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Caris Prepares FDA Submission of NGS Panel, Will Include Microsatellite Instability Testing

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SAN FRANCISCO (GenomeWeb) – On the heels of a validation study of its targeted next-generation sequencing panel to assess microsatellite instability, Caris Life Sciences is preparing to include MSI testing in submission claims to the US Food and Drug Administration. The company continues to seek approval of the pan-cancer NGS assay as a companion diagnostic to guide treatment with approved targeted therapies and immunotherapies.  

The validation of Caris' assay for MSI testing, published last month in Cancer Medicine, is key, since the FDA last year approved Merck's anti-PD-1 immunotherapy Keytruda (pembrolizumab) for patients with unresectable or metastatic solid tumors characterized by high microsatellite instability or mismatch repair deficiency after progressing on other drugs.

Caris President and CSO David Spetzler said that the company has begun the submission process and is in ongoing discussions with the FDA about it, as well as about the clinical trial design for microsatellite instability claims. Spetzler said he anticipates that the approval process will take 12 to 18 months.

The assay will include between 650 and 700 genes, Spetzler said, and will analyze point mutations as well as MSI status, tumor mutational burden, and genome-wide loss of heterozygosity.

The panel will include both markers that meet FDA's current level of evidence for companion diagnostics as well as markers considered to be level 2 and level 3, Spetzler said. Markers considered to be level 2 have evidence of clinical significance, and clinicians can use them to make decisions about a patient's treatment. Level 3 biomarkers have the potential for clinical significance and may help guide patients toward clinical trials. 

For instance, tumor mutational burden is not considered level1, but there is growing evidence suggesting that it is could indicate sensitivity to immunotherapy. There has not yet been a pivotal study resulting in TMB being added to a drug label, but if TMB rises to that level, Caris could submit a supplemental application to expand approval of its assay to TMB, Spetzler said.

Caris' test would compete with other NGS cancer tests, including Foundation Medicine's 324-gene FoundationOne CDx, which recently received FDA approval. That test can inform treatment with 17 FDA-approved therapies.

Currently, Bristol-Myers Squibb is using FoundationOne CDx in a clinical trial for a combination immunotherapy regimen. In February, BMS said it planned to expand that trial to test whether TMB could predict better outcomes with its Opdivo (nivolumab) and Yervoy (ipilimumab) therapies after early evidence indicated that advanced non-small cell lung cancer patients with high TMB who were treated with both therapies as a front-line option had significantly higher progression-free survival than patients treated with chemotherapy.

If that trial results in the approval of BMS' drug combination for TMB-high patients, Caris would look to capitalize on that as well. "That would set the precedent" for a companion diagnostic, Spetzler said. "Then we'd be in a position to do a non-inferiority study to include [TMB testing] in our approved panel," he said.

In its recently published Cancer Medicine study to validate its panel for MSI testing, Caris evaluated tests from more than 11,000 patients with many different cancer types. First, in a cohort of 2,189 patients, researchers retrospectively analyzed data that was available from both Caris' 592-gene NGS test as well as from PCR-based fragment analysis, which is considered the gold standard for MSI testing.

To classify a sample as having high MSI using the NGS assay, which analyzed more than 7,000 microsatellie loci, samples had to have 46 or more altered loci, while those with fewer than 46 altered loci would be classified as stable or low. When compared to the PCR-FA test, sensitivity and specificity were 95.8 percent and 99.4 percent, respectively, across 26 different cancer types, with positive predictive and negative predictive values of 94.5 percent and 99.2 percent, respectively.

In addition, the researchers evaluated the relationship between MSI, TMB, and PD-L1 in 11,348 cases. The three markers all have evidence that they may predict response to immunotherapy. Interestingly, the researchers found that while the three markers overlapped in some cases, they didn't in all cases.

In total, 3 percent of patients were considered MSI-H, 7.7 percent of patients had high TMB, and 25.4 percent of patients were positive for PD-L1. Only 0.6 percent of cases were positive for all three markers. The overlap also differed depending on the cancer type. For instance, TMB and MSI overlapped in 95 percent of colorectal cancer patients. However, among ovarian, neuroendocrine, and cervical cancer cases, a significant were MSI-H but not TMB-high, while for non-small cell lung cancer and melanoma, there were a significant number of high TMB cases, but few or no MSI-H cases.

"The fact that they're independent means that there may be additive potential to the information," Spetzler said, though that would have to be ascertained. Just because MSI may be predictive for one tumor type, it does not mean it will be for another. For instance, there is emerging evidence that being positive for PD-L1 is "not necessarily a great predictor outside certain lineages," he said.

In addition, Spetzler said that it would be important to determine whether the threshold of 46 altered loci is relevant for all cancer types, or whether it would be different depending on the cancer. Originally, MSI was evaluated to determine whether colorectal and endometrioid cancer patients had Lynch syndrome, Spetzler said, and five loci are traditionally evaluated for that purpose. But those five loci "may be insufficient to be fully predictive of clinical benefit as we look outside those cancers," he said. "We're looking broadly" at MSI across the genome, but "how to interpret that to predict clinical benefit is still an unknown," he added.

Caris is now attempting to understand the impact of MSI across all tumor types by evaluating outcomes data from around 20,000 patients that it has tested since 2009. "As more and more people receive pembrolizumab that are MSI-high, that will help us understand and refine those thresholds," Spetzler said.

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