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.
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.
In the subgroup analysis, patients with disease-free interval of up to 12 months (n = 180) had the most notable benefit in the CDK4/6 inhibitor group, with a difference in estimated median PFS of 5.8 months in favor of a CDK4/6 inhibitor plus an aromatase inhibitor vs placebo plus an aromatase inhibitor.
The study authors conclude: "Further research is needed to identify patient subgroups for whom endocrine therapy alone might be appropriate for first-line or second-line treatment of hormone receptor-positive, HER2-negative metastatic breast cancer."
Study is "Clearly Important"
The new work is "clearly important," say Giuseppe Curigliano, MD, University of Milan, Italy, and Sibylle Loibl, MD, German Breast Group, Frankfurt, Germany, in an accompanying editorial.
The editorialists observe that the efficacy analysis was carried out in less common subgroups of patients with breast cancer that cannot be well analyzed in single trials due to their small numbers. These included women with progesterone receptor negative disease; those with a disease-free interval up to 12 months; de-novo metastatic, lobular histology, and bone-only disease; those with visceral metastases; and patients aged 40 years or younger.
The editorialists would like to expand that list, saying "other subgroups might also be of interest."
For example, they suggest that the analysis could be boosted by comparing patients with primary vs secondary endocrine resistance.
Patients with primary endocrine resistance include those with relapse during the first 2 years of adjuvant endocrine therapy or have progressive disease within the first 6 months of first-line endocrine therapy for metastatic breast cancer, while on endocrine therapy.
Patients with secondary endocrine resistance include those who relapse while on adjuvant endocrine therapy after the first 2 years, relapse within 12 months of completing adjuvant endocrine therapy, or have progressive disease at least 6 months after initiating endocrine therapy for metastatic breast cancer, while on endocrine therapy.
Furthermore, identifying patients with varying degrees of endocrine responsiveness according to the minimum cutoff of estrogen receptor expression (> 1% to 100%) "could help to select true non-responders," they add.
There's a lot of work to be done with regard to optimizing the use of CDK4/6 inhibitors, the editorialist comment.
"Across all CDK4/6 inhibitor studies, we still need to further characterize the overall survival outcomes and other exploratory efficacy endpoints in those subgroups of patients with more favorable prognostic factors," they write.
Those include patients who have not previously received endocrine therapy, those with bone-only disease, and those with late recurrence.
Such data, say the pair, "could help to address the question of whether or not CDK4/6 inhibitors should be used as first-line treatment in combination with estrogen therapy or following initial estrogen therapy alone."
They single out the ongoing SONIA study as being potentially helpful. The study aims evaluate whether the sequence of an aromatase inhibitor plus CDK4/6 in first line, followed by fulvestrant in second line, is superior to the sequence of an aromatase inhibitor in first line followed by fulvestrant plus CDK4/6 in second line.
The editorialists also mention early stage disease — that is, the potential use of CDK4/6 inhibitors in the adjuvant setting. Large ongoing studies in this setting, they say, "will provide additional insights into improved patient selection and personalized treatment approaches."
The study authors and Niraula have disclosed no relevant financial relationships. Curigliano reported personal fees from Daichii-Sankyo, a travel grant from Pfizer, and personal fees from Foundation Medicine, outside the submitted work.
Medscape Medical News © 2020
Cite this: Nick Mulcahy. CDK4/6 Inhibitors for Breast Cancer: Who Does, Doesn't Benefit? - Medscape - Jan 08, 2020.