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Study Shows cfDNA EGFR Mutations Linked to Tarceva Outcome in EURTAC Samples

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NEW YORK (GenomeWeb) – Researchers from the Phase III EURTAC study have published a secondary analysis demonstrating high sensitivity and specificity of blood-based EGFR testing compared to the initial tissue testing performed in the trial.

The study also supports growing evidence that the type of EGFR mutation a patient has, either in tumor tissue or in circulating DNA, may be associated with much different responses to the EGFR inhibitors.

In the study, published last week in JAMA Oncology, researchers from the Spanish Lung Cancer Group evaluated blood samples from 97 subjects in the original EURTAC cohort using an RT-PCR method they have developed to detect EGFR mutations in circulating tumor DNA.

According to study author Miguel Molina, the team's ctDNA EGFR test — which relies on a multiplex 5' nuclease real-time PCR (Taqman) assay used in the presence of a PNA clamp designed to inhibit the amplification of wild type alleles — is currently offered commercially by a reference laboratory led by several members of the Spanish Lung Cancer Group, called Pangaea Biotech. The test is available in Europe and South America through an agreement between Pangaea and the European diagnostic lab company Labco.

The original EURTAC trial was the basis for the US Food and Drug Administration's 2013 approval of Roche's Tarceva (erlotinib) as a first-line treatment for a subset of non-small cell lung cancer patients carrying certain EGFR mutations. Along with the drug, the FDA also approved Roche's RT-PCR-based Cobas test, which detects EGFR exon 19 deletions and L858R substitution mutations, to select patients for treatment in this new indication.

The Spanish researchers' new results using their circulating cell-free DNA test found that median overall survival was shorter for patients with ctDNA EGFR L858R mutations than for those with exon 19 deletions — 13.7 versus 30 months respectively.

Previous research using tissue-based testing has also hinted at a discrepancy in outcomes for patients with these two different EGFR mutations when treated with EGFR inhibitors. For example, a study led by Massachusetts General Hospital's Lecia Sequist, presented last year at the Chicago Multidisciplinary Symposium in Thoracic Oncology, found that patients with exon 19 deletions had significantly better outcomes on Boehringer Ingelheim's Gilotrif (afatinib), while those with L858R mutations had a negligible survival advantage on the targeted drug.

"Our data regarding the relationship between EGFR mutations in the blood and outcomes [were] consistent with studies in tissue specimens, reinforcing the negative prognostic impact of L858R and suggesting that more aggressive strategies should be evaluated in patients in which this mutation is detected at baseline," Molina told GenomeWeb in an email.

According to the study authors, confirmation of this finding in the context of a randomized prospective study may be necessary to establish how it could or should affect clinical care.

In addition to revealing this difference in outcomes, the Spanish team's cfDNA study also showed that their test was 78 percent sensitive compared to the known EGFR statuses of the EURTAC study subjects based on Roche Cobas tissue testing initially performed.

According to the study authors, this accuracy marks their test at least in the range of, if not superior to, other competing methodologies. Efforts to commercialize circulating DNA-based diagnostics, especially in lung cancer where tissue biopsies can be difficult and especially invasive, are accelerating across the board.

Qiagen announced in January that it had received a CE-IVD mark for the plasma version of its therascreen EGFR kit, to identify patients likely to benefit from AstraZeneca's Iressa (gefitinib).

In addition to an agreement with Qiagen to develop the therascreen plasma test for Iressa, AstraZeneca has also made a similar pact with Roche, for investigational NSCLC agent AZD9291.

Roche has said it hopes to launch a CE-IVD plasma-based version of its Cobas EGFR test by the end of this year.

That assay, as well as Sysmex Inostics' BEAMing technology and Boreal Genomics' OnTarget platform, is being evaluated by Clovis Oncology as a way to identify candidates for its investigational EGFR inhibitor rociletinib.

According to Molina, Pangaea believes its test has some advantages over other technologies. "Our assay is a simple one, requiring a very minor amount of pipetting and no sophisticated reagents or equipment, just a plain qPCR machine," he said in his email.

"Testing a blood sample by our technique has a cost of around $20 to $30, cheaper than [some] other competing assays," he added.

Pangaea is involved in two ongoing clinical trials in patients with metastatic EGFR-mutant NSCLC in which plasma and serum are being collected in parallel: the Europen Phase II BELIEF trial of erlotinib plus bevacizumab, and the Spanish Lung Cancer Group GOAL Phase II trial comparing gefitinib plus olaparib versus gefitinib alone.

"We hope that these trials will further pave the way for the clinical implementation of EGFR mutations assessment in cfDNA," Molina said.

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