THE FIRST BIOMARKER-DEFINED TUMOR INDICATION:FDA APPROVAL OF PEMBROLIZUMAB FOR MSI-HIGH CANCER

Kenneth Emancipator, MD, DABPMerck & Co., Inc., Kenilworth, NJ, USACompanion Diagnostics Forum 2017 | Princeton NJ | 6 December 2017

What is “microsatellite instability” (MSI)?

• A “microsatellite” is a non-coding region of DNA consisting tandem repeating base pairs, for example:

…-T-T-T-T-T-T-T-T-T-T-…or

…-T-G-T-G-T-G-T-G-T-G-…

• There are thousands of microsatellites in the human genome

• Microsatellites are prone to change in length during DNA replication due to DNA misalignment (figure at right)

• “Microsatellite instability” refers to hyper-variability in the length of microsatellites

Figure courtesy of Dr. Peter Forster, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=40510379

Mismatch Repair Defects Give Rise to Microsatellite Instability

• Mismatch repair proteins correct erroneous base substitutions, additions, or deletions made during DNA replication

• A defect in one of the mismatch repair proteins leads to somatic mutations and …

• Especially to microsatellite instability, since microsatellites are prone to mutation

• The pathobiology stems from the mismatch repair defect and the somatic mutations, but …

• Microsatellite instability can be seen as a functional assay (or endpoint) for mismatch repair defects

MismatchRepairDefect

Micro-Satellite

Instability

There is general acceptance and standardization of testing for both mismatch repair deficiency and microsatellite instability• Mismatch repair protein deficiency (dMMR)

– Deficiency/absence of at least one of four mismatch repair proteins is considered to be dMMRand to be equivalent clinically and biologically to MSI-high• MLH1 (mutL homolog 1), MSH2 (mutS homolog 2), PMS2 (postmeiotic segregation increased 2),

and MSH6 (mutS homolog 6)

• Microsatellite instability (MSI)– Hyper-variability at a minimum of two of five loci is considered “MSI-high”

• Bethesda loci– BAT-25, BAT-26, D2S123, D5S346 and D17S250

• Promega loci– BAT-25, BAT-26, MONO-27, NR-21 and NR-24

– Hyper-variability at only one locus is “MSI-low”– Normal variability at all loci is “microsatellite stable” (MSS)

Origins of Microsatellite Instability as a Predictive Biomarker for Response to Anti-PD-1

• Only one of 16 patients with colorectal cancer responded to anti-PD-1 therapy in a Phase 1 trial

• Routine histologic section of the tumor which responded showed the medullary pattern with abundant lymphocyte infiltration, characteristic of MSI-high

Image courtesy of Robert Anders, MD, Johns Hopkins Medical Institutions

Clinical efficacy of pembrolizumab in colorectal cancer with and without microsatellite instability

Le DT et al. N Engl J Med 2015; 372: 2509.

Radiographic response to pembrolizumab in patients with micro-satellite instability

Le DT et al. N Engl J Med 2015; 372: 2509.

Plausible Biology Underlies MSI-High/dMMR as a Biomarker

POL-D & EMutations

MismatchRepairDefect

HighMutationBurden

Micro-Satellite

Instability

HighTumor

Immuno-genicity

TumorInflammation

PD-L1Positive

Adaptive

Response

EnvironmentalFactors

HomologousRecombination

Deficiency

Regulatory Climate When Merck Trials Started

• Microsatellite instability (MSI) and mismatch repair defect (dMMR) were well-established tests in the field, with accepted consensus standards, at least for colorectal cancer

– Regulatory concept: diagnostic versus companion diagnostic

• FDA had plans to regulate laboratory-developed tests

• However MSI and dMMR were not so well-established for other types of cancer

• FDA-approved test was completely lacking

• Safe and effective use of the therapeutic depends and safe and effective testing

• FDA not necessarily convinced that microsatellite instability (PCR) and mismatch repair defect (IHC) tests are interchangeable; definitely not for non-CRC cancers

Approval was based on mutiple cohorts cobbled together

Response rates were consistent across multiple tumor types

6/11 (55%)

Why did FDA approve pembrolizumab for MSI-high cancer?*• Unmet medical need

• Very comfortable with the science

• Consistency of efficacy across indications

• Climate right to portray FDA as a facilitator of innovation

• Microsatellite instability was well-established as disease entity (at least in colorectal cancer)

• Tests for microsatellite instability are well-defined and have been widely available in accredited clinical laboratories for some time

• FDA was planning to regulate laboratory-developed tests (LDT)– MSI was probably at the top of the list for enforcement– Switched strategy to post-market commitment when LDT Draft Guidance was withdrawn

*These are only the presenter’s speculation, of course

The Tumor Immunogenicity – Inflammation Pathway

POL-D & EMutations

MismatchRepairDefect

HighMutationBurden

Micro-Satellite

Instability

HighTumor

Immuno-genicity

TumorInflammation

PD-L1Positive

Adaptive

Response

This could be the most interesting step

EnvironmentalFactors

Clinically Validated Biomarkers

Investigational BiomarkersHomologousRecombination

Deficiency

Final Thoughts

• What does the oncology community want in a biomarker?– High negative predictive value?– Objective, i.e. not reader-dependent?– MSI and dMMR are neither of these

• Does this mean pharma companies can ignore FDA exhortations and forego companion diagnostic co-development?– Probably not. MSI/dMMR was a very special situation– Co-development arguably might have been easier than a post-market commitment

• The approval for pembrolizumab for MSI-high cancer represents the first time FDA has recognized a biomarker-defined tumor