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Ref Type Journal Article
PMID (37269335)
Authors Drilon A, Sharma MR, Johnson ML, Yap TA, Gadgeel S, Nepert D, Feng G, Reddy MB, Harney AS, Elsayed M, Cook AW, Wong CE, Hinklin RJ, Jiang Y, Brown EN, Neitzel NA, Laird ER, Wu WI, Singh A, Wei P, Ching KA, Gaudino JJ, Lee PA, Hartley DP, Rothenberg SM
Title SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy.
Journal Vol Issue Date Pages Journal Short Title
Cancer discovery 2023 Jun 03 OF1-OF13 Cancer Discov
URL
Abstract Text 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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
PF-07284892 PF-07284892 0 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
PF-07284892 PF 07284892|PF07284892|ARRY-558|ARRY 558|ARRY558 SHP2 Inhibitor 20 PF-07284892 is a small molecule inhibitor of SHP2 that may block MAPK signaling and lead to tumor growth inhibition (PMID: 37269335).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E colorectal cancer sensitive Binimetinib + Encorafenib + PF-07284892 Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of PF-07284892, Mektovi (binimetinib), and Braftovi (encorafenib) inhibited Erk phosphorylation in colorectal cancer cells harboring BRAF V600E in culture and induced tumor regression in a cell line xenograft model (PMID: 37269335). 37269335
EML4 - ALK lung non-small cell carcinoma sensitive Lorlatinib + PF-07284892 Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of PF-07284892 and Lorbrena (lorlatinib) inhibited Erk phosphorylation in non-small cell lung cancer cells harboring EML4-ALK that was resistant to Lorbrena (lorlatinib), and induced tumor regression in a cell line xenograft model (PMID: 37269335). 37269335
EML4 - ALK ALK G1202R lung non-small cell carcinoma predicted - sensitive Lorlatinib + PF-07284892 Case Reports/Case Series Actionable In a clinical case study, the combination of PF-07284892 and Lorbrena (lorlatinib) resulted in a partial response with a 50% tumor reduction after 6 weeks in a patient with non-small cell lung cancer harboring EML4-ALK and ALK G1202R, and the patient remained on the combination for 4.5 months (PMID: 37269335; NCT04800822). 37269335
BRAF V600E colorectal cancer predicted - sensitive Cetuximab + Encorafenib + PF-07284892 Case Reports/Case Series Actionable In a clinical case study, the combination of PF-07284892, Erbitux (cetuximab), and Braftovi (encorafenib) resulted in a 30% tumor reduction in a colorectal cancer patient harboring BRAF V600E, who remained on treatment for 6 months, and the combination inhibited tumor growth in a cell line xenograft model (PMID: 37269335; NCT04800822). 37269335