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Palbociclib improves PFS in patients with HER-2–negative advanced breast cancer
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CHICAGO — The addition of palbociclib to letrozole significantly prolonged PFS in postmenopausal women with ER–positive, HER-2–negative advanced breast cancer who had not previously received systemic therapy for advanced disease, according to the results of the confirmatory phase 3 PALOMA-2 trial presented at the ASCO Annual Meeting.
“For patients with ER–positive breast cancer, hormone therapy represents a mainstay treatment,” Richard Finn, MD, associate professor of medicine in the department of medicine of the division of hematology/oncology at Geffen School of Medicine at UCLA, said in a presentation. “In PALOMA–1, patients who received palbociclib [Ibrance, Pfizer] and letrozole together improved PFS. PALOMA–2 was designed to confirm those results.”
PALOMA–1 was an open-label phase 2 trial that evaluated the addition of palbociclib — a CDK 4/6 inhibitor — to letrozole for patients with ER–positive, HER-2–negative advanced breast cancer. The 10-month improvement in PFS observed in that trial suggested the ability of palbociclib to block the growth of ER-positive, HER-2–negative breast cancer, leading to the agent’s accelerated FDA approval for postmenopausal women in this setting.
In PALOMA-2, Finn and colleagues randomly assigned (2:1) 666 postmenopausal patients with advanced ER-positive, HER-2–negative breast cancer who had no prior systemic therapy for their advanced disease to receive 2.5 mg continuous letrozole plus 125 mg daily oral palbociclib (for 3 consecutive weeks followed by an off week) or placebo every 28 days until disease progression, participant withdrawal or death.
Patients were stratified by disease site and by disease-free interval from the end of neoadjuvant or adjuvant therapy, and whether they had prior adjuvant hormonal therapy.
Investigator-assessed PFS served as the study’s primary endpoint. Secondary endpoints included OS, overall response rate, clinical benefit rate — or complete and partial response plus stable disease for 24 weeks or longer — patient-reported outcomes and safety.
By Feb. 26, 2016, 311 PFS events had occurred.
Median PFS was 24.8 months in the palbociclib–letrozole arm vs. 14.5 months for the control arm (HR = 0.58; 90% CI, 0.46-0.72).
ORR was significantly higher in the palbociclib–letrozole arm (42.1% vs. 34.7; P = .031), especially among patients with measurable disease (55.3% vs. 44.4%; P = .013).
A greater proportion of patients assigned palbociclib–letrozole achieved clinical benefit (84.9% vs. 70.3%; P < .0001).
Common adverse events that occurred in the palbociclib–letrozole and placebo–letrozole arms included neutropenia (79.5% vs. 6.3%), fatigue (37.4% vs. 27.5%), nausea (35.1% vs. 26.1%), arthralgia (33.3% vs. 33.8%) and alopecia (32.9% vs. 15.8%), which was mostly grade 1. Only patients treated with palbociclib and letrozole experienced febrile neutropenia, but the incidence was low (1.6%).
Permanent discontinuation as a result of adverse events occurred in 9.7% of patients in the palbociclib–letrozole arm compared with 5.9% of patients in the control arm.
There have not yet been enough events to calculate OS outcomes.
“These data confirm the clinical safety and significant clinical benefit of palbociclib and letrozole for patients with ER–positive, HER-2–negative metastatic breast cancer who had not received prior systemic therapy," Finn said. – by Nick Andrews
Reference:
Finn R, et al. Abstract 507. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.
Disclosure: Finn reports consultant/advisory roles for and research funding from Pfizer. Please see the abstract for a complete list of relevant financial disclosures.
Perspective
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Kevin Kalinsky, MD, MS
The breast cancer community has been very interested in getting additional information from this trial. Palbociclib (Ibrance, Pfizer) a CDK 4/6 inhibitor was approved in the US based on phase 2 findings that showed improvement in PFS. This phase 3 trial confirms the significant improvement in PFS with first-line palbociclib in patients with hormone receptorpositive HER-2negative metastatic breast cancer.
The significant improvement in PFS mirrored the improvement from the smaller study: the improvement was from approximately 14 months to 24 months. It is a significant advance for patients who are newly diagnosed with metastatic disease for approximately 2 years.
In addition to the benefits, the researchers also reported some side effects, such as neutropenia. But, it is important to note that the amount of febrile neutropenia they saw was really quite low. Other adverse events included fatigue and alopecia.
There are two other drugs in development that are also CDK 4/6 inhibitors. Abemaciclib (LY2835219, Lilly) has breakthrough status with the FDA. Further, in the large phase 2 MONALEESA-2 trial, ribociclib (LEE011, Novartis) also met its primary endpoint. We are awaiting the data to be presented from this trial.
In terms of these agents demonstrating activity, this is a very important class of drugs now in patients with hormone receptorpositive HER-2negative breast cancer. When we see successes in cancer, and when we see trials that demonstrate significant improvement in clinical outcomes, there are always questions that result subsequent to these findings. As a community, we will need to figure out where exactly all of these drugs will be placed in sequence. Another question we will have to eventually answer is whether patients should continue on these agents upon progression. For instance, patients whose cancer is not kept under control with letrozole and palbociclib currently discontinue palbociclib and switch hormone therapy.
Still, its an exciting time, because these are active agents in breast cancer.
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