While cyclin-dependent kinase (CDK)4/6 inhibitors have become a mainstay of treatment for patients with hormone receptor-positive (HR+), HER2-negative (HER2–) metastatic breast cancer (mBC), many patients still receive first-line treatment with chemotherapy, even in the absence of visceral crisis. Lacking head-to-head clinical trials comparing treatment approaches, a recent meta-analysis compared results from phase II and III clinical trials evaluating chemotherapy, hormonal therapy, and targeted therapy in this setting. Across 140 studies that included more than 50,000 patients with HR+, HER2–mBC, the combination of the CDK4/6 inhibitor palbociclib plus letrozole was associated with the longest progression-free survival (PFS) benefit. Importantly, no chemotherapy regimen alone or in combination with a targeted therapy was superior to the combination of a CDK4/6 inhibitor and hormonal therapy in terms of PFS, and there were no statistically significant differences in PFS between available CDK4/6 inhibitor combinations. In terms of another important therapy parameter, overall response rate, paclitaxel plus bevacizumab was the only current regimen to outperform palbociclib plus letrozole. However, the toxicity profiles of the endocrine therapy plus CDK4/6 inhibitor combinations were less severe than those of the chemotherapy combinations, but they were more severe than the (less active) endocrine therapies alone.
Overall, the authors note that this is the largest meta-analysis of therapy combinations in patients with HR+, HER2– mBC, and results are consistent with the current consensus guidelines in this setting. Further research is needed to determine which therapeutic options are optimal in patients with visceral crisis.
High Altitude: This meta-analysis suggests that CDK4/6 inhibitors added to endocrine therapy are superior to other treatment approaches in patients with HR+, HER2– mBC. These data may be used to shape treatment algorithms and inform treatment guidelines for HR+, HER2– mBC moving forward.
Ground Level: This meta-analysis provides a strong impetus for addition of CDK4/6 inhibitors to endocrine therapy in early line treatment for patients with HR+, HER2– mBC who are not in visceral crisis. Although addition of these agents does increase the need for adverse event management compared with endocrine therapy alone, the toxicity burden is relatively lower than that with chemotherapy, while producing longer PFS vs chemotherapy approaches in this setting.