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ALK Mutation Testing for NSCLC on the Rise among Oncologists, BioTrends Survey Finds

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Originally published April 17.

A recent survey tracking the adoption of ALK mutation testing among oncologists suggests that doctors are becoming increasingly comfortable personalizing treatment strategies for non-small cell lung cancer patients based on clinical factors and genomic data.

Six months after the launch of Pfizer's NSCLC drug Xalkori (crizotinib) with a companion ALK mutation test to gauge best responders, BioTrends Research Group surveyed 80 oncologists and found that 82 percent were offering genetic testing in this setting. Meanwhile, 5 percent of respondents indicated it would take them six months or longer to offer such testing; 11 percent said they weren't sure when they would begin conducting such analysis; and 2 percent said they would never offer such testing.

Last August, the US Food and Drug Administration simultaneously approved Xalkori and Abbott's Vysis ALK Break Apart FISH Probe Kit, which determines whether a NSCLC patient has an ALK rearrangement and therefore will respond to treatment.

For its "LaunchTrends Xalkori" report, BioTrends surveyed oncologists to gauge ALK mutation testing rates and also conducted in-depth interviews with 15 doctors to investigate their reasons for and against providing testing in this setting. The firm, which analyzes biopharmaceutical industry data, plans to survey and interview doctors again in October to track adoption one year after the launch of Xalkori.

Physicians on average said they currently provide ALK mutation testing for 54 percent of NSCLC patients, but expect to test 67 percent of such patients within a year (see chart, below).

Among doctors who are not yet offering testing, reasons included difficulty obtaining tissue, concern about the cost of testing, and test accessibility issues.

Xalkori costs more than $115,000 per year. The average Medicare reimbursement for the ALK mutation test is $440, according to Abbott.

"The one doctor that I talked to who hadn't adopted the test … was a rural physician," Dan Winkelman, therapeutics class director with BioTrends Research Group, told PGx Reporter. "I asked him about the barriers to testing … and what was holding him back was that a lot of his patients have to travel quite a bit just to get to him, and if he then has to send them to a hospital to get tested, he was daunted by the distances."

This doctor did indicate that he would "eventually adopt testing," Winkelman added.

For the report, BioTrends surveyed oncologists in a variety of settings: 11 percent from community hospitals; 29 percent from the academic setting; 13 percent from hospital-affiliated outpatient clinics; and 47 percent from private practices. The physician survey cohort was too small to break out genetic testing adoption trends by practice setting, Winkelman said.

Those oncologists who have already begun offering ALK mutation testing cited as one driving factor the robust clinical data for Xalkori showing its effectiveness in patients with ALK-mutated tumors.

The FDA approved Xalkori based on data from two single-arm studies. In one trial involving 136 patients, 50 percent experienced an objective response, with a median response duration of 42 weeks. In a second study with 255 patients, 61 percent saw an objective response and the median response duration was 48 weeks. One percent of patients experienced a complete response when treated with Xalkori (PGx Reporter 9/7/2011).

Since FDA granted accelerated approval for Xalkori, Pfizer must conduct more extensive studies to garner full approval of the drug. In this regard, the drug developer is conducting several Phase III studies comparing the new drug against standard chemotherapy regimens in ALK-positive NSCLC patients.

Additionally, the fact that the National Comprehensive Cancer Network has recommended ALK testing as viable tool for guiding treatment strategies in NSCLC patients appears to have encouraged adoption among oncologists surveyed by BioTrends.

Following approval of Xalkori, NCCN updated its NSCLC treatment guidelines to note that while ALK inhibitors represent "a very effective therapeutic strategy" in NSCLC patients with ALK mutations, most patients who harbor EGFR or KRAS mutations don't usually have ALK mutations.

As such, NCCN recommends first establishing the histology of NSCLC patients — whether they have adenocarcinomas, large cell carcinomas, or an unspecified type of NSCLC — and then testing these patients for EGFR mutations or KRAS mutations. If they are negative for these markers, then NCCN suggests testing for ALK rearrangements. NCCN doesn't recommend EGFR or ALK testing in patients with squamous cell carcinomas.

In the BioTrends survey, 50 percent of doctors said they were testing all advanced NSCLC patients for ALK mutations. The others said they administered testing based on certain patient characteristics, such as whether they had adenocarcinomas, EGFR-negative mutations, were low or non-smokers, or had failed first-line therapy.

Such enrichment strategies for administering ALK testing were recently the subject of a controversial cost-effectiveness analysis published in the British Journal of Cancer by University of Colorado researchers Adam Atherly and Ross Camidge (PGx Reporter 3/28/2012). In their analysis, the researchers found that broadly testing all advanced NSCLC patients in order to identify the small subset of ALK-positive individuals who should be treated with Xalkori did not meet a cost-effectiveness bar of less than $100,000 per quality-adjusted life year gained. However, by applying an enrichments strategy, the researchers found that oncologists could decrease the cost per QALY gained to around $4,756, even though such a paradigm would miss some ALK-positive patients who would benefit from treatment.

Abbott has challenged the BJC analysis, asserting that Atherly and Camidge used incorrect cost assumptions for ALK testing and as a result arrived at the wrong cost-effectiveness conclusions. Furthermore, Stafford O'Kelly, president of Abbott Molecular, told PGx Reporter that enrichment strategies to limit the genetic testing population, such as the one proposed in the BJC paper, have not been validated.

BioTrends noted that several physicians surveyed advocated for testing all advanced NSCLC patients so as not to miss the 5 percent who harbor ALK mutations. Meanwhile, those doctors who do employ enrichment strategies cited cost and test turnaround times as factors, according to Winkelman.

"[I]f they had a patient who has been diagnosed with lung cancer, often oncologists wanted to treat them right away with chemotherapy and not have to wait for genetic test results," Winkelman told PGx Reporter. Doctors indicated experiencing a one- to two-week turnaround time for ALK mutation testing results.

Additionally, some doctors BioTrends interviewed said they wanted to test patients for EGFR mutations first before considering ALK testing. "So they're using this incremental approach, which generally slows everything down," Winkelman said.

Another difficulty oncologists face when trying to personalize treatments for lung cancer patients based on their molecular profiles is the lack of available tumor tissue. As such, several doctors said that they wanted technological improvements that would allow them to run tests on smaller tissue samples and receive results faster.

In the end, patients' experience on Xalkori was the strongest impetus for the ramp-up in ALK testing among physicians surveyed by BioTrends.

During interviews with oncologists, "a few doctors talked about miracle patients," Winkelman said. One oncologist, for example, recounted that one of his patients was so debilitated by lung cancer that the patient required a respirator to breath. However, after treatment with Xalkori the patient was walking around.

"The clinical studies show the average number of responses, and that's impressive," Winkelman reflected. "But what's more impressive to the oncologists is when they can see it work on a patient."

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