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FDA Approves New ROS1 Indication for Xalkori With Post-Marketing CDx Commitment

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NEW YORK (GenomeWeb) – In approving Pfizer's non-small cell lung cancer drug Xalkori (crizotinib) last week in metastatic patients whose tumors have ROS1 gene alterations, the agency curiously didn't clear a companion diagnostic to identify this subpopulation.

The agency approved the new indication with a post-marketing commitment for Pfizer to develop a companion diagnostic in the future. This may be an opportunity for Pfizer to bring to market a next-generation sequencing-based universal CDx, a tool that multiple drug and diagnostics firms are working on developing, recognizing that the rapid pace of genomic research has already made the one-drug, one-biomarker, one-test paradigm obsolete.

Two years ago, the FDA finalized its companion diagnostics guidance and defined a CDx as an in vitro diagnostic that provides "essential" information for the safe and effective use of a drug by identifying, for example, patients who benefit from treatment or are at increased risk for adverse reactions. If the FDA determines that a CDx is essential for a new therapeutic product or indication, the agency generally won't approve the drug without a test.

However, the agency also acknowledged in the guidance, that this ideal scenario of contemporaneous Rx/Dx development and approval might not always be possible. For example, the agency wouldn't hold up approval of a drug for a rare, life-threatening condition where no other options exist — such as metastatic ROS1-positive NSCLC — just because an FDA-approved CDx isn't available.

"We kind of expected that this had the potential to happen," Elizabeth Mansfield, deputy director for personalized medicine within FDA's device center, told GenomeWeb.

In 2016, the American Cancer Society estimates there will be 224,390 new cases of lung cancer and 158,080 deaths due to the disease. Approximately 1 percent of patients with NSCLC, the most common type of lung cancer, have ROS1-positive tumors. Of the 1.5 million new cases of NSCLC worldwide each year, approximately 15,000 cases are characterized by the ROS1 fusion.

Recognizing the unmet need, the FDA approved Xalkori's new indication without a CDx, but asked that in the post-market setting Pfizer "support the availability of a companion diagnostic test to identify patients with ROS1-positive metastatic NSCLC who may benefit from treatment with Xalkori," Pfizer spokesperson Sally Beatty told GenomeWeb.

Beatty also highlighted that the drugmaker inked a deal with Thermo Fisher Scientific last year to develop a next-generation sequencing based companion test that will be used as part of multiple NSCLC drug development programs. But she wouldn't provide further details. 

Gideon Blumenthal, clinical team leader for lung and head and neck cancer within the FDA's drug center, also wouldn't confirm if Pfizer has indeed agreed to develop an NGS-based test that could serve as a CDx for Xalkori. However, Blumenthal noted that the agency is strongly in favor of such tests, especially in lung cancer, where multiple biopsies may be difficult for patients and there are a number of oncogenes for informing therapeutic decisions.

By showing flexibility and allowing Pfizer to develop a CDx in the future, the drugmaker may have some incentive to develop an NGS-based test and have it reviewed by the agency, Blumenthal said, "so that could potentially be a good byproduct of this whole process."

Regulatory flexibility

The FDA first approved Xalkori five years ago for advanced NSCLC patients with ALK-positive tumors, which occur in around 5 percent of lung cancers. The agency approved the drug simultaneously with Abbott Molecular's Vysis ALK Break Apart FISH Probe Kit to identify the subpoulation.

Not long after the FDA approved Xalkori for ALK-positive NSCLC, it became clear that patients whose tumors were driven by ROS1 alterations could experience robust responses to the drug with limited, manageable side effects. In 2012, at the American Society of Clinical Oncology's annual meeting, researchers presented data on 14 evaluable NSCLC patients with ROS1 rearrangements, where one patient experienced a complete response, seven experienced a partial response, four had stable disease, and two experienced disease progression.

Two years later, Pfizer had treated 50 NSCLC patients with this rare genetic fusion, and published data on their responses in the New England Journal of Medicine. The authors, led by Alice Shaw from Massachusetts General Hospital Cancer Center, wrote that patients with ROS1 fusions were similar to those with ALK rearrangements in that they tended to be never smokers and had adenocarcinomas. Moreover, when researchers compared ROS1-positive subjects to an expansion cohort of ALK-positive patients, they had similar response rates to Xalkori, but the former subgroup seemed to fare even better with Xalkori in terms of median duration of response and median progression-free survival compared to the latter group.

Pfizer filed to expand the use of Xalkori, and the FDA last year granted the drug breakthrough therapy designation, priority review status, and orphan drug designation. The FDA approved the new indication ahead of the agency's April decision deadline.

In following the development of Xalkori in the ROS1-positive NSCLC population over the years, "we were quite proactive with the company, encouraging them to submit this data," Blumenthal told GenomeWeb. "Part of the confidence we had was the unprecedented rates of response … as well as the durability of response. We also leveraged the known safety and efficacy profile that was quite impressive with [Xalkori] in the ALK-positive setting."

In order to garner approval for the latest indication, Pfizer submitted data from the 50-patient, single-arm study, in which based on assessment by independent reviewers, 66 percent of patients saw their tumors shrink and the median duration of response was around 18 months.

Moreover, the adverse events that ROS1-positive patients had were similar to the types of events more than 1,600 ALK-positive metastatic NSCLC patients have experienced during clinical trials. The most common side effects associated with the drug include vision disorders, nausea, diarrhea, and vomiting. Serious side effects of the treatment included liver problems, life threatening or fatal lung inflammation, irregular heartbeats, and vision loss in one or both eyes.

"We had a rarer disease in ROS1-positive patients … but we had all this existing data in the ALK-positive setting," Blumenthal said. "And that's why we were so proactive, and in this case used the guidance to display flexibility to allow the approval of the drug without the contemporaneous approval of the companion diagnostic."

Panels are here

In the time since researchers first identified the ROS1 subpopulation as a group likely to benefit from Xalkori and the FDA's approval of this new indication, the practice of medicine has marched on. The American Society of Clinical Oncology last year updated its guidelines for Stage IV NSCLC and recommended patients with ALK or ROS1 fusions receive Xalkori.

Well before the guidelines, many thoracic oncologists had embraced NGS. Raymond Osarogiagbon, an oncologist at Baptist Memorial Health Care in Memphis, Tennessee, located in what he calls "the lung cancer kill-zone of America," has worked for the last four years to standardize testing processes and treatment pathways for patients based on the molecular features of their disease. Within the healthcare network, where there are more than 700 new lung cancer cases each year, Osarogiagbon routinely tests patients with non-squamous, stage IV histology using a commercial NGS test provider, which he declined to name.

He estimated that this program has been able to identify druggable mutations in between 20 percent and 30 percent of patients. "Some of [the mutations] were esoteric," he told GenomeWeb. "We had a couple of BRAF mutations, which are relatively uncommon in lung cancer, but we were able to match patients to a targeted drug, and those patients are still doing well, well over a year passed when you'd expect."

Several BRAF and MEK inhibitors are FDA approved for treating melanoma patients with BRAF mutations, but the agency hasn't approved such treatments in lung cancer.

Osarogiagbon recommends patients with squamous histology, in whom druggable mutations are rare, for clinical trials investigating molecularly-guided treatment approaches, such as Lung-MAP and ALCHEMIST. "In a way, it's a very good deal for the patient, because it gives them free mutation testing," he said.

It's not lost on the FDA that oncologists across the country are eager to get their patients tested for multiple markers at once in the hopes of getting them to the right treatment faster. Rick Pazdur, FDA's director of the Office of Oncology Drug Products, along with Blumenthal and Mansfield wrote in JAMA Oncology in January that the conventional paradigm of a CDx measuring variants in a single gene in the context of one drug, is giving way to a model where an NGS test can detect multiple genetic markers and predict patients' responses to several drugs.

"In the foreseeable future, advanced NSCLC tumor specimens will likely be tested not only for EGFR mutations and ALK rearrangements but also for actionable mutations in other oncogenic drivers to help guide treatment decisions, and comprehensive NGS panel testing may become a standard practice," they wrote.

Thermo Fisher's deal to develop an NGS-based companion test is with Pfizer and Novartis. In 2014, the FDA approved Novartis' Zykadia (ceritinib) for patients who have ALK-positive, advanced NSCLC, and have stopped responding to Xalkori.

The FDA is "very supportive of these multiplexed assays," Blumenthal said, recognizing the difficulty obtaining tissue in lung cancer."We want to spare patients potentially the morbidity of repeated biopsies."

Osarogiagbon said that when NGS was first introduced within Baptist Memorial Healthcare, some patients would have to get biopsied three or four times before there was sufficient quality tissue for testing, but he and his colleagues have worked with pathologists to significantly reduce the biopsy failure rate.

Despite the availability and growing adoption of NGS-based panel testing in NSCLC, Mansfield pointed out that this type to test was not used in the clinical trial that led to Xalkori's approval in the ROS1-positive subpopulation. In the 50-patient study that led to Xalkori's expanded label, researchers used two clinical trials assays — a break-apart FISH test for 96 percent of samples and RT-PCR for the rest — to identify which patients should received the drug.

The FDA would prefer doctors use FISH and RT-PCR to determine patients' ROS1 status before giving Xalkori, "because we understand the performance of those tests," Mansfield said. But, she said the agency clearly recognizes the reality that test developers aren't necessarily going to bring forward a single-gene CDx with the availability of NGS oncopanels.

Industry observers have said that regulating NGS tests will be challenging for the FDA, since the agency can't review the analytical and clinical validity of every marker on an NGS panel and still approve or clear the test in a timely fashion. But the agency has been thinking of new ideas. For example, the FDA has said it would evaluate the analytical validity of a subset of variants on an NGS panel, and is interested in using curated variant databases as a way to evaluate clinical validity.

The FDA has even worked out how oncopanels should be labeled. The agency is planning to list markers gauged by a panel in two tables — one that lists the genetic variants intended for CDx use and associated with response to targeted treatments, and another that lists variants that can be used to guide treatments for patients who have run out of options.

Mansfield couldn't predict in which setting or indications an NGS-based CDx would first be marketed, but said that the NSCLC setting may be "in the front of the pack." Although FDA has yet to approve this type of a CDx, "we certainly hope to before too long," she said. "When something is new, everyone wants to see how the first guy managed to get it done before they [do it]."

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