Piotr Wysocki: No benefit of continuing CDK4/6i beyond progression in advanced ER+/HER2- breast cancer

Piotr Wysocki, Professor of Medicine and Head of the Department of Oncology at Jagiellonian University Hospital, shared on LinkedIn:

“Mayer ER et al. have conducted a phase II clinical trial (PACE) in breast cancer (BC) patients who failed 1st line therapy with CDK4/6i and aromatase inhibitor (AI). Palbociclib was the most common previous CDK4/6i (90.9%) and most (75.9%) patients had received >12 months of CDK4/6i therapy with AI before initiating protocol therapy. The study recruited randomized 220 patients in a 1:2:1 ratio to Fulvestrant alone, Fulvestrant+Palbociclib, or Fulvestrant+Palbociclib+Avelumab.
After a median follow-up of 23.6 months, the median PFS was 4.8 months with Fulvestrant alone and 4.6 months with Fulvestrant+Palbociclib, which translated into a lack of benefit of continuing CDK4/6i beyond 1st line – HR for PFS of 1.11 (90% CI, 0.79 to 1.55). The median PFS with Fulvestrant+Palbociclib+Avelumab was 8.1 months, but compared to Fulvestrant alone, the difference has not reached statistical significance with HR for PFS of 0.75 (90% CI, 0.50 to 1.12).
The median OS was 27.5 months for Fulvestrant, and 24.6 months for Fulvestrant+Palbociclib (HR, 1.02 (90% CI, 0.67 to 1.56). The median OS was 42.5 months for Fulvestrant+Palbociclib+Avelumab (HR for OS vs Fulvestrant – 0.68 [90% CI, 0.40 to 1.15).
The ORR was 7.3% with Fulvestrant, 9.0% with Fulvestrant+Palbociclib, and 13.0% with Fulvestrant+Palbociclib+Avelumab.

The PACE study confirms the lack of benefit of continuing CDK4/6i beyond progression on first-line treatment with CDK4/6i+IA. There may be slight differences between particular CDK4/6 inhibitors. Still, generally, it must be assumed that the resistance to CDK4/6i must be overcome by other targeted approaches e.g. fulvestrant+capivasertib (AKTi) or chemo-endocrine therapies (fulvestrant+capecitabine  or fulvestrant+metronomic chemotherapy) but not by continuing CDK4/6i beyond progression.
The benefit resulting from combining immunotherapy with endocrine treatment and CDK4/6i is surprising and intriguing. It will definitely require further analysis in the first-line setting in CDK4/6i-naïve patients.”

Source: Piotr Wysocki/LinkedIn