Three cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, indicated for hormone receptor (HR) positive, HER2 negative metastatic breast cancer, had similar efficacy when used in combination with fulvestrant but showed different toxicity profiles in previously treated metastatic breast cancer patients, a study said.

The Cancer Treatment and Research Communications published the result of the meta-analysis that compared trials data of Pfizer’s Ibrance (palbociclib), Lilly’s Verzenio (abemaciclib), and Novartis’ Kisqali (ribociclib).

(Source: https://doi.org/10.1016/j.ctarc.2020.100175)
(Source: https://doi.org/10.1016/j.ctarc.2020.100175)

The meta-analysis was based on PALOMA-3 (Ibrance), MONARCH-2 (Verzenio), and MONALEESA-3 (Kisqali) studies that compared each DCD4/6 inhibitor plus fulvestrant with fulvestrant alone, in previously treated metastatic HR-positive, HER2 negative breast cancer patients.

The three agents extended overall survival (OS) significantly when combined with fulvestrant and improved progression-free survival (PFS), compared to fulvestrant alone. Patients treated with the combination therapy had higher objective response rates (ORR) than the fulvestrant alone group.

However, the three drugs showed a difference in serious adverse events.

Ibrance, Verzenio, and Kisqali had some pharmacological differences, the research team said.

Among them, Verzenio was the most potent drug in terms of CDK4/6 inhibition. While Verzenio requires continuous administration, Ibrance and Kisqali need administration for 21 consecutive days, followed by seven days off treatment.

Ibrance and Kisqali have greater lipophilicity compared to Verzenio, and Verzenio inhibits not only CDK4/6 but CDK9, a key enzyme associated with the cell proliferation process, according to the research team.

“Despite the disparities mentioned above, these properties did not seem to affect the clinical efficacy of such agents,” the research team said.

However, the researchers said they found “significant heterogeneity” in assessing serious adverse events, with fewer events reported in the PALOMA-3 trial on Ibrance.

Patients treated with Verzenio or Kisqali combined with fulvestrant reported more serious adverse events than those with fulvestrant monotherapy.

The use of any agent among the three was frequently associated with more leukopenia and neutropenia than the use of fulvestrant alone, the researchers noted.

Some other side effects were distinctive of a particular agent.

Verzenio was associated with high diarrhea rates and low bone marrow toxicity, while only Kisqali showed QT prolongation, the research team said.

“Indeed, current guidelines recommend avoidance of QT-prolonging agents, including fluoroquinolones, ketoconazole, and some antidepressants and antipsychotic agents for patients with concomitant use of ribociclib (Kisqali),” the research team said.

The researchers concluded that physicians should rely on the toxicity profiles of the CDK4/6 inhibitors because there were no efficacy criteria to pick one particular CDK4/6 inhibitor.

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