Background

LUCY interim findings confirmed the clinical effectiveness of olaparib 300 mg twice daily in patients with metastatic breast cancer (mBC) in a real world setting. Findings were consistent with the OlympiAD trial of olaparib vs chemotherapy of physician’s choice. We report results of the final planned analysis.

Methods

Eligible adults had germline (g) or somatic (s) BRCA1- and/or BRCA2-mutated (BRCAm), HER2-negative mBC and had received taxane and/or anthracycline in early or metastatic settings and ≤2 previous lines of chemotherapy for mBC. Pts with hormone receptor-positive (HR+) mBC had previously completed ≥1 line of endocrine therapy (ET) in any setting or were unsuitable for further ET. Primary endpoint: investigator-assessed progression-free survival (PFS; gBRCAm cohort). Overall survival (OS) and safety were secondary endpoints. Final analysis was planned at 130 OS events (gBRCAm). Results are in all pts (gBRCAm and sBRCAm). Prespecified subgroups (gBRCAm only): HR status (HR+ vs triple-negative breast cancer [TNBC]); line of therapy (1st line vs 2nd line+).

Results

During 2018, 255 pts were enrolled (252 gBRCAm, 3 sBRCAm; median [m] age: 45.0 [range 22–75] years; 98.4% female). mPFS: 8.2 months (95% CI 7.0–9.2; 208 events, 81.6%). mOS: 24.9 months (95% CI 21.1–27.9; 142 events, 55.7%). OS rate at 30 months: 41.7% (95% CI 35.2–48.1). Treatment-related adverse events (AEs, >10% pts): nausea (47.8%), anaemia (34.5%), asthenia (20.8%), fatigue (18.0%), vomiting (17.6%), neutropenia (15.3%) and diarrhoea (11.0%). Grade ≥3 AEs (17.6% pts) included anaemia (11.8%). Few pts (4.3%) discontinued treatment due to an AE. Post study therapies will be reported.

Conclusions

The benefit of olaparib was similar across HR status and treatment lines. mOS was longer than reported in OlympiAD. No new safety signals were observed. These results strongly support olaparib as a chemotherapy-free alternative for gBRCAm, HER2-negative mBC. Table: 174P

Subgroup analyses (full analysis set)

Editorial acknowledgement

Medical writing assistance was provided by Elizabeth Gandhi, PhD of PharmaGenesis Cambridge, Cambridge, UK, with funding from AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Legal entity responsible for the study

AstraZeneca.

Funding

This study was funded by AstraZeneca and is part of an alliance between AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

J. Balmana: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: MedSir. 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. S. Delaloge: Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Exact Sciences; Financial Interests, Institutional, Advisory Board: Novartis; Financial Interests, Institutional, Advisory Board: Pierre Fabre; Financial Interests, Institutional, Advisory Board: Orion; Financial Interests, Institutional, Advisory Board: Sanofi; Financial Interests, Institutional, Advisory Board: Rappta; Financial Interests, Institutional, Advisory Board: Cellectis; Financial Interests, Institutional, Advisory Board: Isis/Servier; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Seagen; Financial Interests, Institutional, Invited Speaker: Lilly; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Advisory Board, ad board: Besins Healthcare; Financial Interests, Institutional, Invited Speaker: Roche Genentech; Financial Interests, Institutional, Invited Speaker: BMS; Financial Interests, Institutional, Invited Speaker: Puma; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Orion; Financial Interests, Institutional, Invited Speaker: Sanofi; Financial Interests, Institutional, Funding: GE; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker, clinical research funding to my institution: Taiho; Non-Financial Interests, Invited Speaker, Société Française de Sénologie et Pathologie Mammaire: SFSPM. 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. J. Sohn: Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim. S. Aksoy: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Merck, Merck Sharp & Dohme; Financial Interests, Personal, Invited Speaker: Merck, Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Roche. C.V. Timcheva: Financial Interests, Personal, Invited Speaker, Presentation during national scientific conference: Roche Bulgaria; Financial Interests, Personal, Advisory Board, Discussion on the place of CDK4/6 inhibitors in the treatment of metastatic breast cancer: Eli Lilly; Financial Interests, Personal, Advisory Board, The role of PARP inhibitors in the treatment of breast and ovarian cancer: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker, PI for several clinical trials performing in the hospital: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker, PI for several clinical trials performing in the hospital: Parexel; Financial Interests, Personal and Institutional, Invited Speaker, Pi for several clinical trials perforing in the hospital: Roche; Financial Interests, Personal and Institutional, Invited Speaker, PI for some clinical trials performing in the hospital: Novartis; Financial Interests, Personal and Institutional, Invited Speaker, PI for the clinical trial performing in the hospital: I3Research; Non-Financial Interests, Principal Investigator, Investigator initiated trial on metastatic CRC: Merck; Non-Financial Interests, Member, Created in 2012, Head of BAMO until 2020: Bulgarian Association for Medical Oncology (BAMO). T. Park-Simon: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Pizer; Financial Interests, Personal, Advisory Board: Daiichi; Financial Interests, Personal, Invited Speaker: Daiichi; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Invited Speaker: Gilead; Financial Interests, Personal, Advisory Board: Exact Sciences; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Invited Speaker: GSK; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Invited Speaker: Seagen; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis. E. John: Financial Interests, Institutional, Full or part-time Employment: AstraZeneca. K. Baria: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. G. Walker: Financial Interests, Institutional, Other, I work as a consultant to the company: AstraZeneca. K.A. Gelmon: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Advisory Board: Ayala; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: BMS. All other authors have declared no conflicts of interest.

Background

The phase II trial of the pan-HER inhibitor poziotinib (NCT02418689) demonstrated the clinical effectiveness of poziotinib 12 mg p.o. once daily (QD) in patients with HER2-positive metastatic breast cancer (mBC) in a heavily pretreated setting with median progression free survival (PFS) of 4 months from the primary analysis. Diarrhea and stomatitis were the major toxicities. We now report the results from the final planned analysis of overall survival (OS).

Methods

Eligible patients have received anticancer chemotherapy including taxane and ≥2 prior HER2-directed regimens including trastuzumab. PFS was the primary endpoint. Secondary endpoints included OS and objective response rate (ORR), and safety was evaluated. The database was locked on October 1, 2021 including data from the last patient who received poziotinib for 104 cycles (72.7 months) and transferred to the early access program. The final OS analysis was planned when ≥ 54 deaths occurred. The final OS analysis occurred after 68 deaths.

Results

From April 2015 to February 2016, 106 patients were enrolled at seven sites in Korea. At data cut off on 1 October 2021, the full analysis set included 102 patients. Median age was 51.0 (range 30–76) years. Median number of treatment regimens before poziotinib was 4 (2-16). At the data cut-off, median PFS (95% CI) was 4.0 (3.0–4.4) months. Median OS (95% CI) was 17.7 (95% CI 12.4–20.8) months (68/102 events; 66.7%). OS rate (95% CI) at 36 and 60 months was 18 (10-28)% and 14 (7-24)%, respectively. Most frequent all-grade adverse events (AEs) considered to be treatment related were: diarrhea (96.2%), stomatitis (92.5%), pruritus (63.2%), rash (63.2%), dry skin (38.7%), dermatitis acneiform (32.1%), and decreased appetite (26.4%). Grade ≥3 AEs and serious AEs occurred in 45.3% and 8.5% of patients, respectively.

Conclusions

Poziotinib showed clinically meaningful OS benefit for patients with HER2-positive mBC and the safety profile was as expected for tyrosine kinase inhibitors(TKIs). This encouraging result provide an important update on the clinical effectiveness and safety of poziotinib in HER2-positive mBC patients who were previously heavily treated.

Clinical trial identification

NCT02418689.

Legal entity responsible for the study

The authors.

Funding

Hanmi.

Disclosure

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. J. Sohn: Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim. K.S. Lee: Financial Interests, Institutional, Research Grant: Ono. J.H. Kim: Financial Interests, Institutional, Research Grant: Ono. E. Baek: Financial Interests, Personal and Institutional, Other, Employee: Hanmi. H. Han: Financial Interests, Personal and Institutional, Other, Employee: Hanmi. S. Im: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Institutional, Principal Investigator: MSD; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: Prizer; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Research Grant: Hanmi; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Institutional, Principal Investigator: Lilly; Financial Interests, Institutional, Principal Investigator: Novartis. All other authors have declared no conflicts of interest.

Background

The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients (pts) progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in pts with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in pts with untreated and/or active BM (Murthy et al. 2020, Curigliano et al. 2021). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL).

Trial design

HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T+P as maintenance therapy for HER2+ MBC. Approximately 650 pts will be enrolled. Eligible pts will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, ECOG Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Pts will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T+P once every 21 days. Pts with HR+ disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS (key endpoint), time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a 2-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in the US, with additional sites planned.

Clinical trial identification

NCT05132582.

Legal entity responsible for the study

Seagen Inc.

Funding

Seagen Inc.

Disclosure

V.C. Dieras: Financial Interests, Personal, Other, Travel Expenses: Roche, Novartis, Pfizer, Lilly, AstraZeneca, Daiichi Sankyo, Seagen, Gilead; Financial Interests, Personal, Advisory Board, Consultant/Advisory Board: Roche/Genentech, Novartis, Lilly, Pfizer, AstraZeneca, AbbVie, MSD, Daiichi Sankyo, Seagen, Gilead, Eisai, Pierre Fabre Oncologie; Financial Interests, Personal, Other, Symposia: Roche, Novartis, Pfizer, Lilly, AstraZeneca, Daiichi Sankyo, Seagen, Gilead. M. Martin Jimenez: Financial Interests, Personal, Advisory Board: Roche, Lilly, Novartis, Pierre Fabre, Pfizer, Daiichi Sankyo, Seagen; Financial Interests, Personal, Other, Honoraria: Roche, Lilly, Novartis, Pierre Fabre, Pfizer, Daiichi Sankyo, Seagen; Financial Interests, Personal, Funding, Research Funding/Grants: Puma, Roche, Novartis. C.C.M. O'Sullivan: Financial Interests, Personal, Full or part-time Employment: Mayo Clinic Rochester; Financial Interests, Personal, Funding, Research Funding/Grants: Lilly, Seattle Genetics, Bavarian Nordic, Minnemarita Therapeutics, Biovica. J. Sohn: Financial Interests, Personal, Funding: Seagen Inc. K. Tryfonidis: Financial Interests, Personal, Full or part-time Employment: Merck. L. Santarpia, S. Yang: Financial Interests, Personal, Full or part-time Employment: Seagen Inc. E.P. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Boehringer Ingelheim, Novartis, Dantari, Lilly, Merck, Puma Biotechnology, Silverback Therapeutics, CytomX, Pfizer, Mersana, Black Diamond, H3 Biomedicine, Daiichi Sankyo, AstraZeneca, Arvinas, Deciphera Pharmaceuticals, Eisai, Seagen, Arcus, iTeos, Janssen, Loxo, Relay Therapeutics; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Silverback Therapeutics, Millenium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Fochon, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, Seagen, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Orinove, Leap Therapeutics, Zenith Epigenetics, Harpoon, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, Merck, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Atlas MedX, Ellipses, Incyte, Jacobio, Mabspace Biosciences, Myraid Genetic Labs, ORIC Pharmaceuticals, Pieris Pharmaceuticals; Financial Interests, Institutional: Pionyr Immunotherapeutics.