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

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