Leave no patient behind: how the FDA approval of Keytruda for specific biomarkers will put laboratory testing in the front line - Diaceutics

Leave no patient behind: how the FDA approval of Keytruda for specific biomarkers will put laboratory testing in the front line

June 5th, 2017

Marcos Tadeu dos Santos
Merdol Ibrahim
Dawn Wilkinson

The FDA approval of Merck’s Keytruda (pembrolizumab) “for a specific genetic feature (biomarker)” is leading us into a new era in which the integration of diagnostics and biomarker detection on the treatment pathway is not an option, but mandatory. Marcos Tadeu dos Santos, Senior Director, Merdol Ibrahim, Managing Director and Dawn Wilkinson, Scientific Director, Diaceutics, discuss the ruling and emphasize the importance of test quality, concordance studies, guidelines and education for laboratory best practice.

The recent announcement that the FDA has granted approval to Merck’s Keytruda (pembrolizumab) “for patients whose cancers have a specific genetic feature (biomarker)” and not based on the origin of the cancer, is a landmark decision. It is important not only for the way we understand precision medicine and how physicians make treatment decisions, but also for laboratories running the tests. Laboratories, usually the forgotten stakeholder, are now the protagonists in this very promising new direction for diagnostic testing.

We are now witnessing the start of a new era, in which the old and well-known ‘one-size-fits-all’ approach traditionally used with chemotherapies, is overtaken by the precision medicine concept of targeted therapies. It is an era in which the integration of diagnostics and biomarker detection on the treatment pathway is not an option, but mandatory.

Drug indication according to the biomarker status, regardless of the cancer type, has in fact long been expected as a trend by the scientific community. As far back as the early 19th century, Canadian physician William Osler, said, “It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has”. More recently, diagnostic tests have been developed to highlight mutations as potential drug targets and which are not directed against a specific cancer type. Physicians can now see that drugs based on specific targets are a reality and biomarkers are being used to identify both the genotype and phenotype of a disease.

Keytruda’s new indication covers any advanced solid tumor identified as microsatellite instability-high (MSI-H) or having a deficient mismatch repair (dMMR) status. The drug produced a complete or partial response in 39.6 per cent of patients across 15 cancer types in five open-label Phase I/II1-5.

Correct identification of the eligible patient

Although these are exciting results, this new era will not become truly revolutionary if we forget that drug efficacy is not the only important parameter to consider. The correct identification of the eligible patient, who could benefit from this impressive efficacy, is now as important as, or maybe more important than, the drug itself. We should keep in mind that Keytruda is now an option for patients with advanced solid tumors who have progressed following prior treatment, and for those who have no satisfactory alternative options – patients in the very late stages of the disease. This may be their last line of attack.

What happens if we do not correctly identify MSI-H or dMMR in these patients? Lack of testing quality at this late stage can have major repercussions for the patient’s outcome so there is zero room for error. However, there is no specific companion diagnostic test approved by the FDA to be used alongside Keytruda for this promising new indication. It means that laboratory developed tests (LDTs) are currently the only acceptable means for testing MSI-H and dMMR in these patients. Therefore, standardization and quality control will be extremely important to prevent erroneous results.

Risks associated with laboratory developed tests

Based on the data and experience Diaceutics has accumulated by tracking the MSI and MMR tests provided in the US since 2010, and also by observing results from proficiency testing/external quality assessment (PT/EQA) programs, it is very clear that the quality of these LDTs is a key risk. For instance, they are very sensitive to the quality and quantity of the DNA input. Many other variables, from initial primer design through to the PCR cycling choice, can also influence the quality of results. False negatives are also very common since the analysis is subjective and poorly standardized. It is true that the identification of MSI-high is more robust than the identification of MSI-low, but the threshold separating low from high can vary between labs and also differ greatly from the threshold used in the clinical trials.

Immunohistochemistry (IHC) for dMMR is currently the methodology of choice for most laboratories, and involves the use of four MMR antibodies (MLH1 + PMS2 and MSH2 + MSH6), where loss of expression/staining of either one of the antibodies indicates a potential abnormality in MMR expression. Not only is interpretation of MMR IHC subjective, but there is a major pre-analytical issue with antigenic epitopes for the four anti-MMR antibodies being particularly fixation-sensitive, and as fixation across clinical laboratories is not standardized, this creates uncertainty in the sensitivity and specificity of staining. Furthermore, external quality control data (UK NEQAS, ICC and ISH) also shows an average unacceptable staining rate of 14 per cent, which, if translated into the real world setting, is even more perturbing.

Use of NGS may be more robust, sensitive and less subjective but the current bioinformatics structure required for interpretation is still proving to be a barrier. The long turnaround time associated with NGS is another issue to be considered. However, as all patient samples are subject to the same pre-analytic stages of fixation, its impact on the quality of NGS results still remains to be determined.


The number of MSI tests performed each year is growing fast. From around 1,000 tests performed in 2015 to more than 30,000 predicted for 2017 (US). It shows that the importance of these tests is already being understood by the health system. However, this is based only on colorectal cancer, and the spread to other diseases may be slower, therefore there is a need to educate physicians regarding the clinical utility of this biomarker in other solid tumors. More than ever, we must think how to improve the quality of tests we are offering to patients. Concordance studies, PT/EQA enrolment, international guidelines and education for laboratory best practice are imperative, and pharma companies must have direct involvement in such initiatives from the start of any drug development strategies.

We cannot let relatively easy to fix testing issues leave any patient behind.


1. https://clinicaltrials.gov/ct2/show/NCT02460198?term=keynote-164&rank=1

2. https://clinicaltrials.gov/ct2/show/NCT01848834?term=keynote-012&rank=1

3. https://clinicaltrials.gov/ct2/show/NCT02628067?term=keynote-158&rank=1

4. https://clinicaltrials.gov/ct2/show/record/NCT01876511

5. https://clinicaltrials.gov/ct2/show/NCT02054806?term=KEYNOTE+28&rank=1


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