Topic
Exceptional Responder
About: Exceptional Responder is a research topic. Over the lifetime, 24 publications have been published within this topic receiving 425 citations.
Papers
TL;DR: Whole-exome sequencing of a patient with a 14-month complete response on this trial revealed two concurrent mutations in mTOR, the target of everolimus, suggesting a biologic mechanism for exquisite sensitivity toEverolimus in this patient.
Abstract: Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. One approach to increase this understanding involves detailed studies of exceptional responders: rare patients with unexpected exquisite sensitivity or durable responses to therapy. We identified an exceptional responder in a phase I study of pazopanib and everolimus in advanced solid tumors. Whole-exome sequencing of a patient with a 14-month complete response on this trial revealed two concurrent mutations in mTOR, the target of everolimus. In vitro experiments demonstrate that both mutations are activating, suggesting a biologic mechanism for exquisite sensitivity to everolimus in this patient. The use of precision (or "personalized") medicine approaches to screen patients with cancer for alterations in the mTOR pathway may help to identify subsets of patients who may benefit from targeted therapies directed against mTOR.
291 citations
Baylor College of Medicine1, Van Andel Institute2, University of North Carolina at Chapel Hill3, University of Texas MD Anderson Cancer Center4, Foundation Medicine5, Catalan Institution for Research and Advanced Studies6, University of Arkansas for Medical Sciences7, Nationwide Children's Hospital8
TL;DR: Analysis of tumor biopsies from an unbiased cohort of 111 exceptional responder patients revealed synthetic lethal relationships that may be exploited therapeutically and rare genetic lesions that favor therapeutic success, while also providing a wealth of testable hypotheses regarding oncogenic mechanisms that may influence the response to cancer therapy.
88 citations
TL;DR: Genomic profiling of an exceptional responder with response for over 27 cycles revealed hypermutated genotype with microsatellite instability (MSI) in the regorafenib plus cetuximab combination, which demonstrated early signals of activity in wild-type CRC.
Abstract: BACKGROUND. The combination of multikinase VEGF inhibitor regorafenib and anti-EGFR antibody cetuximab overcomes intrinsic and acquired resistance in both EGFR-sensitive and EGFR-resistant preclinical models of colorectal cancer (CRC).
METHODS. Utilizing a standard 3+3 design, a phase I study was designed to determine safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) of the regorafenib plus cetuximab combination among patients with advanced cancer including CRC. Comprehensive genomic profiling was performed on the exceptional responder.
RESULTS. Among the 27 patients enrolled the median age was 54 years. None of 19 patients treated at dose level 1 (cetuximab i.v. 200 mg/m2 followed by 150 mg/m2 weekly + regorafenib 80 mg daily) experienced a DLT, and 2 of 5 patients treated at dose level 2 (cetuximab i.v. 200 mg/m2 followed by 150 mg/m2 weekly + regorafenib 120 mg daily) experienced a DLT (grade 3 thrombocytopenia [n = 1] and grade 3 intra-abdominal bleed [n = 1]). Most common adverse events were grade 1 or 2 rash (20 patients). Of 24 evaluable patients, 11 (46%) patients had clinical benefit (stable disease > 6 cycles or partial response [PR]) (CRC n = 8, one patient each with head and neck cancer, carcinoma of unknown primary, and glioblastoma). A CRC patient, who progressed on anti-EGFR and regorafenib, achieved a PR (46% decrease per RECIST v1.1) lasting 15 months. Genomic profiling of an exceptional responder with response for over 27 cycles revealed hypermutated genotype with microsatellite instability (MSI).
CONCLUSION. Regorafenib 80 mg daily plus cetuximab 200 mg/m2 loading dose, followed by 150 mg/m2 every week is the MTD/recommended phase II dose. The combination demonstrated early signals of activity in wild-type CRC, including 1 exceptional responder with MSI high.
TRIAL REGISTRATION. clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02095054","term_id":"NCT02095054"}}NCT02095054
FUNDING. The University of Texas MD Anderson Cancer Center is supported by the NIH Cancer Center Support Grant CA016672. This work was supported in part by the Cancer Prevention Research Institute of Texas grant RP110584 and National Center for Advancing Translational Sciences grant UL1 TR000371 (Center for Clinical and Translational Sciences).
28 citations
TL;DR: An 'exceptional responder' programme to see whether outliers from failed cancer trials can open up new drug development avenues is launched in the US.
Abstract: The US National Cancer Institute is launching an 'exceptional responder' programme to see whether outliers from failed cancer trials can open up new drug development avenues.
24 citations
TL;DR: The bevacizumab-naive and sorafenib combination did not meet the pre-specified primary endpoint although some clinical activity was seen in heavily-pretreated bev Bacizumabs-naïve OvCa patients with platinum-resistant disease.
20 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2021 | 2 |
| 2020 | 4 |
| 2019 | 6 |
| 2018 | 2 |
| 2017 | 1 |
| 2016 | 3 |