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Clovis Evaluating Sysmex Inostics Blood Assay to ID EGFR Mutations in ctDNA of NSCLC Patients

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SAN FRANCISCO (GenomeWeb) – Clovis Oncology is evaluating a blood-based assay to detect EGFR mutations in circulating tumor DNA in non-small cell lung cancer patients as a way to better identify candidates for treatment with rociletinib (CO-1686), its investigational EGFR inhibitor, a Clovis scientist said this week.

During a talk at the Cambridge Healthtech Institute Molecular Medicine Tri-Conference held here, Chris Karlovich, principal scientist for molecular diagnostics at Clovis, said that his company is comparing the performance of Sysmex Inostics' BEAMing assay service to that of Qiagen's TheraScreen EGFR PCR test in a subset of patients from the company's "third-generation inhibitor of mutant EGFR lung cancer" (TIGER) clinical trial for rociletinib.

The goal, Karlovich said, is to overcome some of the limitations of tissue-based PCR testing in identifying EGFR mutations, particularly the T790M resistance mutation, which can be used to identify patients who have become resistant to EGFR-directed therapy and thus are candidates for second- or later-line treatment with rociletinib. In addition, Karlovich said, blood-based assays like BEAMing could potentially be used to more easily monitor response to the drug.

Rociletinib was designed to selectively target initial activating EGFR mutations and the T790M resistance mutation, while sparing wild-type EGFR at anticipated therapeutic doses, with an improved toxicity profile, according to Clovis' website.

As such, it has the potential to be a first-line treatment in NSCLC patients with activating EGFR mutations and a second- or later-line treatment in those who have become resistant to EGFR-directed therapy due to the T790M secondary mutation.

In May 2014 the US Food and Drug Administration granted breakthrough therapy designation to rociletinib as a treatment for mutant NSCLC in patients with the T790M mutation after progression on EGFR-directed therapy.

Prior to this, in October 2013 Clovis and Qiagen had announced a partnership to develop a companion diagnostic for rociletinib using Qiagen's Therascreen EGFR assay, a PCR test designed for use with formalin-fixed paraffin-embedded tissue samples. That kit had already been approved by the FDA earlier that year for Boehringer Ingelheim's Gilotrif (afatinib) for metastatic non-small cell lung cancer.

Although Clovis' companion diagnostic development program with Qiagen is still in place, Clovis' Karlovich noted that it's "a good test, but has inherent limitations," chief among them the fact that tissue biopsies may miss important T790M mutations in patients due to tumor heterogeneity – an issue that could be remedied by a blood test. A so-called liquid biopsy also has the advantages of being relatively non-invasive for potential serial monitoring purposes.

Accordingly, Clovis has embarked on a study within its ongoing rociletinib clinical trial program to assess whether a plasma-based test would be sensitive and specific enough to inform patient management.

The company actually has several TIGER clinical trials in various stages to assess rociletinib in different types of patients. The TIGER-X trial is evaluating the drug in two groups of patients: those who have developed the T790M mutation following their first and only EGFR-directed TKI therapy, such as Tarceva or Iressa; and later-line T790M-positive patients after progression on their second or later TKI therapy or subsequent chemotherapy.

Karlovich said that Clovis considered several plasma-based tests including the BEAMing technology. This technology, which Sysmex acquired along with Inostics in 2013, stands for "beads, emulsion, amplification, and magnetics." As the name implies, it combines emulsion-based digital PCR with magnetic beads, hybridization, and flow cytometry, and can detect and enumerate mutant DNA in a background of wild-type DNA at ratios greater than one in 10,000.

Karlovich noted that the EGFR BEAMing test identifies L858R, del19, and rare activating mutations in EGFR, as well as T790M with a sensitivity of approximately 0.02 percent.

As part of its evaluation of the test, Clovis is performing EGFR testing on matched pretreatment tissue and plasma for 139 patients from its TIGER-X trial, Karlovich said. All the patients have metastatic disease and are progressing on previous therapy.

In an initial comparison of BEAMing testing of plasma and corresponding tissue testing, Clovis looked at 119 patients who were positive for activating mutations. Of these, 102 were positive in plasma, yielding a positive agreement of 86 percent with tissue testing. Meantime, 23 patients who were positive in tissue were negative in plasma, but 14 patients were negative in tissue that were positive in plasma. After secondary testing, Clovis came to the conclusion that the negative tissue tests were actually true positives.

Furthermore, BEAMing identified 101 patients that were positive for T790M mutations — the same number that was identified in tissue testing when inadequate tissue specimens were included in the analysis.

Besides the BEAMing assay, Clovis is also evaluating two other plasma tests: Boreal Genomics' OnTarget platform, and a not-yet-commercialized test from Roche, the cobas EGFR plasma test, which a Roche spokesperson said the company hopes to launch with CE-IVD marking this year.

In their comparison study of tissue and plasma samples, the Clovis researchers found that some 20 to 30 percent of T790M tissue-positive samples were not detected in plasma by any of the aforementioned tests. However, analytical data suggests that the plasma assays are sensitive enough, with a limit of detection of as few as three copies per sample, so the Clovis team believes these missed positives are more a "limitation of biology in NSCLC," Karlovich said, adding that it is likely that a small subset of patients just doesn't shed circulating tumor DNA for myriad reasons.

Karlovich said that Clovis is now looking at whether the BEAMing technology can be used to identify tumor-specific mutations in circulating tumor DNA over time to monitor response and relapse with targeted therapies.

He added that serial monitoring of a small number of early-dose cohort patients treated with rociletinib shows that plasma EGFR is a useful pharmacodynamic marker, and that changes in ctDNA detected by BEAMing largely mirror clinical response to the drug.

"I think the test is sensitive and specific enough to inform the clinical management of patients," Karlovich concluded.

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