FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor–Positive, HER2-Negative Metastatic Breast Cancer

Abstract

On February 3, 2015, the FDA granted accelerated approval to palbociclib (IBRANCE, Pfizer Inc.), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. The approval is based on a randomized, multicenter, open-label phase I/II trial (PALOMA-1) in 165 patients randomized to palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg orally daily) or letrozole alone. The phase II portion of the trial was divided into two cohorts: cohort 1 enrolled 66 biomarker-unselected patients and cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigatorassessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared with patients receiving letrozole alone (HR, 0.488; 95% confidence interval, 0.319-0.748). Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 that may be contingent upon verification and description of clinical benefit in the ongoing and fully accrued confirmatory trial PALOMA-2.

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

“…[5][6][7][8][9][10][11] We analyzed the combinatorial effects of palbociclib with the commonly used chemotherapy agents against CRC, as a prelude to possible translation. Chou-Talalay analysis revealed that palbociclib can synergize with a variety of chemotherapies under hypoxia (Fig.…”

“…Palbociclib was approved by the FDA in 2015 in combination with letrozole as initial hormone-plus CDK-targeted therapy for post-menopausal women with ER(C)/Her2(¡) advanced breast cancer. 5 The therapeutic effects of palbociclib have been demonstrated in numerous clinical trials for breast cancer, NSCLC, GBM, lymphoma, and leukemia, in combination with 5-FU and oxaliplatin in solid malignancies (NCT01522989) or with cetuximab in head and neck cancer. 6,7 A combined pharmacological inhibition of MEK and CDK4/6 led to substantial synergy in KRAS-mutated NSCLC in vivo.…”

Inhibition of DNA damage repair by the CDK4/6 inhibitor palbociclib delays irradiated intracranial atypical teratoid rhabdoid tumor and glioblastoma xenograft regrowth

“…5,6 These studies have helped to motivate clinical trial evaluations of the CDK4/6 inhibitor (https://clinicaltrials.gov/ ct2/results?term=Palbociclib&Search=Search), one of which resulted in the recommended use of palbociclib with letrozole for treating postmenopausal women with estrogen receptorpositive, HER2-negative advanced breast cancer, as initial endocrine-based therapy for metastatic disease. 7 We previously determined that the amount of palbociclib present in intracranial GBM xenografts, following oral administration of the drug, was sufficient to achieve an antiproliferative effect. 5 Our GBM xenograft study also demonstrated superior antitumor activity when combining palbociclib with radiation as compared with either radiation or palbociclib monotherapy.…”

Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models

“…Given the activation of these growth-and survivalpromoting pathways after endocrine therapy, current clinical treatment strategies have begun combining endocrine-based agents with small-molecule inhibitors of these pathways (19,20). The increase in progression-free survival demonstrated in clinical studies such as BOLERO-2 and PALOMA-1 where an aromatase inhibitor was combined with everolimus (mTOR inhibitor) or palbociclib (CDK4/6 inhibitor), respectively, highlights the effectiveness of this strategy (21)(22)(23). Furthermore, recent data from the PALOMA-3 trial validate the use of a SERD (fulvestrant) in combination with CDK4/6 inhibitors as a potential new treatment strategy for metastatic disease (24).…”