Plasma Tests Can Complement Tissue Assays in Screening for Drug Resistance Mutation

Heather Wakelee, MD

Plasma and urine tests are often a reliable method for the detection of the T790M mutation in non—small cell lung cancer (NSCLC) patients with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs), according to an oral presentation given Monday at the 2016 ASCO Annual Meeting in Chicago.¹

Such liquid assays were in agreement with tissue assays for the mutation more than 80% of the time, according to a sub-analysis from the TIGER-X trial.

“A positive result is treatment changing, but a negative rate should not be the end of the analysis,” said Heather Wakelee, MD, associate professor of medicine at Stanford University, who also spoke on the topic at a private symposium held June 3. (A previous article inTargeted Oncologygave details on the symposium, the debate, and its background).

The presentation was especially timely, as on June 1, the FDA granted the first approval for a liquid EGFR assay to Roche for the cobas EGFR Mutation Test v2. It should be noted, however, that the assay was approved for EGFR driver mutations—the first mutations which give rise to the initial cancer—not T790M—which often causes later-acquired resistance following treatment with an additional EGFR TKI.

Almost equally timely, the developers of the drug that was the main subject of the TIGER-X trial, rociletinib, halted development after a correction of a formerly higher unconfirmed response rate was published in theNew England Journal of Medicinein late May.²

“The tissue test is supposed to be the gold standard, but it’s a PCR-based test, and it’s not perfect,” said Wakelee in a private interview withTargeted Oncology. “You might do a tissue biopsy, and miss the mutation, because it might be in a different part of the tissue. And if you’re a patient, you’re going to prefer that we do other tests before we do a biopsy,” she explained.

T790M Mutation Important in Patients with Drug Resistance

“About 10% of lung adenocarcinomas have an endothelial growth factor receptor (EGFR) driver mutation, so when a patient is diagnosed, we will test for them, because if we find a drug that inhibits it, the patient can have a dramatic response very quickly. But eventually the cell figures out a way around it, and what first- and second-generation EGFR inhibitors have in common is that 60% of the time drug resistance develops, there is a new mutation called T790M developing in the background,” Wakelee explained.

In TIGER-X, 331 out of 417 metastatic lung cancer patients with resistance to first- and second-generation EGFR inhibitors were determined by tissue assay to have the T790M mutation. When a plasma test was conducted for the mutation in 242 subjects, it found that 189 out of them had the mutation. Additionally, 136 out of 139 subjects tested positive for the mutation by urine assay.

The urine assay found the mutation in 83.8% cases (or 136 patients) identified as T790M positive by tissue test, while the plasma assay found such cases in 81.5% of the cases (or 195 patients).

Intriguingly, the plasma test was a better predictor of response to treatment by the target lesion(P= .006), according to the abstract.

As of September 2015, out of 417 subjects enrolled in the TIGER-X trial, plasma tests identified 14 patients as having the mutation although the tissue test classified them as not having it, while the urine test identified 7 such patients classified as T790M-negative.

Three Tests Perfectly Consistent Only 57% of the Time

However, all 3 tests were in agreement only 57% of the time, Wakelee noted. Plasma testing is more effective than the urine assay when the disease has spread beyond the lungs, and the difference is statistically significant(P<.001).

&ldquo;The mutation is going to be in the plasma most of time, especially if the metastatic disease is not just in the lungs. But when the disease is only inside the lung, the urine assay looks a little bit more sensitive,&rdquo; she added. However, study authors noted in the presentation that that difference was not found to be statistically significant.

The first liquid assay approved by the FDA on June 1 is a blood assay, which was approved only to search for the activating mutation, but any test that looks for 2 of the activating EGFR mutations can also find T790M, Wakelee added.

Wakelee H, Gadgeel S, Goldman J, et al. Epidermal growth factor receptor (EGFR) genotyping of matched urine, plasma and tumor tissue from non-small cell lung cancer (NSCLC) patients (pts) treated with rociletinib.J Clin Oncol34, 2016 (suppl; abstr 9001).

Sequist LV, Soria JC, Camidge DR. Update to Rociletinib Data with the RECIST Confirmed Response Rate. [Published online May 11, 2016]N Engl J Med.2016;374(23):2296-2297.