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FDA Okays Boehringer's Gilotrif, Qiagen EGFR Test, Providing New PGx Options for Advanced NSCLC

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With the US regulatory approval for Boehringer Ingelheim's Gilotrif (afatinib), late-stage non-small cell lung cancer patients whose tumors are being driven by mutations that lead to the overexpression of the epidermal growth factor receptor now have two pharmacogenomic treatment options to battle their disease.

The US Food and Drug Administration last week approved Boehringer's Gilotrif, a next-generation tyrosine kinase inhibitor, as a first-line treatment for metastatic NSCLC patients whose tumors harbor EGFR exon 19 deletions or exon 21 L858R substitutions. The agency simultaneously approved Qiagen's Therascreen EGFR RGQ PCR Kit to help healthcare providers pick out patients who have these mutations and therefore have an increased chance of responding well to Gilotrif.

Gilotrif's approval comes a couple of months after the FDA okayed a new first-line indication for Roche/Genentech's Tarceva (erlotinib) with Roche's Cobas EGFR Mutation test as the companion test (PGx Reporter 5/15/2013). EGFR mutations occur in 10 percent to 15 percent of the approximately 200,000 people diagnosed with advanced NSCLC each year in the US.

Lauding Gilotrif's approval, Trever Bivona, assistant professor of hematology and oncology at University of California, San Francisco, said "it is terrific that multiple targeted therapy options now exist for EGFR mutated lung cancer patients." Bivona's lab at UCSF is applying advanced genomic technologies to increase lung cancer patients' responses to molecularly targeted treatments. Given the two therapeutic options in treating EGFR-mutated NSCLC, Bivona said he will likely continue to use Tarceva for most patients, but begin to integrate Gilotrif to treat those who are refractory to Tarceva due to mutations not targeted by the first-generation tyrosine kinase inhibitor.

The FDA reviewed data on Gilotrif's safety and effectiveness from the LUX-Lung 3 study involving 345 NSCLC patients with EGFR-mutated tumors. The patients were randomized to receive Gilotrif or the chemotherapy drugs pemetrexed and cisplatin. In the trial, Gilotrif-treated patients lived for 4.2 months longer without their tumors progressing than those in the chemotherapy arm – experiencing a median progression-free survival of 11.1 months compared to 6.9 months.

In patients with the most common EGFR mutations, exon 19 deletions or exon 21 L858R substitutions, median progression-free survival was 13.6 months on Gilotrif versus 6.9 months on chemotherapy. "Safety and efficacy of Gilotrif have not been established in patients whose tumors have other EGFR mutations," the FDA-approved label for the drug states.

The LUX-Lung 3 trial, however, showed no statistically significant difference between the study populations in terms of overall survival. In its approval letter to Boehringer, the FDA stated that the company is required to submit its final analysis on the impact of Gilotrif on NSCLC patients' survival by April 2014.

"While the overall survival data from the LUX-Lung 3 trial are not yet mature, there was no statistically significant difference for overall survival between the treatment arms at the interim analysis conducted at 84 percent of the planned events for the final analysis," a Boehringer spokesperson told PGx Reporter.

Gilotrif-treated patients in the study commonly experienced side effects such as diarrhea, acne-like skin breakouts, dry skin, itching, inflammation of the mouth, skin infection around the nails, decreased appetite, weight loss, bladder inflammation, nose bleeds, fever, eye inflammation, and low potassium levels. Serious side effects associated with Gilotrif included diarrhea progressing to kidney failure and severe dehydration, severe rash, inflammation of the lungs, and liver toxicity.

A multi-plex companion Dx

The ability of Qiagen's companion test to accurately gauge EGFR mutations was established in LUX-Lung 3, in which 90 percent of study participants harbored the most common EGFR mutations, exon 19 deletions or exon 21 L858R substitutions. In order to garner FDA approval for its test, Qiagen submitted to the agency analytical studies to establish the assay's accuracy, repeatability, reproducibility, and detection limits.

The Therascreen EGFR RGQ PCR Kit includes seven assays that gauge a total of 29 mutations. There are four singleplex assays that assess T790M, L858R, L861Q and S768I mutations, and three multiplex assays that gauge a number of deletions, insertions, and G719X mutations. The singleplex assays gauge specific mutations, while the multiplex assays indicate when a mutation is detected but does not distinguish between specific mutations.

"Qiagen has companion diagnostics contracts in place with most of US clinical labs," through which the test kit will be available, a company spokesperson said without naming specific labs.

According to pricing guidelines issued by Medicare contractor Palmetto GBA, a genetic test that gauges common EGFR variants in NSCLC patients is reimbursed at $225. However, a Qiagen spokesperson told PGx Reporter that the company is working to negotiate a higher rate for its FDA-approved EGFR test kit.

"Although current reimbursement policies fail to nationally recognize the differences in FDA-approved companion diagnostics and [laboratory-developed tests], Qiagen has successfully secured a differential reimbursement rate for its FDA-approved Therascreen KRAS test under Palmetto GBA jurisdictions and is seeking to do the same with Therascreen EGFR," the spokesperson said. "Qiagen believes price differentials should recognize the clinical value and significant resources required to ensure FDA-approved tests have been scientifically validated through rigorous clinical trials."

According to Palmetto, testing for the KRAS gene garners a Medicare reimbursement of $246.40. Qiagen has been able to negotiate a reimbursement rate of $385 per test for its FDA-approved KRAS companion test, which gauges best responders to two colorectal cancer drugs. "This differential reimbursement amount proves that CMS understands the significant costs and time associated with securing FDA-approved companion diagnostics and Qiagen is expecting a similar trend for EGFR," Tadd Lazarus, Qiagen's CMO, told PGx Reporter.

As the US Centers for Medicare & Medicaid Services has moved to establish new reimbursement rates for molecular tests with new CPT codes, Qiagen has been a strong proponent of pricing FDA-approved test kits at a higher rate than lab-developed tests in order to incentivize other labs to adopt the agency-approved kit instead of maintaining existing LDTs that gauge the same analytes.

For example, in launching the pharmacogenomically targeted melanoma drug, Zelboraf, Roche experienced difficulties getting labs to adopt its FDA-approved BRAF mutation test, since many hospitals had certain LDT platforms already in place for many years that they used to gauge BRAF mutations (PGx Reporter 9/28/2011).

As long as FDA-approved kits and non-agency cleared LDTs gauging the same analytes exist simultaneously on the market, developers of companion diagnostic kits, such as Roche and Qiagen, will face competition from LDT providers and find it challenging to differentiate their kits. A higher reimbursement rate for FDA-approved companion tests is one proposed strategy to give labs a reason to migrate from LDTs to the newer kits.

Life Technologies recently commercially launched Pervenio Lung RS, a PCR-based assay that gauges the expression of 14 genes and is intended for early-stage non-small cell lung cancer patients after they've had their tumors removed with surgery. The test analyzes formalin-fixed, paraffin-embedded tumor specimens and assesses the expression of genes associated with lung cancer progression, such as KRAS, BRAF, EGFR, HER2, ALK, and p53. The Laboratory Corporation of America also markets an LDT that gauges EGFR mutations and Quest Diagnostics offers a lab test that assesses mutations in EGFR, ALK, and KRAS oncogenes.

"Recognizing that there is a need for a differential reimbursement for the FDA-approved test is an extremely important start," Lazarus said. "It is motivational to in vitro diagnostics manufacturers to take the time and to spend the dollars needed to complete the clinical trials required by the PMA process. It also helps labs to use [FDA-approved] test kits."

UCSF's Bivona expressed no particular preference for any one diagnostic test to gauge EGFR mutations when deciding whether to treat a patient with an EGFR tyrosine kinase inhibitor. "Any validated, CLIA-certified test is sufficient to screen patients for EGFR tyrosine kinase inhibitor treatment," Bivona said. "Many academic labs use validated assays developed in house in fact."

Qiagen's other efforts to encourage adoption of its test to prescribe Gilotrif will be service oriented, such as 24-hour reimbursement support, help in validating the kit's implementation in a particular lab, and co-marketing the test with labs to help them grow testing volume.

Qiagen and Boehringer will also work together to educate pathologists and oncologists about EGFR testing. Anticipating the market launch of Gilotrif, Boehringer launched the "Let's Test" campaign last year (PGx Reporter 10/24/2012). Through this effort, the drug developer has been laying the groundwork to inform healthcare providers about the importance of collecting tissue samples from their lung cancer patients early on and more readily test patients for EGFR mutations and ALK rearrangements.

Through education, however, EGFR testing is becoming more commonplace in lung cancer treatment. Market data cited by Boehringer found that in the fourth quarter of 2012 EGFR mutation testing in advanced non-squamous NSCLC patients was being performed for approximately 70 percent of the patient population — up from around 40 percent in the last quarter of 2011.

A PGx choice

With the FDA approval of Gilotrif, late-stage NSCLC patients with certain EGFR mutations now have a choice in terms of their pharmacogenomically guided treatment options. The few other markets where subsets of patients have multiple options to treat genomically characterized cancers are HER-2 overexpressed breast cancer, colorectal cancer without KRAS mutations, and Philadelphia-chromosome-positive leukemias.

The FDA reviewed Gilotrif under its priority review scheme. Boehringer and Qiagen submitted their applications for the drug and the companion test at the end of last year. Boehringer has heralded the LUX-Lung 3 trial as the largest study conducted in the EGFR-mutation positive NSCLC population.

Throughout the development of Afatinib, Boehringer has distinguished the drug from older tyrosine kinase inhibitors, such as Tarceva and AstraZeneca's Iressa (gefitinib), by highlighting the newer agent's souped up properties. Unlike older tyrosine kinase inhibitors, Gilotrif is an irreversible inhibitor, and as such, Boehringer has claimed that its drug will be more effective than these earlier products.

Afatinib covalently binds to EGFR, HER2, and HER4 receptors that are overexpressed in certain cancers. Once the drug permanently attaches to the cell receptors, the idea is that it will be able to better block these receptors and inhibit cell signaling pathways that cause tumor cells to proliferate.

Treatment with Gilotrif in LUX-Lung 3 showed a median progression-free survival improvement of 4.2 months in the overall study population and of 6.7 months in those with the most common EGFR mutations. In comparison, in the pivotal trial for Tarceva's approval in NSCLC patients with EGFR mutations, treatment with the drug improved progression-free survival by 5 months compared to chemotherapy.

"There are no clinical data demonstrating that [Gilotrif] is superior to Tarceva in EGFR-mutated lung cancer patients," UCSF's Bivona said. "A head-to-head trial has not been conducted."

Bivona acknowledged that Gilotrif's ability to irreversibly bind to EGFR receptors "does offer a potential advantage over first generation EGFR tyrosine kinase inhibitors because it has activity against EGFR T790M as well as the EGFR activating mutations, L858R and Exon 19 deletions." Tarceva targets L858R and Exon 19 deletions but the drug doesn't work once patients become refractory to the treatment due to EGFR T790M mutations.

A spokesperson for Boehringer noted that comparisons of the safety and efficacy profiles of Tarceva and Gilotrif in EGFR-mutated NSCLC patients will be more appropriate based on the results from a head-to-head comparison. Boehringer is currently conducting a head-to-head trial of Gilotrif and Tarceva in LUX-Lung 8, involving patients with advanced squamous-cell carcinoma as a second-line therapy following first-line platinum-based chemotherapy.

One year of treatment with Tarceva costs $70,000, but Boehringer would not detail the price of Gilotrif, noting that the firm is still figuring out the details of the drug's commercial launch. "The company will announce details around availability and access at a later date," a company spokesperson said. "Pricing for Gilotrif will be available at the time of availability."

A spokesperson for the company couldn't provide a specific date for when Gilotrif will be launched.

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