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Results of Phase III Trial Suggest Greater Benefit from Xalkori in First-line Setting

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NEW YORK (GenomeWeb) — Results of Pfizer's Phase III trial of Xalkori (crizotinib) in the first-line treatment of ALK-positive non-small cell lung cancer has confirmed interim results suggesting that the drug is associated with significantly longer progression-free survival than standard chemotherapy.

The study, which appeared last week in the New England Journal of Medicine, found that median progression-free survival for patients in the Xalkori arm was 10.9 months compared to only 7 months in the chemotherapy arm, expanding on interim data from the trial presented earlier this year at the annual meeting of the American Society of Clinical Oncology.

Benjamin Solomon, the publication's first author and a professor at the Peter MacCallum Cancer Centre inMelbourne, Australia, told GenomeWeb that the new results solidify the conclusion that newly-diagnosed lung cancer patients should be tested for ALK rearrangements and be treated accordingly.

Solomon said that though trial-to-trial comparisons can be unreliable, patients in the newly published first-line trial appeared to do even better on Xalkori — responding more often and living slightly longer without disease progression — than those who received the drug in Pfizer's prior Phase III study of Xalkori in patients previously treated with chemo.

"It's not really fair to do trial-to-trial comparison, but what we saw in this trial is that when crizotinib is given first-line, the response rate is higher and the duration of control is longer than when it's given in second-line. This suggests it's best to get these drugs to patients at the earliest opportunity," he said.

According to Solomon, the US Food and Drug Administration's approval and labeling of Xalkori has allowed leeway in the US in terms of where in the course of treatment the drug can be used. Ahead of publication of this new first-line trial, PROFILE 1014, US physicians could, and have, prescribed the drug as an initial treatment for lung cancer patients harboring a sensitizing ALK translocation.

Outside the US, there has been less flexibility, Solomon said, so the full publication of the PROFILE 1014 results is an important milestone in establishing the drug in the first-line setting more globally.

"Different countries have different regulatory approval mechanisms and they'll review this and make or not make approvals, but it's hard to imagine more, better evidence for the superiority of crizotinib than what we show in this trial," he said.

In PROFILE 1014, researchers from several international institutions recruited a total of 340 patients with NSCLC positive for an ALK rearrangement as established by the Abbott's Vysis ALK breakapart FISH test.

These patients were randomized to one of two arms, either treatment with Xalkori, or with one of two standard-of-care chemotherapy regimens. Patients who progressed with chemo were allowed to crossover to the Xalkori arm and vice versa.

The cutoff for data in the current publication of the study included a median follow-up time of 17.4 months for patients assigned Xalkori and 16.7 months for those receiving chemotherapy.

As of the data cutoff, median progression-free survival for the Xalkori arm was 10.9 months, and PFS for the chemotherapy arm was 7 months. The objective response rate for Xalkori was also significantly higher than that of chemo, the authors wrote — 74 percent versus 45 percent.

In Pfizer's previous trial of Xalkori in the second-line setting, the overall response rate to the drug was only 65 percent, and median PFS was 7.7 months. Though a direct comparison is problematic, the authors wrote that the significantly higher response rates and PFS seen in the first-line trial reflect a real benefit in earlier use of the drug.

The study also measured safety and adverse events. According to the authors, the most common adverse events of any cause whose incidence was higher in the crizotinib group than the chemo group were vision disorders, occurring in about 70 percent of the patients; diarrhea, in about 60 percent; and edema, in about half.

Side effects more prevalent in the chemo group than the Xalkori group were fatigue in about 40 percent of patients, anemia in about 30 percent, and neutropenia also in 30 percent. Most events in both patient groups were grade 1 or 2 in severity.

Overall, adverse events causing discontinuation of treatment occurred in 12 percent of the patients treated with Xalkori, and 14 percent of those given chemotherapy. The trial investigators deemed only 5 percent of the events ending treatment with Xalkori to actually be related to the treatment itself, and only 8 percent of the events leading to a discontinuation of chemo to be chemo-related.

Solomon said that because of the crossover-allowing trial design the results so far do not show a statistically significant benefit for Xalkori in terms of overall survival.

Survival analyses are still immature he said, with most patients still alive, and most — both those initially randomized to Xalkori, and those who crossed over from the chemo arm — still being treated with the targeted drug.

The researchers will continue to follow up with the trial participants, Solomon said, but because of the confounding issue of crossover, longer term data still may not demonstrate a large improvement in overall survival.

Ultimately, response to Xalkori, whether used in the first or second line of treatment, is not limitless. Most patients eventually relapse, with research showing numerous mechanisms through which the disease reemerges. As a result, Pfizer and others drugmakers are also pursuing a number of new ALK-inhibitors for NSCLC patients who become resistant to the current mainstay.

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