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Long-term outcomes of dual vs single HER2-directed neoadjuvant therapy in NSABP B-41

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Abstract

Background

The primary aim of this randomized neoadjuvant trial in operable, HER2-positive breast cancer, was to determine the efficacy on pathologic complete response (pCR) of substituting lapatinib (L) for trastuzumab (T) or adding L to T, in combination with weekly paclitaxel (WP) following AC. Results on pCR were previously reported. Here, we report data on planned secondary endpoints, recurrence-free interval (RFI) post-surgery, and overall survival (OS).

Methods

All patients received standard AC q3 weeks × 4 cycles followed by WP (80 mg/m2) on days 1, 8, and 15, q28 days × 4 cycles. Concurrently with WP, patients received either T (4 mg/kg load, then 2 mg/kg) weekly until surgery, L (1250 mg) daily until surgery, or weekly T plus L (750 mg) daily until surgery. Following surgery, all patients received T to complete 52 weeks of HER2-targeted therapy. 522 of 529 randomized patients had follow-up. Median follow-up was 5.1 years.

Results

RFI at 4.5 years was 87.2%, 79.4% (p = 0.34; HR = 1.37; 95% CI 0.80, 2.34), and 89.4% (p = 0.37; HR = 0.70; 0.37, 1.32) for arms T, L, and TL, respectively. The corresponding five-year OS was 94.8%, 89.1% (p = 0.34; HR = 1.46; 0.68, 3.11), and 95.8% (p = 0.25; HR = 0.58; 0.22, 1.51), respectively. Patients with pCR had a much better prognosis, especially in the ER-negative cohort: RFI (HR = 0.23, p < 0.001) and OS (HR = 0.28, p < 0.001).

Conclusions

Although pCR, RFI, and OS were numerically better with the dual combination and less with L, the differences were not statistically significant. However, achievement of pCR again correlated with improved outcomes, especially remarkable in the ER-negative subset.

Clinical trials registration

NCT00486668

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Data availability

Data are available from the authors upon reasonable request and with permission of the NSABP Foundation.

Code availability

Data and programming codes are available from the authors upon reasonable request and with permission of the NSABP Foundation.

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Acknowledgements

The authors would like to acknowledge Dr. André Robidoux for his invaluable contributions to this study. The authors would also like to thank Elaina Harper, Data Manager for this study; Christine I Rudock, Publications and Graphics Specialist; and Wendy L. Rea, Editorial Associate. They are all employees of NSABP, and were not compensated beyond their normal salaries for this work.

Funding

NSABP Foundation, Inc, and GlaxoSmithKline, during the course of the study. GlaxoSmithKline (GSK) provided lapatinib to all study sites as well as trastuzumab in Canada along with funding support. GSK provided input on the study design, but did not participate in data collection, data analysis, data interpretation, or writing of the report.

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Authors and Affiliations

  1. NSABP Foundation, Inc, Pittsburgh, PA, USA

    Priya Rastogi, Saima Hassan, Charles E. Geyer Jr, Catherine A. Azar, Gustav C. Magrinat, J. Marie Suga, Harry D. Bear, Luis Baez-Diaz, Shakir Sarwar, Jean-Francois Boileau, Adam M. Brufsky, Henry R. Shibata, Soonmyung Paik, Sandra M. Swain, Eleftherios P. Mamounas & Norman Wolmark

  2. UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Priya Rastogi, Charles E. Geyer Jr, Adam M. Brufsky & Norman Wolmark

  3. Magee-Women’s Hospital, Pittsburgh, PA, USA

    Priya Rastogi

  4. NRG Oncology SDMC, and the University of Pittsburgh, Pittsburgh, PA, USA

    Gong Tang, Hanna Bandos & Greg Yothers

  5. Centre Hôspitalier de l’Université de Montréal, Montréal, QC, Canada

    Saima Hassan

  6. Arizona Cancer Center, Tucson, AZ, USA

    Catherine A. Azar

  7. Cone Health Cancer Center/SCOR-NCORP, Richmond, VA, USA

    Gustav C. Magrinat

  8. Kaiser Permanente Oncology Clinical Trials Northern CA, Novato, CA, USA

    J. Marie Suga

  9. Virginia Commonwealth University School of Medicine Massey Cancer Center, Richmond, VA, USA

    Harry D. Bear

  10. MBCCOP San Juan, San Juan, PR, USA

    Luis Baez-Diaz

  11. OhioHealth, Columbus, OH, USA

    Shakir Sarwar

  12. Jewish General Hospital, McGill University, Montréal, QC, Canada

    Jean-Francois Boileau

  13. Royal Victoria Hospital, Montréal, QC, Canada

    Henry R. Shibata

  14. Theragenbio, Inc, and Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of South Korea

    Soonmyung Paik

  15. Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, and MedStar Health, Washington, DC, USA

    Sandra M. Swain

  16. Orlando Health Cancer Institute, Orlando, FL, USA

    Eleftherios P. Mamounas

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  1. Priya Rastogi
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  2. Gong Tang
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  19. Norman Wolmark
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Corresponding author

Correspondence to Priya Rastogi.

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Conflict of interest

The authors had full access to all the data and had final responsibility for the decision to submit for publication.

Ethical approval

NSABP B-41 was approved by local human investigations committees or institutional review boards in accordance with assurances filed with and approved by the US Department of Health and Human Services. Written informed consent was required.

Competing Interests

SH: Research funding for unrelated projects from Pfizer and Exact Sciences; Honorary Fees from Exact Sciences and Merck for Advisory Board meetings. CEG, Jr: Abbvie: Contracted Research (Terminated, Jul 1, 2022), Writing assistance (Terminated, Jul 1, 2022); AstraZeneca: Contracted Research (Ongoing), Writing assistance (Ongoing); Daiichi/Sankyo: Contracted Research (Ongoing); Exact Sciences: Consulting Fees (e.g., advisory boards) (Ongoing); F. Hoffman-La Roche Ltd: Contracted Research (Ongoing); Genentech: Contracted Research (Ongoing), Writing assistance (Ongoing) HDB: Non-relevant disclosures: Talks/honoraria, Genentech. J-FB: Honoraria/speaker’s fee: Roche, Exact Sciences, Merck, AstraZeneca; Advisory boards or speakers’ bureaus: Pfizer, Novartis, Merck. AstraZeneca, Lilly, Roche; Funded grants or clinical trials: Institutional PI, clinical trial: Roche, Merck, Lilly, Novartis, Pfizer, Bristol Myers Squibb, AstraZeneca (also Steering Committee). AMB: Consultant for AstraZeneca, Roche, Puma, Seattle Genetics, Macrogenics, Daiichi Sankyo. SMS: Grants/contracts: Genentech/Roche, Kailos Genetics, BCRF; Consulting fees: Roche/Genentech, Molecular Therapeutics; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events: Genentech/Roche, Daiichi Sankyo; Support for attending meetings and/or travel: Genentech/Roche travel to Boston 11/2019; Participation on a Data Safety Monitoring Board or Advisory Board: DSMB AstraZeneca; Ad Board: AstraZeneca, Daiichi Sankyo, Exact Sciences, Biotheranostics, Natera, Merck, Silverback Therapeutics, Athenex, Lilly; Scientific Advisory Board: Inivata. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: NSABP Vice chairman; CCF, ASCO Director; Receipt of equipment, materials, drugs, medical writing, gifts or other services: Third-party writing: Genentech/Roche and AstraZeneca. EPM: Genentech/Roche, Exact Sciences, Merck: Consultant, Speaker’s Bureau; Biotheranostics, Puma Biotechnology, Agendia, AstraZeneca: Consultant. All other authors have no other potential COIs to report.

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Supplementary Information

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CONSORT Diagram. Supplementary file1 (PDF 237 KB)

10549_2023_6881_MOESM2_ESM.eps

Forest Plots Comparing Arms L and TL to Arm T in Recurrence-free Interval: B-41. The hazard ratios (HR) and their 95% CIs are obtained from the corresponding Cox proportional hazards models. HR>1 implies the superiority of arm T. Supplementary file2 (EPS 525 KB)

10549_2023_6881_MOESM3_ESM.eps

Forest Plots Comparing Arms L and TL to Arm T in Overall Survival: B-41. The hazard ratios (HR) and their 95% CIs are obtained from the corresponding Cox proportional hazards models. HR>1 implies the superiority of arm T. Supplementary file3 (EPS 292 KB)

10549_2023_6881_MOESM4_ESM.eps

Kaplan-Meier Estimates of Recurrence-free Interval by pCR Status among HR-positive Patients: B-41. Supplementary file4 (EPS 303 KB)

10549_2023_6881_MOESM5_ESM.eps

Kaplan-Meier Estimates of Recurrence-free Interval by pCR Status among HR-negative Patients: B-41. Supplementary file5 (EPS 305 KB)

10549_2023_6881_MOESM6_ESM.eps

Kaplan-Meier Estimates of Overall Survival by pCR Status among HR-positive Patients: B-41. Supplementary file6 (EPS 294 KB)

10549_2023_6881_MOESM7_ESM.eps

Kaplan-Meier Estimates of Overall Survival by pCR Status among HR-negative Patients: B-41. Supplementary file7 (EPS 294 KB)

Supplementary file8 (DOCX 21 KB)

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Rastogi, P., Tang, G., Hassan, S. et al. Long-term outcomes of dual vs single HER2-directed neoadjuvant therapy in NSABP B-41. Breast Cancer Res Treat 199, 243–252 (2023). https://doi.org/10.1007/s10549-023-06881-8

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