Background

This analysis evaluated the cost effectiveness of pembrolizumab in combination with chemotherapy as neoadjuvant treatment and continued as a single agent as adjuvant treatment after surgery compared with neoadjuvant chemotherapy for patients with high-risk early-stage triple-negative breast cancer (eTNBC). The analysis was conducted from a US third-party public healthcare payer perspective.

Methods

A multi-state transition model including four mutually exclusive health states: event-free, locoregional recurrence, distant metastasis, and death was developed to simulate patients’ disease course over lifetime. Efficacy and safety data were derived from the KEYNOTE-522 randomized clinical trial. The model Quality-adjusted life-years (QALYs) were calculated based on EuroQoL-5 Dimensions (EQ-5D) utility data collected in the trial. Costs ($US, in 2021 values) for drug acquisition/administration, adverse events, disease management and subsequent therapies were included. Costs and outcomes were discounted at 3% per year. A series of deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results.

Results

In the base-case scenario, pembrolizumab plus chemotherapy followed by pembrolizumab resulted in an expected gain of 3.37 life-years (LYs) and 2.90 QALYs and an incremental cost of $US79,046 compared with chemotherapy alone. The incremental cost per QALY gain was $US27,285/QALY and the incremental cost per LY gain was $US23,489/LY, which were lower than all cost-effectiveness thresholds cited in the literature. Sensitivity analyses showed the results to be robust over plausible values of key model inputs.

Conclusions

Compared with neoadjuvant chemotherapy, pembrolizumab in combination with chemotherapy as neoadjuvant treatment and continued as a single agent as adjuvant treatment after surgery is projected to be a cost-effective option for high-risk eTNBC in the US.

Legal entity responsible for the study

The authors.

Funding

Merck & Co., Inc.

Disclosure

P.A. Fasching: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Merck, Sharp & Dohme; Financial Interests, Personal, Invited Speaker: Merck, Sharp & Dohme; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Hecal; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Invited Speaker: Seagen; Financial Interests, Personal, Advisory Board: Agendia; Financial Interests, Personal, Other, Medical Writing Support: Roche; Financial Interests, Institutional, Invited Speaker: BioNTech; Financial Interests, Institutional, Invited Speaker: Cepheid; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Member: Arbeitsgemeinschaft für Gynäkologische Onkologie e.V.; Non-Financial Interests, Member: Translational Research in Oncology; Non-Financial Interests, Member: Deutsche Gesellschaft für Senologie e.v. M. Huang, A. Haiderali, W. Pan, P. Hu, M. Chaudhuri, C. Le Bailly De Tilleghem, N. Cappoen: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc. W. Xue, Z. Zhou: Financial Interests, Institutional, Funding: Merck. J. O'Shaughnessy: Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Advisory Board: Agendia; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Aptitude Health; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: G1 Therapeutics; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: Immunomedics; Financial Interests, Personal, Advisory Board: Ipsen Biopharmaceuticals; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Myriad; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Ondonate; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Puma; Financial Interests, Personal, Advisory Board: prIME Oncology; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Syndax; Financial Interests, Personal, Advisory Board: Carrick Therapeutics; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Gilead Sciences; Financial Interests, Personal, Advisory Board: Ontada; Financial Interests, Personal, Advisory Board: Pierre Fabre Pharmaceuticals; Financial Interests, Personal, Advisory Board: Samsung Bioepis; Financial Interests, Personal, Advisory Board: Sanofi.

Background

Pembrolizumab in combination with chemotherapy showed significantly longer progression-free survival (PFS) and overall survival (OS) compared with chemotherapy alone and manageable safety as first-line treatment in patients with locally recurrent inoperable and metastatic triple-negative breast cancer (mTNBC) with PD-L1-positive (Combined Positive Score [CPS]≥ 10) tumors in the KEYNOTE-355 (KN355) trial. The objective of this analysis was to gain insights on the clinical benefits and risks of pembrolizumab in terms of quality-adjusted survival among patients in the trial.

Methods

KN355 is a double-blind, randomized, controlled, global phase III trial. This analysis was based on the final analysis of KN355. The Quality-adjusted Time without Symptoms of disease progression or Toxicity of treatment (Q-TWiST) analysis was used to compare the treatment arms. Survival time of each patient was partitioned into three health states: time before disease progression with toxicity (TOX), time before disease progression without toxicity (TWiST), and disease progression until death. Toxicities considered in the analysis were grade 3+ adverse events (AEs). Mean utility scores for the three health states were estimated using EQ-5D-3L data collected in the KN355 trial. Q-TWiST calculated as the utility-weighted sum of the mean health state durations. The published criterion for a ‘clearly clinically important’ improvement in Q-TWiST is 15% of mean OS in a study.

Results

Patients randomized to pembrolizumab plus chemotherapy had 5.44 months longer mean PFS, which consisted of 3.03- and 2.41-months gains in TOX and TWiST, respectively, compared to those randomized to chemotherapy alone with 44 months of follow-up. The improvement in Q-TWiST was 3.71 months (P=0.003, about 18% of mean OS). Results showed an increase in trend for the Q-TWiST improvement of pembrolizumab over time.

Conclusions

Despite higher risks for AEs, pembrolizumab combined with chemotherapy showed statistically significant and clinically meaningful improvement in quality-adjusted survival compared to chemotherapy alone as first-line treatment for PD-L1-positive mTNBC.

Legal entity responsible for the study

The authors.

Funding

Merck & Co., Inc.

Disclosure

P.A. Fasching: Financial Interests, Personal, Advisory Board: Roche, Novartis, Pfizer, Daiichi Sankyo, Eisai, Merck Sharp & Dohme, AstraZeneca, Hecal, Lilly, Pierre Fabre, Seagen, Agendia; Financial Interests, Personal, Invited Speaker: Novartis, Daiichi Sankyo, Eisai, Merck Sharp & Dohme, AstraZeneca, Lilly, Seagen; Financial Interests, Personal, Other, Medical Writing Support: Roche; Financial Interests, Institutional, Invited Speaker: BioNTech, Cepheid; Non-Financial Interests, Member: ASCO, Arbeitsgemeinschaft für Gynäkologische Onkologie e.V., Translational Research in Oncology, Deutsche Gesellschaft für Senologie e.v. M. Huang, A. Haiderali, W. Pan, P. Hu, M. Chaudhuri, N. Cappoen: Financial Interests, Personal, Full or part-time Employment: Merck.

C. Le Bailly De Tilleghem: Financial Interests, Personal, Full or part time Employment: MSD.

J. O’Shaughnessy: Financial Interests, Personal, Advisory Board: AbbVie, Agendia, Amgen, Aptitude Health, AstraZeneca, Bristol Myers Squibb, Celgene, Eisai, G1 Therapeutics, Genentech, Immunomedics, Ipsen Biopharmaceuticals, Lilly, Merck, Myriad, Novartis, Ondonate, Pfizer, Puma, prIME Oncology, Roche, Seattle Genetics, Syndax, Carrick Therapeutics, Daiichi Sankyo, Gilead Sciences, Ontada, Pierre Fabre Pharmaceuticals, Samsung Bioepis, Sanofi.

Background

HER2 IHC1+ or IHC2+ and in situ hybridization (ISH)-negative results are sometimes referred to as HER2-Low. SG is a novel antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to SN-38 via a proprietary, hydrolyzable linker. SG is approved in mTNBC for the second line (2L) onwards. In the ASCENT study, SG had significant progression-free survival (PFS) and overall survival (OS) benefit vs chemotherapy of physician’s choice (TPC). This ASCENT post hoc subgroup analysis evaluates SG efficacy in HER2 IHC0 and HER2-Low mTNBC.

Methods

Patients (pts) with mTNBC refractory/relapsing after ≥2 prior chemotherapies (≥1 in the metastatic setting) were randomized 1:1 to receive SG (10 mg/kg IV on d 1 and 8, every 21 d) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until unacceptable toxicity/progression. Primary endpoint was PFS per RECIST 1.1 by central review. Pts with known HER2-positive disease were ineligible, but HER2 status was not assessed centrally in ASCENT. Local HER2 IHC results were analyzed retrospectively.

Results

In the intent-to-treat (ITT) population (SG vs TPC), 149 vs 144, 63 vs 60, and 55 vs 58 pts had HER2 IHC0, HER2-Low, and missing HER2 IHC results, respectively; 79% of the ITT population was HER2-evaluable. Baseline characteristics between HER2 IHC0 vs HER2-Low were comparable and similar to the ITT population. Median PFS and OS were significantly improved, and objective response rate was numerically higher with SG vs TPC in the HER2 IHC0 and HER2-Low groups (Table). HER2-Low had numerically better outcomes vs HER2 ICH0 in both the SG and TPC arms.

Conclusions

Clinical benefit with SG in HER2 IHC0 and HER2-Low mTNBC was consistent with that of the ASCENT ITT population, regardless of HER2 status. SG should be considered an effective treatment option for pts with mTNBC eligible for 2L or later therapy. Table: 168P

Clinical trial identification

NCT02574455.

Editorial acknowledgement

Editorial support was provided by Yao Bian, PhD, of Team 9 Science and funded by Gilead Sciences, Inc.

Legal entity responsible for the study

Gilead Sciences, Inc.

Funding

Gilead Sciences, Inc.

Disclosure

S.A. Hurvitz: Financial Interests, Personal, Invited Speaker: Clinical Care Options; Financial Interests, Personal, Invited Speaker: aptitude health; Financial Interests, Personal, Invited Speaker: axis medical; Financial Interests, Personal, Invited Speaker: cancer expert now; Financial Interests, Personal, Invited Speaker: ICHE; Financial Interests, Personal, Invited Speaker: MJH Associates; Financial Interests, Personal, Invited Speaker: PER; Financial Interests, Personal, Invited Speaker: Primo; Financial Interests, Personal, Invited Speaker: Projects in Knowledge; Financial Interests, Personal, Invited Speaker: Prova Education; Financial Interests, Personal, Invited Speaker: Research to Practice; Financial Interests, Personal, Invited Speaker: Ultimate Medical Academy; Financial Interests, Personal, Invited Speaker: Vaniam; Financial Interests, Personal, Invited Speaker: WebMD; Financial Interests, Personal, Invited Speaker: Rockpointe; Financial Interests, Personal, Invited Speaker: OBR; Financial Interests, Personal, Invited Speaker: Peer Education; Financial Interests, Personal, Invited Speaker: Spire Learning; Financial Interests, Personal, Invited Speaker: PrecisCA; Financial Interests, Personal, Stocks/Shares, stock options: NK Max; Financial Interests, Personal, Stocks/Shares, spouse owns: ROM Tech; Financial Interests, Personal, Ownership Interest, spouse: Ideal Implant; Financial Interests, Personal, Royalties, author medical book: McGraw; Financial Interests, Personal, Royalties: Elsevier; Financial Interests, Personal, Royalties: Springer; Financial Interests, Personal, Royalties: Sage; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Royalties: Wiley; Financial Interests, Institutional, Invited Speaker: Ambrx; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Arvinas; Financial Interests, Institutional, Invited Speaker: Bayer; Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Genentech/Roche; Financial Interests, Institutional, Invited Speaker: Gilead; Financial Interests, Institutional, Invited Speaker: GSK; Financial Interests, Institutional, Invited Speaker: Immunomedics; Financial Interests, Institutional, Invited Speaker: Lilly; Financial Interests, Institutional, Invited Speaker: Macrogenics; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: OBI Pharma; Financial Interests, Institutional, Invited Speaker: Pieris; Financial Interests, Institutional, Invited Speaker: Puma; Financial Interests, Institutional, Invited Speaker: Radius; Financial Interests, Institutional, Invited Speaker: sanofi; Financial Interests, Institutional, Invited Speaker: Seattle Genetics; Financial Interests, Institutional, Invited Speaker: Dignitana; Financial Interests, Institutional, Invited Speaker: Zymeworks; Financial Interests, Institutional, Invited Speaker: Phoenix Molecular Designs, Ltd.; Financial Interests, Institutional, Research Grant: Samumed; Financial Interests, Institutional, Research Grant: Ambrx; Non-Financial Interests, Advisory Role: Daiichi Sankyo; Non-Financial Interests, Principal Investigator: Daiichi Sankyo; Non-Financial Interests, Advisory Role: Novartis; Non-Financial Interests, Principal Investigator: Genentech; Non-Financial Interests, Principal Investigator: Seattle Genetics; Non-Financial Interests, Advisory Role: Ambrx; Non-Financial Interests, Advisory Role: 4DPharma; Non-Financial Interests, Advisory Role: Dantari; Non-Financial Interests, Advisory Role: Macrogenics; Non-Financial Interests, Advisory Role: Lilly; Non-Financial Interests, Advisory Role: Artios; Non-Financial Interests, Advisory Role: Roche; Non-Financial Interests, Advisory Role: Pyxis; Non-Financial Interests, Advisory Role: Amgen; Non-Financial Interests, Advisory Role: Pieris; Non-Financial Interests, Advisory Role: Arvinas; Non-Financial Interests, Advisory Role: Immunomedics/Gilead; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Member: AACR; Non-Financial Interests, Other, speaker: National Breast Cancer Coalition; Non-Financial Interests, Member, site representative for breast cancer guidelines: National Comprehensive Cancer Network. A. Bardia: Financial Interests, Institutional, Financial Interests, grants: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health/Menarini, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Eli Lilly; Financial Interests, Personal, Financial Interests, consulting fees: Pfizer, Novartis, Genentech, Merck, Radius Health/Menarini, Immunomedics/Gilead, Sanofi, Daiichi Pharma/AstraZeneca, Phillips, Eli Lilly, Foundation Medicine. K. Punie: Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Advisory Board: Novartis; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Advisory Board: Roche; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Advisory Board: Vifor Pharma; Financial Interests, Institutional, Advisory Board: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Mundi Pharma; Financial Interests, Institutional, Advisory Board: Pierre Fabre; Financial Interests, Institutional, Advisory Board: McCann Health; Financial Interests, Institutional, Advisory Board: Roularta; Financial Interests, Institutional, Advisory Board: Teva; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Advisory Board: Gilead Sciences; Financial Interests, Institutional, Advisory Board: Pfizer; Financial Interests, Institutional, Other, Consultancy: Roche; Financial Interests, Institutional, Funding: Sanofi; Non-Financial Interests, Principal Investigator: EORTC 1745-ETF-BCG trial; Non-Financial Interests, Other, Committee member: ESMO Young Oncologists Committee; Non-Financial Interests, Invited Speaker: BSMO; Non-Financial Interests, Other, Committee Member: ESMO Resilience Task Force; Non-Financial Interests, Advisory Role: Commission personalized medecine Federal Government Belgium. K. Kalinsky: Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Immunomedics; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Cyclacel; Financial Interests, Personal, Advisory Board: Oncosec; Financial Interests, Personal, Advisory Board: 4D Pharma; Financial Interests, Personal, Advisory Board: Puma; Financial Interests, Personal, Stocks/Shares, Employment + Stock = spouse: Grail; Financial Interests, Institutional, Invited Speaker: Incyte; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: Genentech; Financial Interests, Institutional, Invited Speaker: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Calithera; Financial Interests, Institutional, Invited Speaker: Immunomedics; Financial Interests, Institutional, Invited Speaker: Acetylon; Financial Interests, Institutional, Invited Speaker: Seattle Genetics; Financial Interests, Institutional, Invited Speaker: Amgen; Financial Interests, Institutional, Invited Speaker: Zentalis; Financial Interests, Institutional, Invited Speaker: CytomX Therapeutics; Other, Support for attending meetings and/or travel: Eli Lilly; Other, Support for attending meetings and/or travel: AstraZeneca; Other, Support for attending meetings and/or travel: Pfizer; Other, Steering Committee: Immunomedics; Other, Steering Committee: AstraZeneca; Other, Steering Committee: Ambryx; Other, Steering Committee: Genentech. J. Cortés: Financial Interests, Personal, Financial Interests, stock: Leuko, MedSIR, Nektar; Financial Interests, Personal, Financial Interests, honoraria: Novartis, Eisai, Celgene, Pfizer, Roche, Samsung, Lilly, Merck Sharp & Dohme, Daachi Sankyo; Financial Interests, Personal, Financial Interests, consulting or advisory role: Celgene, Cellestia Biotech, AstraZeneca, Roche, Seattle Genetics, Daachi Sankyo, ERYTECH Pharma, Polyphor, Athenex, Lilly, Servier, Merck Sharp & Dohme, GlaxoSmithKline, Leuko, Clovis Oncology, Bioasis, Boehringer, Ingelheim, Ellipses Pharma, HiberCell; Financial Interests, Institutional, Financial Interests, research funding: Ariad, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer, Eisai Farmaceutica, Guardaanth Health, Merck Sharp & Dohme, Pfizer, Puma Co, Queen Mary University of London, Roche, Piqur; Financial Interests, Personal, Financial Interests, travel, accomodations, expenses: Roche, Pfizer, Eisai, Novartis, Daiichi Sankyo. J. O'Shaughnessy: Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Advisory Board: Agendia; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Aptitude Health; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: G1 Therapeutics; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: Immunomedics; Financial Interests, Personal, Advisory Board: Ipsen Biopharmaceuticals; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Myriad; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Ondonate; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Puma; Financial Interests, Personal, Advisory Board: prIME Oncology; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Syndax. 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. O.K. Yoon: Financial Interests, Personal, Financial Interests, employee, stock options: Gilead. Y. Pan: Financial Interests, Personal, Financial Interests, employee: Gilead. R.J. Delaney: Financial Interests, Personal, Financial Interests, employee, stock or stock options: Gilead. S. Hofsess: Financial Interests, Personal, Financial Interests, employee, meeting attendance, stock options: Gilead; Non-Financial Interests, Personal, Non-Financial Interests, unpaid: Chair of the William Paterson University Professional Science Master’s External Advisory Board. P. Hodgkins: Financial Interests, Personal, Financial Interests, employee, stock options: Gilead Sciences. S. Phan: Financial Interests, Personal, Financial Interests, employee, grants or contracts, meeting attendance, stock or stock options, receipt of materials: Gilead. V. Dieras: Financial Interests, Personal, Financial Interests, consulting fees: Roche Genentech, Novartis, Pfizer, Lilly, AbbVie, Eisai, AstraZeneca, Daiichi Sankyo, Seagen, Gilead, MSD, Pierre Fabre Oncologie; Financial Interests, Personal, Financial Interests, honoraria: Novartis, Pfizer, Lilly, AstraZeneca, Seagen, Daiichi Sankyo, Gilead, MSD; Financial Interests, Personal, Financial Interests, meeting attendance and/or travel: Roche, Novartis, Pfizer, Seagen, Lilly, AstraZeneca, Daiichi Sankyo, Gilead; Financial Interests, Personal, Financial Interests, data safety monitoring board or advisory board: Roche Genentech, Novartis, Pfizer, Lilly, AbbVie, Eisai, AstraZeneca, Daiichi Sankyo, Seagen, Gilead, MSD, Pierre Fabre Oncologie. All other authors have declared no conflicts of interest.

Background

Targeting the androgen receptor (AR) may be the next important endocrine therapy for advanced breast cancer. Enobosarm is an oral selective AR targeting agonist that activates the AR in breast cancer. Enobosarm has an extensive clinical experience in 25 clinical trials including in 2 phase 2 studies conducted in patients (pts) with AR+ ER+ HER2- metastatic breast cancer (MBC). An open-label, parallel design phase 2 study, was conducted in 136 women with heavily pretreated ER+ HER2- MBC that were randomized to oral daily enobosarm at a dose of 9 or 18 mg. The primary endpoint of clinical benefit rate (CBR) at 24 weeks was 32% (9 mg) and 29% (18 mg). A post-hoc AR expression subset analysis conducted in the ITT population with measurable disease at baseline revealed that the best overall response rate (ORR) was significantly higher in pts with ≥40% AR nuclei staining versus <40%, 34% and 2.7% respectively (p=0.0003) and the CBR at 24 weeks was significantly higher for ≥40% AR versus <40%, 52% and 14% respectively (p<0.0004). Overall, enobosarm was well tolerated with significant positive effects on quality-of-life measurements.

Trial design

The ARTEST trial is an ongoing phase 3 multicenter, international, randomized, and open-label study. Approximately, 210 pts with AR+ ER+ HER2- MBC and with AR nuclei staining ≥40% are being randomized 1:1 to either enobosarm 9 mg oral daily dose or an active comparator (physician’s choice of exemestane ± everolimus or SERM). Pts must have previously received a nonsteroidal AI inhibitor, fulvestrant, and a CDK 4/6 inhibitor for MBC and had a ≥ 6 months response to hormone therapy for MBC. The primary endpoint is imaging based progression free survival as measured by RECIST 1.1. The secondary endpoints on this study include the ORR, duration of response, overall survival, change from baseline in Short Physical Performance Battery (SPPB) and change in EORTC Quality of Life Questionnaire (EORTC-QLQ).

Clinical trial identification

NCT04869943.

Legal entity responsible for the study

Veru Inc.

Funding

Veru Inc.

Disclosure

A. Brufsky: Financial Interests, Personal, Advisory Role: Veru Inc. H. Linden, H.S. Rugo, C. Vogel, J. O'Shaughnessy, E. Mayer: Financial Interests, Institutional, Research Grant: Veru Inc. R.H. Getzenberg, K.G. Barnette, D. Rodriguez, M.S. Steiner: Financial Interests, Personal, Full or part-time Employment: Veru Inc.

Background

HER2-targeted therapies have changed the treatment landscape for pts with HER2-positive (+) breast cancer (BC), but the clinical benefit of these first-generation HER2 targeted agents is just emerging for patients with HER2-low disease. HER2-low, defined as IHC 1-2+ without HER2 gene amplification, comprises between 40-65% of HER2-negative breast cancer. While HER2-positive BC comprises approximately 20% of newly diagnosed cases, a greater proportion of patients (∼50%) have BC categorized as HER2-low (IHC 1-2+ but ISH negative) and have a high unmet medical need. Even with the success of anti-HER2 treatments for HER2+ patients, many patients become resistant or are refractory to treatment. A new generation of anti-HER2 targeted agents has recently demonstrated both clinical activity and safety in HER2-low BC, including ARX788, an anti-HER2 antibody drug conjugate (ADC). ARX788 is a site-specific conjugated ADC that consists of a HER2 targeting monoclonal antibody (mAb) with payload AS269, a highly potent tubulin inhibitor. Site-specificity, high homogeneity, and stable covalent conjugation of ARX788 leads to its slow release and prolonged peak of serum pAF-AS269, which may contribute to the lower systemic toxicity and increased targeted delivery of payload to tumor cells at a lower effective dose compared to other HER2 ADCs.

Trial design

ACE-Pan tumor-01 (NCT03255070) is a global phase 1 study to assess efficacy and safety of ARX788 in patients with metastatic HER2+ BC, HER2-low BC, HER2+ GC (gastric cancer), or other advanced solid tumors with HER2 overexpression or activating mutations (including BC). Eligibily includes non-operable Stage III-IV disease, measurable lesions. HER2+ cohort must be resistant/refractory to T-DM1, and/or T-DXd, and/or tucatinib containing regimens, while HER2 low cohort must have no standard curative/palliative measures. Endpoints: ORR, DOR, TTR, BOR, DCR, PFS, and OS using RECIST1.1. Safety assessed by PE, AEs, VS, ECG, and lab tests PK, immunogenicity, biomarkers to be analyzed. Descriptive statistics will be used. As of Feb/2022, 28 patients with ongoing enrollment.

Clinical trial identification

NCT03255070.

Legal entity responsible for the study

Ambrx, Inc.

Funding

Ambrx, Inc.

Disclosure

D. Xu, M. Li, T. Le: Financial Interests, Personal, Full or part-time Employment: Ambrx. J. Yan: Financial Interests, Personal, Member of the Board of Directors: Ambrx. All other authors have declared no conflicts of interest.