By: Nick Mulcahy
One of the success stories in recent years in the treatment of metastatic, hormone-receptor positive breast cancer has been the addition of drugs acting as inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) on top of endocrine therapy. Three such drugs are now available — palbociclib (Ibrance, Pfizer), ribociclib (Kisqali, Novartis), and abemaciclib (Verzenio, Lilly). However, many patients also respond well to endocrine therapy alone — without the extra cost and extra toxicity of adding on a CDK4/6 inhibitor.
So a pressing clinical question is which patients should get these new drugs?
In search of an answer to this question, researchers from the US Food and Drug Administration (FDA) investigated whether it was possible to identify patients who respond and those who do not.
To do so, the team conducted the first comprehensive pooled data analysis of randomized clinical trials of all marketed CDK4/6 inhibitors to assess efficacy in subgroups of patients with metastatic disease that is hormone-receptor positive.
The idea was to evaluate treatment effects in “less common” clinicopathological subgroups of patients, who are widely “believed to have differing degrees of endocrine sensitivity,” write the authors, led by Jennifer Gao, MD, of the FDA’s Center for Drug Evaluation and Research, Office of Oncologic Diseases.
The team speculated that some subgroups would have lesser benefit from the new drugs.
However, they found that the addition of CDK4/6 inhibitors to endocrine therapy “seemed to benefit all clinicopathological subgroups of interest in this pooled analysis,” the authors conclude.
The study was published online December 16 in the Lancet Oncology.
Approached for comment, Saroj Niraula, MD, from the University of Manitoba and CancerCare Manitoba, said that these researchers asked a “noble question,” but their finding “did not add a lot to what we already know.”
Most notably, “the study has not identified those who can be spared the combination,” Niraula told Medscape Medical News.
Niraula explained that study was unable to identify patients for whom endocrine therapy alone might result in similar outcomes to endocrine therapy plus a CDK4/6 inhibitor.
“It’s an excellent study and a commendable use of the FDA’s privileged access to individual-level patient data” he said, adding that it is a “strong” meta-analysis.
The study “adds value” to the literature because some of the prognostic subgroups analyzed have results in keeping with the primary data in terms of having significantly improved outcomes, he commented.
“We still don’t know the answer to the most important question with CDK4/6 inhibitors which is: What is most sensible sequence of use of CDK4/6 inhibitors in treatment of metastatic breast cancer,” he added.
Niraula lobbied for using single-agent endocrine therapy initially in appropriate metastatic patients and suggests saving CDK4/6 inhibitors for progression. Later-line use is also supported by current data, he said. “Efficacy results appear stronger in the second-line setting from the data we have so far,” he said.c
The meta-analysis encompassed seven phase 3 clinical trials with a total of 4200 patients with advanced disease randomized to CDK4/6 inhibitors plus endocrine therapy or placebo plus endocrine therapy (in both the first-line and second-line settings). Endocrine therapies included letrozole or anastrozole (aromatase inhibitors) or fulvestrant, but excluded tamoxifen. All studies had a primary endpoint of progression-free survival (PFS).
In the pooled analysis, the difference in estimated median PFS between all patients who received CDK4/6 inhibitors and those given placebo was 8.8 months (hazard ratio [HR], 0.59).
At a median follow-up of 22.6 months, 993 (24%) of the 4200 patients had died, with an estimated overall survival HR of 0.89.
Notably, the PFS survival results favored the CDK4/6 inhibitor group in all clinicopathological subgroups.
Barbara Jacoby is an award winning blogger that has contributed her writings to multiple online publications that have touched readers worldwide.