Palbociclib in Breast Cancer: New Overall Survival Data

Alexander M. Castellino, PhD

October 21, 2018

MUNICH — The new class of cyclin-dependent kinase (CDK) 4/6 inhibitors offer hope for patients with advanced breast cancer who have stopped responding to endocrine therapy.

But where exactly they should fit into the treatment algorithm is still under some debate, and this debate has now been stirred up by eagerly awaited overall survival (OS) data with the first of these agents to be approved, palbociclib (Ibrance, Pfizer).

The new data come from the PALOMA-3 trial, conducted in patients with advanced hormone receptor-positive (HR+) and human epidermal receptor 2 negative (HER2-) advanced breast cancer who had stopped responding to endocrine therapy.

Addition of palbociclib to fulvestrant improved OS by 7 months compared with fulvestrant alone, but this difference was not statistically significant.

For patients on the combination of palbociclib and fulvestrant, median OS was 34.9 months versus 28.0 months for patients on fulvestrant alone (hazard ratio [HR] for death, 0.81; P = .09). Median follow-up for the OS observations was 44.8 months, with a 60% data maturity.

Massimo Cristofanilli, MD

These data were presented (abstract LBA2) at a presidential symposium during the European Society for Medical Oncology (ESMO) 2018 Congress by Massimo Cristofanilli, MD, of the Feinberg School of Medicine, Northwestern University, Chicago, Illinois, and simultaneously published in the New England Journal of Medicine.

Cristofanilli indicated that in patients with advanced HR+, HER2- breast cancer who had progressed or relapsed on prior endocrine therapy, the combination of palbociclib and fulvestrant should be the standard of care.

He noted that when patients were analyzed based on prior endocrine sensitivity the results shook out in favor of patients who were sensitive to prior endocrine therapy. For these patients difference in median OS with palbociclib and fulvestrant was 10 months (39.7 vs 29.7 months with fulvestrant alone; HR, 0.72; 95% CI, 0.55 - 0.94). However, for patients without sensitivity to prior endocrine therapy, median OS was shorter for the combination (20.2 vs 26.2 months).

In addition, among 413 postmenopausal women, median OS was significant for the combination (34.8 vs 27.1 months; HR, 0.73; 95% CI, 0.57 - 0.95). However, there was no difference in median OS for premenopausal women (38.0 months for each group).

The primary endpoint for median progression-free survival (PFS) was reported previously and was significant for the combination (11.2 vs 4.6 months; HR, 0.50). Cristofanilli noted that the magnitude of treatment effect seen with the PFS endpoint carried over into OS. The treatment effect for PFS and OS was 6.6 and 6.9 months, respectively.

"This is very important for patients, as it shows that the improvement in PFS observed in previous studies may have a positive impact on OS, an ultimate goal of treatment, therefore improving the chance for a long-term life in spite of advanced disease," Cristofanilli said in an ESMO press statement.

"The demonstration of a positive impact on OS also provides additional confidence to clinicians and patients as to the benefits of this combination as an appropriate and effective treatment approach," he added.

At a press conference, Cristofanilli was asked whether clinicians who had been on the fence about using CDK4/6 inhibitors in the absence of OS results would now be swayed by these new data.

In his answer, he emphasized that after PFS there was a significant delay in starting chemotherapy.

Median time to patients receiving chemotherapy was 17.6 months for patients receiving the combination and 8.8 months for patients receiving fulvestrant alone.

Not a New Standard of Care

At the Presidential Symposium, Fatima Cardoso, MD, director of the breast unit at the Champalimaud Clinical Center in Lisbon, Portugal, discussed the PALOMA 3 data and was skeptical that the ESMO guidelines would list the combination of palbociclib and fulvestrant as a standard of care for HR+ HER2- advanced breast cancer.

She suggested that based on the PALOMA 3 data in its totality, the ESMO guidelines will apply its magnitude of clinical benefits scale and, noting that OS was not significant, the guidelines are likely to be amended to read: "The addition of a CDK4/6 inhibitor to fulvestrant in patients previously exposed to endocrine therapy provided a significant improvement in median PFS (6 to 7 months), a nonstatistical improvement in OS (7 months), and an improvement in quality of life, and is the preferred treatment option if a CDK4/6 inhibitor was not previously used."

"We cannot write it as a new standard of care," she said.

However, she also had other comments pertinent to clinical practice. In PALOMA 3, she noted that 20% of women were premenopausal and 60% had visceral metastases at baseline.

"Many trials in HER+ advanced breast cancer have not included premenopausal women," Cardoso said. Yet, we recommend young women with HR+ advanced breast cancer should have adequate ovarian suppression or ablation and then be treated in the same way as postmenopausal women with endocrine agents with or without targeted therapies, she added.

She stressed that endocrine therapy is the preferred treatment option even for women with visceral metastases unless there is visceral crisis or concern of endocrine resistance. "We do not need chemotherapy for a vast number of our patients with visceral metastases," Cardoso said. "They could be given several lines of endocrine therapy," she said.

Noting that PALOMA 3 was not powered to achieve significant OS, she also emphasized that PFS should not be the sole goal of any study. "OS must at least be a coprimary endpoint," Cardoso said. To achieve this she suggested there should be fewer, but larger, sufficiently powered trials that would allow for collection of post-progression data.

Several questions remain to be answered, according to Cardoso:

  • Can we identify which patients benefit and/or which ones do not benefit from endocrine therapy plus CDK4/6 inhibition?

  • Is it better to use a CDK4/6 inhibitor in first- or second-line – that is, in patients who are endocrine therapy naive or in patients who have used endocrine therapy?

  • Will there be a rationale for continuing therapy [with the CDK4/6 inhibitor] beyond progression?

  • How does endocrine therapy with CDK4/6 inhibition compare with endocrine therapy combined with mTOR or PI3K inhibition?

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

Cardoso called for a collaboration to perform a meta-analysis on all the CDK4/6 inhibitors. "Let us not repeat the mistakes of two decades ago," she pleaded. She was referring to the large trials that were undertaken and huge resources spent on determining which of the three aromatase inhibitors — letrozole, exemestane, or anastrozole — was superior, which she suggested was a waste of efforts. Better to consider the three CDK4/6 inhibitors that are now available (palbociclib, ribociclib, and abemaciclib) as a new class of drugs and decide how to use this new class, rather than try to pinpoint differences between them, she suggested.

What Other Experts Are Saying

Commenting on the findings for ESMO, Carmen Criscitiello, MD, PhD, of the European Institute of Oncology, Milan, Italy, said: "These data were much awaited, as the clinical benefit obtained with CDK4/6 inhibitors was incontestable, but there was the hot question of whether the PFS benefit translates into OS benefit. This randomized phase 2 trial shows for the first time an improvement in OS with a CDK4/6 inhibitor in the metastatic setting for ER+/HER2- breast cancer."

She noted that the study was not powered for OS and the data need to be interpreted with caution. "Although the results strongly suggest that the PFS benefit may translate into OS benefit, the other trials conducted with CDK4/6 inhibitors will contribute to confirm the estimate of the OS benefit observed in this study," Criscitiello said.

ESMO expert commentator Nadia Harbeck, MD, PhD, of the breast center at the University of Munich, Germany, indicated there was some uncertainty as to when to give patients CDK4/6 inhibitors, which ones to give, and whether payers would pay.

Cristofanilli has reported receiving personal fees from Pfizer during the conduct of the study, and Novartis and Merus outside the submitted work. Cardoso has reported being a 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.

European Society for Medical Oncology (ESMO) 2018 Congress. Abstract LBA2.

N Engl J Med. Published October 20, 2018. Abstract

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