Mitch Dowsett, PhD

In the neoadjuvant setting, adding palbociclib to letrozole significantly enhanced the suppression of malignant cell proliferation, as measured by Ki67 levels, in patients with primary estrogen receptor–positive breast cancer but did not increase the clinical response rate over 14 weeks, according to results from the multinational randomized phase II PALLET trial presented at the 2018 San Antonio Breast Cancer Symposium by Mitch Dowsett, PhD, of the Institute of Cancer Research in London.¹ The findings were simultaneously published in the Journal of Clinical Oncology.²

In hormone receptor–positive disease, a decrease in the proliferation marker Ki67 (a protein encoded by the MKI67 gene) in response to endocrine therapy has been validated as a marker of treatment benefit and a predictor of recurrence-free survival. Since palbociclib has an antiproliferative effect, the suppression of Ki67 was seen as a rational endpoint for estimating whether palbociclib adds benefit to an aromatase inhibitor in the neoadjuvant setting, Dr. Dowsett said.

PALLET Specifics

PALLET is a phase II randomized multicenter trial with parallel United Kingdom and National Surgical Adjuvant Breast and Bowel Project Foundation North American protocols. The study evaluated 307 postmenopausal women with estrogen receptor–positive, HER2-negative primary breast cancer whose tumors were ≥ 2 cm. Patients were randomly assigned to letrozole (2.5 mg/d) for 14 weeks (group A); letrozole for 2 weeks, then palbociclib plus letrozole to 14 weeks (group B); palbociclib for 2 weeks, then palbociclib plus letrozole to 14 weeks (group C); or palbociclib plus letrozole for 14 weeks (group D). The parallel 4-group design with a 2-week change for groups B and C allowed investigators to assess the role of each drug alone or in combination in the suppression of Ki67.

Palbociclib was administered at 125 mg/d orally on a 21-days-on, 7-days-off schedule. Core-cut biopsies were taken at baseline and at 2 and 14 weeks. The co-primary endpoints for letrozole alone vs the three palbociclib-plus-letrozole groups (A vs B+C+D) were a change in Ki67 between baseline and 14 weeks and clinical response by ultrasound after 14 weeks.

Ki67 Suppressed With Palbociclib but Response Not Enhanced

Of the 307 patients recruited, 279 (90.8%) had clinical response data and 190 (61.9%) had paired Ki67 measurements available (ie, baseline and week 14). Clinical responses were not significantly different between the letrozole alone (group A), where 49.5% of patients responded, and the palbociclib regimens (groups B+C+D), where 54.4% responded (P = .20); rates of complete response were the same at 2.2%. Progressive disease as best response was observed in 5.4% and 3.2%, respectively.

Although clinical response rates were not improved with palbociclib, the median log-fold change in Ki67 was greater with the combinations (–4.1) compared with letrozole alone (–2.2; P < .001). This was equivalent to a geometric mean change of −97.4% vs −88.5%, Dr. Dowsett reported.

Exploratory Endpoints

An exploratory endpoint was complete cell-cycle arrest, defined as Ki67 ≤ 2.7%. This was achieved by more patients on palbociclib/letrozole (90%) than letrozole alone (59%), which yielded an odds ratio of 6.83 (P < .001).

Another exploratory endpoint was change (suppression) at 14 weeks in cleaved poly (ADP-ribose) polymerase (c-PARP), an indicator of apoptosis. Median log-fold change in c-PARP was greater with palbociclib/letrozole (−0.80) than with letrozole alone (−0.42; P < .003).

“With chemotherapy, you see an increase in apoptosis. In contrast, with an aromatase inhibitor alone, you see a decrease in apoptosis, and with the addition of palbociclib, there is a statistically significant further decrease that translated here into a percentage change of 31% vs 57%,” he said.

It’s been known for many years that the signals that promote proliferation also promote apoptosis, so the withdrawal of the proliferation signals also means the withdrawal of the signal of apoptosis.

— Mitch Dowsett, PhD

Tweet this quote

“Comparing these two sets of data—the suppression of Ki67 and c-PARP—is instructive. It’s been known for many years that the signals that promote proliferation also promote apoptosis, so the withdrawal of the proliferation signals also means the withdrawal of the signal of apoptosis. While there is a greater decrease in c-PARP with the combination, it’s only 0.4 log–fold, compared to a 2-log–fold decrease in Ki67 [by adding palbociclib]. This is massively in favor of the decrease in proliferation compared to cell death,” Dr. Dowsett said.

This reduction in cell death could explain why clinical response—ie, overall tumor volume as determined by ultrasound—did not substantially change, nor did the surgical breast-conservation rate, despite the markedly enhanced antiproliferative effect, he suggested.

The researchers also reported that pathologic complete responses occurred infrequently, and there was no evidence of a difference between letrozole alone compared with palbociclib plus letrozole. The pathologic complete response rates in the breast were 1.1% and 3.3%, respectively (P = .43).

Grade ≥ 3 toxicity was more common with palbociclib/letrozole (49.8% vs 17.0%; P < .001), mainly because of asymptomatic neutropenia. One patient in group B (letrozole followed by palbociclib plus letrozole) had grade 4 neutropenic sepsis. The study did not identify any new safety signals with these regimens. Comprehensive secondary biomarker analyses are ongoing, he said. ■

DISCLOSURE: Dr. Dowsett is a member of the oncology advisory board for Radius; has received lecture fees from Myriad, an institutional grant from Pfizer, and an Institute of Cancer Research Reward for Inventors (for abiraterone); and has provided ad hoc advice to Orion.

REFERENCES

1. Dowsett M, Jacobs S, Johnston S, et al: PALLET: A neoadjuvant study to compare the clinical and antiproliferative effects of letrozole with and without palbociclib. 2018 San Antonio Breast Cancer Symposium. Abstract GS3-02. Presented December 6, 2018.

2. Johnston S, Puhalla S, Wheatley D, et al: Randomized phase II study evaluating palbociclib in addition to letrozole as neoadjuvant therapy in estrogen receptor-positive early breast cancer: PALLET trial. J Clin Oncol 37:178-189, 2019.