A randomized, phase II trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibition (CDK 4/6i) in patients (pts) with unresectable or hormone receptor–positive (HR+), HER2-negative metastatic breast cancer (MBC): MAINTAIN trial.

Abstract

LBA1004 Background: CDK 4/6i has demonstrated benefit in progression free survival (PFS) and overall survival (OS) in pts with HR+, HER2- MBC when combined with endocrine therapy (ET). While observational data demonstrate a potential benefit of continuing CDK 4/6i and switching ET at progression, no prospective trials have evaluated this approach. We conducted a phase II, multi-center, randomized, trial to evaluate the efficacy of fulvestrant or exemestane +/- ribociclib in pts with HR+HER2- MBC whose cancer previously progressed on any CDK 4/6i + any ET. Methods: In this investigator-initiated, phase II, double-blind, placebo-controlled trial, men or women with measurable or non-measurable HR+/HER2- MBC whose cancer progressed during CDK 4/6i and ET were randomized 1:1 to fulvestrant or exemestane +/- ribociclib. Pts treated with prior fulvestrant received exemestane as ET in the randomization; if prior exemestane fulvestrant was the ET; if neither, fulvestrant or exemestane was per investigator discretion, though fulvestrant was encouraged. PFS was the primary endpoint, defined as time from randomization to progression of disease or death. A one-sided log-rank test with a sample size of 120 randomized and evaluable pts with a significance level alpha of 2.5%, achieves 80% power to detect an effect size (difference in PFS) of 3 months. Results: Of the 120 randomized evaluable pts, 1 pt was removed due to not taking ET along with ribociclib/placebo. All but 1 pt was female, the median age was 57.0 years, 88 pts (74%) were white, and 21 (17.6%) were Hispanic. For ET, 99 pts received fulvestrant (83%) and 20 pts exemestane (17%). In terms of prior CDK 4/6i, 100 pts previously received palbociclib (84%), 13 pribociclib (11%), 2 abemaciclib (2%), and 4 palbociclib and another CDK 4/6i (3%). There was a statistically significant PFS improvement for pts randomized to fulvestrant or exemestane + ribociclib [median: 5.33 months, 95% CI (Confidence Interval): 3.25–8.12 months] vs. placebo (median: 2.76 months, 95% CI: 2.66–3.25 months): Hazard Ratio (HR) = 0.56 (95% CI: 0.37-0.83), p = 0.004. Similar results were seen in the subset of pts treated with fulvestrant, with a median PFS for those randomized to ribociclib (5.29 months) vs. placebo (2.76 months), HR = 0.59 (95% CI: 0.38-0.91), p = 0.02. At 6 months, 42% were progression-free on the ribociclib arm vs. 24% on placebo. At 12 months, 25% were progression-free on the ribociclib arm vs. 7% on placebo. Additional endpoints will be reported, including overall response rate and safety. Conclusions: In this randomized, placebo-controlled trial, there was a significant PFS benefit for pts with HR+/HER2- MBC to switch ET and receive ribociclib after progression on CDK 4/6i. Clinical trial information: NCT02632045.

Oral Selective Estrogen Receptor Degrader After Endocrine Therapy With a Cyclin-Dependent Kinase 4/6 Inhibitor

“…2,3 The MAINTAIN trial reported that ribociclib plus endocrine therapy (fulvestrant or exemestane) led to a statistically significant improvement in PFS compared with placebo plus endocrine therapy in patients with disease progression following prior CDK4/6 inhibitors. 4 Real-world data analysis shows that the use of CDK4/6 inhibitors in second-line therapy after CDK4/6 inhibitors in first-line therapy has reached approximately 40%. 5 Researchers are performing clinical trials to assess a similar strategy in oral SERD (eg, ClinicalTrials.gov identifier: NCT04964934).…”

Seize the engine: Emerging cell cycle targets in breast cancer

“…A retrospective, multi‐centre cohort of 87 patients treated with abemaciclib after progression to palbociclib reported a 6‐month PFS of 37%, and a randomised phase 3 trial of this strategy is ongoing 47 . Consistently, the MAINTAIN phase II trial reported that the combination of ET plus ribociclib showed a modest benefit over fulvestrant monotherapy after progression on first‐line ET plus CDK4/6i (84% of patients had received palbociclib), adding to the potential role for CDK4/6i switching following progression 48 . In contrast, the PACE study, evaluating palbociclib added to fulvestrant after progression on an AI plus CDK4/6i (mostly palbociclib), failed to show benefit 49 .…”

Systemic therapy for hormone receptor‐positive/human epidermal growth factor receptor 2‐negative early stage and metastatic breast cancer

“…Data presented at the ASCO 2022 meeting at a median followup of 18.2 months showed that the median PFS for patients in the ribociclib group was 5.29 versus 2.76 months for patients in the placebo group, suggesting that switching CDK4/6 inhibitors after progression on prior CDK4/6 inhibitor improved outcomes. 181 The phase 2 BioPER study (ClinicalTrials.gov identifier NCT03184090) evaluated the efficacy of continuing palbociclib plus ET beyond progression on prior palbociclib-based regimens for HR-positive/HER2negative MBC. Among 33 patients enrolled, the CBR was 34.4%, and 13.0% of tumors showed loss of retinoblastoma protein expression, meeting both primary end points.…”

“…The phase 2 trial MAINTAIN (ClinicalTrials.gov identifier NCT02632045) randomized 120 patients with HR‐positive/HER2‐negative MBC whose disease had progressed on ET plus any CDK4/6 inhibitor to receive fulvestrant or exemestane with or without ribociclib. Data presented at the ASCO 2022 meeting at a median follow‐up of 18.2 months showed that the median PFS for patients in the ribociclib group was 5.29 versus 2.76 months for patients in the placebo group, suggesting that switching CDK4/6 inhibitors after progression on prior CDK4/6 inhibitor improved outcomes 181 . The phase 2 BioPER study (ClinicalTrials.gov identifier NCT03184090) evaluated the efficacy of continuing palbociclib plus ET beyond progression on prior palbociclib‐based regimens for HR‐positive/HER2‐negative MBC.…”