Reference Detail

Ref Type

Journal Article

PMID

(26144315)

Authors

Zou HY, Friboulet L, Kodack DP, Engstrom LD, Li Q, West M, Tang RW, Wang H, Tsaparikos K, Wang J, Timofeevski S, Katayama R, Dinh DM, Lam H, Lam JL, Yamazaki S, Hu W, Patel B, Bezwada D, Frias RL, Lifshits E, Mahmood S, Gainor JF, Affolter T, Lappin PB, Gukasyan H, Lee N, Deng S, Jain RK, Johnson TW, Shaw AT, Fantin VR, Smeal T

Title

PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer cell	28	1	2015 Jul 13	70-81	Cancer Cell

URL

Abstract Text

We report the preclinical evaluation of PF-06463922, a potent and brain-penetrant ALK/ROS1 inhibitor. Compared with other clinically available ALK inhibitors, PF-06463922 displayed superior potency against all known clinically acquired ALK mutations, including the highly resistant G1202R mutant. Furthermore, PF-06463922 treatment led to regression of EML4-ALK-driven brain metastases, leading to prolonged mouse survival, in a superior manner. Finally, PF-06463922 demonstrated high selectivity and safety margins in a variety of preclinical studies. These results suggest that PF-06463922 will be highly effective for the treatment of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors because of secondary ALK kinase domain mutations and/or brain metastases.

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Showing 1 to 7 of 7 entries

Molecular Profile	Treatment Approach
EML4 - ALK ALK F1174L	Lorlatinib
EML4 - ALK ALK G1269A	Lorlatinib
EML4 - ALK ALK I1171T	Lorlatinib
EML4 - ALK ALK L1152R	Lorlatinib
EML4 - ALK ALK L1196M	Lorlatinib
EML4 - ALK ALK S1206Y	Lorlatinib
EML4 - ALK ALK V1180L	Lorlatinib

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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Lorlatinib	Lorlatinib	285	18

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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Lorlatinib	Lorbrena	PF-06463922\|Lorviqua	ALK Inhibitor 33 ROS1 Inhibitor 23	Lorbrena (lorlatinib) is a small molecule inhibitor of Alk and Ros1 fusion proteins, which may result in suppression of Alk and Ros1-mediated signaling thereby inhibiting cell growth and causing tumor regression (PMID: 26144315). Lorbrena (lorlatinib) is FDA approved for use in patients with ALK-positive non-small cell lung cancer (FDA.gov).

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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
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Showing 1 to 9 of 9 entries

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4 - ALK	lung non-small cell carcinoma	sensitive	Lorlatinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Lorbrena (lorlatinib) inhibited Alk phosphorylation and proliferation of non-small cell lung carcinoma cells harboring EML4-ALK fusion, and reduced intracranial tumor size in cell line xenograft models (PMID: 26144315).	26144315
EML4 - ALK ALK G1202R	lung cancer	conflicting	Lorlatinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Lorbrena (lorlatinib) inhibited Alk phosphorylation, reduced proliferation, and induced apoptosis in transformed cells over expressing ALK G1202R in the context of EML4-ALK in culture and in cell line xenograft models (PMID: 26144315).	26144315
EML4 - ALK ALK L1196M	lung non-small cell carcinoma	sensitive	Lorlatinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Lorbrena (lorlatinib) inhibited Alk phosphorylation and proliferation of non-small cell lung carcinoma cells over expressing ALK L1196M in the context of EML4-ALK in culture, and resulted in tumor regression in cell line xenograft models (PMID: 26144315).	26144315
EML4 - ALK ALK G1269A	lung non-small cell carcinoma	sensitive	Lorlatinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, Lorbrena (lorlatinib) inhibited Alk phosphorylation and growth of non-small cell lung cancer (NSCLC) cells over expressing ALK G1269A in the context of EML4-ALK in culture and in cell line xenograft models, as well as inhibited growth of patient derived NSCLC cells harboring EML4-ALK ALK G1269A in culture (PMID: 26144315).	26144315
EML4 - ALK ALK I1171T	lung non-small cell carcinoma	sensitive	Lorlatinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, Lorbrena (lorlatinib) inhibited Alk phosphorylation and cell growth in patient derived non-small cell lung cancer cells harboring ALK I1171T in the context of EML4-ALK in culture (PMID: 26144315).	26144315
EML4 - ALK ALK F1174L	Advanced Solid Tumor	sensitive	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Lorbrena (lorlatinib) inhibited Alk phosphorylation and cell proliferation of transformed cells over expressing ALK F1174L in the context of EML4-ALK in culture (PMID: 26144315).	26144315
EML4 - ALK ALK L1152R	Advanced Solid Tumor	sensitive	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Lorbrena (lorlatinib) inhibited Alk phosphorylation and cell proliferation of transformed cells over expressing ALK L1152R in the context of EML4-ALK in culture (PMID: 26144315).	26144315
EML4 - ALK ALK S1206Y	Advanced Solid Tumor	sensitive	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Lorbrena (lorlatinib) inhibited Alk phosphorylation and cell proliferation of transformed cells over expressing ALK S1206Y in the context of EML4-ALK in culture (PMID: 26144315).	26144315
EML4 - ALK ALK V1180L	lung non-small cell carcinoma	sensitive	Lorlatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Lorbrena (lorlatinib) inhibited Alk phosphorylation, reduced proliferation, and induced apoptosis of non-small cell lung carcinoma cells harboring ALK V1180L in the context of EML4-ALK in culture (PMID: 26144315).	26144315

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