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Pfizer's PGx NSCLC Drug Yields Promising PFS Results; More Research Needed to Map Disease Mechanism


Originally published June 7.

By Turna Ray

CHICAGO – Interim Phase I results for Pfizer's pharmacogenomically targeted non-small cell lung cancer drug crizotinib have yielded impressive data on progression-free survival, but there is still a lot to be learned about the drug's intended patient population and the mechanism of cancer resistance.

At the American Society of Clinical Oncology's annual meeting here this week, Pfizer presented interim progression-free survival data for patients with ALK-positive advanced non-small cell lung cancer treated with the investigational ALK inhibitor. The study, led by Ross Camidge of the University of Colorado, is an ongoing, open-label, multi-center, Phase I trial in which 116 crizotinib-treated patients had a preliminary median progression-free survival of 10 months. Median overall survival has not yet been reached in the trial.

Last month, Pfizer and companion diagnostic partner Abbott filed applications with the FDA for a drug/diagnostic combination product comprising crizotinib and a test that detects the ALK gene fusion associated with response to the drug (PGx Reporter 05/25/2011). Based on early-stage research on crizotinib, the FDA has granted Pfizer's drug application Fast Track status and priority review, placing it on a six-month review clock. The firm is currently recruiting patients for late-stage studies.

Pfizer also received orphan drug status for crizotinib, since the drug will be indicated for a small subset of the NSCLC population. The National Cancer Institute reported that there were 222,520 newly diagnosed cases of NSCLC last year, and 157,300 deaths from the disease. It is estimated that between three percent and five percent of NSCLC tumors harbor ALK gene fusions.

"The median progression-free survival [with crizotinib] far exceeds anything that one would expect with standard therapy in this heavily pretreated group," Nasser Hanna of Indiana University said in a presentation at ASCO reviewing the data presented by Camidge.

Patients received a 250 mg dose of crizotinib twice a day in a 28-day cycle. Many study participants had been heavily pretreated for their cancer, with 44 percent having received three or more prior treatments. These results represent data from the second part of the two-part Phase I study. Last year, researchers reported interim study data involving 76 patients (PGx Reporter 06/09/2010).

In the currently evaluated patients, at a median 11-month follow up, the objective response rate was 61 percent; two patients experienced a complete response and 69 patients had a partial response. The clinical benefit rate, which comprises patients who had complete responses, partial responses, and stable disease, was 88 percent. Patients who had complete and partial responses to crizotinib did so rapidly, around eight weeks after starting treatment, according to an abstract describing the study. Researchers reported a preliminary median response duration estimate of 48 weeks.

So far, patients in the study have experienced common Grade 1and 2 drug-related adverse reactions such as vision disorder (63 percent) and gastrointestinal events, such as nausea (54 percent), diarrhea (49 percent), and vomiting (40 percent). According to Camidge, who discussed the findings at an ASCO plenary session, these AEs typically manifested during the first cycles of the drug and went away as treatment continued. In particular, vision disturbances, during which patients reported seeing colored streaks of lights, "were amusing to patients, rather than disturbing, and get better over time," Camidge said.

In conclusion, Camidge and colleagues found after the interim analysis that "the efficacy of crizotinib was robust, rapid, durable and clinically meaningful" in patients with ALK-positive NSCLC. "Crizotinib may offer a new standard of care for patients with ALK-positive advanced NSCLC, a subgroup that currently lacks any approved agent specific to the molecular diagnosis," the researchers wrote in the abstract.

Hanna noted, however, that there are still some uncertainties regarding how the molecular characteristics of the ALK gene fusion might impact patient response. He pointed out that nine of the 35 evaluable patients in the Phase I/II crizotinib study "had a variant EML4-ALK fusion partner that wasn't tested for or had a non-EML4 fusion partner altogether."

So far, he said, "we don't have any subset data on the fusion variants and whether they had variable responses. We know EML4 is the most common fusion partner but it's certainly not the only one."

Also, while it is more common for people who have never smoked to harbor the EML4-ALK fusion, the first person described to have the translocation was a smoker. And since 28 percent of patients in the latest study were former or current smokers, "smoking status by itself cannot be discriminatory," Hanna said. "This is more commonly seen in adenocarcinoma and that may be helpful in screening as it is rare in squamous cell cancer."

Although Pfizer is currently working with Abbott to develop a FISH-based companion test to gauge best responders to crizotinib, different technology platforms would pick up other kinds of molecular events in the ALK gene. For example, while FISH tests will detect ALK rearrangements, PCR-based tests can hone in the specific ALK fusion partner, and immunohistochemistry tests can gauge the expression of the ALK protein. For the time being, as more research is done to establish how ALK rearrangements and other fusion variants impact crizotinib resonse, FISH testing is the standard, Hanna said.

In advancing knowledge about the pharmacogenomic response to ALK inhibitors, there is a growing focus among researchers to try to elucidate the mechanisms of resistance. There are other classes of agents that are also active in ALK-positive disease, and as such, Hanna noted that drug developers must "learn to combine ALK inhibitors with other biologically targeted agents."

For example, a study published in October in the New England Journal of Medicine associated C1156Y and L1196M, two mutations within the kinase domain of EML4-ALK, with crizotinib resistance. These mutations "resulted in nucleotide substitutions and ultimately different translation of amino acids, which were bulkier and ultimately interfered with the binding of the tyrosine kinase inhibitor," Hanna explained, adding that such mechanisms have also been seen in BCR-ABL and EGFR resistance.

For resistance mutations, such as F1174L, that aren't in contact with the binding site of the drug, it may be possible to treat patients with higher doses of crizotinib, with HSP90 inhibitors, or with more active ALK inhibitors, Nasser said. "Disruption of HSP90 function does look promising in ALK-positive patients," he noted.

At the ASCO meeting, researchers presented data on an HSP90 inhibitor called ganetespib, developed by Synta Pharmaceuticals. In an open-label Phase II study, the researchers analyzed 76 patients by their mutation status for KRAS, EGFR, BRAF, PIK3CA, ERBB2 and MET, as well as by ALK translocation. In 76 evaluable patients, the overall disease control rate at eight weeks was 54 percent and the overall objective response rate was 5.3 percent. Grade 3 adverse events associated with the drug were dyspnea in 12 patients, fatigue in 12 patients, diarrhea in nine patients, and hyponatremia in five patients.

Have topics you'd like to see covered in Pharmacogenomics Reporter? Contact the editor at tray [at] genomeweb [.] com.

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