SAN ANTONIO – Pfizer Inc. is headed into Phase III testing with a novel cell synthesis blocking agent that worked in combination with aromatase inhibitor letrozole in Phase II to increase progression-free survival for a group of postmenopausal women with advanced estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, the company reported Dec. 5 at the San Antonio Breast Cancer Symposium.

Women treated with PD-03392991 plus letrozole (Novartis AG’s Femara and generics) had a median progression-free survival of 26.1 months, a statistically significant increase over 7.5 months for letrozole alone, lead investigator Richard Finn, University of California Los Angeles, said during a press briefing on the Phase II results.

In addition, the response rate for the combination therapy was 45% compared to 31% for letrozole alone, and the clinical benefit rate was 70% compared to 44%, Finn reported. Pfizer will launch a Phase III trial based on those results early in 2013.

Patients were stratified by factors such as tumor burden, measurable disease (visceral versus bone only versus other), and disease-free interval – whether they had gone 12 months or more from the end of adjuvant therapy to recurrence or de novo metastases.

“Though it’s early, we’ve looked and we see a consistent benefit with the addition of PD-991 and its effects when added to letrozole through all subgroups, whether patients had de novo metastatic disease, late relapses or early relapses,” Finn said.

Pfizer will launch a Phase III trial early in 2013, making an approval based on progression-free survival possible in the 2016-2018 timeframe.

The first-in-class compound, PD-991, is an oral selective inhibitor of cyclin-dependent kinase 4/6, which prevents cellular DNA synthesis by blocking cell cycle progression during the G1 phase of replication.

The randomized Phase II trial had two parts. The first enrolled 66 patients randomized to letrozole with and without PD-991. Part two, an exploratory analysis, enrolled 99 additional women with the same eligibility criteria but screened for two specific biomarkers identified in a retrospective profiling of the patients in part one: amplification of cyclin D1 and/or loss of p16, both genes found in the cell signaling pathway. Retroactive analysis from part one suggests clinical benefit for PD-991 regardless of the biomarkers.

The results presented in San Antonio are consistent with data from the first part of the trial, presented in May at the European Society for Medical Oncology’s IMPAKT Breast Cancer Conference in Brussels, Finn said.

The part one data were presented at the San Antonio meeting in combination with median part two data collected at the point where 57 progression-free events (half of the events needed for the final analysis) had occurred, Finn said. Part two of the study closed in May and the final results will be presented at a future medical meeting.

The most frequently reported treatment-related Grade 3/4 adverse events in patients who received the combination were neutropenia, leucopenia, anemia and fatigue. Finn called the drug’s toxicity profile “very manageable” because the neutropenia, which was anticipated because of the drug’s mechanism of action, was not clinically significant. It was managed with dose reduction and dose modifications with “no requirement for or use of growth factors.” There was some alopecia, but it was all grade one, with thinning but no complete hair loss.

HER2-negative estrogen receptor positive breast cancer represents approximately 60% of around 200,000 cases diagnosed in the United States each year. Roche/Genentech Inc. received accelerated approval for an Avastin/paclitaxel combination to treat that population but famously had marketing approval revoked by FDA after the PFS results couldn’t be confirmed Also see "Avastin Loses Its Breast Cancer Claim; FDA’s Hamburg Opts For Withdrawal Over Restrictions" - Pink Sheet, 21 November, 2011..

In an e-mail bulletin reacting to the news from San Antonio, ISI Group analyst Mark Schoenebaum predicted PD-991 “could be big enough to move Pfizer’s needle.” If it gains approval in the front-line setting, the drug has potential to generate $2 billion to $6 billion worldwide in this indication alone, Schoenebaum said.

Pfizer Breast Cancer Drug Could Fill Void Left By Avastin Withdrawal

More from Clinical Trials

More from R&D