Clinical trial data released earlier this month offered some of the first evidence that measuring tumor mutational burden can help guide the use of cancer immunotherapy not only in advanced cases, but also for patients who have early-stage tumors and a chance of a cure.

In the study, which was presented at the annual meeting of the American Association for Cancer Research and simultaneously published in the New England Journal of Medicine, researchers used a genome-wide sequencing approach furnished by Baltimore-based Personal Genome Diagnostics to analyze samples from patients with stage 1-3 non-small cell lung cancer treated with Bristol-Myers Squibb’s Opdivo (nivolumab) before surgery.

Based on early analysis from the trial, the investigators reported that patients with high TMB according to the PGDx exome analysis looked like they got more benefit from the drug than those with low TMB.

Investigators, led by researchers from Johns Hopkins University and the Memorial Sloan Kettering Cancer Center, administered Opdivo to a small cohort of adults with untreated, surgically respectable non-small cell lung cancer. Of 21 tumors that were removed in the trial, 20 were completely resected. Nine of those 20 showed a “major pathological response,” meaning the tumors shrank during the pre-operative treatment.  According to the authors, there was a significant correlation between this strong pathological response and TMB as measured before treatment.

PGDx currently offers a variety of sequencing services to analyze both tissue samples and blood samples for cancer mutations. But it has also been working behind the scenes to create a set of in vitro diagnostic test kits in partnership with genomics tools giant Illumina.

As of last year, PGDx had been working on creating a small panel plasma-based TMB IVD called MutatorDETECT, but the firm’s Director of Translational Science and Diagnostics John Simmons said last week that the mutation thresholds that are emerging as the most clinically relevant are lower than the company’s smaller panel could deliver.  Instead of continuing to pursue a smaller panel, the firm has doubled down on releasing tissue and plasma kit versions of its 500-plus gene panel, which will cover various clinically actionable markers, plus allow TMB assessment.

PGDx aims to launch its IVD products in early 2019, Marketing VP Megan Bailey said last week. And the time appears to be ripe, considering the attention now being paid to TMB by clinical researchers and pharmaceutical companies.

Based on other new data this month in advanced lung cancer, for example, the field could soon see the first US Food and Drug Administration approval of TMB in a companion diagnostic indication — for Foundation Medicine’s Foundation One CDx alongside a combination of Bristol-Myers Squibb’s Opdivo (nivolumab) and Yervoy (ipilimumab).

At the same time, recent commercial announcements — like BMS’s plans to also develop TMB tests with Illumina — have raised questions about what the future landscape may look like in terms of TMB test availability, regulation, concordance, and competition.

Concordance was a subject of much concern at the recent AACR meeting, considering the complications that arose with PD-L1 testing in this same area of immuno-oncology. As various PD-L1 assays emerged as companions to different immunotherapy drugs, it became clear that results from any one test might not be translatable from one drug to another, meaning if a doctor wanted to consider different therapies, they would be required to perform or order multiple PD-L1 tests.

With the CDx version of Foundation One now approved by the FDA, Foundation Medicine has said it is planning to change the way it reports TMB — avoiding qualitative description (high- or low-TMB status) in favor of a numerical value only. In this way, if TMB is at some point approved as a companion to a specific therapy, Foundation could adjust the format of its report to reflect a specific cutoff based on FDA drug labelling.

But a cutoff point defined on the Foundation 300-gene panel wouldn’t necessarily be directly applicable if using a different sequencing method like Illumina’s TruSight Oncology 500 panel, Memorial Sloan Kettering’s MSK-IMPACT, Guardant Health’s GuardantOmni assay, or the IVD kits for comprehensive targeted sequencing being advanced by Illumina and PGDx.

Simmons said that PGDx has been working with other test makers and pharma companies in a program led by Friends of Cancer Research to develop a standardized method for calculating and reporting TMB that can be used across sequencing panels, allowing clinicians to potentially apply a variety of different cutoff points without the need to retest patients with different sequencing panels.

This type of diagnostic flexibility is something that the FDA has had to struggle to create a space for in its regulation of medical tests, but Simmons said that the agency’s recent approvals of MSK-IMPACT and Foundation One have set a new precedent for the coexistence of regulatory requirements and rapid evolution in clinical practice.

“What you see in the last six months with this tumor profiling category that the FDA has introduced … is that it opens up flexibility for analytically validated readouts … for specific cutoffs or thresholds that are directly associated with inclusion criteria for certain drugs,” he said.

In the context of simpler precision medicine biomarkers, it’s a little easier to see how individual companion diagnostic associations (EGFR mutations and EGFR inhibitors, for example) can map across multiple different FDA-approved sequencing panels.

With TMB it’s a little more complicated, Simmons added, which is why the FOCR harmonization program is so exciting.

What the future holds in terms of commercial competition is less clear, although a recent announcement by PGDx has suggested the possibility of future IP disputes.

In February, PGDx announced that it had been granted exclusive rights to develop both tissue- and blood-based diagnostics using Memorial Sloan Kettering’s TMB-related intellectual property, which reinforces other existing license agreements it has with Johns Hopkins University.

CEO Doug Ward said in a statement at the time that PGDx was “confident that the combined patent estate adequately protects our extensive investment and development plans for TMB-enabling tests.”

“I can’t speak to our IP strategy,” Simmons said. “But I can say that the JHU, and especially the MSK, IP really represents the seminal advancement and introduction of TMB as an actionable biomarker related to checkpoint therapies.”

“We felt strongly [about] the value of TMB and the need for our company to have a protected place [in that regard,]” he added.

https://www.genomeweb.com/cancer/promising-data-early-stage-nsclc-pgdx-…