The CDK 4/6 inhibitor palbociclib did not extend overall survival when combined with hormonal therapy as a first-line treatment in people with hormone-receptor positive, HER2-negative metastatic breast cancer. This finding was despite multiple past trials that showed a significant impact on progression-free survival for adding palbociclib to an anti-estrogen regimen.
These final clinical trial results from the phase III PALOMA-2 clinical trial differ from some recent findings from clinical trials of the other two FDA approved CDK 4/6 inhibitors. They were presented June 4 in Chicago at the annual meeting of the American Society of Clinical Oncology.
CDK 4/6 inhibitors are a form of targeted therapy used to treat breast cancer. They work by stopping cells from growing and dividing. The FDA has approved three drugs in this category for the treatment of hormone-receptor positive, HER2-negative metastatic breast cancer. The first, palbociclib (Ibrance), gained approval in 2015, and was the drug under study in PALOMA-2. The FDA then approved abemaciclib (Verzenio) in 2017 and ribociclib (Kisqali) in 2018.
These targeted therapies have changed the treatment landscape for people with HR+/HER2- metastatic breast cancer. Nearly 70% of breast cancers are hormone-receptor positive and HER2-negative. Today, most people newly diagnosed with this form of breast cancer receive a CDK 4/6 inhibitor plus anti-estrogen therapy as a first treatment, rather than chemotherapy. However, questions remain about whether and what differences exist among these three medications. Research continues to explore which CDK inhibitor therapy offers the best outcome, as well as whether it’s helpful to switch to a different CDK inhibitor if cancer grows despite treatment.
Multiple past studies have shown that palbociclib works well when combined with hormonal therapy. In earlier reports from PALOMA-2, the drug exceeded expectations for progression-free survival, the period of time the cancer did not grow. This study presents the final results on overall survival, how long trial participants lived after starting on the study.
The PALOMA-2 clinical trial compared the length of overall survival of one group of people given palbociclib with the hormonal therapy letrozole (Femara) to another group given letrozole plus placebo (an inactive pill) for HR+/HER2- metastatic breast cancer.
The trial began with 666 participants randomly assigned to one of two groups, with two-thirds of study participants getting palbociclib and letrozole, and one-third receiving the standard treatment at that time of letrozole and the placebo. The trial included people whose breast cancer was metastatic at diagnosis (38%), also called de novo metastatic, as well as people who had been disease-free for less than 12 months (22%) and more than 12 months (40%) from an early-stage diagnosis. None had been treated previously for metastatic breast cancer.
Participants took palbociclib plus letrozole for a median length of 22 months. Those who took letrozole alone took it for a median duration of 13.8 months. Participants in the study whose cancer grew received treatment after this time, often hormonal therapies or CDK 4/6 inhibitors, including palbociclib.
Earlier reports from this trial showed that palbociclib improved progression-free survival. This report looks at overall survival, finding no difference between the two groups. The median overall survival was over four years for both groups – 53.9 months for those receiving palbociclib and 51.2 months for those who had letrozole alone. This difference of two months was not statistically significant.
At the time of follow-up, approximately 60% of participants in both groups had died. Of those who remained, about one-third were no longer in the study, a large number for a study of this kind. These individuals withdrew consent to participate, perhaps because palbociclib became FDA approved during the course of the trial, and many others were lost to follow-up over time.
What these findings mean for you
During a discussion panel following the trial presentation, the doctors noted that multiple past studies have shown the benefits of palbociclib in controlling HR+/HER2- metastatic breast cancer. And while they observed that other trials had shown overall survival benefits for the other two CDK inhibitors available, differences in the trials makes it impossible to compare these drugs head-to-head. In fact, trials comparing some of the CDK inhibitors to one another are now being conducted, such as HARMONIA.
Nevertheless, a similar past clinical trial found that ribociclib plus letrozole was more effective than letrozole alone, adding a full year in overall survival. Palbociclib and ribociclib function in much the same way and are used interchangeably by doctors. These trials, combined with today’s findings from PALOMA-2, led some physicians at the meeting to say they are more likely to recommend ribociclib or abemaciclib in the future. An informal Twitter poll of more than 500 oncologists conducted by Erika P. Hamilton, MD, suggests doctors may be reluctant to start new patients on palbociclib, choosing one of the other CDK inhibitors instead. Few said they would shift patients who are currently taking palbociclib to another CDK inhibitor.
Research continues to support the role of CDK inhibitors in the treatment of HR+/HER2- metastatic breast cancer but leaves unanswered questions about which drug to use first. Look for more studies on these drugs to help clarify how and when they can be most effective.
If you are taking palbociclib and have concerns about these findings, talk with your doctor. Ask how similar your situation is to the ones examined in these clinical trials. The study presenter, Richard S. Finn, MD, of the David Geffen School of Medicine at UCLA, said that when PALOMA-2 opened in 2012, the researchers had predicted survival with the addition of palbociclib would extend life by 34 months. In the conclusion of his talk, he noted, “the median survival of over 50 months in this population represents a significant improvement in the natural history of HR+ breast cancer.”