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Ref Type Journal Article
PMID (39269178)
Authors Lin JJ, Horan JC, Tangpeerachaikul A, Swalduz A, Valdivia A, Johnson ML, Besse B, Camidge DR, Fujino T, Yoda S, Nguyen-Phuong L, Mizuta H, Bigot L, Nobre C, Lee JB, Yu MR, Mente S, Sun Y, Kohl NE, Porter JR, Shair MD, Zhu VW, Felip E, Cho BC, Friboulet L, Hata AN, Pelish HE, Drilon A
Title NVL-655 Is a Selective and Brain-Penetrant Inhibitor of Diverse ALK-Mutant Oncoproteins, Including Lorlatinib-Resistant Compound Mutations.
Journal Vol Issue Date Pages Journal Short Title
Cancer discovery 2024 Sep 13 OF1-OF20 Cancer Discov
URL
Abstract Text Three generations of tyrosine kinase inhibitors (TKI) have been approved for anaplastic lymphoma kinase (ALK) fusion-positive non-small cell lung cancer. However, none address the combined need for broad resistance coverage, brain activity, and avoidance of clinically dose-limiting TRK inhibition. NVL-655 is a rationally designed TKI with >50-fold selectivity for ALK over 96% of the kinome tested. In vitro, NVL-655 inhibits diverse ALK fusions, activating alterations, and resistance mutations, showing ≥100-fold improved potency against ALKG1202R single and compound mutations over approved ALK TKIs. In vivo, it induces regression across 12 tumor models, including intracranial and patient-derived xenografts. NVL-655 inhibits ALK over TRK with 22-fold to >874-fold selectivity. These preclinical findings are supported by three case studies from an ongoing first-in-human phase I/II trial of NVL-655 which demonstrate preliminary proof-of-concept clinical activity in heavily pretreated patients with ALK fusion-positive non-small cell lung cancer, including in patients with brain metastases and single or compound ALK resistance mutations. Significance: By combining broad activity against single and compound ALK resistance mutations, brain penetrance, and selectivity, NVL-655 addresses key limitations of currently approved ALK inhibitors and has the potential to represent a distinct advancement as a fourth-generation inhibitor for patients with ALK-driven cancers.

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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
NVL-655 NVL-655 40 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
NVL-655 NVL655|NUV-655|NUV655 ALK Inhibitor 32 NVL-655 is a brain-penetrant inhibitor of ALK, with activity against ALK fusions and mutations, which may result in decreased cell growth and tumor regression (PMID: 39269178).
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
EML4 - ALK ALK I1171N ALK D1203N Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) did not inhibit viability of cells expressing EML4-ALK, ALK I1171N, and D1203N in culture (PMID: 39269178). 39269178
EML4 - ALK ALK G1202R lung non-small cell carcinoma predicted - sensitive NVL-655 Preclinical - Pdx & cell culture Actionable In a preclinical study, NVL-655 inhibited Alk signaling and growth in patient-derived non-small cell lung cancer cell lines harboring EML4-ALK and ALK G1202R in culture and decreased brain tumor growth and improved survival in a patient-derived intracranial xenograft model (PMID: 39269178). 39269178
EML4 - ALK ALK I1171S Advanced Solid Tumor predicted - sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 moderately inhibited viability of cells expressing EML4-ALK and ALK I1171S in culture (PMID: 39269178). 39269178
EML4 - ALK ALK G1202R Advanced Solid Tumor predicted - sensitive NVL-655 Preclinical Actionable In a preclinical study, NVL-655 inhibited viability of cells expressing EML4-ALK and ALK G1202R in culture and inhibited tumor growth in a transplant model (PMID: 39269178). 39269178
EML4 - ALK ALK E1210K Advanced Solid Tumor sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 inhibited viability of cells expressing EML4-ALK and ALK E1210K in culture (PMID: 39269178). 39269178
EML4 - ALK ALK L1196M ALK G1202R lung non-small cell carcinoma resistant Lorlatinib Preclinical - Patient cell culture Actionable In a preclinical study, a patient-derived non-small cell lung cancer cell line harboring EML4-ALK, ALK G1202R, and ALK L1196M was resistant to Lorbrena (lorlatinib) treatment in culture (PMID: 39269178). 39269178
EML4 - ALK ALK S1206F Advanced Solid Tumor sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 inhibited viability of cells expressing EML4-ALK and ALK S1206F in culture (PMID: 39269178). 39269178
EML4 - ALK ALK L1196M ALK G1202R lung non-small cell carcinoma resistant Brigatinib Preclinical - Patient cell culture Actionable In a preclinical study, a patient-derived non-small cell lung cancer cell line harboring EML4-ALK, ALK G1202R, and ALK L1196M was resistant to Alunbrig (brigatinib) treatment in culture (PMID: 39269178). 39269178
EML4 - ALK ALK L1196M ALK G1202R lung non-small cell carcinoma resistant Crizotinib Preclinical - Patient cell culture Actionable In a preclinical study, a patient-derived non-small cell lung cancer cell line harboring EML4-ALK, ALK G1202R, and ALK L1196M was resistant to Xalkori (crizotinib) treatment in culture (PMID: 39269178). 39269178
EML4 - ALK ALK I1171T Advanced Solid Tumor predicted - sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 moderately inhibited viability of cells expressing EML4-ALK and ALK I1171T in culture (PMID: 39269178). 39269178
EML4 - ALK ALK I1171N Advanced Solid Tumor predicted - sensitive NVL-655 Preclinical Actionable In a preclinical study, NVL-655 moderately inhibited viability cells expressing EML4-ALK and ALK I1171N in culture and inhibited tumor growth in a transplant model (PMID: 39269178). 39269178
EML4 - ALK ALK T1151M ALK G1202R Advanced Solid Tumor sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 inhibited viability of cells expressing EML4-ALK, ALK G1202R, and ALK T1151M in culture (PMID: 39269178). 39269178
EML4 - ALK ALK G1269A Advanced Solid Tumor predicted - sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 moderately inhibited viability of cells expressing EML4-ALK and ALK G1269A in culture (PMID: 39269178). 39269178
EML4 - ALK ALK S1206Y Advanced Solid Tumor sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 inhibited viability of cells expressing EML4-ALK and ALK S1206Y in culture (PMID: 39269178). 39269178
EML4 - ALK ALK L1198F Advanced Solid Tumor sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 inhibited viability of cells expressing EML4-ALK and ALK L1198F in culture (PMID: 39269178). 39269178
EML4 - ALK ALK T1151dup Advanced Solid Tumor sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 inhibited viability of cells expressing EML4-ALK and ALK T1151dup (reported as T1151insT) in culture (PMID: 39269178). 39269178
EML4 - ALK ALK T1151M ALK G1202R lung non-small cell carcinoma sensitive NVL-655 Preclinical - Pdx & cell culture Actionable In a preclinical study, NVL-655 inhibited Alk signaling and viability of a patient-derived non-small cell lung cancer cell line expressing EML4-ALK, ALK G1202R, and ALK T1151M in culture and induced tumor regression in a patient-derived xenograft (PDX) model (PMID: 39269178). 39269178
EML4 - ALK ALK I1171N ALK D1203N Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) did not inhibit viability of cells expressing EML4-ALK, ALK I1171N, and ALK D1203N in culture (PMID: 39269178). 39269178
EML4 - ALK ALK L1196M ALK G1202R Advanced Solid Tumor sensitive NVL-655 Preclinical Actionable In a preclinical study, NVL-655 inhibited viability of cells expressing EML4-ALK, ALK G1202R, and ALK L1196M in culture and induced tumor regression in a transplant model and decreased brain tumor volume and increased survival in an intracranial transplant model (PMID: 39269178). 39269178
EML4 - ALK ALK L1196Q Advanced Solid Tumor sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 inhibited viability of cells expressing EML4-ALK and ALK L1196Q in culture (PMID: 39269178). 39269178
ALK del exon2-3 ALK amp neuroblastoma sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 inhibited viability of an ALK-amplified neuroblastoma cell line harboring a deletion of ALK exons 2-3 in culture (PMID: 39269178). 39269178
EML4 - ALK ALK G1202R ALK G1269A Advanced Solid Tumor predicted - sensitive NVL-655 Preclinical Actionable In a preclinical study, NVL-655 inhibited viability of cells expressing EML4-ALK, ALK G1202R, and ALK G1269A in culture and induced tumor regression in a transplant model (PMID: 39269178). 39269178
EML4 - ALK lung non-small cell carcinoma sensitive NVL-655 Preclinical - Cell line xenograft Actionable In a preclinical study, NVL-655 inhibited growth of a patient-derived non-small cell lung cancer cell line harboring EML4-ALK in culture and inhibited growth of a cell line xenograft model (PMID: 39269178). 39269178
EML4 - ALK ALK V1180L Advanced Solid Tumor sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 inhibited viability of cells expressing EML4-ALK and ALK V1180L in culture (PMID: 39269178). 39269178
EML4 - ALK ALK I1171N ALK D1203N Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorbrena (lorlatinib) did not inhibit viability of cells expressing EML4-ALK, ALK I1171N, and ALK D1203N in culture (PMID: 39269178). 39269178
EML4 - ALK ALK L1196M ALK G1202R lung non-small cell carcinoma resistant Ceritinib Preclinical - Patient cell culture Actionable In a preclinical study, a patient-derived non-small cell lung cancer cell line harboring EML4-ALK, ALK G1202R, and ALK L1196M was resistant to Zykadia (ceritinib) treatment in culture (PMID: 39269178). 39269178
EML4 - ALK ALK L1196M Advanced Solid Tumor predicted - sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 moderately inhibited viability of cells expressing EML4-ALK and ALK L1196M in culture (PMID: 39269178). 39269178
EML4 - ALK ALK T1151M ALK G1202R lung non-small cell carcinoma resistant Ceritinib Preclinical - Patient cell culture Actionable In a preclinical study, a patient-derived non-small cell lung cancer cell line harboring EML4-ALK, ALK G1202R, and ALK T1151M was resistant to Zykadia (ceritinib) treatment in culture (PMID: 39269178). 39269178
EML4 - ALK ALK G1202del Advanced Solid Tumor sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 inhibited viability of cells expressing EML4-ALK and ALK G1202del in culture (PMID: 39269178). 39269178
EML4 - ALK ALK L1196M lung non-small cell carcinoma sensitive NVL-655 Preclinical - Patient cell culture Actionable In a preclinical study, NVL-655 inhibited Alk signaling and growth in a patient-derived non-small cell lung cancer cell line harboring EML4-ALK and ALK L1196M in culture (PMID: 39269178). 39269178
ALK del exon2-17 sarcoma sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 inhibited viability of a soft tissue sarcoma cell line harboring a deletion of ALK exons 2-17 in culture (PMID: 39269178). 39269178
EML4 - ALK ALK F1174L ALK G1202R Advanced Solid Tumor sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 inhibited viability of cells expressing EML4-ALK, ALK G1202R, and ALK F1174L in culture (PMID: 39269178). 39269178
EML4 - ALK ALK T1151M ALK G1202R lung non-small cell carcinoma resistant Lorlatinib Preclinical - Patient cell culture Actionable In a preclinical study, a patient-derived non-small cell lung cancer cell line harboring EML4-ALK, ALK G1202R, and ALK T1151M was resistant to Lorbrena (lorlatinib) treatment in culture (PMID: 39269178). 39269178
EML4 - ALK ALK L1196M ALK G1202R lung non-small cell carcinoma sensitive NVL-655 Preclinical - Pdx & cell culture Actionable In a preclinical study, NVL-655 inhibited Alk signaling and viability of a patient-derived non-small cell lung cancer cell line harboring EML4-ALK, ALK G1202R, and ALK L1196M in culture and induced tumor regression in a patient-derived xenograft (PDX) model and a cell line xenograft model (PMID: 39269178). 39269178
EML4 - ALK ALK T1151M ALK G1202R lung non-small cell carcinoma resistant Brigatinib Preclinical - Patient cell culture Actionable In a preclinical study, a patient-derived non-small cell lung cancer cell line harboring EML4-ALK, ALK G1202R, and ALK T1151M was resistant to Alunbrig (brigatinib) treatment in culture (PMID: 39269178). 39269178
EML4 - ALK ALK I1171N ALK D1203N Advanced Solid Tumor resistant NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 did not inhibit viability of cells expressing EML4-ALK, ALK I1171N, and ALK D1203N (PMID: 39269178). 39269178
EML4 - ALK ALK F1174C ALK G1202R lung adenocarcinoma sensitive NVL-655 Case Reports/Case Series Actionable In a Phase I trial (ALKOVE-1), NVL-655 treatment resulted in a partial response with treatment ongoing for at least 9 months in a patient with metastatic lung adenocarcinoma harboring EML4-ALK with ALK G1202R and F1174C in cis (PMID: 39269178; NCT05384626). 39269178
EML4 - ALK ALK I1171N ALK L1198F Advanced Solid Tumor predicted - sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 moderately inhibited viability of cells expressing EML4-ALK, ALK I1171N, and ALK L1198F in culture (PMID: 39269178). 39269178
EML4 - ALK ALK L1198F ALK G1202R Advanced Solid Tumor sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 inhibited viability of cells expressing EML4-ALK, ALK G1202R, and ALK L1198F in culture (PMID: 39269178). 39269178
EML4 - ALK ALK C1156Y Advanced Solid Tumor sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 inhibited viability of cells expressing EML4-ALK and ALK C1156Y in culture (PMID: 39269178). 39269178
EML4 - ALK ALK T1151M Advanced Solid Tumor sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 inhibited viability of cells expressing EML4-ALK and ALK T1151M in culture (PMID: 39269178). 39269178
EML4 - ALK ALK L1196M ALK G1202R lung non-small cell carcinoma resistant Alectinib Preclinical - Patient cell culture Actionable In a preclinical study, a patient-derived non-small cell lung cancer cell line harboring EML4-ALK, ALK G1202R, and ALK L1196M was resistant to Alecensa (alectinib) treatment in culture (PMID: 39269178). 39269178
EML4 - ALK ALK G1202R ALK G1269A lung adenocarcinoma predicted - sensitive NVL-655 Case Reports/Case Series Actionable In a Phase I trial (ALKOVE-1), NVL-655 treatment resulted in a partial response with treatment ongoing for at least 5 months in a patient with metastatic lung adenocarcinoma harboring EML4-ALK, ALK G1202R, and ALK G1269A (PMID: 39269178; NCT05384626). 39269178
EML4 - ALK lung adenocarcinoma sensitive NVL-655 Case Reports/Case Series Actionable In a Phase I trial (ALKOVE-1), NVL-655 treatment resulted in a complete response in the central nervous system metastases and an overall partial response with treatment ongoing for at least 9 months in a patient with metastatic lung adenocarcinoma harboring EML4-ALK (PMID: 39269178; NCT05384626). 39269178
EML4 - ALK Advanced Solid Tumor predicted - sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 inhibited viability of cells expressing EML4-ALK in culture (PMID: 39269178). 39269178
ALK F1174L neuroblastoma sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 inhibited viability of neuroblastoma cell lines harboring ALK F1174L in culture (PMID: 39269178). 39269178
EML4 - ALK ALK T1151M ALK G1202R lung non-small cell carcinoma resistant Alectinib Preclinical - Patient cell culture Actionable In a preclinical study, a patient-derived non-small cell lung cancer cell line harboring EML4-ALK, ALK G1202R, and ALK T1151M was resistant to Alecensa (alectinib) treatment in culture (PMID: 39269178). 39269178
EML4 - ALK ALK D1203N Advanced Solid Tumor predicted - sensitive NVL-655 Preclinical - Cell culture Actionable In a preclinical study, NVL-655 moderately inhibited viability of cells expressing EML4-ALK and ALK D1203N in culture (PMID: 39269178). 39269178
EML4 - ALK ALK I1171N ALK D1203N Advanced Solid Tumor resistant TPX-0131 Preclinical - Cell culture Actionable In a preclinical study, TPX-0131 did not inhibit viability of cells expressing EML4-ALK, ALK I1171N, and ALK D1203N in culture (PMID: 39269178). 39269178
EML4 - ALK ALK T1151M ALK G1202R lung non-small cell carcinoma resistant Crizotinib Preclinical - Patient cell culture Actionable In a preclinical study, a patient-derived non-small cell lung cancer cell line harboring EML4-ALK, ALK G1202R, and ALK T1151M was resistant to Xalkori (crizotinib) treatment in culture (PMID: 39269178). 39269178
EML4 - ALK ALK I1171N ALK D1203N Advanced Solid Tumor resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) did not inhibit viability of cells expressing EML4-ALK, ALK I1171N, and ALK D1203N in culture (PMID: 39269178). 39269178
EML4 - ALK ALK I1171N ALK D1203N Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, Alecensa (alectinib) did not inhibit viability of cells expressing EML4-ALK, ALK I1171N, and ALK D1203N in culture (PMID: 39269178). 39269178