Biotech Values

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Some more details of PFE's ALK inhibitor. Ariad's is more specific (sometimes good and sometimes bad) and more potent (good). Hopefully it hits the clinic soon.

ALK testing should quickly become ubiquitous in all lung cancer once a drug is approved. RGDX and Genzyme Genetics are the only companies I know of that are offering it now outside of PFE's clinical trials.

Crizotinib Holds Promise for Lung Cancer, and for Pfizer Oncology
The Pink Sheet Daily. 2010 Jun 6, MJ Laffler

CHICAGO - Pfizer's promising targeted lung cancer candidate - the ALK inhibitor crizotinib - exemplifies the dream of all oncology sponsors. The company had a home-grown agent already in the clinic when new research suggested a potential genetic marker and, after some readjustment, Pfizer has evidence of activity in a molecularly identified subset of patients in very short order.

Data from an expanded Phase I trial of crizotinib (PF-02341066), showing tumor shrinkage in over 90 percent of patients positive for the EML4-ALK fusion gene, were highlighted during the plenary session of the American Society of Clinical Oncology annual meeting in Chicago on June 6.

Pfizer has already started a Phase III trial. The oncology community is heralding the early signs of activity as offering another advance in personalized therapy for non-small cell lung cancer, akin to the situation with EGFR-mutations in NSCLC, where the presence of a gene rearrangement signals that a patient is appropriate for a particular therapy.

The company holds a firm lead in the field. Crizotinib is the only ALK inhibitor in clinical trials, and represents an impressive accomplishment in drug development. The EML4-ALK fusion gene was identified as an oncogenic driver of non-small cell lung cancer in only 2007, in an article in the journal Nature. The fusion gene leads to the creation of an activated ALK protein, causing tumor growth.

Having an agent targeting that pathway in late-stage development within three years is an impressive timeline.

"That's just an amazing example of the power of how once we understand a cancer cell, we can come up with a treatment very quickly," Mark Kris, Memorial Sloan-Kettering Cancer Center, said in explaining why such an early study had been selected for one of the four plenary slots at ASCO.

Seizing A Ready-Made Opportunity

It also reflects flexibility on Pfizer's part. The Phase I trial actually got started in 2006 - the compound has activity along the c-MET pathway as well as ALK - but when the Nature article came out, "quickly the study was adapted to have a focus on EML4-ALK," Pfizer Senior Director Jamey Skillings, the global clinical lead for crizotinib, said in an interview.

Two patients with the EML4-ALK were enrolled in the escalating portion of the study and had signs of dramatic activity. "It was [those] two patients that gave us the first signal, and then academic institutions like the Mass General Hospital stated looking at their patients and found many more. So we enrolled really quite quickly," Skillings said.

With strong signs of activity in Phase I, Pfizer has bypassed intervening Phase II studies. The sponsor started enrolling patients in a Phase III study, called PROFILE 1007, early in 2010. Pfizer is also running a companion Phase II study (PROFILE 1005) in tandem, which will provide supportive evidence for regulatory filings.

"At Pfizer, we felt that we had thoroughly established the activity of the drug, and we didn't need to do more testing to determine safety and activity before going to Phase III," Skillings explained. "We've had discussions with regulatory authorities globally. There's agreement."

The Phase III study has enrolled the first 30 of a planned 318 patients who have had one prior chemotherapy,and will compare crizotinib directly against standard second-line chemotherapy with either pemetrexed or docetaxel. The primary endpoint is progression-free survival; one event-driven interim analysis has been built in to the design.

The Phase II study is enrolling 250 patients who do not qualify for the Phase III or who fail the chemotherapy in Phase III (all patients are pre-selected for the ALK marker) and are allowed to cross over to receive crizotinib in the companion Phase II trial. That trial is collecting additional safety and activity information and "some data from that study will be submitted to regulatory authorities in support of an early submission," Skillings said.

The Early Evidence

In the Phase I data presented by lead investigator Yung-Jue Bang, Seoul National University, of 82 evaluable patients with advanced NSCLC "almost all patients had some degree of tumor shrinkage by the treatment."

When the tumor shrinkage was greater than 30 percent, it was considered an objective response. The objective response rate for the reported dataset was 57 percent. Those responses have been durable, up to 15 months in 30 patients, Bang noted. Median progression-free survival has not yet been reached in the ongoing trial, and 70 percent of patients are still being followed.

Seventy-two percent of patients remained progression free at six months after treatment, Bang reported. He pointed out that this was achieved in patients who had previously completed several lines of chemotherapy. "More than half of patients had already completed two or more chemotherapy regimens."

Those patients reported that crizotinib was an "easier" treatment and "less disruptive of their lifestyle," Kris commented. Crizotinib was well-tolerated in the Phase I trial, Bang reported, with about half of patients experiencing mild nausea, vomiting or diarrhea. Almost all were Grade 1 and occurred during the first cycle of treatment; there were no Grade 3/4 toxicities.

There was one unique adverse event. "Forty-two percent of patients had visual symptoms, but these mostly were mild and over time became ... decreased in severity and frequency," he said. At the plenary presentation, Bang observed that the visual disturbance resolved with continued treatment.

New Frontiers Of Personalization

Kris underscored that the precise targeting of the therapy to the oncogene makes the crizotinib effort important, on the very cusp of personalized medicine. It was the identification of the driver mutation in the cancer cell that led to the possibility of coming up with a treatment to negate the effects of that driver mutation, he explained. "We've seen dramatic developments along those same lines of thought in chronic myelogenous leukemia, GIST tumors and in EGFR mutated NSCLC. Patients who have this somatic mutation (in the tumor, not the human being), these people can expect dramatic benefit," he said.

"We can do a test on their tumor specimen that can say this drug will almost surely lead to important benefits in terms of tumor shrinkage and time free of cancer," Kris noted. "And this technology is here now," he added.

"We've been very helped by the EGFR mutation story, because already we have a machinery in place to take tumor specimens and once they're tested for EGFR, if they're present we treat for that lesion, if not we can treat for this."

Though EML4-ALK is present in fewer lung cancer patients than the EGFR mutations, Kris noted that as a different group, they expand the possible candidates for personalized cancer therapy. Thus, in addition to the roughly 20,000 patients with EGFR mutations who can be offered a tailored therapy, there's now an additional 10,000 patients in the U.S., approximately, who can be screened and treated with "a very effective therapy for them," he said.

As the EML4-ALK fusion gene is present in an estimated 3 percent to 5 percent of NSCLC patients, that translates to 40,000 patients worldwide. The majority of those patients are younger and non-smokers.

Dual Purpose To The Phase III Program

Though patients can currently be screened for EML4-ALK with a FISH assay, which was used for the initial study enrollment, Pfizer intends to roll out a specific companion diagnostic. A collaboration with Abbott Molecular was announced in August 2009 and the Phase III program will also be used to validate the companion diagnostic. Abbott is running central labs to select patients for the late-stage trials.

"There have been discussions between Abbott Molecular and regulatory authorities, they're working toward submitting data on the diagnostic to get an approved diagnostic," Skillings reported. The companion diagnostic is basically the same as the FISH test, but Abbott is crafting an official companion diagnostic.

Martin Edelman, University of Maryland, commenting on the crizotinib study during the plenary session, noted that there is a need for "a good and correct screening strategy," as there are significant areas of overlap with EGFR and KRAS mutations and there have been false negatives with FISH screening. Edelman termed the existing FISH test a "tempermental assay" that "is difficult due to the close proximity of the two genes."

Validating the new Abbott Molecular test in combination with the Phase III clinical trial is a method of companion diagnostic development favored in FDA's previous frameworks for drug/diagnostic co-development, though the agency is due to release a new guidance by the end of the year.

Successful completion of the crizotinib program - with the accelerated development program and an early approval - would be a meaningful validation for Pfizer Oncology. The pharma giant made a play to become an oncology powerhouse just a few years ago, creating a dedicated business unit and allocating significant resources to the effort.

Some of the early work on the platform behind crizotinib came from Sugen, which was acquired by Pharmacia in 1999 and then rolled in to Pfizer in 2003. The molecule itself was developed later, in house at the La Jolla, Calif. site under the Pfizer logo.