The addition of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor to endocrine therapy significantly improved not only progression-free but overall survival (OS) compared with endocrine therapy alone in patients with hormone-receptor (HR) positive, ERBB2-negative metastatic breast cancer, a systematic review and meta-analysis found.
In an analysis of 9 studies involving a total of 5,043 patients with metastatic breast cancer, the addition of a CDK4/6 inhibitor to endocrine therapy increased OS by 33% (Hazard Ratio [HR] of 1.33 [95% CI, 1.19-1.48; P<0.001]) compared with endocrine therapy alone, senior author Jiuda Zhao, MD, Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining, China, and colleagues reported in JAMA Network Open.
An OS advantage for additional CDK4/6 inhibition therapy was also seen in multiple subgroup analyses, the researchers reported.
“Endocrine therapy combined with CDK4/6 inhibitors is a reasonable option for treatment of HR-positive, ERBB2-negative metastatic breast cancer,” Zhao and colleagues wrote. “These results may aid physicians in selecting an effective therapeutic regimen for patients with hormone receptor-positive, ERBB2-negative metastatic breast cancer.”
Nearly two-thirds of patients with metastatic breast cancer are HR-positive, and about one-quarter of patients with breast cancer will experience recurrence after surgery, they pointed out.
In the 9 studies deemed eligible for the meta-analysis, OS data were reported in 6 studies while progression-free survival (PFS) and overall response rates (ORR) were reported in all 9 studies. All but one of the studies analyzed were phase 3 trials, while one was a phase 2 study, as the authors noted. The CDK4/6 inhibitors included in the analysis were ribociclib (PrKISQALITM, Novartis), palbociclib (Ibrance, Pfizer), and abemaciclib (Verzenio, Eli Lilly).
The addition of a CDK4/6 inhibitor to endocrine therapy doubled the ORR (odds ratio 2.02 [95% CI, 1.61-2.53; P<0.001]) compared with endocrine therapy alone, researchers observed. The same additional therapy increased PFS by 84% (HR 1.84 [95% CI, 1.70-1.98; P <0.001]) compared with endocrine therapy alone, they added.
In multiple subgroup analyses, the same additional CDK4/6 inhibition benefited all subgroups analyzed. For example, when used either as first-line or second-line therapy, the combination of a CDK4/6 inhibitor plus endocrine therapy improved OS compared with endocrine therapy alone.
Given as fist-line therapy, treatment with additional CDK4/6 inhibition increased OS by 35% (HR 1.35 [95% CI, 1.18-1.54; P<0.001]) while when used as second-line therapy, additional CDK4/6 inhibition improved OS by 30% (HR 1.30 [95% CI, 1.09-1.54; P<0.001]), researchers reported.
Similarly, the same additional therapy improved OS in both premenopausal and postmenopausal patients — by 32% (HR 1.32 [95% CI, 1.04-1.66; P<0.001]) in premenopausal women and by 34% (HR 1.34 [95% CI, 1.18-1.52; P<0.001]) in postmenopausal women.
The same therapeutic strategy also benefited patients with both visceral metastases as well as those with metastasis to bone only. For patients with visceral metastasis, the addition of a CDK4/6 inhibitor improved OS by 31% (HR 1.31 [95% CI, 1.12-1.53; P<0.001]) while for those with bone-only metastasis, an additional CDK4/6 inhibitor prolonged OS by 22% (HR 1.22 [95% CI, 0.88-1.68; P<0.001]), both compared with endocrine therapy alone.
Looking at patients younger than the age of 65 and those 65 years of age and older, treatment with a CDK4/6 inhibitor again improved OS compared with endocrine therapy alone.
For patients under the age of 65, additional CDK4/6 inhibition prolonged OS by 25% (HR 1.25 [95% CI, 1.06-1.49; P<0.001]) while for those 65 years of age and older, the same additional treatment prolonged OS by 38% (HR 1.38 [95% CI, 1.11-1.72; P<0.001]), as Zhao and colleagues observed.
“Given that AEs (adverse events) are the main reason for the termination of the majority of treatment programs, we analyzed the main grade 3, 4 AEs to assess their association with the treatment of patients with CDK4/6 inhibitors plus ET (endocrine therapy) or ET alone,” researchers noted.
Not unexpectantly, rates of AEs were significantly higher in patients who received additional CDK4/6 inhibitor therapy compared with those who received endocrine therapy alone.
For example, the combination of the 2 treatments increased the risk of neutropenia by 57-fold (HR 57.05 [95% CI, 38.26-85.05; P<0.001]).
The risk of leukopenia was also increased by 36-fold (HR 36.36 [95% CI, 19.35-68.34; P<0.001]) in patients who received additional CDK4/6 inhibition while the addition of a CDK4/6 inhibitor to endocrine therapy increased the risk of diarrhea by almost 5-fold (HR 4.97 [95% CI, 2.84-8.69; P<0.001]).
However, as investigators noted, different CDK4/6 inhibitors were associated with different AEs, palbociclib and ribociclib having more hematologic toxicities while abemaciclib was associated with more diarrhea and fatigue.
Commenting on the meta-analysis, James Martin, MD, and Lori Goldstein, MD, University Hospitals/Seidman Cancer Center, Cleveland, Ohio, pointed out that the development of inhibitors of the cyclin dependent kinases 4 and 6 was arguably one of the most clinically importantly discoveries for patients with HR-positive, ERBB2-negative metastatic breast cancer.
They also noted that the FDA itself had previously carried out a pooled analysis of all 7, phase III studies in which the CDK4/6 inhibitors were evaluated. In this analysis some 4200 participants had received a CDK4/6 inhibitor in combination with an aromatase inhibitor either in the frontline setting or with fulvestrant (Faslodex) in any setting.
“Among participants who received the CDK4/6 inhibitor with an aromatase inhibitor in the frontline setting, the difference in median PFS was 13.1 months (HR, 0.55),” the editorialists noted. For those who received a CDK4/6 inhibitor with fulvestrant in the second-line setting or beyond, the difference in median PFS was 6.9 months and this benefit was also seen in patients with progesterone receptor-negative disease among many other subgroups, as they also noted.
“Additional meta-analyses have previously been published and confirmed similar findings,” Martin and Goldstein wrote. “These data support the current clinical practice of discussing the potential benefits of CDK4/6 inhibitors with nearly all patients living with HR-positive, ERBB2-negative metastatic cancer as recommended by the National Comprehensive Cancer Network guidelines.”
The addition of a CDK4/6 inhibitor to endocrine therapy significantly increased overall survival compared with endocrine therapy alone in metastatic, HR-positive, ERBB2-negative breast cancer.
The combination of a CDK4/6 inhibitor to endocrine therapy significantly increased the risk of adverse events although the additional AEs observed were different depending on the CDK4/6 inhibitor used.
Pam Harrison, Contributing Writer, BreakingMED™
The study was funded in part by a grant from the Innovation Team for the Study of Pathogenesis and Anti-tumor Mechanisms of Chinese-Tibetan Medicine in the Qinghai area.
Neither the authors nor the editorialists had any conflicts of interest to declare.
Cat ID: 22
Topic ID: 78,22,22,691,192,925