Genome Profiling May Help Predict Response to Keytruda in Head-Neck Cancer Patients

Genome Profiling May Help Predict Response to Keytruda in Head-Neck Cancer Patients
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Genome profiling

Profiling the genome of patients with head and neck squamous cell carcinoma (HNSCC) for mutations and interferon (IFN)-gamma-induced gene expression may independently predict patients’ response to immunotherapy with Keytruda (pembrolizumab), according to results of an ongoing clinical trial.

The study, “Genomic determinants of response to pembrolizumab in head and neck squamous cell carcinoma (HNSCC),” was recently presented at the 2017 American Society Of Clinical Oncology (ASCO) Annual Meeting June 2-6 in Chicago.

Somatic mutations are the errors in our DNA (mutations) that occur in any of the cells within our body except the germ cells — the sperm and egg. This means that somatic mutations are not inheritable, so they’re not passed on to children.

The number of somatic mutations — the mutational load — is known to influence patients’ response to immunotherapies, like those targeting the immune checkpoints CTLA-4 and PD-1, in several cancers. These immune checkpoints are often highly expressed in a plethora of cancers to inhibit anti-tumor responses from the immune system.

In this study, researchers investigated the link between somatic mutational load and IFN-gamma gene expression profile with clinical outcomes in patients with HNSCC treated with the immunotherapy drug Keytruda. INF-gamma is a key factor (cytokine) of the immune system’s innate and adaptive responses. They looked specifically at gene expression profile of HNSCC patients receiving this type of immunotherapy.

Researchers sequenced the whole genome of patients with advanced head and neck cancer (cohorts B1 and B2) participating in an ongoing Phase 1 clinical trial (NCT01848834) that is testing Keytruda’s safety, tolerability, and anti-tumor activity.

The B1 and B2 cohorts included 25 and 48 patients, respectively, for a total of 73 patients where all patients were negative for infections with Epstein-Barr virus (EBV) and human papillomavirus (HPV).

The analysis of B1 and B2 cohorts showed that the association between patients’ mutational load and gene expression profile with objective response was significant.

The U.S. Food and Drug Administration (FDA) defined objective response rate (ORR) as “the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period.”

As such, these results support that the mutational load and INF-gamma gene expression profile carry an independent predictive value of HNSCC patients (HPV/EBV) response to Keytruda. The predictive value of patients’ genetic expression profile was not affected in patients carrying signs of infection with either HPV or EBV, but the mutational load was not associated with response rates in these patients.

Overall, the “mutational load and gene expression profile may have utility in characterizing responses to anti PD-1 therapies and novel cancer regimens in HNSCC,” the study concluded.

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