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CHICAGO -- Progression-free survival (PFS) in advanced hormone receptor (HR)-positive/HER2-negative breast cancer improved significantly in patients who received ribociclib (Kisqali) and a different endocrine therapy after progression on an initial CDK4/6 combination, a randomized trial showed.

Median PFS increased from 2.76 months with endocrine therapy and placebo to 5.29 months with ribociclib and endocrine therapy. Almost twice as many patients in the ribociclib arm were alive and progression-free at 6 months, and 12-month PFS was three times greater.

Patients who switched to fulvestrant or exemestane also experienced the PFS benefit. An exploratory analysis suggested the benefit with fulvestrant was limited to patients with ESR1 wild-type tumors, reported Kevin Kalinsky, MD, of Emory University and Winship Cancer Institute in Atlanta, at the American Society of Clinical Oncology (ASCO) annual meeting.

"This is the first randomized trial to show the benefit of ribociclib in switching endocrine therapy after progression on a CDK4/6 inhibitor," said Kalinsky. "Ribociclib plus endocrine therapy led to a statistically significant improvement in progression-free survival compared to placebo plus endocrine therapy in participants with tumor progression following a CDK4/6 inhibitor. Palbociclib [Ibrance] was the prior CDK4/6 inhibitor in the majority of participants."

"It is worth noting that fulvestrant alone in this population had a limited median progression-free survival of 2.76 months after CDK4/6 inhibitor progression, and these data are consistent with other recent trials in the same space. In an exploratory analysis, the benefits seem limited to the ESR1 wild-type population in the fulvestrant subgroup. However, the ESR1 mutation cohort was small and had a higher rate of [other mutations], so these data are hypothesis generating," he added.

These randomized trial data addressed an important issue in the management of advanced HR-positive breast cancer, said ASCO invited discussant Claudine Isaacs, MD, of Georgetown University and MedStar Health in Washington, D.C. Nonetheless, the results are just a first step toward providing answers about optimal therapy for patients whose breast cancer progresses on frontline CDK4/6 inhibition and endocrine therapy.

"Up until now we have only had data from small retrospective studies, predominantly with abemaciclib [Verzenio]," said Isaacs. "Now we have results from a well-designed randomized phase II trial. However, based on these results, it is unclear if one needs to switch both the endocrine therapy as well as the CDK4/6 inhibitor. While this trial is a good proof of concept, it is still a small randomized phase II study, and in my mind is not practice changing."

Several ongoing trials are addressing the overall question of optimal post-CDK4/6 therapy and others are specifically focused on whether switching the endocrine therapy and continuing with the same CDK4/6 inhibitor is sufficient, Isaacs added.

CDK4/6 inhibition plus endocrine therapy has become standard of care in metastatic HR-positive/HER2-negative breast cancer, and ribociclib plus endocrine therapy has been shown to improve PFS and overall survival (OS) in that setting, said Kalinsky.

The antiproliferative effect of CDK4/6 inhibition can reverse upon discontinuation, and observational data suggest a potential benefit for treatment with a CDK4/6 inhibitor and switching endocrine therapy after progression on prior CDK4/6 inhibition, he continued. However, no prospective randomized trials had investigated the strategy.

Kalinsky reported findings from the randomized trial involving 119 patients with metastatic HR-positive/HER2-negative breast cancer that had progressed on CDK4/6 inhibition and endocrine therapy. All patients received a different endocrine agent from the prior therapy and were randomized to ribociclib or placebo.

The trial initially specified fulvestrant as the endocrine agent for all patients, but the protocol was modified to allow use of exemestane, which Kalinsky said was consistent with current clinical practice. Ultimately, 99 patients received fulvestrant and 20 received exemestane. Palbociclib was the prior CDK4/6 inhibitor for 103 of 119 patients, ribociclib for 14 patients, and abemaciclib for three patients.

The primary endpoint of PFS showed that ribociclib combination treatment reduced the hazard for disease progression or death by 43% (95% CI 0.39-0.95, P=0.006). Additionally, 41.2% of patients in the ribociclib arm were progression-free at 6 months versus 23.9% in the control group. The 12-month PFS rate was 24.6% with ribociclib and 7.4% with placebo. The PFS improvement achieved statistical significance in the patients who received fulvestrant (HR 0.60, 95% CI 0.39-0.94) and was numerically superior in the exemestane subgroup (HR 0.41, 95% CI 0.14-1.24).

The PFS benefit with ribociclib was consistent across analyzed subgroups, including patients who received prior palbociclib (HR 0.58, 95% CI 0.38-0.90) or prior ribociclib (HR 0.50, 95% CI 0.15-1.70). Response rate (20% vs 11%) and clinical benefit rate (43% vs 25%) also favored ribociclib.

Hematologic treatment-related adverse events (TRAEs) occurred more often in the ribociclib arm, including neutropenia, anemia, and thrombocytopenia, but non-hematologic TRAE rates were similar between treatment groups.

An exploratory analysis of PFS with fulvestrant by ESR1 mutation status yielded a hazard ratio of 0.30 with ribociclib versus placebo in the ESR1 wild-type subgroup (n=45), whereas the hazard ratio favored placebo for the ESR1-mutant subgroup (n=33, HR 1.22). Kalinsky emphasized that the findings should be considered hypothesis generating because of the small numbers.

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