NEW YORK (GenomeWeb) – Following the initial US regulatory approval of Thermo Fisher Scientific's next-generation sequencing-based companion diagnostic panel, the company is hoping to rapidly expand the indications for the test into new drug/biomarker combinations and cancer types.
"This is a long game and the true opportunity for this test will only be realized if Thermo is successful in keeping up with adding additional markers," said Ryan Keeling, chief operating officer at Diaceutics, a company that consults drugmakers in their personalized drug development efforts.
Thermo Fisher Scientific's Oncomine Dx Target Test can be used to identify best responders to AstraZeneca's EGFR inhibitor Iressa (gefitinib), Pfizer's ALK and ROS1 inhibitor Xalkori (crizotinib), and the combination of Novartis' MEK inhibitor Mekinist (trametinib) and RAF inhibitor Tafinlar (dabrafenib). The FDA-approved label for the test will indicate its use to predict which patients with EGFR mutations, ROS1 rearrangements, and BRAF mutations are likely to derive benefit from Iressa, Xalkori, and the Mekinist/Tafinlar combo, respectively.
Tafinlar and Mekinist were originally approved in 2013 as single-agent treatments for BRAF-mutated, advanced melanoma, and in 2014, the agency approved the combination in the same molecularly defined subpopulation. In concert with its approval of Thermo Fisher's universal companion test, the FDA extended the indication of the Tafinlar/Mekinist combination into BRAF-mutated, advanced NSCLC. Between 1 percent and 3 percent of NSCLC tumors are characterized by BRAF gene mutations.
Iressa is approved for between 10 percent and 20 percent of advanced NSCLC patients in the US with EGFR mutations. Xalkori is approved for the 4 percent of advanced NSCLC patients harboring ALK rearrangements and the 1 percent of patients with ROS1 rearrangements.
The FDA extended the indication for Xalkori to ROS1-positive NSCLC last year with a post-marketing commitment for Pfizer to develop a companion test in the future. With the approval of the Oncomine Dx Target Test, Pfizer appears to have met that commitment. However, the panel, which industry players have been calling a "universal companion diagnostic" in the hopes that it would shift the field away from the current one drug-one test-one analyte model, doesn't yet include a predictive indication for Xalkori in ALK-positive NSCLC.
The National Comprehensive Cancer Network recommends testing for advanced NSCLC patients for EGFR, ROS1, ALK alterations to inform use of targeted treatments, and PD-L1 expression testing to guide immunotherapy decisions. The guidelines body also advises testing for other markers that may help patients get on personalized therapy or a clinical trial, including BRAF V600E mutations, MET amplifications, MET exon 14 skipping mutations, RET gene rearrangements, and HER2 mutations.
Thermo Fisher noted that this initial approval will enable it to work quickly to expand the test's indications. Moreover, doctors and patients will learn the presence of other gene variants that are detected by the panel but not linked to the three treatments.
The panel analyzes 23 genes in total, and the test report will not only indicate whether patients have ROS1, EGFR, and BRAF alterations linked to the three FDA-approved treatments, but also the presence or absence of variants in other genes. ALK is not one of the genes among the 23 on the panel.
"We are working with our pharma partners to submit a supplemental premarket approval application for ALK," a Thermo Fisher spokesperson said. Novartis' recently approved Zykadia (ceritinib) and Pfizer's Xalkori (crizotinib) are competitors in the ALK-positive NSCLC market.
Keeling noted that the absence of ALK from the panel could be due to a number of reasons, including competition between pharma companies, as well as technical or regulatory challenges. He acknowledged that competition is always likely to be a factor when different drugmakers are involved, but he also lauded Novartis and Pfizer for jointly investing in an effort that aims to provide a more complete testing solution for lung cancer patients where it is often challenging to acquire sufficient tissue for sequential biomarker testing that is currently standard practice.
Previously, the FDA approved Iressa, Tafinlar, Mekinist, and Xalkori with companion diagnostics that gauged alterations in single genes. There are FDA-approved PCR tests that gauge EGFR and BRAF mutations, and an FDA-approved immunohistochemistry test for detecting ALK rearrangements.
Usually, NSCLC patients are first screened for EGFR mutations. If results are negative, then they are screened for the next most prevalent marker. "However, the low amount of tissue that is obtainable from NSCLC patients combined with the hierarchical sequential testing approach … creates the risk that the less prevalent mutations frequently go undetected," a Novartis spokesperson said.
The Oncomine Dx Target Test is based on Thermo Fisher's Ion AmpliSeq technology and will run on its PGM Dx System, for which the FDA also granted 510(k) clearance for analysis of formalin-fixed paraffin embedded tissue samples. The technology can gauge multiple genetic markers from 10 nanograms of DNA, a feature Thermo Fisher highlighted given the challenge of procuring large biopsy samples from advanced lung cancer patients.
According to Thermo Fisher, between 30 and 40 percent of NGS testing currently cannot be performed due to insufficient DNA in the tumor sample. Comparatively, some NGS platforms require between 100 and 200 nanograms of DNA, which is often not possible to procure from frail, stage IV lung cancer patients.
"The whole idea of having a panel is you have to test the patient once and not sequentially," Joydeep Goswami, president of clinical next-generation sequencing and oncology at Thermo Fisher, said in an interview. "It allows for a much faster turnaround and selection of the right therapy from the start instead of a trial and error sort of effort."
The company claims that with this panel advanced lung cancer patients will have results that can inform their therapy within days instead of the weeks it can take to test for single genes via different tests.
Competing with LDTs
There are a number of NGS-based panels being performed at single, CLIA-certified labs, such as Foundation Medicine and Caris Life Sciences, that can analyze these and hundreds of other oncogenes. Though these panels don’t have FDA approval, Thermo Fisher's test will compete with them.
Goswami acknowledge that there are always going to be customers that prefer an LDT over a kit, especially labs that want to do cutting-edge research. However, he noted there are also customers just interested in getting clinically actionable information from a test, and they will appreciate having an FDA-approved kit. "They have a patient, they need quick turnaround, and they want something that's approved and [markers] that are tied to specific drugs," Goswami said. "And if they want additional information, they can get it with very little effort."
The FDA last year also approved Foundation Medicine's FoundationFocus CDxBRCA, which analyzes two genes, BRCA1 and BRCA2, and it was the first NGS companion test to receive the agency's nod. As a lab-developed test, it can only be performed at Foundation's lab and is indicated to direct treatment with one drug, Clovis Oncology's PARP inhibitor Rubraca (rucaparib). In comparison, Thermo Fisher's test is a kit that can be performed at different CLIA-certified, CAP-accredited labs, and identify responders to three treatments.
But in order to drive adoption of the test, Keeling emphasized that it will be critical for Thermo Fisher to continue to expand the panel's indications into new drug/biomarker combinations and additional cancer types — something the test developer has said it is actively working on.
In the short term, he predicted that not having ALK may influence some labs' decision to not adopt the test, since around 80 percent of labs offering NGS panels for NSCLC cannot detect chromosome rearrangements and so they are reflexing to testing for ALK rearrangements via IHC or fluorescent in situ hybridization. The fact that Thermo's panel already detects ROS1 rearrangements suggests that it may not be a big technical hurdle to add the capability to assess ALK rearrangements.
"If Thermo can add ALK then there is certainly a gap in the market to be filled," Keeling said.
LDTs will continue to play a major role in personalizing NSCLC treatment until regulation or reimbursement demands otherwise, he predicted. "Regarding Thermo's strategy here, adding additional markers to an already established test is actually quite efficient. Additional applications become easier as all parties become more comfortable with what is required," he said. "From a lab perspective, with every new marker, it becomes more and more attractive. If we get to a stage where all the common biomarkers are on this panel, then it could compete very strongly with LDTs, assuming cost of testing is in line with reimbursement."
The work required to garner this initial approval, however, was not insignificant, Goswami admitted. The final submission file to the FDA for the test was more than 220,000 pages. "[It was] a huge burden, but people should feel really comfortable that we, the drug companies, and the FDA have done a really thorough job in getting it to where it is," Goswami said.
In order to garner approval, Thermo Fisher had to submit data from a variety of studies demonstrating, for example, that its test kit could consistently detect genetic alterations when performed at different labs and by different operators. A CDx of this type must contend with "multiple types of cancer samples, multiple operators, multiple instruments, and different folks that are going to interpret the results," Goswami said.
The FDA wanted to see data ensuring the reliability of the Oncomine Dx Target Test in these types of scenarios. Goswami said that Thermo Fisher had to work with different labs to collect this data as part of the premarket review process. LabCorp's diagnostics and Covance businesses, NeoGenomics Laboratories, and Cancer Genetics, are among the first labs with trained staff to offer the Oncomine Dx Target Test to ordering oncologists, according to Thermo Fisher.
It's still unclear if FDA-approved companion diagnostic kits will be more readily adopted than LDT genomic profiling assays, observed Rita Shaknovic, chief medical officer at Cancer Genetics, since the former carry higher costs and take longer to develop in line with FDA regulations. "I see success of companion diagnostics dependent on indirect factors like reimbursement policies. If insurance companies require a CDx as a prerequisite for the reimbursement of the associated drug, then the CDx device is here to stay," Shaknovic said. "My prediction is that properly priced and easily accessible companion diagnostic [devices] will stay. The rest will be crowded out by LDTs."
The NGS platform developer advanced the companion diagnostic in collaboration with Novartis and Pfizer. According to a Thermo Fisher spokesperson, because the Oncomine Dx Target Test will serve as the primary CDx for ROS1-positive and BRAF-mutated NSCLC patients considering treatment with Xalkori or Mekinist/Tafinlar, the two drugmakers and the test developer partnered to access the clinical trial data on the therapies.
The inclusion of AstraZeneca's Iressa was the result of FDA's guidance to Thermo Fisher, the spokesperson said. Because there is already an FDA-approved CDx for this drug that gauges EGFR mutations, Thermo Fisher only had to submit a study showing concordance with its NGS test.
Separately, AstraZeneca, Janssen Biotech, and Sanofi are also involved in a collaboration with Thermo Fisher competitor Illumina to advance a "universal companion diagnostic" based on the MiSeqDx NGS system.
Meanwhile, Thermo Fisher is actively working to expand the indications for the Oncomine Dx Target Test. The firm recently inked a companion diagnostic deal with Agios Pharmaceuticals that could enable the use of the panel to predict which patients with IDH1 mutated bile duct cancer will respond to the investigational drug ivosidenib.
"We are currently in discussions with several pharmaceutical companies that are interested in validating other genes on our panel, including applications beyond lung cancer, and submitting for FDA approval," Goswami said in a statement. "This is an important component of our companywide effort to advance precision medicine."