Fast As A Whip, Pfizer Files Personalized Lung Cancer Drug Crizotinib

One of three Pfizer cancer drugs to be filed in 2011, crizotinib may help to turn the tide on pipeline setbacks. Axitinib and bosutinib filings are still to come.

Pfizer Inc. may be hoping that the targeted nature of its non-small cell lung cancer agent crizotinib helps the agent gain accelerated approval at a time when the Subpart H program seems to be under scrutiny at FDA.

Pfizer itself has recent familiarity with the dangers of accelerated approval. Six months ago, its leukemia agent Mylotarg (gemtuzumab) became the first complete withdrawal of an accelerated approval; there were high death rates in post-market reports and in the confirmatory trial (Also see "Mylotarg Pulled Off Market, But Pfizer Continues Search For Appropriate Population" - Pink Sheet, 21 Jun, 2010.).

FDA has also started the process of rescinding the accelerated approval for Roche/Genentech's Avastin (bevacizumab) in breast cancer (Also see "Avastin's Next Stop May Be Hearing As FDA Starts Withdrawal Process For Breast Cancer Claim" - Pink Sheet, 16 Dec, 2010.). The agency has scheduled an Oncologic Drugs Advisory Committee meeting for Feb. 8 to look at several drugs with the goal of improving the accelerated approval process.

But still, Pfizer is pressing on with limited data in hand. The company announced Jan. 12 that it has started a rolling NDA for its first-in-class oral ALK (anaplastic lymphoma kinase) inhibitor under Subpart H. Pfizer expects the submission will be completed in the middle of this year.

Pfizer Has Only Early Stage Data In Hand

Crizotinib, formerly called PF-02341066, only gained fast track status, a prerequisite for accelerated approval, in December 2010.

The whole program has moved with incredible speed. The molecular target of the EML4-ALK fusion gene was only identified as an oncogenic driver in NSCLC in 2007. Phase I data was presented at the 2010 American Society of Clinical Oncology annual meeting in June, showed tumor shrinkage in over 90% of patients positive for EML4-ALK fusion gene, and Pfizer said it early data supported moving right into Phase III. The company also said at that time that it was starting a Phase II trial in tandem, as support for a regulatory filing .

Rather than serving as support to the Phase III trial, it seems that partial data from the Phase II trial will be used along with the Phase I data as the basis of the NDA. Though Pfizer did not comment on which trials were in the application, in a public press briefing in late October, Mace Rothenberg, senior VP of clinical development and medical affairs for Pfizer's oncology business unit, said the filing would be based on the Phase I expansion study and a cohort of patients from an open-label Phase II trial. Furthermore, the executive said at the time, the company hopes to use results from the Phase III study to convert from accelerated to full approval.

The Phase III study, PROFILE 1007, compares crizotinib to the standard of care intravenous chemotherapy in 318 patients with previously treated ALK-positive advanced NSCLC. The primary endpoint is progression-free survival, and secondary endpoints include objective response rates, overall survival, safety and tolerability and disease control rate. The Phase II trial, PROFILE 1005, is taking patients who did not qualify for the Phase III or failed on the chemotherapy, with a target enrollment of 250. All patients in the entire program are pre-selected for the ALK marker.

Further results of the expansion of the Phase I trial were published in the New England Journal of Medicine Oct. 28, 2010. Interim data from 82 patients in the Part 2 expansion cohort of the study show that 57% of patients with ALK-positive advanced NSCLC treated with crizotinib had either a complete or partial response to treatment.

Targeted Therapy With A Companion Diagnostic From The Start

Having a means of molecular identification of a subset of patients shown to respond should make a strong case for FDA. The crizotinib development program has focused on patients who have tumors that test positive for the ALK protein, a genetic aberration found in from 3% to 5% of the total patient population. ALK has been linked to tumor growth in NSCLC and very poor outcomes, with low survival rates. Some 40,000 patients worldwide could be candidates for the targeted treatment.

Pfizer inked a deal with Abbott Laboratories Inc. in August 2009 to develop a specific fluorescent in situ hybridization (FISH) diagnostic to test for the EML4-ALK fusion gene linked to ALK.

Rothenberg indicated at the October briefing that crizotinib and the companion diagnostic will go through separate approval processes but that Pfizer would like representatives from both the Office of Oncology Drugs and the Center for Devices and Radiological Health be involved. In advance of an alternate co-development pathway, separate reviews are the current approach, and FDA has stressed the value of collaboration between the centers.

"Sometimes in order to make forward progress you need a catalyst," Rothenberg said at the time. "I think crizotinib is that catalyst to really allow us to understand a regulatory pathway for bringing diagnostics and therapeutics forward together."

Companion diagnostics have fared better when developed alongside the targeted agent, rather than being retrofitted for that purpose.

Pfizer declined to comment on whether the diagnostic has yet been filed.

The company did note its plans to file two other cancer drugs in the U.S. and Europe this year. An oral and selective inhibitor of vascular endothelial growth factor receptors 1, 2 and 3, axitinib will be filed for metastatic renal cell carcinoma, and bosutinib, an oral dual Src and Abl kinase inhibitor, will be submitted for chronic myeloid leukemia.

Pfizer has made oncology a priority but the company has suffered multiple setbacks, including the failure to expand the reach of cancer drug Sutent (sunitinib), and recently had a major pipeline overhaul (Also see "Pfizer Clears Out Pipeline: After Oncology Disappointments, Talks Up Diabetes" - Pink Sheet, 4 Oct, 2010.).

Pipeline news lately has been much brighter. The company is at the lead of the race to develop oral drugs for rheumatoid arthritis with its JAK inhibitor tasocitinib, which has blockbuster potential . Five other Phase III studies of that drug are due out by the middle of 2011 and Pfizer plans to file as soon as possible.

In December, Pfizer also submitted an sNDA to extend the use of its pneumococcal disease vaccine Prevnar 13 to adults age 50 and up.

- Emily Hayes ([email protected])