FDA’s accelerated approval of Pfizer Inc.’s CDK4/6 inhibitor Ibrance (palbociclib) in previously untreated metastatic breast cancer hits the first goal in a broad development program that crosses lines of therapy and encompasses different tumor types.

FDA granted accelerated approval for the drug Feb. 3, more than two months ahead of its April 13 user fee date, as an add-on to the standard hormonal therapy letrozole (Femara and generics) for initial treatment of metastatic breast cancer in postmenopausal ER-positive/HER2-negative patients.

This marks the first approval of an inhibitor of cyclin-dependent kinases (CDK4 and CDK6), proteins that promote cancer growth. With its unique mechanism of action and impressive efficacy, palbociclib had gained “breakthrough” therapy status with FDA.

Pfizer feels that the combination of blocking CDK4/6 and blocking hormonal receptor signaling “may be the perfect storm” in breast cancer, with very significant impact, Mace Rothenberg, chief medical officer of oncology, said in an interview.

Pfizer priced the drug at $9,850 per month and product shipped to specialty pharmacies within hours of approval. “Consider it launched,” Rothenberg said, adding that “there’s a supply that’s ready for patients who need it.”

Some 300,000 patients are diagnosed in the U.S. every year with breast cancer, of whom 60% are ER+/HER2-, so the market opportunity is substantial Also see "Pfizer Oncology: Big Strides But Not Blockbuster Size" - Pink Sheet, 27 May, 2013.. Pfizer estimates that each year in the U.S., about 22,000 women with ER+/HER2- metastatic breast cancer could be candidates for treatment with Ibrance based on the initial indication. “This is a large patient population,” Rothenberg noted.

Palbociclib’s early approval and pricing support expectations for a $3 billion to $5 billion opportunity for CDK4/6 inhibitors in first-line advanced ER+/HER2- breast cancer, Leerink analyst Seamus Fernandez commented in a Feb. 4 note.

Pfizer is positioning the drug across lines of therapy in breast cancer, with Phase III trials ongoing in recurrent mBC and high-risk early stage breast cancer. Including the opportunity in the approved indication plus these two settings, Fernandez estimates the market opportunity in breast cancer is worth $10 billion+, with Pfizer holding a “meaningful lead” over competitors. Eli Lilly & Co. and Novartis AG are also developing CDK4/6 inhibitors for breast cancer.

FDA Sped Drug To Market

Palbociclib’s first approval was supported by the Phase II PALOMA-I study of 165 ER+/HER2- women, in which the drug doubled progression-free survival compared to letrozole alone (20.2 months vs. 10.2 months). Results had been presented at the American Association of Clinical Research meeting in April 2014 and were published in the Lancet Oncology that December Also see "Pfizer Gets Palbociclib To NDA Finish Line On Phase II Data" - Pink Sheet, 18 August, 2014.. An expanded access program has been open since August 2014 in the U.S.

Pfizer has already completed enrollment in two Phase III trials of Ibrance, though data is not yet available.

There had been some uncertainty about whether FDA would want to wait for Phase III data for approval. PALOMA-2 tests the drug with letrozole in the same population as PALOMA-I (first-line mBC) while PALOMA-3 pairs palbociclib with the estrogen receptor antagonist fulvestrant (Faslodex) in mBC that progressed after endocrine therapy. However, more recently, analysts have expected accelerated approval after FDA said it was not planning to hold an advisory committee and Pfizer guided that it was in late-stage discussions with the agency about labeling ([A#14150127002]).

For full approval, FDA is asking for final analyses from PALOMA-2 on overall survival and to confirm the PFS benefit. The trial is set to complete around the end of 2016, and the PFS analysis is due in June 2017 with the OS data in November 2020.

In this disease setting, it takes years to assess overall survival and results are confounded because patients receive multiple other therapies, Rothenberg pointed out, but Pfizer has been tracking overall survival in Phase III. According to the exec, OS is not required to convert to full approval.

FDA will be looking to see that the benefit:risk relationship remains acceptable, the company noted. Labeling has no boxed warnings. It does state that side effects include neutropenia and leukopenia, as well as upper respiratory infection and nausea.

More To Come?

While approval in metastatic breast cancer hits a major milestone, the company is hoping this is just the beginning of the story for the CDK4/6 inhibitor.

At the J.P. Morgan Healthcare Conference in January, the company highlighted its broad development program for palbociclib, with a range of trials reading out between 2015 and 2019 (see graphic below).

The company has bigger ambitions for Ibrance, however, with plans to expand into other tumors that are dependent on CDK4/6, including lung, head and neck and melanoma. There is compelling preclinical evidence to suggest the class’s role is not just limited to breast cancers, and trials will determine whether it has similar robust efficacy in other tumor types, Rothenberg said.

“We are much earlier on in that journey, but we have every reason to be encouraged,” the exec said.

Pfizer's Grand Development Plan For Ibrance

Palbociclib In Position Across Lines Of Breast Cancer

At the J.P. Morgan Healthcare Conference in January, Pfizer shared rough timelines for palbociclib development in new breast cancer indications, but also different tumor types.

Pfizer

First-Line Breast Cancer Approval Opens The Door For Pfizer’s Palbociclib

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