CDK 4/6 INHIBITORS WITH AI BETTER THAN CAPECITABINE?

A new study shows that the combination of a CDK4/6 blocker plus endocrine therapy is better than chemotherapy in young women with advanced breast cancer.  

Specifically, these were premenopausal women with metastatic hormone receptor-positive (HR+) and human epidermal receptor 2-negative (HER2–) breast cancer. 

The CDK4/6 inhibitor palbociclib (Ibrance, Pfizer) plus endocrine therapy significantly improved progression-free survival compared with single-agent chemotherapy in the Korean KCSG-BR15-10 study.

The study was published online October 24 in Lancet Oncology.

Despite "chemotherapy preference (guideline nonadherence), CDK4/6 combination endocrine therapy can be a standard treatment" in HR+, HER2– metastatic breast cancer," lead researcher Yeon Hee Park, MD, of Samsung Medical Center in Seoul, South Korea, told Medscape Medical News.

In the article, Park and colleagues note that clinical guidelines recommend endocrine therapy as the preferred treatment for premenopausal as well as postmenopausal women with HR+, HER2– metastatic breast cancer.

"In real-world clinical practice, however, a substantial number of patients are treated with chemotherapy," they point out.  

One "major" reason for this has been the lack of evidence from randomized trials comparing endocrine treatment with chemotherapy in the first-line setting, comment Marie Robert, MD, and Nicholas Turner, MD, PhD, from The Royal Marsden Hospital, London, UK, writing in an accompanying editorial.

Park told Medscape Medical News that the new results "can be interpreted in conjunction with the MONALEESA-7 study, in which CDK4/6 inhibitors showed a marked overall survival benefit compared with the endocrine-only group."

In the MONALEESA-7 study, reported earlier this year, the CDK4/6 inhibitor ribociclib (Kisqali, Novartis) plus endocrine therapy significantly improved overall survival for younger women with advanced HR+/HER2– breast cancer compared with endocrine therapy alone.

Several studies have now demonstrated that CDK4/6 inhibitors improve overall survival, note the editorialists. "Across all studies with CDK4/6 inhibitors, a consistent benefit for CDK4/6 inhibitors has been seen in patients with visceral disease," they write.

“All of these findings, combined with the KCSG-BR15-10 results reported by Park and colleagues, confirm that CDK4/6 inhibitors in combination with endocrine therapy should now be the standard of care in first-line treatment for estrogen receptor-positive, HER2– breast cancers," Robert and Turner conclude.

Details of the New Study 

KCSG-BR15-10 was a multicenter, open-label, randomized, phase 2 trial that enrolled premenopausal women with HR+, HER2– metastatic breast cancer that had relapsed or progressed during or after previous tamoxifen therapyA total of 184 eligible patients were randomly assigned (1:1) to receive palbociclib plus combination endocrine therapy (oral exemestane 25 mg/day for 28 days and oral palbociclib 125 mg/day for 21 days every 4 weeks plus leuprolide 3.75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m² twice daily for 2 weeks every 3 weeks).

Six patients in the capecitabine group withdrew from the study before drug administration, leaving 86 patients in the capecitabine group and 92 patients in the palbociclib plus endocrine therapy group for the modified intention-to-treat analysis. 

During a median follow-up of 17 months, median progression-free survival, the primary endpoint, was significantly longer with palbociclib plus endocrine therapy than with capecitabine (20.1 vs 14.4 months; hazard ratio, 0.66; 95% CI, 0.44 - 0.99; one-sided P = .0235). 

Post-hoc subgroup analysis suggested that patients who had not received chemotherapy before enrollment and who did not have visceral metastases derived the greatest benefits from palbociclib plus endocrine therapy compared with chemotherapy. However, this result should be interpreted with caution because of the small number of patients, the researchers said.

There were no life-threatening toxicities in either group. Asymptomatic grade 3–4 neutropenia was more common in the palbociclib plus endocrine therapy group than the capecitabine group (75% vs 16%), whereas several other symptomatic adverse events (any grade) were more common with capecitabine than palbociclib plus endocrine therapy, including nausea (34% vs 12%), diarrhea (39% vs 14%), and hand–foot syndrome (100% vs 1%).

Two patients in the capecitabine group and one in the palbociclib group discontinued treatment because of adverse events. No treatment-related deaths were reported.

"The one remaining area of clinical uncertainty remains patients with visceral crisis, for whom optimal management is still unclear," Robert and Turner note in their editorial.  

"Should these patients receive chemotherapy followed by CDK4/6 inhibitors plus endocrine therapy in maintenance, or should chemotherapy be continued until disease progression, or could endocrine and CDK4/6 inhibitor combinations also supplant chemotherapy for these patients? Ongoing studies will address the optimal management in this remaining small group of patients," they write.