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Ventana Submits ALK CDx Premarket Application; Won't Disclose ALK Inhibitor Drug Partner


NEW YORK (GenomeWeb) – In an unusual move, Roche subsidiary Ventana Medical Systems last week completed a premarket approval application with the US Food and Drug Administration for a companion diagnostic that identifies patients with ALK-positive lung cancers, without specifying which drug the test is meant to accompany.

According to Doug Ward, VP and lifecycle leader of Ventana Companion Diagnostics, the firm is currently providing testing for drug trials ongoing at Novartis and Roche subsidiary Genentech; the former markets the new ALK inhibitor Zykadia (ceritinib) and the latter is developing the next-generation ALK inhibitor alectinib. "We are currently the enrollment assay for ongoing clinical studies for ceritinib and alectinib," Ward told GenomeWeb. "We have not disclosed the partner for our regulatory submission."

Ventana pursued a rolling PMA submission for the immunochemistry-based test, dubbed the ALK (D5F3) CDx Assay. This latest submission was the fourth and final module in that process. Ward described the test as identifying "a conserved protein sequence common to known variants of ALK mutations."  Around 5 percent of non-small cell lung cancer patients have ALK rearrangements in their tumors.

Abbott Molecular in 2011 received FDA approval for its florescence in situ hybridization-based ALK test, which is intended to be used for identifying patients who have ALK-positive tumors and would benefit from Pfizer's ALK inhibitor Xalkori (crizotinib). Then, in April last year, Novartis received FDA approval for Zykadia, which is indicated for late-stage NSCLC patients who were previously treated with Xalkori but have stopped responding to it.

Zykadia's approval didn't come with a simultaneous nod for a companion diagnostic. Since the drug was approved in a refractory NSCLC population, the patients who would receive Zykadia would have already been tested for ALK mutations before receiving Xalkori. Moreover, at the time of Zykadia's approval, a Novartis spokesperson highlighted that "there are several diagnostics available" to gauge the ALK status of tumors. Pfizer worked with Abbott Molecular to advance the Vysis FISH test as a companion test for Xalkori in the US and in Japan. Additionally, Ventana’s IHC ALK test is marketed in China and "is gaining use globally," the Novartis representative had said.

Although a companion test may not have been necessary for the refractory indication for Zykadia, Novartis is studying the drug in earlier treatment settings, and this is where its partnership with Ventana will come into play. Novartis is conducting two Phase II, single-arm trials in previously treated and previously untreated ALK-positive NSCLC patients.

At the American Society of Clinical Oncology's annual meeting last year, a Phase I study provided promising results for Zykadia in more than 250 previously untreated NSCLC patients. That trial enrolled subjects into three arms: those pretreated with Xalkori, those naïve to such treatment, and those with cancers other than NSCLC. All patients received Zykadia at 750 mg/day. For the 83 treatment-naïve patients in the study, the overall response rate was 66 percent, and progression-free survival hadn't been reached at the last data cutoff.

As for Genentech's alectinib, the next-generation ALK inhibitor caused much excitement last year at the ASCO annual meeting, showing in preliminary data on 35 patients to be efficacious in patients who are pretreated with Xalkori, as well as those who were treatment naïve. Furthermore, after alectinib yielded a 93.5 percent response rate in a Japanese study involving advanced or recurrent NSCLC patients, regulatory authorities in that country approved the drug last July.

In the US, the FDA has granted the drug breakthrough designation, but Genentech hasn't submitted an NDA yet. According to a company spokesperson, Genentech currently has a US and a global Phase I/II trial ongoing in NSCLC lung cancer patients who are ALK-positive and who have progressed on Xalkori. The company is planning to present data from these studies at medical meetings in the first half of the year. 

Similar to the strategy for Zykadia, Genentech won't require a companion diagnostic for alectinib in the refractory population, but a test will be necessary when the company attempts to launch the drug for first-line use. In this regard, Genentech enrolled the first patient in the ALEX trial in the third quarter of 2014. The study is randomizing more than 280 treatment-naive NSCLC patients with ALK rearrangements to receive either alectinib or Xalkori.

Emerging testing strategies

For the time being, in the US Abbott's FISH-based ALK test is the only FDA-approved companion diagnostic. However, since Xalkori came on the market, researchers have been experimenting with other testing methods to figure out the most accurate method or combination of methods for identifying patients with ALK rearrangements. Pfizer, for example, has been working with a number of institutions to explore different testing strategies to identify best responders to Xalkori using NanoString's nCounter technology and RT-PCR methods. Additionally, Pfizer researchers have published a paper describing a method using the Ion Torrent PGM to sequence the ALK kinase domain of patients' tumor DNA and employing an algorithm to detect the resistance mutations of patients who relapsed on Xalkori.

FISH-based assays, which healthcare providers have reported to be useful in identifying specific genetic translocations, are costly and require pathologist expertise to accurately run the test and interpret the results. IHC, by comparison, is more broadly available at different healthcare institutions, but there is no standardized way to interpret the results at this time.

Several studies, meanwhile, have tested NSCLC patient samples with both IHC and FISH tests and found that a significant portion of the results are discordant. For example, a study published last year in the Journal of Thoracic Oncology tested more than 3,200 NSCLC with the two types of ALK tests, and identified 150 cases that were ALK positive by either technology. The two types of tests agreed for 80 specimens, and yielded discordant results for the rest.

Based on the results, the study authors, led by Florian Cabillic of the University of Rennes in France, recommended using a screening strategy that involves both IHC and FISH, since the study showed that using only one type of assay would have missed 25 percent of patients who could benefit from an ALK inhibitor.

Ultimately, as the field of personalized medicine matures, many industry observers believe that pharma needs to get away from the one-drug-one-test companion diagnostic model. Since tissue samples are hard to procure in lung cancer particularly, the need for so-called universal platforms is particularly acute. Drugmakers are starting to explore novel CDx models, but Ventana's Ward noted that such solutions won't come in the near term.

"As a global leader in tissue-based cancer diagnostics, we work with our pharma partners and physician KOLs very closely on future technologies that allow multiple tests from one tissue sample," Ward said over e-mail. "There is no technology available today nor in the immediate future that enables this. Because it takes four to seven years from the initiation of a drug program in humans to registration, it is essential to work with the technology that is currently available, can be approved, and has the geographic reach to allow patients to gain access to the diagnostic test," he added.

Moreover, given the variety of markers that might be important for diagnosing and treating a particular cancer, there will always be a need for multiple tests that can assess different sample types. As such, Ward doesn't necessarily see universal platforms to be a panacea to the tissue problem faced in cancer diagnostics today. "One technology that uses multiplexing … may not cover other mechanisms of the disease (such as protein, RNA, and DNA)," he said. "Consequently, we will continue to require multiple platforms, rather than a universal platform, and in addition, for the near term, the availability of tissue may remain a limiting factor regardless of platform."

The headline of this article has been changed to reflect that Ventana hasn't publicly disclosed the drug its CDx will accompany; the company has specified the drug in its premarket approval application with the FDA.