Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study

Swain, Sandra M.; Miles, David; Kim, Sung‐Bae; Im, Young‐Hyuck; Im, Seock‐Ah; Семиглазов, Владимир; Ciruelos, Eva; Schneeweiß, Andreas; Loi, Sherene; Monturus, Estefanía; Clark, Emma; Knott, Adam; Restuccia, Eleonora; Benyunes, Mark C.; Cortés, Javier; Agajanian, Richy; Ahmad, Rizvana; Aktas, Bahriye; Alencar, Victor Hugo Medeiros; Amadori, Dino; Andrade, Jurandyr Moreira de; Franke, Fábio; Angiolini, Catia; Aogi, Kenjiro; Armor, Jess F.; Arpornwirat, Wichit; Assersohn, L.; Audeh, William; Aulitzky, Walter; Azevedo, Sérgio Jobim; Bartoli, Maria Alejandra; López, Norberto Batista; Bianconi, María Inés; Biganzoli, Laura; Birhiray, Ruemu E.; Bitiņa, Marianna; Blachy, Ron; Blackwell, Kimberly; Blanchard, Rita A.; Blanchet, Paulette; Boiangiu, Ion; Bower, B.; Brezden-Masley, Christine; Brufsky, Adam; Budde, Leanne S.; Caguioa, Priscilla B.; Calvo, Lourdes; Campone, Mario; Carroll, Robert R.; Castro, Hugo R.; Chan, Valorie F.; Charu, Veena; Cinieri, Saverio; Clemens, Michael; Conejo, Emilio Alba; Côrtes, Eduardo; Coudert, Bruno; Cronemberger, Eduardo; Cubero, Daniel de Iracema Gomes; Dakhil, Shaker R.; Daniel, Brooke R.; Davidson, N.; Gauí, Maria de Fátima Dias; Cruz, Susana De La; Pilar, María del; Delgado, Gilson Luchezi; Ellerton, John; Estuardo, César; Fehrenbacher, Louis; Ferrero, Jean-­Marc; Flynn, Patrick J.; Foszczyńska-Kłoda, Małgorzata; Franco, Sandra; Fujii, Hirofumi; Gallagher, Chris; Gamucci, Teresa; Giacomi, N; Gil, Miguel Gil; Martín, Antonio González; Gorbunova, Vera; Gotovkin, E.; Green, Nathan; Grincuka, Elza; Grischke, Eva‐Maria; Hansen, Vincent; Hargis, Jeffrey B.; Hauschild, Maik; Hegg, Roberto; Hendricks, Carolyn B.; Hermann, Róbert; Hoff, Paulo M.; Horiguchi, Jun; Muguiro, Javier Hornedo; Iacobelli, Stéfano; Inoue, Kenichi; Ismael, Gustavo; Itoh, Yoshinori; Iwata, Hiroji; Jendiroba, D; Jochim, Rosa; Jones, Alison; Just, Marianne; Kallab, Andre M.; Karwal, Mark; Kashiwaba, Masahiro; Kato, Giraldo; Kaufman, Peter A.; Kellokumpu‐Lehtinen, Pirkko; Kirsch, Andreas; Kiselev, Igor; Klein, Paula; Kohno, Norio; Kopp, Mikhail V.; Kostovska-Maneva, Liljana; Kotliar, Mauricio; Kudaba, Iveta; Kümmel, Sherko; Kuroi, Katsumasa; Lacava, J.; Latini, Luciano; Lee, Soo‐Chin; Lichinitser, Mikhail; Lobo, Christopher; Maintz, Christoph; Maneecahvakajorn, Jedzada; Marmé, Alexander; Martı́nez, Gloria; Masuda, Norikazu; Matwiejuk, Mario; Merculov, Vladimir; Michaelson, Richard A.; Miguel, L Silva; Monroy, Hernandez; Montemurro, Filippo; Morales, S.; Moura, Rodrigo Scaliante de; Mueller, Volkmar; Mulatero, C; Nakagami, Kazuhiko; Nakayama, Takahiro; Neidhart, Jeff; Nguyen, An; Nishimura, Reiki; Ogata, Haruki; O’Reilly, Susan E.; O’Rourke, Timothy J.; Reye, Douglas Otero; Ouyang, Xin; Patel, Ravi; Patel, Taral; Pedrini, José Luiz; Pereira, Rodrigo R.; Perez, A. Garcia-Palomo; Peterson, Carol; Pieńkowski, Tadeusz; Pinczowski, Hélio; Polikoff, Jonathan; Polkowski, Wojciech; Price, P; Prill, Sue; Priou, Frank; Purkalne, Gunta; Pyrhoenen, Seppo; Quackenbush, Robert C.; Rai, Yoshiaki; Ribelles, Nuria; Ro, Jungsil; Robinson, A.; Robles, Robert; Rodriguez, Gladys; Roman, L.; Saji, Shigehira; Sánchez‐Rovira, Pedro; Sato, Nobuaki; Schmidt, Marcus; Schumacher, Claudia; Senecal, Frank M.; Sharma, Priyanka; Shen, Zhenzhou; Shirinkin, Vadim; Simoncini, Edda; Sirisinha, Thitiya; Smith, Raymond E.; Sohn, Joohyuk; Soldić, Željko; Soria, Tania; Spicer, Darcy; Srimuninnimit, Vichien; Sriuranpong, Virote; Starosławska, Elżbieta; Stefanovski, Petar; Sunpaweravong, Patrapim; Taguchi, Julie; Takeda, Koji; Téllez-Trevilla, Gabriel; Thomas, Randal; Thomssen, Christoph; Toache, Zetina; Tokuda, Yutaka; Tomczak, Piotr; Tosello, C.; Tsugawa, Koichiro; Tudtud, Dennis; Ueno, Takayuki; Eyll, Brigitte Van; Varela, Mirta; Vasev, Nikola; Vrbanec, Damir; Wang, Xiaojia; Wang, Liwei; Watanabe, Junichiro; Waterhouse, David; Wesenberg, Birgitta; Wheatley, Duncan; Wong, Zee Wan; Yadav, Sanjay Kumar; Yardley, Denise A.; Yau, Tsz‐Kok; Park, Yeon Hee; Cheng, Ying; Oh, Do Youn

doi:10.1016/s1470-2045(19)30863-0

Cited by 594 publications

(477 citation statements)

References 29 publications

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“…In terms of treatment sensitivity, it has been consistently demonstrated that HER2+/HR+ breast cancer patients have a reduced sensitivity to neoadjuvant chemotherapy + anti-HER2 agents, as documented by the lower chance to achieve a pathological complete response vs HER2 +/HR-patients [5]. Nevertheless, HER2+/HR+ breast cancer patients derive a similar degree of relative benefit from trastuzumab added to adjuvant chemotherapy [6] and, in the metastatic setting, standard treatments such as first-line trastuzumab + pertuzumab + taxane or T-DM1 have shown similar relative efficacy in registrative trials in both the HR+ and HR-subgroups [7,8]. Despite these results do not justify a substantially different clinical approach to HER2+/HR+ and HER2+/HR-breast cancer, growing evidence strongly suggests that HER2+/HR+ patients may deserve more personalized treatment options.…”

Section: Her2+/hr+ Breast Cancer As a Distinct Subtypementioning

confidence: 99%

Should triple-positive breast cancer be recognized as a distinct subtype?

Dieci

Guarneri

2020

Expert Review of Anticancer Therapy

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Section: Her2+/hr+ Breast Cancer As a Distinct Subtypementioning

confidence: 99%

Should triple-positive breast cancer be recognized as a distinct subtype?

Dieci

Guarneri

2020

Expert Review of Anticancer Therapy

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“…In this primary and nal analysis of 412 patients with HER2-positive MBC, the safety pro le of rst-line H SC plus P IV and D IV was tolerable and consistent with that of CLEOPATRA, in which H was delivered intravenously within the same combination regimen and in a similar patient population [1- 3,5]. No new safety signals were identi ed and AEs of particular interest to P + H therapy, including diarrhea, rash, mucosal in ammation, and febrile neutropenia, occurred less frequently in MetaPHER than in the CLEOPATRA secondary interim OS analysis [2].…”

Section: Discussionmentioning

confidence: 87%

“…Based on these results, H IV plus P IV and D IV is the rst-line standard of care for these patients [4]. The CLEOPATRA end-of-study analysis at 99-month follow-up (maximum 120 months) has continued to show improved OS bene t of this regimen (57.1 vs. 40.8 months, HR 0.69), and con rmed the consistency of its long-term safety, including maintained cardiac safety, compared with placebo, H IV, and D IV [5].…”

Section: Introductionmentioning

confidence: 96%

Subcutaneous Trastuzumab with Pertuzumab and Docetaxel in HER2-Positive Metastatic Breast Cancer: Final Analysis of MetaPHER, A Phase 3b Single-Arm Safety Study

Kümmel

Tondini

Abraham

et al. 2020

Preprint

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BACKGROUND Intravenous trastuzumab, pertuzumab, and docetaxel is first-line standard of care for patients with HER2-positive metastatic breast cancer. Subcutaneous trastuzumab plus intravenous pertuzumab and chemotherapy has shown similar safety and tolerability to intravenous trastuzumab in patients with HER2-positive early and metastatic breast cancer; however, in the metastatic setting, this has yet to be shown globally.METHODS In this open-label, single-arm, multicenter phase 3b study, eligible patients were ≥18 years old with histologically/cytologically confirmed previously untreated HER2-positive metastatic breast cancer. All patients received ≥1 dose of subcutaneous trastuzumab (fixed-dose 600 mg) plus intravenous pertuzumab (loading dose: 840 mg/kg; maintenance dose: 420 mg/kg) and docetaxel (≥6 cycles; initial dose 75 mg/m2) every 3 weeks. The primary objective was safety and tolerability; secondary objectives included efficacy.RESULTS At clinical cutoff, 276 patients had completed the study; median duration of follow-up was 27 months. The most common any-grade adverse events were diarrhea, alopecia, and asthenia. The most common grade ≥3 adverse events were neutropenia, febrile neutropenia, and hypertension. There were no cardiac deaths and mean left ventricular ejection fraction was stable over time. Median investigator-assessed progression-free survival was 18.7 months; objective response rate was 75.6%.CONCLUSIONS Efficacy/safety results of subcutaneous trastuzumab plus intravenous pertuzumab and docetaxel in metastatic breast cancer are consistent with historical evidence of intravenous trastuzumab. These findings further support the body of evidence indicating that subcutaneous administration does not affect the safety and efficacy profile of trastuzumab in HER2-positive breast cancer. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02402712 (date of registration: 30th March 2015)

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“…In the phase III CLEOPATRA study which compared pertuzumab combined with trastuzumab and docetaxel (TTPH) with trastuzumab and docetaxel in treatment-naïve patients with advanced HER2-positive breast cancer, doublet anti-HER2 agents significantly improved both PFS (18.5 versus 12.4 months, p < 0.001) and OS (57.1 versus 40.8 months, p < 0.001). 52 In the post hoc analysis, pertuzumab also delayed the time of onset of CNS metastasis from 11.9 months to 15.0 months. 53 Since patients with baseline brain metastases were excluded in this study, the efficacy of intracranial control of pertuzumab cannot be evaluated.…”

Section: Introductionmentioning

confidence: 93%

Local and systemic treatment for HER2-positive breast cancer with brain metastases: a comprehensive review

Chan

Lam

et al. 2020

Ther Adv Med Oncol

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The management of human epidermal growth factor receptor (HER2)-positive breast cancer has improved over the past decade. However, despite improvements in systemic control, a substantial proportion of patients with advanced HER2-positive breast cancer suffer from central nervous system metastases and even intracranial progression after aggressive local treatment. There is paucity of data and no consensus on the systemic therapies for patients with intracranial progression. This review discusses both local and systemic treatments for HER2-positive breast cancer with brain metastases with a special focus on the response of central nervous system metastases. A recommended practical treatment algorithm to guide physicians in selecting the most appropriate anti-HER2 therapy for their patients is suggested.

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Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study

Cited by 594 publications

References 29 publications

Should triple-positive breast cancer be recognized as a distinct subtype?

Should triple-positive breast cancer be recognized as a distinct subtype?

Subcutaneous Trastuzumab with Pertuzumab and Docetaxel in HER2-Positive Metastatic Breast Cancer: Final Analysis of MetaPHER, A Phase 3b Single-Arm Safety Study

Local and systemic treatment for HER2-positive breast cancer with brain metastases: a comprehensive review

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