Reference Detail

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
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
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
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