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Foundation Medicine Positions Blood-Based TMB Test as Companion Dx to First-Line Immunotherapy

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NEW YORK (GenomeWeb) – Foundation Medicine said last week that it is advancing a blood-based version of its tumor mutational burden test as a companion diagnostic to Roche/Genentech’s immunotherapy drug Tecentriq (atezolizumab) in first-line treatment of non-small cell lung cancer patients.

The assay is moving forward in two clinical trials. In a single-arm trial called B-F1RST, investigators are retrospectively analyzing blood-based TMB status in NSCLC patients treated with first-line Tecentriq regardless of their biomarker status.

Simultaneously, the test is being used to select patients in Roche's prospective, randomized Blood First Assay Screening Trial (BFAST), which funnels patients to either first-line Tecentriq for those with high TMB, or first-line Alecensa (alectinib) for those with ALK and RET mutations.

In the Tecentriq section of the study, efficacy of the drug in the TMB-selected cohort will be compared to two different chemotherapy regimens, with the goal of an approval of the drug/test combination in this first-line NSCLC setting.

As immune checkpoint inhibitors have rapidly advanced over the last few years, a variety of biomarker strategies have been explored. Immunohistochemical assays that measure PD-L1 expression have led the pack, but because PD-L1 has limited utility, the US Food and Drug Administration has found itself approving immuno-oncology drugs both with and without PD-L1 companion tests — or with a new category of so-called complementary diagnostics.

Tecentriq, for example, is currently approved in the US for some lung and bladder cancers regardless of PD-L1 expression levels.

Some survey results have suggested that a lack of highly predictive tests coupled with growing popular excitement around this new class of drugs may be leading to broad prescription, even in patients who could benefit more from a genomically targeted therapy, or even from standard cytotoxic chemotherapies.

In light of this, the need for additional biomarkers is cementing among clinical researchers.

Foundation began presenting on its strategy for measuring tumor mutation burden in early 2016, making a tissue-based TMB calculation available to ordering physicians as part of its FoundationOne test later that year.

Researchers had previously shown using exome sequencing that more highly mutated tumors were more responsive to immunotherapy, but Foundation showed that it could closely replicate those genome-wide results using the more efficient panel of 300 genes in its FoundationOne test.

Dave Fabrizio, leader of cancer immunotherapy at Foundation Medicine, said this week that the company immediately began looking at transitioning from tissue to a non-invasive blood-based method, with the goal of being able to provide an assay for Roche's planned BFAST trial.

Foundation Medicine launched its 62-gene cell-free DNA mutation test, FoundationAct, last spring, but till this week the company had not shared information on a blood-based strategy for TMB, which would likely require targeting a much larger portion of the genome.

Over the weekend, investigators from Foundation presented two abstracts at the European Society for Medical Oncology Congress in Madrid that describe the initial development and validation of the new blood-based TMB test (bTMB) to garner approval by the FDA to use it in the BFAST study.

"Because this is being used in a first-line setting, it requires getting a thumbs-up from the FDA to [perform] the assay in patients," Fabrizio explained.

According to Foundation's ESMO abstract presentations, the adapted bTMB assay delivers a count of somatic base substitutions down to 0.5 percent allele frequency across 394 genes from as little as 1 percent tumor content in a cell free DNA sample.

The company said that it looked at two different cutoff points for "high" bTMB, comparing orthogonally, to its validated tissue TMB platform. According to the firm, positive predictive value across both blood-based cutoffs was 100 percent with a limit of detection defined as 1 percent tumor content in at least 20 ng of cell-free DNA.

To validate the assay for use in Roche's BFAST trial, researchers retrospectively analyzed plasma samples from 211 patients in the Phase II POPLAR study of atezolizumab — correlating bTMB with Tecentriq clinical activity as established in the trial.

The team then applied the approach to 583 patient samples from a second trial called OAK. In both cases, the company reported that high bTMB correlated strongly with longer progression-free survival in patients treated with the checkpoint inhibitor.

In addition, patients' bTMB results did not appear to correlate with PD-L1 expression levels, suggesting that the test provides independent predictive information that can't be determined using PD-L1.

Foundation Medicine is not alone in its enthusiasm for tumor mutational burden, nor in developing a non-invasive approach to calculating TMB.

Personal Genome Diagnostics announced this February that it is also developing a non-invasive next-gen sequencing assay, called MutatorDETECT, which infers a patient's overall tumor mutation load from analysis of circulating cell-free DNA to help identify which cancer patients have the best chance at responding to treatment with immune checkpoint inhibitors.

Liquid biopsy firm Guardant Health has also said that the 500-gene circulating tumor DNA panel it has designed for use in clinical trials can support TMB analysis.

And OmniSeq has said it hopes to take an even broader approach, with a combined assay that interrogates a patient's immune profile using five different modalities: RNA-Seq, PD-L1 and PD-L2, mutational burden, and microsatellite instability.

Meanwhile, Roche is not the only pharmaceutical firm with immunotherapies in the pipeline for which TMB could be relevant.

The FDA this year approved Merck's PD-1/PD-L1 inhibitor Keytruda (pembrolizumab) for patients with solid tumors with microstatellite instability-high (MSI-H) status or mismatch repair deficiency (dMMR) — the first such approval for a biomarker-defined population regardless of where in the body their cancer occurred.

Tumor cells with MSI-H and dMMR have impaired DNA repair capabilities — one mechanism that can lead to the highly mutated profiles that TMB tests detect.

Researchers working with Bristol-Myers Squibb recently published a paper in the New England Journal of Medicine in which they assessed the effect of TMB on treatment outcomes of patients treated with BMS's Opdivo (nivolumab).

David Carbone, the study's first author, said in an email earlier this year that correlation between TMB — whether blood- or tissue-derived — and immunotherapy response will require prospective testing (as in the context of the Roche BFAST study.)

Although Foundation Medicine also has a collaboration with BMS in the immunotherapy space, Fabrizio said that the firm has not shared any details that program. 

In the meantime, clinicians who order FoundationOne for a patient can already use tissue-based TMB, if they choose to, to guide treatment decisions.

Fabrizio said that since the company launched TMB analysis last year, the company has analyzed tens of thousands of patients.

Though not every clinician considers or uses TMB, "Everyone who gets Foundation One also gets TMB, so this gives an idea of the clinical volume," he said.

In terms of clinical utility, he added, there is data supporting TMB from multiple studies representing more than 1,000 patients. "In every case, the conclusion [points to] utility," he said.

"The tenor of the conversation has really changed dramatically just in the last six to nine months," he added. "And I think it's now coming to bear that this will be heavily investigated across multiple [immunotherapies]."

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