Promising data for ribociclib after progression on ET plus CDK4/6 inhibitors in HR-positive/HER2-negative metastatic breast cancer

Patients with unresectable or HR-positive/HER2-negative metastatic breast cancer who progressed on anti-oestrogen therapy (ET) plus CDK4/6 inhibitors displayed a longer progression-free survival (PFS) when switching to ET plus ribociclib compared with ET plus placebo.

ET plus CDK4/6 inhibition is the standard-of-care for patients with HR-positive/HER2-negative metastatic breast cancer [1]. Although observational data supports switching ET while continuing CDK4/6 inhibitors after patients progress, no prospective, randomised trials have evaluated this approach [2]. The phase 2 MAINTAIN trial (NCT02632045), presented by Prof. Kevin Kalinsky (Winship Cancer Institute of Emory University, GA, USA) randomised 119 patients with HR-positive/HER2-negative metastatic breast cancer who progressed on ET plus CDK4/6 inhibitors to a switch of ET plus ribociclib or ET plus placebo [3]. PFS was the primary endpoint of this study.

Patients who received ribociclib had a significantly longer median PFS than patients who received placebo (2.76 vs 5.29 months; HR 0.57; P=0.006). In addition, the 12-month PFS rate was approximately 3 times higher in the ribociclib arm (24.6% vs 7.4%). The results appeared to be consistent across subgroups, including the ‘prior fulvestrant/exemestane’ and ‘prior palbociclib/ribociclib’ subgroups.

ET plus ribociclib had a manageable safety profile. Neutropenia with a grade ≥3 was more common in patients on ribociclib (38% vs 0%) but only 2 patients experienced febrile neutropenia. Furthermore, 2 patients on ribociclib had pneumonitis (1 grade 3), and 3 patients experienced grade 3 infections, compared with 0 in the placebo group.

Interestingly, an exploratory analysis showed that patients with ESR1 wildtype mutational status may benefit more from additional ribociclib than patients with ESR1-mutated tumours (HR 0.30 vs HR 1.22). Prof. Kalinsky stressed that these were exploratory outcomes and should be interpreted as hypothesis-generating data only.

Prof. Claudine Isaacs (Georgetown University, Washington DC, USA) responded to these results with enthusiasm and caution. “This is the first well-designed, randomised trial to assess the applicability of CDK4/6 inhibitors and switch of ET after disease progression. However, the current study is too small to deliver practice-changing data in my opinion and it remains unclear whether we need to switch both ET and CDK4/6 inhibitors. Fortunately, other phase 2 and 3 trials are underway to investigate these issues.”

1. Hortobagyi GN, et al. N Engl J Med. 2022;386:942–950.
2. Wander SA, et al. J Natl Compr Canc Netw. 2021;1–8.
3. Kalinsky K, et al. 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. LBA1004, ASCO 2022 Annual Meeting, 3‒7 June, Chicago, IL, USA.

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Posted on 5 August 2022