Matthew J. Ellis, MB, BChir, PhD, FACP
The final results of the phase III PALLAS trial1 are “deeply disappointing,” said session moderator Matthew J. Ellis, MB, BChir, PhD, FACP, Professor of Medicine and Director of the Lester and Sue Smith Breast Center at Baylor College of Medicine. The results of the final primary analysis of PALLAS stand in contrast to the positive results for the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor abemaciclib in monarchE,2 and experts have been struggling to explain this discrepancy between two similar CDK4/6 inhibitors.
Dr. Ellis suggested the different dosing schedules may underlie these differences—a possibility Dr. Gnant also alluded to in his presentation of the data. Palbociclib is given at a dose of 125 mg/d for 3 weeks on, 1 week off, whereas abemaciclib is administered continuously at 150 mg twice daily.
“The importance of continuous dosing has been my hypothesis for a while, based on an observation from a neoadjuvant clinical trial we conducted some years ago,” Dr. Ellis said in an interview with The ASCO Post.
Consideration of Phase II Neoadjuvant Trial
Dr. Ellis’ team at Washington University in St Louis assessed the antiproliferative activity of palbociclib in primary breast cancer in the single-arm phase II neoadjuvant NeoPalAna trial,3 which was designed to assess the degree to which palbociclib inhibited the cell cycle when added to anastrozole beyond that achieved with anastrozole alone. Complete cell-cycle arrest (Ki67 < 2.7%) was significantly improved after palbociclib was added to anastrozole after 14 days of treatment (P < .001). However, 2-week washout of palbociclib was required prior to surgery 14 weeks later (for safety). In the surgical sample, they observed that Ki67 levels increased back to baseline or even higher in some cases. They concluded that the estrogen receptor–positive cancer cells were not dying—they were held in the G0 phase of the cell cycle, and they rapidly reentered the cell cycle when palbociclib was stopped. When palbociclib was continued through to the day of surgery in a later cohort, the Ki67 remained suppressed.
“Continuous abemaciclib keeps cancer cells in G0 permanently, and perhaps they finally die as a result. However, when the cancer cells are allowed to recover every 3 weeks because palbocicib is held for a week for white cell recovery, there are populations of cells that are periodically expanding,” Dr. Ellis continued. “This could create an environment conducive to the emergence of resistance mutations, because the cell populations are not continuously repressed,” he added.
It is also possible that the chemical structures of the two drugs are just different enough to account for differences in benefit. “These small-molecule inhibitors are interacting with proteins other than the advertised drug target,” he said. “It’s possible there could be some off-target interactions that could affect the efficacy of palbociclib, and that’s something we are also looking into.”
DISCLOSURE: Dr. Ellis has served as a consultant to AstraZeneca, Pfizer, Novartis, Lilly, and Sermonix and has received royalty payments from NanoString and Veracyte on an issued patent for the Prosigna breast cancer prognostic test.
REFERENCES
1. Gnant M, Dueck CC, Frantal S, et al: Adjuvant palbociclib in HR+/HER2– early breast cancer: Final results from 5,760 patients in the randomized phase III PALLAS trial. 2021 San Antonio Breast Cancer Symposium. Abstract GS1-07. Presented December 7, 2021.
2. Johnston SRD, Harbeck N, Hegg R, et al: Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2–, node-positive, high-risk, early breast cancer (monarchE). J Clin Oncol 38:3987-3998, 2020.
3. Ma CX, Gao F, Luo J, et al: NeoPalAna: Neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer. Clin Cancer Res 23:4055-4065, 2017.
