Microsatellite Instability as a Pharmacogenomic Marker of Therapeutic Response to Immune Checkpoint Inhibition

TITLE

Microsatellite Instability as a Pharmacogenomic Marker of Therapeutic Response to Immune Checkpoint Inhibition              

CASE NUMBER

C13241

UNMET NEED

The programmed death 1 (PD-1) pathway is a negative feedback system that represses Th1 cytotoxic immune responses and that, if unregulated, can damage the host. It is up-regulated in many tumors and in their surrounding microenvironment. Blockade of this pathway with antibodies to PD-1 or its ligands has led to remarkable clinical responses in patients with many different types of cancer, including melanomas, non–small-cell lung cancer, renal-cell carcinoma, bladder cancer, and Hodgkin’s lymphoma. The expression of PD-1 ligands (PD-L1 or PD-L2) on the surface of tumor cells or immune cells is an important — but not a definitive — predictive biomarker of response to PD-1 blockade.     

DISEASE INDICATION

Cancers

TECHNICAL DESCRIPTION

This trial was conducted using a parallel two-stage design to simultaneously evaluate the efficacy of MK-3475 and MSI as a treatment selection marker for anti-PD-1 therapy. It consisted of two-stage phase 2 studies in parallel in three cohorts of patients. These include, patients with MSI positive colon cancer, patients with MSI negative colon cancer and patients with other MSI positive cancers. The study agent, MK-3475, was administered at 10 mg/kg intravenously every 14 days. The co-primary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate.

MAJOR RESULTS

1.       This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab.

2.       Changes in serum levels of protein biomarkers, such as CEA, corresponded with clinical benefit after a single dose of therapy.

3.       The evaluation of tumor genomes can help guide immunotherapy.

4.       Identification of an approach for the treatment of a specific class of tumors based solely on genetic status.

ASSOCIATED PUBLICATIONS

- N Engl J Med. 2015 Jun 25;372(26):2509-20 -

TECHNOLOGY CLASSIFICATION

Primary Category: Clinical Diagnostics

Primary Subcategory: Immunotherapy

ASSOCIATED REPORTS OF INVENTION (ROIs) AND INTELLECTUAL PROPERTY (IP) FILING NUMBERS

ROI #                               TITLE                                                        STATUS       PRIORITY DATE        IP FILING NUMBERS

C13241    CHECKPOINT BLOCKADE AND MICROSATELLITE INSTABILITY       PCT Pending       11/13/2014                   US 62/190,977, PCT/US2015/060331