Faculty, Staff and Student Publications
Publication Date
8-4-2023
Journal
Cancer Discovery
Abstract
Rationally targeted therapies have transformed cancer treatment, but many patients develop resistance through bypass signaling pathway activation. PF-07284892 (ARRY-558) is an allosteric SHP2 inhibitor designed to overcome bypass-signaling-mediated resistance when combined with inhibitors of various oncogenic drivers. Activity in this setting was confirmed in diverse tumor models. Patients with ALK fusion–positive lung cancer, BRAFV600E-mutant colorectal cancer, KRASG12D-mutant ovarian cancer, and ROS1 fusion–positive pancreatic cancer who previously developed targeted therapy resistance were treated with PF-07284892 on the first dose level of a first-in-human clinical trial. After progression on PF-07284892 monotherapy, a novel study design allowed the addition of oncogene-directed targeted therapy that had previously failed. Combination therapy led to rapid tumor and circulating tumor DNA (ctDNA) responses and extended the duration of overall clinical benefit.
Significance:
PF-07284892–targeted therapy combinations overcame bypass-signaling-mediated resistance in a clinical setting in which neither component was active on its own. This provides proof of concept of the utility of SHP2 inhibitors in overcoming resistance to diverse targeted therapies and provides a paradigm for accelerated testing of novel drug combinations early in clinical development.
See related commentary by Hernando-Calvo and Garralda, p. 1762.
This article is highlighted in the In This Issue feature, p. 1749
Keywords
Humans, Protein-Tyrosine Kinases, Protein Kinase Inhibitors, Proto-Oncogene Proteins, Lung Neoplasms, Oncogenes, Patient-Centered Care
DOI
10.1158/2159-8290.CD-23-0361
PMID
37269335
PMCID
PMC10401072
PubMedCentral® Posted Date
6-3-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes