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Diagnostic Challenges in the Era of Genetically Targeting Master Brands


Companies developing potential master brands need to begin work much earlier in the clinical development program to ensure reliable diagnostics will be available to all potential patients, writes Barri Blauvelt.

The announcement by the US FDA on May 23 of the accelerated approval of Merck’s newest master brand Keytruda (pembrolizumab) according to the tumor’s biomarker was a wonderful surprise to most. This was because to those involved in genetic and clinical research, they had low expectation that government agencies would do the logical thing and approve cancer treatment based on a common biomarker instead of approving one tumor type at a time.

Accelerated approvals of targeted therapies are not new, but until now targeted solid-tumor therapies have tended to be site specific. The first of these genetically-targeting master brands was Herceptin (trastuzumab).  When Herceptin was pending regulatory approval in 1998, the challenge to Genentech was whether or not to launch with the FISH test. Launching with it, the market value was estimated to be about 70% lower than without it.  However, governments felt that due to the high price, it was obligatory for Genentech in the US and its partner Roche outside of the US to provide FISH tests so that the drug would be used only in patients who were likely to respond.  Genentech/Roche’s decision to launch with the FISH test set the course for future targeted therapies to be approved along with biomarker diagnostics.  

Today we say, “Of course!” to the expectation for companion diagnostics. Yet it was not an obvious choice 20 years ago. FISH tests were simply not available around the globe. Moreover, oncologists weren’t used to asking for it to be done. And finally, women with breast cancer themselves were demanding to be given Herceptin, not understanding that the drug would only help them if they were HER2 positive.

Why is it, then, that even today, new genetically-targeting therapeutics continue to be challenged by limitations of biomarkers at launch? 

The Case of Familial Hypercholesterolemia:  In the May 4, 2017 issue of the New England Journal of Medicine, the benefits of the new class of PCSK9-inhibitors in preventing cardiovascular death and stroke were demonstrated as early as within one year of adding a PCSK9 inhibitor to statin therapy.An editorial on this (in the same issue) concluded, “It is anticipated that the results of the FOURIER trial will soon be implemented in international guidelines regarding the treatment of high-risk patients, directing clinicians in the use of this new and expensive class of drugs.”2

The findings of the FOURIER trial were not that surprising to most cardiologists. Yet uptake of this potential class of drugs has been slow, even in countries willing to reimburse for it.

To better understand why uptake has been so slow, we look to NICE, CDC and other agencies. The EU approved the first of these drugs in 2014.  At that time, NICE, the CDC and other agencies called for not only the testing for gene-encoding proprotein convertase subtilisin–kexin type 9 (PCSK9), but that this should be followed by cascade testing in suspected cases of Familial Hypercholesterolemia (FH).  However, according to Stanford University, at the time of launch, there were only a few laboratories in the US and internationally that could test for PCSK9.  So along with high price, lack of such testing being able to be done in accordance with NICE and other guidelines helped governments and physicians alike not to prescribe and reimburse for a potential new master brand for FH.

Diagnostic challenges for master brand Keytruda

So let’s turn again to Keytruda (pembrolizumab). Keytruda helps the body’s immune system fight cancer cells by blocking the cellular pathway PD-1/PD-L1. The FDA previously approved Keytruda for the treatment of patients with metastatic melanoma, metastatic non-small cell lung cancer (NSCLC), recurrent or metastatic head and neck cancer, refractory classical Hodgkin lymphoma, and urothelial carcinoma testing positive for PD-L1. Keytruda targets MSI-H and dMMR tumors containing abnormalities that affect the proper repair of DNA inside the cell. These are most commonly found in colorectal, endometrial and gastrointestinal cancers, and may also be found in breast, prostate, bladder, thyroid gland and other primary sites and in metastatic cancers. So the FDA’s en masse approval to allow for use based on a tumor’s biomarker instead of prolonging the inevitable approval of one tumor at a time is a huge leap forward.

Here’s the rub.

Keytruda is approved for use with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test (the first test designed to detect PD-L1 expression). However, PD-L1 testing is largely prognostic for patients beginning pembrolizumab treatment. This is because PD-L1 assays are unable to conclusively identify non-benefitting patients. How can that be?

We have to remember that the PD-L1 gene is not typically mutated or amplified and is constantly evolving as part of the immune system. This means that PD-L1 expression can be ever changing in space and over time, as well as be impacted by other treatments, such as radiation or chemotherapy. Finally, there are challenges as to diagnostic accuracy based upon assay testing variability, concerns about quality (e.g. variability in staining intensity and patterns) and lack of standardization pertaining to tissue fixation, storage, and antigen retrieval resulting in PD-L1 degradation. These combined effects may explain why PD-L1 positivity has had such widely varying clinical significance.

So over the past 20 years, what have (or haven’t) we learned?  

It’s a simple, yet surprisingly often-overlooked critical success factor: In the era of genetically targeted therapies, companies developing potential master brands need to begin work much earlier in the clinical development program to ensure that reliable diagnostics will be available to all potential patients when the therapeutic is approved. 


1.     Sabatin MS, Guigliano RP, Keech AC, et al. "E volocumab and Clinical Outcomes in Patients with Cardiovascular Disease". N Engl J Med 2017; 376:1713-22.

2.     Dullart, RPF. "PCSK9 Inhibition to Reduce Cardiovascular Events". N Engl J Med 2017; 376:1790-1791.


Barri M Blauvelt is CEO of Innovara, Inc.


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