Opened Fall 2014, the National Cancer Institute (NCI)’s Exceptional Responders Initiative (ClinicalTrials.gov Identifier: NCT02243592) is seeking “to understand the molecular underpinnings of exceptional responses to treatment, primarily via chemotherapy,” in patients with cancer.

To do this, researchers are analyzing previously collected tissue samples using whole exome sequencing and/or targeted next generation sequencing.1 Their goal is to identify biomarkers related to how well patients respond to treatment.

Barbara A. Conley, MD, associate director of the Cancer Diagnosis Program in the NCI’s Division of Cancer Treatment and Diagnosis in Bethesda, Maryland, is responsible for 2 of the Institute’s precision medicine initiatives: Exceptional Responders and NCI MATCH (Molecular Analysis for Therapy Choice).

Dr Conley told Cancer Therapy Advisor that the Exceptional Responders trial is nearing its target of successfully profiling 100 cases. These include “a number of rare cancers” — 9 brain cancers, an adnexal carcinoma, an ampulla of Vater, and 8 types of blood cancer — “although the biggest numbers are in lung, colon, and breast as well as GI [gastrointestinal], as you would expect, because those are the more prevalent types of cancers.”

One of the interesting findings to date is that “most of the patients that were proposed to us are still living,” she said, which was “kind of a surprise” in that many had metastatic disease. “We are going to see what we can find out about the status of the immune system of the patients based on sequencing their tumors.”

The impetus for the initiative was that 1 patient with metastatic bladder cancer enrolled in a phase 2 trial of everolimus had a durable and ongoing complete response, despite the study failing to achieve its primary endpoint of progression-free survival.2

Whole genome sequencing identified a loss-of-function in the tuberous sclerosis complex 1 (TSC1) gene, which regulates mTOR pathway activation. After analyzing an additional 13 patients from the same trial, the authors found 3 tumors that harbored nonsense mutations in TSC1, including 2 patients with minor responses to everolimus. A fourth patient had minimal tumor regression.

In contrast, 8 of the 9 patients with disease progression were TSC1 wild type.