Norikazu Masuda1, Shoichiro Ohtani2, Toshimi Takano3, Kenichi Inoue4, Eiji Suzuki5, Rikiya Nakamura6, Hiroko Bando7, Yoshinori Ito8, Kazushige Ishida9, Takashi Yamanaka10, Katsumasa Kuroi11, Hiroyuki Yasojima1, Hiroi Kasai12, Tsuyoshi Takasuka13, Takaki Sakurai14, Tatsuki R Kataoka14, Satoshi Morita15, Shinji Ohno16, Masakazu Toi17. 1. Department of Surgery, Breast Oncology, National Hospital Organization Osaka National Hospital, Osaka, Japan. 2. Department of Breast Surgery, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan. 3. Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan. 4. Division of Breast Oncology, Saitama Cancer Center, Saitama, Japan. 5. Department of Breast Surgery, Kyoto University Hospital, Kyoto, Japan. 6. Division of Breast Surgery, Chiba Cancer Center, Chiba, Japan. 7. Breast and Endocrine Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. 8. Breast Medical Oncology Department, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan. 9. Department of Surgery, Iwate Medical University, Morioka, Japan. 10. Department of Breast and Endocrine Surgery, Kanagawa Cancer Center, Yokohama, Japan. 11. Department of Breast Surgery, Tokyo Metropolitan Health and Hospitals Corporation Ebara Hospital, Tokyo, Japan. 12. Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan. 13. Oncology Lifecycle Management Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan. 14. Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan. 15. Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan. 16. Breast Oncology Center, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan. 17. Breast Cancer Unit, Kyoto University Hospital, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan. toi@kuhp.kyoto-u.ac.jp.
Abstract
PURPOSE: The standard of care in the neoadjuvant setting for human epidermal growth factor receptor 2 (HER2)-positive breast cancer is dual HER2-targeted therapy. However, a need to minimize treatment-related toxicity and improve pathological complete response (pCR) rates, particularly in luminal HER2-positive disease, exists. METHODS: Neopeaks, a randomized, phase 2 study, compared docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP; 6 cycles; group A), TCbHP (4 cycles) followed by trastuzumab emtansine + pertuzumab (T-DM1+P; 4 cycles; group B), and T-DM1+P (4 cycles; group C) regimens in HER2-positive primary breast cancer patients; concurrent hormone therapy with T-DM1+P was administered in case of estrogen receptor positivity (ER+). Based on tumor shrinkage, nonresponders in group C were switched to 5-fluorouracil + epirubicin + cyclophosphamide (FEC; 4 cycles). Primary endpoint was pCR (comprehensive pCR ypN0 [ypT0-TisypN0]). RESULTS: Of 236 patients enrolled, 204 were randomized to groups A (n = 51), B (n = 52), and C (n = 101). In group C, 80 (79%) patients continued T-DM1+P following favorable response, whereas 21 (21%) nonresponders switched to FEC. pCR rate was numerically higher with the TCbHP → T-DM1+P regimen (71%) versus the standard TCbHP (57%) and T-DM1+P (57%) regimens. The rate in group C was higher among responders continuing T-DM1+P (63%) versus nonresponders who switched to FEC (38%). pCR rates after initial 4 cycles of T-DM1+P (group C; 57%) and standard TCbHP regimen (57%) were equivalent. pCR rate in patients with ER+ was significantly higher in group B (69%) than groups A (43%) and C (51%), but was comparable in patients with ER- (67-76%). Compared with the T-DM1-based arm, the incidence of adverse events was higher in the taxane-based arms. CONCLUSION: In the neoadjuvant setting, the pCR rate with the standard TCbHP → T-DM1+P regimen was numerically better than the TCbHP regimen alone and significantly better in patients with ER+. Personalization of the T-DM1+P regimen could serve as a reasonable approach to minimize toxicity while maintaining efficacy. Trial registration ID: UMIN-CTR: UMIN000014649.
RCT Entities:
PURPOSE: The standard of care in the neoadjuvant setting for human epidermal growth factor receptor 2 (HER2)-positive breast cancer is dual HER2-targeted therapy. However, a need to minimize treatment-related toxicity and improve pathological complete response (pCR) rates, particularly in luminal HER2-positive disease, exists. METHODS: Neopeaks, a randomized, phase 2 study, compared docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP; 6 cycles; group A), TCbHP (4 cycles) followed by trastuzumab emtansine + pertuzumab (T-DM1+P; 4 cycles; group B), and T-DM1+P (4 cycles; group C) regimens in HER2-positive primary breast cancerpatients; concurrent hormone therapy with T-DM1+P was administered in case of estrogen receptor positivity (ER+). Based on tumor shrinkage, nonresponders in group C were switched to 5-fluorouracil + epirubicin + cyclophosphamide (FEC; 4 cycles). Primary endpoint was pCR (comprehensive pCR ypN0 [ypT0-TisypN0]). RESULTS: Of 236 patients enrolled, 204 were randomized to groups A (n = 51), B (n = 52), and C (n = 101). In group C, 80 (79%) patients continued T-DM1+P following favorable response, whereas 21 (21%) nonresponders switched to FEC. pCR rate was numerically higher with the TCbHP → T-DM1+P regimen (71%) versus the standard TCbHP (57%) and T-DM1+P (57%) regimens. The rate in group C was higher among responders continuing T-DM1+P (63%) versus nonresponders who switched to FEC (38%). pCR rates after initial 4 cycles of T-DM1+P (group C; 57%) and standard TCbHP regimen (57%) were equivalent. pCR rate in patients with ER+ was significantly higher in group B (69%) than groups A (43%) and C (51%), but was comparable in patients with ER- (67-76%). Compared with the T-DM1-based arm, the incidence of adverse events was higher in the taxane-based arms. CONCLUSION: In the neoadjuvant setting, the pCR rate with the standard TCbHP → T-DM1+P regimen was numerically better than the TCbHP regimen alone and significantly better in patients with ER+. Personalization of the T-DM1+P regimen could serve as a reasonable approach to minimize toxicity while maintaining efficacy. Trial registration ID: UMIN-CTR: UMIN000014649.