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Expert Point of View: Nadia Harbeck, MD, PhD, and Fatima Cardoso, MD


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Nadia Harbeck, MD, PhD

Nadia Harbeck, MD, PhD

Fatima Cardoso, MD

Fatima Cardoso, MD

Serving as European Society for Medical Oncology (ESMO) expert at a press briefing, Nadia Harbeck, MD, PhD, Head of the Breast Center at the University of Munich, called the findings “practice-changing” in some parts of the world and “practice-reinforcing” in others. She said the 10-month survival benefit in endocrine-sensitive patients in the second-line setting is an “unprecedented” result, which will likely “change people’s hearts who were not sure. In my personal opinion, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor is the drug to take, preferably already in the first-line setting,” she added.

However, speculating about the implications in Europe, invited discussant Fatima Cardoso, MD, Director of the Breast Unit at the Champalimaud Clinical Center in Lisbon, predicted that the findings would not advance the combination of palbociclib (Ibrance) plus fulvestrant (Faslodex) to standard-of-care status in the ESMO Clinical Practice Guidelines. Instead, based on the totality of the data, she predicted the Guidelines would apply the magnitude of clinical benefits scale—noting the significant improvement in progression-free survival, the nonsignificant improvement in overall survival, and the improvement in quality of life (delaying chemotherapy)—to recommend the regimen as the preferred treatment in patients without prior exposure to a CDK4/6 inhibitor. “We cannot write it as a new standard of care,” she stated.

Dr. Cardoso praised PALOMA-3 for including premenopausal patients (20% of the study population), who are often excluded from studies in estrogen receptor–positive advanced disease. She also noted that 60% of the population had visceral metastases, and they are typically treated with chemotherapy. The study showed, she said, “we do not need chemotherapy for a vast number of our patients with visceral metastases. They could be given several lines of endocrine therapy instead.”

Dr. Cardoso said she would have liked for PALOMA 3 to have had overall survival as a co-primary endpoint, since a progression-free survival benefit should never be the sole goal of any trial. In the future, she suggested there be fewer, but larger, sufficiently powered trials and that post–disease progression data should be analyzed.

Unanswered Questions

The results, Dr. Cardoso continued, bring to the fore several unanswered questions: Which patients benefit most from endocrine therapy plus CDK4/6 inhibition? Is the optimal use of this class in patients who are naive to endocrine therapy or exposed to it? Is there a benefit to continuing CDK4/6 inhibitors beyond disease progression? And how do these regimens compare with endocrine therapy combined with mammalian target of rapamycin or phosphoinositide 3 kinase inhibition?

“There are many available options for luminal-like advanced breast cancer, but which is the best sequence for the individual patient?” she asked.

Finally, Dr. Cardoso called for a meta-analysis of the three available CDK4/6 inhibitors: palbociclib, ribociclib (Kisqali), and abemaciclib (Verzenio). “Let us not repeat the mistakes of 2 decades ago,” she said, referring to multiple redundant studies comparing three aromatase inhibitors. It is a better use of resources, she suggested, to determine the benefit of the class as a whole, rather than to pinpoint small differences among them. 

DISCLOSURE: Dr. Cardoso is a paid consultant for Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, Roche, Sanofi, Seattle Genetics, and Teva. Dr. Harbeck reported honoraria for lectures and consulting from Agendia, Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Genomic Health, Lilly, MSD, NanoString, Novartis, Odonate, Pfizer, Roche, Sandoz/Hexal, and Seattle Genetics.


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