386MO - Trastuzumab duocarmazine versus physician's choice therapy in pre-treated HER2-positive metastatic breast cancer: Final results of the phase III TULIP trial

Background

Trastuzumab duocarmazine (T-Duo, SYD985) is a HER2-targeting antibody-drug conjugate comprised of trastuzumab bound to the DNA alkylating agent duocarmazine with a drug-antibody ratio of 2.4 to 2.8. TULIP is a randomized, international, multicenter, phase 3 study in patients with pre-treated HER2-positive metastatic breast cancer (MBC). The initial analysis of the primary endpoint progression free survival (PFS) showed a clinically meaningful and statistically significant difference in favor of T-Duo versus physician's choice (PC) (Saura et al., ESMO 2021). At that time, preliminary overall survival (OS) data were reported. Final OS and updated secondary outcomes are reported here.

Methods

The TULIP trial randomly assigned patients with HER2-positive locally advanced or MBC with ≥2 previous HER2-targeting MBC regimens or pretreated with T-DM1, in a 2:1 ratio between T-Duo (1.2 mg/kg q3w) and PC. PC could be either trastuzumab combined with capecitabine or vinorelbine or eribulin or lapatinib plus capecitabine. The primary endpoint was PFS by blinded, independent, central review. Key secondary endpoints are PFS by investigator, OS, overall response rate, QoL, duration of response and safety.

Results

A total of 291 patients were randomized to the T-Duo group and 146 to the PC group. At the data cut off, the median follow-up of the T-Duo and PC groups were 35.6 months and 32.0 months, respectively. Median OS was 21.0 months in the T-Duo group and 19.5 months in the PC group. The hazard ratio was 0.87 (95% CI 0.68, 1.12) p=0.236. The 1-year survival estimate was 70% in the T-Duo group and 68% in the PC group. The primary endpoint PFS (7.0 vs 4.9 months, HR 0.63, p=0.002) and other secondary efficacy outcomes did not change in this analysis compared to the initial analysis. No new safety findings were observed with longer follow-up.

Conclusions

T-Duo showed a meaningful and statistically significant improvement in PFS in patients with pre-treated HER2-positive MBC. The final OS results confirm a trend towards a numerically prolonged OS (statistically non-significant) in the T-Duo group compared with PC group. Safety was aligned with the primary analysis, with no new signals identified.

Clinical trial identification

NCT03262935, Eudract 2017-001994-18.

Editorial acknowledgement

Legal entity responsible for the study

Byondis B.V.

Funding

Byondis B.V.

Disclosure

P.G. Aftimos: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Macrogenics, Roche, Novartis, Amcure, Servier, G1 Therapeutics, Radius, Deloitte, Menarini, Gilead, Novartis, Eisai, Lilly; Financial Interests, Personal, Invited Speaker: Synthon, Amgen; Financial Interests, Institutional, Research Grant: Roche. N. Turner: Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Novartis, Pfizer, Roche/Genentech, GSK, Zentalis pharmaceuticals, Repare therapeutics, GSK, Relay therapeutics, Gilead, Inivata, Guardant, Exact Sciences; Financial Interests, Institutional, Funding: AstraZeneca, Pfizer, Roche/Genentech, Merck Sharpe and Dohme, Invitae, Inivata, Personalis, Natera; Financial Interests, Institutional, Other, provision of materials: BioRad; Financial Interests, Institutional, Other, Provision of assays: Guardant Health. 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. E. van den Tweel: Financial Interests, Personal, Full or part-time Employment, Clinical Project Leader: Byondis B.V.. M. Oesterholt: Financial Interests, Personal, Full or part-time Employment, Clinical Project leader: Byondis BV. S. Escrivá-de-Romaní: Financial Interests, Personal, Advisory Board: Roche, Daiichi Sankyo/AstraZeneca, Seagen, Pierre-Fabre, COR2ED; Financial Interests, Personal, Invited Speaker: Roche, Daiichi Sankyo/AstraZeneca, Pfizer, Seagen, Novartis; Financial Interests, Personal, Other, Travel grants: Pfizer, Kern; Financial Interests, Institutional, Local PI: Roche, Synthon, Byondis, Lilly, MedSIR, Zymeworks, Daiichi Sankyo/AstraZeneca, SOLTI. N. Quenel Tueux: Financial Interests, Personal, Advisory Board: Pfizer, Astra Zenica, Daiichi; Financial Interests, Personal, Other, Support for congresses: Novartis, Lilly, MSD, Seagen, Gilead, Astra Zenica, Daiichi. T.J.Y. Tan: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Everest Medicines (Singapore) Pte Ltd, DKSH; Financial Interests, Personal, Invited Speaker: DKSH, AstraZeneca, Novartis, MSD; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Local PI: Roche, Novartis, AstraZeneca, Daiichi Sankyo, Genentech, Sanofi; Non-Financial Interests, Member: ASCO; Other, Conference sponsorship: DKSH, AstraZeneca, Novartis. J. Lim: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, AstraZeneca, DKSH, MSD, Everest Medicine; Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD; Financial Interests, Institutional, Local PI: Synthon pharmaceuticals, Daiichi, Taiho pharmaceuticals; Financial Interests, Institutional, Funding: CTI biopharma. S. Ladoire: Financial Interests, Personal, Advisory Board, advisory board: Pfizer, Novartis, AstraZeneca, Sanofi, Daiichi, Gilead, Menarini-Stemline; Financial Interests, Personal, Advisory Board, advisory board, expert testimony: Astellas; Financial Interests, Personal, Advisory Board, expert testimony, invited speaker: Janssen, Ipsen; Financial Interests, Personal, Invited Speaker, invited speaker: BMS, Seagen, Exact Science; Financial Interests, Personal, Invited Speaker, invited speaker, expert testimony: Lilly; Financial Interests, Institutional, Research Grant, research grant: Novartis, Eisai, BMS. A.C. Armstronh: Financial Interests, Personal, Advisory Role: AstraZeneca, MSD, Gilead; Financial Interests, Personal, Stocks/Shares, Spousal Shares: AstraZeneca; Financial Interests, Institutional, Research Funding, to institution: AstraZeneca; Non-Financial Interests, Personal, Other, Clinical lead: RCOG Breast Cancer and Pregancy Guideline; Non-Financial Interests, Personal, Other, Clinical Advisor: NICE Menopause Guideline (update). A. Stradella: Financial Interests, Personal, Advisory Board, Advisory about CAPITELLO 291 trial: AstraZeneca; Financial Interests, Personal, Advisory Board, Advisory on new activities for residents: Novartis; Financial Interests, Personal, Invited Speaker, Trastu-Deruxtecan clinical case meeting: Daiichi; Financial Interests, Personal, Invited Speaker, meeting on new data on cyclin inhibitors: Novartis. G.V. Bianchi: Financial Interests, Personal, Advisory Board: Novartis, Lilly, Roche, AstraZenica/Daiichi, MSD, Seagen. M.A. Colleoni: Financial Interests, Institutional, Research Grant: Roche; Non-Financial Interests, Leadership Role, CO-Chair Scientific Committee: International Breast Cancer Study Group. K. Punie: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Roche, Vifor Pharma, Eli Lilly, Pierre Fabre, McCann Health, Roularta, Teva, Gilead Sciences, Pfizer, Gilead, MSD; Financial Interests, Institutional, Invited Speaker: Pfizer, Roche, Novartis, Eli Lilly, Mundi Pharma, MSD, Medscape; Financial Interests, Institutional, Other, Consultancy: Roche; Financial Interests, Personal, Other, Consultancy: Gilead, Novartis, MSD, Roche; Financial Interests, Personal, Invited Speaker: Sanofi, AstraZeneca, Exact Sciences, Focus Patient, Pfizer, Gilead Sciences; Financial Interests, Personal, Advisory Board: Seagen, AstraZeneca, Pfizer; Financial Interests, Personal, Ownership Interest: Need Inc.; Financial Interests, Institutional, Funding: Sanofi; Financial Interests, Institutional, Trial Chair: MSD; Non-Financial Interests, Other, Committee member: ESMO Young Oncologists Committee; Non-Financial Interests, Leadership Role, Vice President: Belgian Society of Medical Oncology BSMO; Non-Financial Interests, Other, Committee Member: ESMO Resilience Task Force; Non-Financial Interests, Leadership Role: EORTC Breast Cancer Task Force Steering Committee Member; Non-Financial Interests, Institutional, Product Samples, Drug provision for academic research: Gilead Sciences; Non-Financial Interests, Advisory Role: Commission personalized medecine Federal Government Belgium; Non-Financial Interests, Advisory Role, External Scientific Advisor: European Medicine Agency. X. Song: Financial Interests, Personal, Advisory Board: EMD, BMS, Novartis, Pfizer, merck; Financial Interests, Institutional, Local PI: AstraZeneca, BMS, Gilead, Novartis, Pfizer, Roche, Seagen. N. Koper: Financial Interests, Personal, Full or part-time Employment, VP Clinical Development: Byondis B.V.. C. Saura Manich: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol Meyers Squibb, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann - La Roche Ltd, Gilead, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Piere Fabre, PintPharma, Puma, Roche Farma, Sanofi-Aventis, SeaGen, Zymeworks, Genentech, Innoup, Millenium, Pharmalex Spain SLU; Financial Interests, Personal, Other, SC: Byondis B.V., Glaxo, Macrogenics, Menarini, Merus, Synthon Biopharpaceuticals; Financial Interests, Institutional, Research Grant: AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Cytomx Therapeutics, Daiichi Sankyo, Eli Lilly and Company, F. Hoffmann-La Roche Ltd, Genentech, GSK, Immunomedics, Innoup Farma, Macrogenics, Menarini Ricerche, Merus, Novartis, Pfizer, Puma, Roche, Sanofi-Aventis, Seattle Genetics; Financial Interests, Institutional, Coordinating PI: Byondis B.V.; Non-Financial Interests, Member: Spanish Society of Medical Oncology (SEOM), American Society for Clinical Oncology (ASCO), Geicam (Spanish Breast Cancer Research Group), European Society for Medical Oncology (ESMO), Sinology Society of the Official College of Physicians of Barcelona (COMB); Non-Financial Interests, Member, Junta Directiva y Comité Científico: SOLTI group (Academic research group in breast cancer). All other authors have declared no conflicts of interest.