medwireNews: Patients with metastatic breast cancer who progress during combination treatment with a CDK4/6 inhibitor and endocrine therapy may benefit from switching endocrine therapy and combining it with ribociclib, MAINTAIN study findings indicate.
The strategy significantly improved progression-free survival (PFS) versus an endocrine therapy switch plus placebo, and MAINTAIN is the “first randomized trial to show the benefit of ribociclib and switching endocrine therapy after progression on a CDK4/6 inhibitor,” said Kevin Kalinsky (Emory University, Atlanta, Georgia, USA) at the 2022 ASCO Annual Meeting in Chicago, Illinois, USA.
The phase 2 study included 119 patients (99.2% women, median age 57 years) with hormone receptor-positive, HER2-negative metastatic breast cancer that had progressed during treatment with any CDK4/6 inhibitor plus any endocrine therapy.
Regardless of their prior CDK4/6 inhibitor, participants were randomly assigned to receive ribociclib 600 mg/day in a 3 weeks on, 1 week off schedule or placebo. Participants in both arms also switched endocrine therapy; if they were previously treated with fulvestrant they were given exemestane and vice versa. Patients previously treated with neither fulvestrant nor exemestane were given investigators’ choice of either of these drugs, but fulvestrant was encouraged.
In all, 83% of participants received fulvestrant and 17% were given exemestane. The most common prior CDK4/6 inhibitor was palbociclib (84%) followed by ribociclib (11%), palbociclib plus another CDK4/6 inhibitor (3%), and abemaciclib (2%).
Kalinsky reported that the primary endpoint of PFS was significantly longer in the ribociclib arm than in the placebo arm, at a median of 5.3 versus 2.8 months, which corresponded to a significant 43% lower risk for disease progression or death with ribociclib.
At 6 and 12 months, the PFS rates were 41.2% and 24.6%, respectively, in the ribociclib group and a corresponding 23.9% and 7.4% in the placebo group.
The overall response rates were 20% with ribociclib and 11% with placebo, while the clinical benefit rates were a respective 43% and 25%, both nonsignificant differences. Median response durations were 18.8 and 14.8 months, respectively.
Similar results were observed when only the 99 patients who received fulvestrant were included in the analysis. In this case there was a significant 40% lower risk for disease progression or death with ribociclib versus placebo, with median PFS at 5.3 versus 2.8 months.
Kalinsky noted that 42% of 78 mutation-evaluable participants who received fulvestrant carried an ESR1 mutation at study entry, and subgroup analyses by ESR1 mutation status indicated that the benefits of ribociclib were restricted to patients who were wild-type for ESR1.
Specifically, median PFS was 8.3 months in the 24 ESR1 wild-type patients who received ribociclib plus fulvestrant versus 2.8 months in their 21 counterparts who received placebo plus fulvestrant, a significant difference.
By contrast, median PFS was 3.0 months in both the ribociclib (n=18) and placebo (n=19) arms of the subgroup of patients with an ESR1 mutation.
However, Kalinsky pointed out that half of the patients with an ESR1 mutation who received ribociclib also had a co-occurring CCND1 and/or FGFR1 amplification, which may be associated with resistance to CDK4/6 inhibition. Conversely, none of the ESR1 wild-type participants in the ribociclib arm carried these amplifications, and the presenter said that the findings “are hypothesis generating.”
Discussant Claudine Isaacs, from Georgetown University Medical Center in Washington, DC, USA, said that the “well-designed” trial addressed the important question of CDK4/6 inhibition following progression on a CDK4/6 inhibitor.
However, she added: “While this trial is a good proof-of-concept, it is still a small phase 2 study and in my mind is not practice changing.”
Issacs noted that a number of ongoing trials – PALMIRA, PACE, EMBER-3, and PostMONARCH – may provide further clarification on the best strategy to use postprogression on a CDK4/6 inhibitor.
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2022 ASCO Annual Meeting; Chicago, Illinois, USA: 3–7 June