Originally published June 3.
CHICAGO – Based on promising results from earlier studies, Pfizer is moving ahead with a Phase III trial to study the investigational agent palbociclib in estrogen receptor-positive, HER2-negative breast cancer patients.
Palbociclib, which received a Breakthrough Therapy designation from the US Food and Drug Administration in April, is being developed in combination with letrozole as a treatment for advanced breast cancer patients who have not received prior systemic treatment for their illness and whose tumors don't overexpress the HER2 protein. The Phase III trial, called Study 1008, is currently enrolling patients.
"Among post-menopausal patients with advanced or metastatic breast cancer, ER-positive, HER2-negative is the largest molecular subgroup, representing approximately 60 percent of cases," Sophia Randolph, Pfizer's clinical development lead for palbociclib, told PGx Reporter at the annual ASCO meeting held here this week,. "Despite currently available treatments, survival rates for advanced breast cancer remain low."
Conversely, approximately 20 percent of breast cancer patients have HER2-positive disease, and for these women, HER2-targeted drugs, such as Roche/Genentech's Herceptin (trastuzumab), GlaxoSmithKline's Tykerb (lapatinib), or newer generation HER2-targeted drugs are appropriate. At ASCO, Pfizer presented preliminary pharmacokinetic data on PF-05280014, a potential biosimilar to Herceptin, for this subset of patients.
Since the launch of Herceptin around 15 years ago with a companion genetic test, doctors have become increasingly comfortable conducting molecular testing to establish the HER2 status of breast cancer patients and to guide treatment strategies. There are several FDA-approved tests on the market that gauge HER2 status of tumors, including Dako's HER2 FISH PharmDx, Ventana's Inform Dual ISH, and Life Technologies' Invitrogen SPOT-Light HER2 CISH test.
As such, in developing a new breast cancer treatment option for HER2-negative patients and in developing a biosimilar to Herceptin, Pfizer will take advantage of the widespread availability of HER2 diagnostic tests, and likely not have to develop HER2 companion tests that are specific to these drugs.
In the planned double-blind Phase III study of palbociclib, researchers from Pfizer, the University of California, Los Angeles, and elsewhere will study approximately 450 women with advanced metastatic or recurrent breast cancer who are eligible to receive letrozole as a first-line treatment. These patients will be randomized to receive either palbociclib and letrozole or a placebo plus letrozole.
Researchers will collect tumor tissue samples from study participants. In the trial, investigators are aiming to prove that the palbociclib-containing regimen improves medial progression-free survival in patients compared to just letrozole, yielding a hazard ratio of at least 0.7. The secondary endpoints in the study include overall survival, objective response, duration of response, clinical benefit, safety and tolerability, patient-reported outcomes of health-related quality of life, and disease- or treatment-related symptoms.
Pfizer launched this Phase III trial after positive results from a Phase II trial showed that post-menopausal women with ER-positive, HER2-negative, advanced breast cancer who hadn't received any prior anticancer treatment lived significantly longer without their tumors progressing while receiving palbociclib in combination with letrozole compared to those receiving just letrozole (median PFS 26.1 versus 7.5 months). At last year's San Antonio Breast Cancer Symposium, data presented from this study also showed that women treated with the palbociclib-containing regimen tolerated the treatment well, with neutropenia as the most common side effect.
"We are encouraged by the magnitude of the clinical activity we have observed among those in this patient population treated with palbociclib," Randolph said.
Although Pfizer is developing palbociclib in a molecularly defined patient subset, it isn't developing a companion test to identify best responders. "Routine testing for HER2 is recommended for most women diagnosed with advanced breast cancer because the results may affect treatment recommendations and decisions," Randolph said. She added that "Pfizer does not have plans to develop a companion diagnostic test for palbociclib in breast cancer."
Palbociclib inhibits cyclin-dependent kinases 4 and 6 that are involved in cell progression necessary for DNA replication and cell division. Blocking these kinases stops the deactivation of the tumor suppressor protein called RB1 and hinders tumor cell progression. "We are working closely with breast cancer experts to understand the role that CDK 4 and 6 play in other breast cancer populations and identify additional settings in which palbociclib should be evaluated," Randolph said.
The FDA's Breakthrough Therapy designation places palbociclib on a faster track through regulatory review and gives Pfizer access to more intensive FDA guidance. Under a provision in the FDA Safety and Innovation Act, sponsors can apply to the agency to request the Breakthrough designation for a particular drug for a serious, life-threatening condition where there is an unmet medical need. The FDA is developing formal guidance that will lay out the regulatory requirements that Breakthrough Therapies will have to fulfill. As such, the requirements that Pfizer will have to meet for the palbociclib regulatory submission is not yet defined, according to Randolph.
"We are discussing with regulatory authorities the Phase II data evaluating palbociclib in post-menopausal women with ER-positive, HER2-negative advanced breast cancer," she said. "Pfizer will continue to work with the FDA to better understand the implications of Breakthrough Therapy designation on the palbociclib development program and to generate evidence needed to support a potential regulatory submission."
FDA Commissioner Margaret Hamburg highlighted during a plenary session at ASCO's annual meeting that as of the end of May, sponsors had submitted 51 applications for Breakthrough Therapy designation to the agency's drug division, and the FDA has so far granted around 20 applications, eight of which are for oncology treatments.
Potential Herceptin biosimilar
Another potential addition to Pfizer's breast cancer product pipeline is PF-05280014, a drug that the company is investigating as a biosimilar to Herceptin. At the ASCO meeting, Pfizer shared data from a trial comparing the pharmacokinetics, safety, and immunogenicity of PF-05280014, the US version of Herceptin, and the EU version of Herceptin.
Researchers from Pfizer enrolled more than 100 healthy male volunteers and randomized them to receive a 6 mg/kg IV dose of the three agents and tracked the pharmacokinetics, immunogenicity, and safety of the agents for 70 days. "The baseline demographics for the 101 subjects evaluable for PK were similar among three treatment arms," Pfizer researchers led by Donghua Yin reported in the abstract. "The three study drugs exhibited similar characteristics of target-mediated disposition and similar PK parameters."
Although no patients reported serious adverse events in the trial, more than 71 percent of those treated with PF-05280014, nearly 69 percent of those receiving Herceptin-EU, and around 66 percent of participants receiving Herceptin-US experienced treatment-related adverse reactions.
Based on this data, Yin >et al. reported that that the "study demonstrated PK similarity of PF-05280014 to both trastuzumab-US and trastuzumab-EU," and that the three treatments "also showed similar safety profiles."
Charles Zacharchuk, Pfizer's asset lead for PF-05280014, told PGx Reporter that following this PK study, the company will begin discussions with the FDA to gain input on what it should do next to advance development of the product.
Biosimilars are products with an active agent that is made from a living organism or developed with the help of recombinant DNA. Also known as a follow-on biologic, a biosimilar is a version of a biologic drug that is made by a different sponsor after the patent on the original product has expired.
Yin et al. noted in their abstract that PF-05280014 "has an identical amino acid sequence and similar physicochemical and in vitro functional properties to trastuzumab."
Due to the molecular complexity of biologics, it is not easy to develop an agent with comparable safety and efficacy. Still, with impending patent cliffs, biosimilars are a major focus for future investment and growth for drug developers.
Although Pfizer will have to show in later studies that PF-05280014 has a similar efficacy and safety profile to Herceptin, Zacharchuk noted that the company likely won't develop a companion test for the Herceptin biosimilar. "We believe that HER2 tests already on the market provide the necessary information to determine a patient’s HER2 status independent of treatment," he said. "As such, we currently do not have plans to develop a companion diagnostic for PF-5280014."
There are a number of companies in addition to Pfizer developing biosimilars to Herceptin, including Amgen and Novartis. Herceptin is slated to lose patent exclusivity in 2014 in Europe or in 2018 or 2019 in the US.
Although Herceptin is still one of Roche's top selling drugs, bringing in close to $6 billion in worldwide sales last year, the company now has several next-generation HER2-targeted drugs in its product portfolio to replace the older treatment once it loses patent protection. The FDA approved Roche/Genentech's Kadcyla (trastuzumab emtansine) in February, and Perjeta (pertuzumab) last year, with companion tests, for advanced breast cancer patients with HER2-positive disease.
A full course of Herceptin costs around $70,000. It is not yet known how biosimilars to this drug will be priced in comparison. During a recent presentation to investors, Amgen officials highlighted six biosimilar molecules the company is developing and noted that biosimilars represent a multi-billion dollar opportunity for the company.