Palbociclib Combination Misses Primary End Point of PENELOPE-B in HR+, HER2- Early Breast Cancer

Palbociclib (Ibrance) in combination with standard endocrine therapy did not improve invasive disease-free survival (iDFS) in patients with hormone receptor (HR)-positive, HER2-negative early breast cancer who have residual invasive disease after completing neoadjuvant chemotherapy, missing the primary end point of the phase 3 PENELOPE-B trial (NCT01864746).

Findings from the randomized, double-blind, placebo-controlled study were reported in a press release by the German Breast Group in collaboration with the developer of Palbociclib, Pfizer Oncology, Inc. The study did not reveal any new safety signals were observed with palbociclib or endocrine therapy. It was also announced that detailed findings from the study will be presented at an upcoming medical congress.

PENELOPE-B was curated to serve an unmet medical need in this patient population, which Sibylle Loibl, professor and chair of the German Breast Group explained in a statement.

“Reducing the risk of disease recurrence in patients who have residual disease after neoadjuvant chemotherapy is a complex clinical challenge,” said Loibl, in a statement. “This unique trial was made possible through the collaboration and support from all the research partners involved. Despite this outcome, we believe that key learnings will emerge from the large number of biomarkers being analyzed from collected tumor tissue, which will help inform future breast cancer research.”

To execute its goal in the field of breast cancer, PENELOP-B enrolled individuals with histologically confirmed unilateral or bilateral primary invasive breast cancer who had residual invasive disease post-neoadjuvant either in the breast or as residual nodal invasion, centrally confirmed HR-positive and HER2-negative disease, centrally assessed Ki-67, pRB, and Cyclin D1 status, and were previously treated with neoadjuvant chemotherapy of at least 16 weeks.

At baseline, patients were also required to have an ECOG status or 0 or 1, a clinical-pathologic stage - estrogen/grade (CPS-EG) score of ≥3,and a life expectancy of at least 5 years irrespective of breast cancer diagnosis.

Patients were excluded from the study given they presented with hypersensitivity ro palbociclib or a similar compound, had inadequate organ function, evidence of infection, a prior malignancy within 5 years, severe acute or uncontrolled chronic systemic disease, and/or any condition that may interfere with treatment in the PENELOPE-B trial.

“This is the first randomized Phase 3 study to establish mature iDFS results for a CDK4/6 inhibitor as part of the adjuvant treatment for early breast cancer. While we are disappointed with this result, we look forward to continuing to work with our research partners to understand subgroup data and how these could inform the development of our next-generation CDK inhibitors in early breast cancer,” said Chris Boshoff, MD, PhD, chief development officer, Oncology, Pfizer Global Product Development. “We are proud of the transformative impact IBRANCE has had on the treatment of HR+, HER2- metastatic breast cancer - a vastly different treatment setting than early breast cancer.”

Palbociclib is an oral inhibitor of CDK4/6. The mechanism of action associated with palbociclib includes the ability to regulate the cell cycle to halt disease progression. The agent is currently indicated for use in adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as an initial endocrine-based therapy in postmenopausal women or in men. Palbociclib is also indicated in combination with fulvestrant in patients with disease progression following endocrine therapy.

Adverse events (AEs) that can occur with palbociclib treatment include neutropenia, severe, life-threatening, or fatal interstitial lung disease and/or pneumonitis, fetal harm in females, and infertility in males. These AEs were previously observed with the agent across 3 clinical trials, PALOMA-1 (NCT00721409), PALOMA-2 (NCT01740427), andPALOMA-3 (NCT01942135).

According to PALOMA-2 data, the most common AEs observed with palbociclib in combination with letrozole were neutropenia (80% vs 6%), infections (60% vs 42%), leukopenia (39% vs 2%), fatigue (37% vs 28%), nausea (35% vs 26%), alopecia (33% vs 16%), stomatitis (30% vs 14%), diarrhea (26% vs 19%), anemia (24% vs 9%), rash (18% vs 12%), asthenia (17% vs 12%), thrombocytopenia (16% vs 1%), vomiting (16% vs 17%), decreased appetite (15% vs 9%), dry skin (12% vs 6%), pyrexia (12% vs 9%), and dysgeusia (10% vs 5%).

The agent also led to grade ≥3 events in more than 5 % of patients, which included neutropenia (66% vs 2%), leukopenia (25% vs 0%), infections (7% vs 3%), and anemia (5% vs 2%).

_References:

_{PENELOPE-B trial of ibrance® (palbociclib) in early breast cancer did not meet primary endpoint. News Release. Pfizer Oncology, Inc. October 9, 2020. Accessed October 9, 2020. https://bit.ly/3luKsT7​}