1. 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
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Stefano Iacobelli, Malgorzata Foszczynska-Kloda, Soo-Chin Lee, Richard A. Michaelson, Juan Lacava, Raymond Smith, Vichien Srimuninnimit, Mauricio Kotliar, William Audeh, Damir Vrbanec, Young-Hyuck Im, Paola Edith Price, Maria Del Pilar, Barbara Bower, Tadeusz Pienkowski, Jedzada Maneecahvakajorn, Seppo Pyrhoenen, Alexander Marmé, Saverio Cinieri, Vladimir Semiglazov, Luciano Latini, Luis Miguel, Thitiya Sirisinha, Mario Matwiejuk, Jose Luiz Pedrini, John Allan Ellerton, Maik Hauschild, Xiaojia Wang, Christoph Maintz, Joohyuk Sohn, Estefania Monturus, Kenjiro Aogi, Eugeny Gotovkin, Ron Blachy, Douglas Otero Reye, Rita Blanchard, Bahriye Aktas, Adam Knott, Norberto Batista Lopez, L Roman, Reiki Nishimura, Piotr Tomczak, Duncan Wheatley, Emilio Alba Conejo, Yoshinori Itoh, Giraldo Kato, Petar Stefanovski, Rosa Jochim, Christoph Thomssen, Brigitte Van Eyll, Yutaka Tokuda, S O'Reilly, Paulette Blanchet, Ion Boiangiu, Nikola Vasev, Sherko Kümmel, Julie Taguchi, Do Youn Oh, David Miles, Jurandyr Andrade, Nora Giacomi, Volkmar Mueller, Eduardo Côrtes, Paula Klein, Eleonora Restuccia, Xuenong Ouyang, Leanne Budde, Andre Kallab, Elżbieta Starosławska, Takayuki Ueno, Taral Patel, Jun Horiguchi, Gilson Delgado, Sue Prill, Carol Peterson, Lourdes Calvo, Andreas Kirsch, Gustavo Ismael, Liwei Wang, Veena Charu, Dino Amadori, Pirkko Kellokumpu-Lehtinen, Brooke R. Daniel, Frank Senecal, Sanjay Yadav, Vera Gorbunova, Mikhail Kopp, Patrapim Sunpaweravong, Hiroji Iwata, Frank Priou, Kazuhiko Nakagami, Alejandra Perez, Michael R. Clemens, Marcus Schmidt, Denise A. Yardley, Birgitta Wesenberg, Priscilla Caguioa, Haruki Ogata, An Nguyen, Sung Bae Kim, Tsz-Kok Yau, Vladimir Merculov, Mikhail Lichinitser, Valorie Chan, Yoshiaki Rai, Neville Davidson, Walter E. Aulitzky, Gloria Martinez, Koji Takeda, Sherene Loi, Junichiro Watanabe, Louis Fehrenbacher, Gunta Purkalne, Shaker R. Dakhil, Claudia Schumacher, Rizvana Ahmad, Winnie Yeo, Christine Brezden-Masley, Alison Jones, Seock-Ah Im, Zetina Toache, Jeffrey Hargis, Celia Tosello, Tania Soria, Catia Angiolini, Maria De Fatima Gaui, Ravi Patel, Christopher Lobo, Andreas Schneeweiss, Priyanka Sharma, Cesar Estuardo, Randall Thomas, Adam Brufsky, Virote Sriuranpong, Zhenzhou Shen, Sandra Franco, Clive Mulatero, Wojciech Polkowski, Maria Alejandra Bartoli, Shigehira Saji, Patrick J. Flynn, Kimberly L. Blackwell, Gladys Rodriguez, Robert Robles, Timothy J. O'Rourke, Fabio Franke, Gabriel Tellez-Trevilla, Robert R. Carroll, Laura Biganzoli, Cheng Ying, Peter A. Kaufman, Mark Karwal, Mirta Varela, Darcy Spicer, Jonathan Polikoff, Roberto Hegg, Jungsil Ro, Pedro Sánchez-Rovira, Takahiro Nakayama, Edda Simoncini, María Bianconi, Liljana Kostovska-Maneva, Hugo Castro, Elza Grincuka, Jeff Neidhart, Anne Robinson, Nathan B. Green, Robert Hermann, Laura Assersohn, Teresa Gamucci, Dennis Tudtud, Nobuaki Sato, Antonio Gonzalez Martin, Victor Hugo Alencar, Jess Armor, Bruno Coudert, Nuria Ribelles, Eva Ciruelos, Daniel Cubero, Iveta Kudaba, Eduardo Cronemberger, Norikazu Masuda, Norio Kohno, Sergio J Azevedo, Vadim Shirinkin, Miguel Gil I Gil, Serafin Morales, Hirofumi Fujii, Chris Gallagher, Hernandez Monroy, Katsumasa Kuroi, Rodrigo Moura, Richy Agajanian, Zeljko Soldic, Jean-Marc Ferrero, Kenichi Inoue, Mark C. Benyunes, Davi Jendiroba, Filippo Montemurro, Masahiro Kashiwaba, Robert Quackenbush, Koichiro Tsugawa, Paulo M. Hoff, Eva-Maria Grischke, Susana De La Cruz, Vincent Hansen, Marianna Bitina, Carolyn B. Hendricks, Javier Cortes, Zee Wan Wong, Igor Kiselev, David Waterhouse, Javier Hornedo Muguiro, Mario Campone, Marianne Just, Emma Clark, Rodrigo Pereira, Sandra M Swain, Ruemu E. Birhiray, Helio Pinczowski, and Wichit Arpornwirat
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0301 basic medicine ,medicine.medical_specialty ,Receptor, ErbB-2 ,Population ,Phases of clinical research ,Breast Neoplasms ,Docetaxel ,Placebo ,Antibodies, Monoclonal, Humanized ,Loading dose ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Trastuzumab ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Clinical endpoint ,Humans ,Neoplasm Metastasis ,education ,Aged ,education.field_of_study ,business.industry ,Middle Aged ,Survival Analysis ,030104 developmental biology ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Female ,Pertuzumab ,business ,medicine.drug - Abstract
Summary Background CLEOPATRA was a phase 3 study comparing the efficacy and safety of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. In the primary analysis and subsequent reports, progression-free and overall survival were significantly improved in the pertuzumab group compared with the placebo group. Here, we report the end-of-study analysis of CLEOPATRA. Methods This was a double-blind, randomised, placebo-controlled, phase 3 trial that was done at 204 centres in 25 countries. Eligible patients were 18 years or older, had HER2-positive, metastatic breast cancer, had not received previous chemotherapy or biological treatment for their metastatic disease, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. All study drugs were given intravenously, every 3 weeks. Patients were assigned to receive either pertuzumab or placebo at a loading dose of 840 mg, and 420 mg thereafter; plus trastuzumab at 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at 75 mg/m2, escalating to 100 mg/m2 if tolerated. Pertuzumab or placebo and trastuzumab were given until disease progression; docetaxel was given for six cycles, or longer at the investigators’ discretion. Randomisation (1:1) was done by use of an interactive voice-response system and was stratified by geographical region (Asia, Europe, North America, or South America) and previous treatment (previous adjuvant or neoadjuvant chemotherapy vs none). The primary endpoint was independent review facility-assessed progression-free survival, which has been reported previously. Since the confirmatory overall survival analysis had also occurred before this prespecified end-of-study analysis, analyses presented here are descriptive. Overall survival analyses were based on the intention-to-treat population with crossover patients analysed in the placebo group; analyses were not adjusted for crossover to the pertuzumab group and are likely to be conservative. Safety analyses were based on treatment received; crossover patients were counted in the placebo group up to the day before first pertuzumab dose. This trial is registered with ClinicalTrials.gov , number NCT00567190 . Findings Between Feb 12, 2008, and July 7, 2010, 1196 patients were assessed for eligibility, of whom 808 were enrolled and randomly assigned. 402 patients were assigned to receive docetaxel plus trastuzumab plus pertuzumab, and 406 patients were assigned to receive docetaxel plus trastuzumab plus placebo. Clinical cutoff for this analysis was Nov 23, 2018. Between July 2012 and clinical cutoff, 50 patients crossed from the placebo to the pertuzumab group. Median follow-up was 99·9 months in the pertuzumab group (IQR 92·9–106·4) and 98·7 months (90·9–105·7) in the placebo group. Median overall survival was 57·1 months (95% CI 50–72) in the pertuzumab group and 40·8 months (36–48) in the placebo group (hazard ratio 0·69, 95% CI 0·58–0·82); 8-year landmark overall survival rates were 37% (95% CI 31–42) in the pertuzumab group and 23% (19–28) in the placebo group. The most common grade 3–4 adverse event was neutropenia (200 [49%] of 408 patients in the pertuzumab group, 183 [46%] of 396 patients in the placebo group). Five (1%) of 408 patients in the pertuzumab group and six (2%) of 396 patients in the placebo group had treatment-related deaths. One new serious adverse event suggestive of congestive heart failure (pertuzumab group) and one new symptomatic left ventricular systolic dysfunction (post-crossover) occurred since the previous analysis. Interpretation Our analysis shows that the previously observed improvements in overall survival with pertuzumab, trastuzumab, and docetaxel versus placebo, trastuzumab, and docetaxel were maintained after a median of more than 8 years of follow-up. The long-term safety and cardiac safety profiles of pertuzumab, trastuzumab, and docetaxel were maintained in the overall safety population and within crossover patients. HER2-targeted therapy has changed the natural history of HER2-positive metastatic breast cancer, with the dual blockade of pertuzumab and trastuzumab, with docetaxel, demonstrating an 8-year landmark overall survival rate of 37%. Funding F Hoffmann-La Roche and Genentech.
- Published
- 2019