12:00 AM
Aug 22, 2016
 |  BioCentury  |  Product Development

The devil is in the assay

How unique PD-L1 assays make it difficult to compare BMS, Merck NSCLC data

The failure of a Phase III trial of Bristol-Myers Squibb Co.'s Opdivo nivolumab in first-line NSCLC doesn't shed much light on what PD-L1 expression level predicts patient benefit, because the uniqueness of the different assays used by the leading immuno-oncology companies makes comparison near impossible.

While Opdivo's failure may give Merck & Co. Inc.'s Keytruda pembrolizumab a lift, it may not matter if forthcoming combination therapies provide a similar or greater benefit than Keytruda in the front-line setting independent of PD-L1 status.

On Aug. 5, BMS announced Opdivo monotherapy missed the primary endpoint of progression-free survival (PFS) in first-line non-small cell lung cancer patients compared to investigator's choice of chemotherapy.

The trial enrolled patients whose tumors expressed PD-L1 at 1% or more; the primary endpoint was evaluated in patients with 5% or more PD-L1 expression.

The data from the 541-patient CheckMate-026 trial sent BMS shares tumbling $12.04 (16%) to $63.28, a loss of over $20 billion in market cap that day.

Those data came two months after Merck stopped early the Phase III KEYNOTE-024 trial in which Keytruda posted positive results in the same front-line NSCLC setting. In the 305-patient trial, Keytruda monotherapy met the primary endpoint of PFS and the secondary endpoint of overall survival vs. standard of care platinum-based chemotherapy.

That study enrolled untreated patients whose PD-L1 tumor proportion score was at least 50%.

The reaction to the CheckMate-026 data appeared to suggest some investors believe patients don't benefit from PD-1 inhibitor monotherapy when PD-L1 expression is as low as 5% ; however, Opdivo and Keytruda are being used with companion or complementary diagnostics in a setting that's proving difficult to parse for companies and physicians alike.

Part of the challenge is that positive PD-L1 status has not consistently predicted patient benefit across cancer types, with PD-L1 negative patients also deriving benefit from anti-PD-1 mAbs, albeit typically in smaller numbers.

Compounding the issue, however, is that each of the five mAbs against PD-1 or PD-L1 in Phase III testing or beyond has its own assay to determine PD-L1 expression, with each assay possessing its own scoring algorithm and method of measuring cells.

Given these differences, according to one assay developer who spoke to BioCentury, it is unlikely that a generic cutoff for PD-L1 expression to predict patient benefit can be determined without a prospective trial involving all the therapies and assays.

Correlation conundrum

Bristol-Myers and Merck both collaborated with Agilent Technologies Inc.'s Dako A/S unit to develop immunohistochemistry (IHC) assays specific for their PD-1/PD-L1 mAbs. But the assays were developed based on clinical data for the specific companion therapeutic, which means the reagents, scoring algorithm and resulting interpretation are different (see "Assessing the Assays," page 8).

"You can't compare one to the other," Benjamin Creelan told BioCentury. "What might be 5% using the assay for Bristol-Myers might be more like 50% using the 22C3 Merck antibody." Creelan is a medical oncologist at the H. Lee Moffitt Cancer Center and Research Institute.

Priti Hegde, Genentech's cancer immunotherapy franchise biomarker lead, echoed that point. "It is so difficult to compare a 5% of Bristol-Myers' 28-8 to 50% of 22C3 for Merck, the nuances are such that it is really difficult to do a cross-trial comparison between the two diagnostic positive subgroups," she said. According to Hans Christian Pedersen, Dako's head of companion diagnostic marketing, the only way to truly compare the PD-L1 assays would be a prospective trial that included both assays and therapeutics.

"That is really where there will be a roadblock for harmonization - to create the...

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