CHICAGO — Progression-free survival (PFS) in hormone receptor (RH) positive/HER2 negative advanced breast cancer improved significantly in patients who received ribociclib (Kisqali) and different endocrine therapy after progression on an initial combination of CDK4/6, a randomized trial showed.
Median PFS decreased from 2.76 months with hormone therapy and placebo to 5.29 months with ribociclib and hormone therapy. Nearly twice as many patients in the ribociclib arm were alive and progression-free at 6 months, and PFS at 12 months was three times higher.
Patients who switched to fulvestrant or exemestane also experienced the benefit of PFS. An exploratory analysis suggested that the benefit of fulvestrant was limited to patients with CSR1 wild-type tumors, Kevin Kalinsky, MD, of Emory University and the Winship Cancer Institute in Atlanta, reported at the annual meeting of the American Society of Clinical Oncology (ASCO).
“This is the first randomized trial to show the benefit of ribociclib in switching hormone therapy after progression on a CDK4/6 inhibitor,” Kalinsky said. “Ribociclib plus hormone therapy resulted in a statistically significant improvement in progression-free survival compared to placebo plus hormone therapy in participants with tumor progression following a CDK4/6 inhibitor. Palbociclib [Ibrance] was the former CDK4/6 inhibitor in the majority of participants.”
“It should be noted 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 In an exploratory analysis, the benefits appear to be limited to the CSR1 wild-type population in the fulvestrant subgroup. However, the CSR1 mutation cohort was small and had a higher rate of [other mutations]so this data generates hypotheses,” he added.
These randomized trial data addressed an important issue in the management of advanced HR-positive breast cancer, said ASCO guest discussant Claudine Isaacs, MD, of Georgetown University and MedStar Health in Washington. , DC. Nevertheless, the results are only a first step towards providing answers. on optimal therapy for patients whose breast cancer progresses on first-line CDK4/6 inhibition and hormone therapy.
“Until now, we only had data from small retrospective studies, mostly with abemaciclib [Verzenio]”, said Isaacs. “We now have the results of a well-designed randomized phase II trial. However, based on these results, it is unclear whether to switch both hormone therapy and the CDK4/6 inhibitor. Although this trial is a good proof of concept, it is still a small randomized phase II study and in my mind the practice is not changing.”
Several ongoing trials address the overall question of optimal post-CDK4/6 therapy and others focus specifically on whether switching endocrine therapy and continuing with the same CDK4/6 inhibitor is sufficient, Isaacs added.
CDK4/6 inhibition plus hormone therapy has become the standard of care in HR-positive/HER2-negative metastatic breast cancer, and ribociclib plus hormone therapy has been shown to improve PFS and overall survival (OS) in this context, Kalinsky said.
The antiproliferative effect of CDK4/6 inhibition may reverse on discontinuation, and observational data suggest a potential benefit for treatment with a CDK4/6 inhibitor and changing hormone therapy after progression on prior inhibition of CDK4/6, he continued. However, no prospective randomized trial had investigated the strategy.
Kalinsky reported the results of the MAINTAIN randomized trial involving 119 patients with HR-positive/HER2-negative metastatic breast cancer that had progressed on CDK4/6 inhibition and hormone therapy. All patients received a different endocrine agent than the previous treatment and were randomized to receive ribociclib or placebo.
The trial initially specified fulvestrant as the endocrine agent for all patients, but the protocol was changed to allow the use of exemestane, which Kalinsky said was consistent with current clinical practice. In the end, 99 patients received fulvestrant and 20 received exemestane. Palbociclib was the prior CDK4/6 inhibitor for 103 of the 119 patients, ribociclib for 14 patients and abemaciclib for three patients.
The primary PFS endpoint showed that combined treatment with ribociclib reduced the risk of disease progression or death by 43% (95% CI 0.39-0.95, P=0.006). In addition, 41.2% of patients in the ribociclib arm were progression-free at 6 months versus 23.9% in the control group. The PFS rate at 12 months was 24.6% with ribociclib and 7.4% with placebo. The improvement in PFS reached statistical significance in patients who received fulvestrant (HR 0.60, 95% CI 0.39-0.94) and was numerically greater in the exemestane subgroup (HR 0, 41, 95% CI 0.14-1.24).
The PFS benefit with ribociclib was consistent across the subgroups analyzed, including patients who received palbociclib (HR 0.58, 95% CI 0.38-0.90) or ribociclib (HR 0. 50, 95% CI 0.15-1.70). Response rate (20% versus 11%) and clinical benefit rate (43% versus 25%) also favored ribociclib.
Hematologic treatment-related adverse events (ETRAs) occurred more often in the ribociclib arm, including neutropenia, anemia, and thrombocytopenia, but non-hematologic ETRA levels were similar between treatment groups.
An exploratory analysis of PFS with fulvestrant by CSR1 mutation status gave a hazard ratio of 0.30 with ribociclib versus placebo in the CSR1 wild-type subgroup (n=45), while the hazard ratio favored placebo for the CSR1-mutant subgroup (n=33, HR 1.22). Kalinsky stressed that the results should be considered hypothesis-generating due to the small numbers.
The study was sponsored by Columbia University in conjunction with Novartis.
Kalinsky disclosed his relationships with Array BioPharma, GRAIL, Pfizer, 4D Pharma, AstraZeneca, Biotheranostics, Cyclacel, Daiichi Sankyo/AstraZeneca, Eisai, Genentech/Roche, Immunomedics, Ipsen, Lilly, Merck, Mersana, Novartis, Oncosec, Puma Biotechnology, Seattle Genetics, Acetylon Pharmaceuticals, Amgen, Calithera Biosciences, CytomX Therapeutics, Incyte, and Zeno Pharmaceuticals.
Isaacs disclosed relationships with AstraZeneca/MedImmune, Biotheranostics, Eisai, Genentech/Roche, Ion Solutions, Novartis, Pfizer, Puma Biotechnology, Sanofi/Aventis, Seattle Genetics, Merck, and Tesaro, as well as patent/royalty/ intellectual property.