novartis, AstraZeneca, Context Therapeutics, Daiichi Sankyo, Genentech/Roche; Macrogenics, Merck, Seagen; Financial Interests, Institutional, Other, Grants: Genentech/Roche, Macrogenics, Pfizer. M. Ruiz Borrego: Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: AstraZeneca. P. Neven: Financial Interests, Institutional, Other, Consulting or advisory role: Eli Lilly, Gilead, Novartis, Pfizer, Roche, AstraZeneca; Financial Interests, Institutional, Other, Travel, accommodations, expenses: Amgen, AstraZeneca, Eisai, Eli Lilly, Mylan, Novartis, Pierre Fabre, Pfizer, Roche; Financial Interests, Institutional, Research funding non-profit organization: Kom op Tegen Kanker, Think Pink. Y.H. Park: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Other, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Institutional, Other, Research Grant: Pfizer; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Research Grant: Roche; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Institutional, Other, Research Grant: MSD; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Non-Financial Interests, Principal Investigator: AstraZeneca; Non-Financial Interests, Principal Investigator: Pfizer; Non-Financial Interests, Principal Investigator: Novartis; Non-Financial Interests, Principal Investigator: MSD; Non-Financial Interests, Principal Investigator: Lilly; Non-Financial Interests, Principal Investigator: Roche; Non-Financial Interests, Principal Investigator: Daiichi Sankyo. D. Yardley: Financial Interests, Institutional, Other, Research funding: AbbVie, Amgen, Biomarin, Biothera Pharmaceuticals, Clovis Pharma, Dana Farber Cancer Institute, Lilly, Roche/Genentech, Inycte, Innocrin Pharmaceuticals, MacroGenics, MedImmune, Medivation, Merck, Merrimack Pharmaceuticals, Nektar Therapeutics, Novartis, NSABP, Pfizer, Tesaro, Polyphor; Financial Interests, Institutional, Other, Consulting/Advisory role: Athenex, bioTheranostics, G1 Therapeutics, Immunomedics, Lilly, Merck, Novartis, Pfizer, Sanofi-Aventis. K. Jhaveri: Financial Interests, Personal, Other, Consulting/Advisory role fees: AbbVie, AstraZeneca, Blueprint Medicines, Biotheranostics, BMS, Genentech, Jounce Therapeutics, Lilly Pharmaceuticals, Novartis, Pfizer, Seattle Genetics, SunPharma Pvt Ltd, Taiho Oncology; Financial Interests, Institutional, Other, Research funding: ADC Therapeutics, AstraZeneca, Clovis Oncology, Debio Pharmaceuticals, Genentech, Immunomedics, Novartis, Lilly Pharmaceuticals, Merck/VelosBio, Novartis, Novita Pharmaceuticals, Pfizer, Puma Biotechnology, Zymeworks. C. Arce, M. Akdere: Financial Interests, Personal, Full or part-time Employment: Novartis; Financial Interests, Personal, Stocks/Shares: Novartis. E. Gu: Financial Interests, Personal, Full or part-time Employment: Novartis; Financial Interests, Personal, Other, Travel: Novartis. 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.

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.