1. Goodwin, Peter M.

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MUNICH- Patients with HR+ HER2-negative (HER-) advanced breast cancer who were treated with a combination of the CDK4/6 inhibitor palbociclib in combination with fulvestrant lived longer than those receiving a placebo with fulvestrant in the prospective, randomized, double-blind, phase III PALOMA-3 study from which overall survival (OS) data were reported at the 2018 ESMO Annual Congress.

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"This combination should be the standard of care for patients progressing on endocrine therapy," said senior investigator Massimo Cristofanilli, MD, FACP, Professor of Medicine at the Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University in Chicago. "There's no doubt there is a clinical and meaningful strong benefit-not only in delaying the disease but also [in] survival. This should replace the use of chemotherapy."


Study Details

Patients taking the CDK4/6 inhibitor with fulvestrant lived a median of 6.9 months longer than those in the control group treated with placebo and fulvestrant.


About 30 percent of the 521 patients enrolled in PALOMA-3 received more than three lines of prior therapy and half of all patients had visceral metastases-such as in the liver and lung. "So it was quite aggressive disease for these patients," said Cristofanilli.


A significant extension of 6.6 months in progression-free survival (PFS) had already been reported at the interim analysis of the PALOMA-3 data and superior PFS had clearly been followed by a similar superiority in OS.


In the overall "intention-to-treat" group patients treated with the palbociclib/fulvestrant combination lived a median of 34.9 months compared with 28.0 months median in the control group-giving a statistically significant hazard ratio (HR) of 0.79.


Among the 410 patients who were sensitive to endocrine therapy, the OS superiority of the combination was even bigger-39.7 months median survival compared with 29.7 months in patients treated with placebo and fulvestrant (a significant HR of 0.72).


In the 111 patients who were resistant to endocrine therapy, no statistically significant survival advantage was found. Their median survival with the combination was measured as 20.2 months compared with 26.2 months in the placebo-treated patients.


The investigators had chosen palbociclib because the CDK4/6 pathway had been known to be activated in estrogen-resistant cell lines. Pre-clinical work had shown that inhibiting this pathway increased sensitivity to endocrine therapy.


"This is a common situation that we see in the clinic," noted Cristofanilli. "And when we actually look at the genomic data [we find that] amplification of mutations in these genes are very common in breast cancer. So it was a natural choice for this agent to be chosen for this combination."


He stated that patients had improvements in symptoms, and the only major side effect had been bone marrow toxicity with neutropenia that stabilized after the first 3 months. Patients had been able to continue treatment for "quite a long time" for up to 3 years. And patients benefited irrespective of the site of metastatic disease-bone, visceral, or non-visceral.


Cristofanilli described the CDK4/6 pathway as "currently the most important pathway in endocrine resistance." He regarded palbociclib as a safe drug to target this pathway in patients with metastatic breast cancer. "Palbociclib has been shown to be the most important targeted agent [and] to be very effective [and] safe," he said.


When asked what clinicians should make of these findings so far, Cristofanilli said they should be feeling more comfortable about using the combination of fulvestrant and palbociclib in patients with endocrine resistance. Not only did the drug give the chance to improve PFS, it also delayed chemotherapy, had an impact on overall survival, and "certainly is something that they can feel safe and confident to use."


But it is also important to look at the impact of this therapy on the subsequent treatments patients were likely to need beyond their therapy with this new combination. PALOMA-3 had shown that any gains from using the CDK4/6 inhibitor had not been lost further down the line. "In this study, the same magnitude of difference transferred to the overall survival-meaning that what you gain up front you maintain over time no matter what treatment you get later," Cristofanilli explained.


Expert Commentary

Commenting on the findings for ESMO, Carmen Criscitiello, MD, PhD, from the European Institute of Oncology Milan, noted: "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 III trial shows-for the first time-an improvement in OS with a CDK4/6 inhibitor in the metastatic setting for ER+/HER2- breast cancer."


But, she added a warning. "The study was unpowered for OS so the data should be cautiously interpreted. 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."


Matteo Lambertini, MD, ESMO Fellow at the Institut Jules Bordet, Brussels, also called for more OS data. "Collecting mature OS data at longer follow-up from randomized trials that investigate the combination of endocrine therapy and CDK4/6 inhibitors is crucial to have a clearer understanding on the benefit of these expensive agents," he stated. "The limited OS data that we had so far from these trials are now supported by the PALOMA-3 updated results-which strongly suggest that this treatment should become widely available for women with advanced HR+/HER2- disease."


Co-author of the PALOMA study, Nadia Harbeck, MD, PhD, Professor of Gynecology and Head of the Breast Center, University of Munich, commented that there had still been a lot of confusion over CDK4/6 inhibitors since three different agents all improved PFS.


"[But] I think this is now going to change. Ten months overall survival benefit in a CDK4/6 inhibitor study in the second-line setting is unprecedented," Harbeck said. She thought it could change attitudes among clinicians who previously had not been quite sure about the benefit. "I think we can now confidently say to our patients that this is the drug to take."


Cristofanilli also suggested the study had brought clarity. "There is no doubt in my mind that these data will contribute to convince oncologists [who] have been on the fence for the use of CDK4/6 inhibitors that this is definitely the best drug for second-line treatment."


Peter M. Goodwin is a contributing writer.