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Randomized Phase II Trial of Capecitabine and Lapatinib with or without IMC-A12 (Cituxumumab) in Patients with HER2-Positive Advanced Breast Cancer Previously Treated with Trastuzumab and Chemotherapy: NCCTG N0733 (Alliance)

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Abstract

Purpose

To compare efficacy and safety of capecitabine and lapatinib with or without IMC-A12 (cituxumumab) in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab.

Patients and methods

Following an initial safety run-in cohort, patients were randomized 1:2 to Arm A (capecitabine and lapatinib) or to Arm B (capecitabine, lapatinib, and cituxumumab). Given the frequency of non-hematologic grade ≥ 3 adverse events in those receiving the three-drug combination in the safety cohort, lapatinib and capecitabine doses were reduced in Arm B only. The primary objective was to determine if the addition of cituxumumab to capecitabine and lapatinib improved progression-free survival (PFS) compared with capecitabine and lapatinib. Secondary objectives included a comparison between arms of other clinical endpoints, safety, change in overall quality of life (QOL) and self-assessed fatigue, rash, diarrhea, and hand-foot syndrome.

Results

From July 2008 to March 2012, 68 patients (out of 142 planned) were enrolled and 63 were evaluable, including 8 for the safety run-in and 55 for the randomized cohort. Study enrollment was stopped early due to slow accrual. The addition of cituxumumab to capecitabine and lapatinib did not improve PFS (HR 0.93, 95% CI: 0.52–1.64). Furthermore, no difference in objective response rate or overall survival (OS) was observed. No difference between arms was observed in grade ≥ 3 adverse events, overall QOL change from baseline after 4 cycles of treatment.

Conclusion

The addition of cituxumumab to lapatinib and capecitabine did not improve PFS or OS compared with lapatinib and capecitabine in patients with HER2-positive MBC.

Clinical trial registry

ClinicalTrials.gov Identifier: NCT00684983

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Data availability

Data collection and statistical analyses were conducted by the Alliance Statistics and Data Center and is available upon request. All data generated or analyzed during this study are included in this published article.

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Acknowledegments

The authors extend their gratitude to the patients who participated in this clinical trial. They further recognize and thank the clinical research staff at each of the participating study sites, as well as the breast cancer research committee leadership and centralized administrative support provided by the NCCTG and Alliance for Clinical Trials in Oncology.

Funding

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology), UG1CA232760, U10CA180820 and UG1CA189859 (ECOG-ACRIN), U10CA180868 (NSABP/NRG Oncology), UG1CA189821 and U10CA180888 (SWOG), and https://acknowledgments.alliancefound.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Mayo Clinic, 200 1st Street SW, Rochester, MN, 55905, USA

    Tufia C. Haddad, Ciara C. O’Sullivan, Beiyun Chen, Kathleen S. Tenner, Paul Haluska & Matthew P. Goetz

  2. Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN, USA

    Jun He

  3. Mayo Clinic, Scottsdale, AZ, USA

    Donald Northfelt & Amylou C. Dueck

  4. Weill Cornell Medical College, New York, NY, USA

    Karla V. Ballman

  5. Seattle Cancer Care Alliance, Seattle, WA, USA

    Hannah Linden

  6. Montefiore Medical Center, Bronx, NY, USA

    Joseph A. Sparano

  7. Southeast Clinical Oncology Research (SCOR) Consortium, Winston-Salem, NC, USA

    Judith O. Hopkins

  8. Kaiser Permanente-Rock Creek, Lafayette, CO, USA

    Chamath De Silva

  9. Mayo Clinic, Jacksonville, FL, USA

    Edith A. Perez

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  1. Tufia C. Haddad
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Contributions

Paul Haluska, Karla Ballman, Amylou Dueck, and Beiyun Chen contributed to the study conception and design. Material preparation, data collection and analysis, and interpretation of results were performed by Tufia Haddad, Jun He, Kathleen Tenner, and Amylou Dueck. The first draft of the manuscript was written by Tufia Haddad with critical review and support by Ciara O’Sullivan and Jun He. Donald Northfelt, Hannah Linden, Joseph A. Sparano, Judith O. Hopkins, Chamath De Silva, and Edith A. Perez, Paul Haluska, and Tufia Haddad led study sites and/or cooperative groups that enrolled patients and collected data for the analysis. Beiyun Chen served as pathologist throughout the trial and participated in study design. Matthew Goetz and Paul Haluska supervised all aspects of the study. Matthew Goetz supervised data interpretation and provided critical review of the manuscript. All authors reviewed and approved the final manuscript.

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Correspondence to Tufia C. Haddad.

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Conflicts of interest

Jun He, Beiyun Chen, Donald Northfelt, Amylou C. Dueck, Karla V. Ballman, Kathleen S. Tenner, Hannah Linden, Joseph A. Sparano6, Judith O. Hopkins7, Chamath De Silva, Edith A. Perez. Ciara C. O’Sullivan declares research funding to institution (Mayo) from the following companies: Lilly, Seattle Genetics, Bavarian Nordic, Minnemarita Therapeutics, and Biovica. Matthew P. Goetz declares funding acknowledgement to named Professorship: Erivan K. Haub Family Professor of Cancer Research Honoring Richard F. Emslander, M.D., and consulting fees to institution from Eagle Pharmaceuticals, Lilly, Biovica, Novartis, Sermonix, Context Pharm, Pfizer, and Biotheranostics, and grant funding to institution from Pfizer, Sermonix, and Lilly. Paul Haluska discloses he is a current employee and stockholder of Bristol Myers Squibb. Tufia C. Haddad declares grant funding to the Mayo Clinic from Takeda Oncology.

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Patients signed informed consent regarding publishing their data.

Ethical Approval

The study was conducted in accordance with the Declaration of Helsinki, and this phase II therapeutic trial was monitored at least twice annually by the Data and Safety Monitoring Board, a standing committee composed of individuals from within and outside of the Alliance.

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Haddad, T.C., He, J., O’Sullivan, C.C. et al. Randomized Phase II Trial of Capecitabine and Lapatinib with or without IMC-A12 (Cituxumumab) in Patients with HER2-Positive Advanced Breast Cancer Previously Treated with Trastuzumab and Chemotherapy: NCCTG N0733 (Alliance). Breast Cancer Res Treat 188, 477–487 (2021). https://doi.org/10.1007/s10549-021-06221-8

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