More Robust Tools Needed to Predict who will Respond to Immune Checkpoint Inhibitors

Investigators at Sarah Cannon look to next-generation sequencing for molecular signatures that may correlate with response.

By: Andrew McKenzie, PhD

on: June 21, 2022In: Evolving Standards of Care

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Andrew McKenzie, PhD

Immune checkpoint inhibitors (ICIs) have revolutionized cancer care. However, current biomarker strategies are only able to predict response to ICIs in a minority of patients. The advent of agents targeting different aspects of the cancer immune system requires more sophisticated patient selection techniques to maximize tumor response to these novel immunotherapies.1,2

Current patient selection strategies for approved ICIs include immunohistochemical staining of PD-L1, polymerase chain reaction (PCR) or next-generation sequencing (NGS) for microsatellite instability (MSI); immunohistochemical staining or PCR for DNA mismatch repair deficiency (dMMR); and NGS for tumor mutation burden (TMB).

However, these techniques predict response to ICIs for only a minority of patients, and methods for detecting these biomarkers can be complex and tissue- or ICI-specific.3

Recently, NGS has been used to detect the somatic mutation landscape and calculate tumor mutation burden (TMB). The FDA recently approved tumor mutation burden as a predictive biomarker for response to immunotherapies.4,5 This strategy, however, is imperfect. The overall response rate to pembrolizumab in patients harboring high TMB was 29% in the KEYNOTE-158 study.4

Further confounding patient selection, TMB values can vary between vendors and between the type of sample being analyzed—i.e. tissue samples versus circulating tumor DNA (ctDNA).6,7 Similarly, dMMR is a robust marker for predicting response to ICIs, but only a minority of cancers have dMMR and many MMR-proficient tumors still respond to ICI treatment.8,9

The complexity outlined above coupled with the relatively low predictive value of these biomarkers demonstrates the need for more robust tools to identify patients who are likely to respond to ICIs and, just as importantly, spare patients the time, expense, and toxicity of trying therapies from which they will not derive benefit.

We have initiated work at Sarah Cannon Research Institute, Nashville, Tennessee, to elucidate molecular signatures from NGS that correlate with response to ICIs. To do this, we rely on NGS performed as a part of standard of care from our network of community-based general medical oncologists. Comprehensive genomic profiling via NGS is now recommended for many tumor types for identifying patients who might respond to targeted therapies. We aim to expand the utility of these tests to identify patients who may be more likely to respond to ICIs.10

There is precedent for this line of investigation as mutations in DNA damage repair pathway genes (including POLD1, POLE, and MSH2) in non-small-cell lung cancers (NSCLC) harboring TMB have shown response to ICIs. Conversely, NSCLC tumors harboring mutations in STK11 demonstrate a lack of response to single-agent ICI treatment.11,12,13

Predictably, in our analysis, different tumors respond differently to ICI treatment. For example, we’ve seen longer overall survival with melanomas and lung cancers compared to non-colon GI, colorectal, and breast cancers.

Somewhat surprisingly, it appears overall survival on ICIs could be increased by personalizing treatment based on mutations in certain genes. For instance, colorectal tumors harboring mutations in NOTCH1 had a nearly 5-fold increase in median overall survival compared to their NOTCH1 wild-type counterparts.

Similarly in NSCLC, tumors harboring mutations in LRP1B had a 1.4-fold increase in median overall survival compared to their LRP1B wild-type counterparts (Fig. 1).

Adjusted overall survival in patients receiving immune checkpoint inhibitors with non-small-cell lung cancer. Light red and light blue lines represent mutant and wild type, respectively. Schlauch D, Fu X, Jones SF, et al. Tumor-Specific and Tumor-Agnostic Molecular Signatures Associated With Response to Immune Checkpoint Inhibitors. JCO Precis Oncol.

In our research, we have observed that NSCLCs harbor numerous genes numerous genes with mutations that are associated with a better response to ICIs. Interestingly, mutations in genes associated with growth factor or mitogen signaling (EPHA3, GNAS, ERBB2, NF1, and ALK) generally had prolonged response to ICIs with EGFR being the exception. EGFR mutations were associated with lack of response to ICIs, as has been previously shown.

For each tumor type analyzed, we were able to elucidate mutations in certain genes that corresponded with longer overall survival on ICIs than their wild-type counterparts—indicating that there may be genomic signatures