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NanoString Releases Details on Tumor Inflammation Signature Assay From Merck CDx Collaboration

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NEW YORK (GenomeWeb) – Last week, NanoString Technologies provided the first details on its companion diagnostic for Merck's anti-PD-1 drug pembrolizumab (Keytruda), a gene expression assay looking at 18 markers for immune system response to a tumor.

On a conference call following the release of the Seattle-based firm's second quarter financial results, NanoString CEO Brad Gray introduced the "Tumor Inflammation Signature" assay.

Merck is using the assay in three new Phase III clinical trials to expand the indication for Keytruda, which has been approved as a second-line drug for non-small cell lung cancer (NSCLC) when used with a PDL-1 immunohistochemistry companion diagnostic assay. NanoString has already started lining up additional pharmaceutical companies for pilot projects to explore whether it could be used as a companion diagnostic for other drugs.

The tumor inflammation signature assay measures the expression of 18 genes, which indicate the type and functional status of immune cells within the tumor. "These are important metrics for predicting patient response," Gray told GenomeWeb. Keytruda, a PDL-1 checkpoint inhibitor, seems to work best when the immune system is responding to a tumor but is being thwarted by the tumor's PDL-1 camouflage. "You want to look for where inflammation exists but is not successful in killing the tumor," he said.

Each marker falls into roughly one of four categories: T cell presence, natural killer cell presence, antigen presenting biology, and interferon gamma signaling. Based on the expression of those 18 genes, an algorithm creates a score, and using that a cutoff can be determined for those likely or unlikely to benefit from treatment.

"What's important clinically is the negative predictive value," Gray said. "We want to be confident that those who are considered negative, or not inflamed, by the test, will not benefit from these drugs. It's the only way to ethically deny patients these therapies."

"It's looking at not only if T cells have infiltrated the tumor, but whether they're activated," he added. "That captures a broader set of biology than a single IHC marker ever could. The first wave of [IHC] companion diagnostics [for checkpoint inhibitors] really only look at one marker. We're looking at a much broader set of biology."

NanoString's announcement came at a critical time for the development of checkpoint inhibitor companion diagnostics. Last week, Bristol Myers Squibb announced that a clinical trial to expand the indication for its PDL-1 inhibitor Opdivo to a first-line drug for NSCLC failed to meet its primary endpoint, triggering a 20 percent drop in market capitalization for the firm. Opdivo is approved as a second-line NSCLC drug. Many are pointing to the IHC-based companion diagnostic and the cutoff used to select patients as at least contributing to the failure.

"We haven't seen data, so we don't know exactly what happened, but most people believe the combo of test and the cutoff for the test was not right for this," Gray said. "It didn't perform the basic function of selecting patients that were likely to respond."

Meanwhile, Merck's stock rose on the news. The firm is also running a clinical trial to expand the indication of Keytruda as a first-line NSCLC drug.

"The choice of the right diagnostic has tremendous and economic importance for drug companies that are competing with each other," Gray said. Bristol Myers Squibb's failure could have upside for NanoString. "We think with [the] tumor inflammation signature, we have a much better approach to selecting patients than IHC-based tests."

NanoString has progressed quickly on development of the test. Though Merck has been a longtime customer and the companies began collaborating on this project back in 2015, it was only at the beginning of this year that they officially launched development of test. Merck started with a set of 680 genes, and with NanoString's help whittled it down to the 18-gene panel for the final product, Gray said.

Already, NanoString has collected on $8.5 million out of a possible $12 million in development milestones, all in the second quarter, spurring the firm to raise its full year 2016 revenue guidance. "That's a good indication that things are going ahead of plan," Gray said.

The firm has delivered the assay for Merck to use in several clinical trials. Two trials, called Keynote 180 and 181, will use the assay to try and expand the indication for Keytruda to include esophageal cancer. A third is a basket trial including patients with 10 different tumor types. This basket trial seeks to enroll over 1,000 patients and will be a test of the pan-cancer nature of NanoString's assay.

NanoString's deal stipulates that it keeps rights to the test and can try to pair it with drugs from other companies. NanoString has been engaged in a pilot program with 17 different pharma companies running 33 projects to explore the use of its gene expression assays to identify patients for clinical trials. The program was growing even before NanoString began discussions to offer up the tumor inflammation signature — in the second quarter, it began seven new projects.

Now it's in discussion with several companies to start pilot projects based on the tumor inflammation signature.

"People were very interested with what we were doing with Merck when Merck's data came out at [the American Society of Clinical Oncology meeting], showing the biology we're looking at and how robust that biology is across many tumor types," Gray said. "The interest has grown a lot in the last few months, and I expect interest will grow even more in the visible failure of [Bristol Myers Squibb's] Checkmate 026 study.

"It's kind of raising the stakes on companion diagnostic strategy," he said. 

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