11:52 AM
Mar 15, 2018
 |  BC Innovations  |  Tools & Techniques

Shared burden

How test developers are seeking harmony for tumor mutational burden assays

Having learned their lesson with PD-L1, companies are collaborating on assay standards for tumor mutation burden -- a likely contender for the next major biomarker in immuno-oncology. A Friends of Cancer Research-led consortium of pharmas and diagnostics companies is driving the charge and plans to publish a white paper with its recommendations this year.

The coalition has been gathering members and momentum since it began meeting in September to create a framework for comparing tests on tumor mutation burden (TMB).

So far, discussions have included representatives from Friends, FDA, six test developers and six pharmas -- AstraZeneca plc, Bristol-Myers Squibb Co., the Genentech Inc. unit of Roche, the EMD Serono Inc. subsidiary of Merck KGaA, Merck & Co. Inc. and Pfizer Inc.

The partners are aiming to avoid the problems created for drug developers by the lack of harmony over assays for PD-L1. Four immunohistochemistry (IHC) assays, each with its own scoring algorithm and method of measuring cells, were used to support trials for at least five Phase III mAbs against PD-1 or PD-L1. That has made it nearly impossible to compare results across the class and determine what level of PD-L1 expression predicts patient benefit.

In 2015, a group of 10 companies, regulatory agencies and cancer associations launched the Blueprint Project to compare PD-L1 assays, standardize scoring and recommend best practices. The project published the first phase of its analysis last year in the Journal of Thoracic Oncology.

Since TMB could upstage PD-1/PD-L1 for stratifying patients in cancer immunology, stakeholders are pooling heads now to define common assay parameters for the new biomarker.

“We saw this play out with the PD-L1 IHC story, and we wanted to get ahead of the problem,” said David Fabrizio, leader of cancer immunotherapy at Foundation Medicine Inc., a member of the consortium.

Evidence has been growing in the literature that TMB, a sign of how immunogenic a tumor is, could be a better predictor than PD-L1 of how a patient will respond to an immunotherapy.

BMS acted on that evidence, opting to switch from PD-L1 status to TMB level for a subset of patients in its Phase III CheckMate -227 trial. On Feb. 5, BMS announced Opdivo nivolumab plus Yervoy ipilimumab met the progression-free survival (PFS) endpoint vs. chemotherapy in first-line non-small cell lung cancer (NSCLC) patients with high TMB.

The decision followed BMS’s 2016 high profile Phase III miss in CheckMate -026. In that trial, Opdivo monotherapy missed the endpoint of improving PFS vs. chemotherapy in first-line NSCLC patients whose tumors expressed PD-L1 at ≥5%. Post-hoc whole exome sequencing suggested the compound would have met in TMB-high patients.

TMB is a measure of the number of somatic mutations in a tumor genome, which correlates with the number of neoantigens on tumor cell surfaces. Because T cells recognize neoantigens, which are not found in normal cells, the more neoantigens are present, the higher the likelihood and potential potency of a T cell-mediated antitumor response.

“I think the jury is still out from a prospective perspective, but there...

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