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Ref Type Abstract
PMID
Authors T. Fujino L. Nguyen S. Yoda M. Yu H. Mizuta L. Bigot C. Nobre A. Tangpeerachaikul H.E. Pelish L. Friboulet J. Lee B. Cho A.N. Hata
Title Preclinical activity of NVL-655 in patient-derived models of ALK cancers, including those with lorlatinib-resistant G1202R/L1196M compound mutation
URL https://www.ejcancer.com/article/S0959-8049(22)01008-5/fulltext
Abstract Text Introduction: Five tyrosine kinase inhibitors (TKIs) have been approved for treatment of ALK-positive non-small cell lung cancer (NSCLC), including first- (crizotinib), second- (ceritinib, alectinib, and brigatinib), and third-(lorlatinib) generation therapies. Durability of response is limited partly by emergence of ALK resistance mutations. The most frequent ALK mutations after relapse on first- and second-generation ALK TKIs are L1196M and G1202R, respectively, together representing 20–40% of resistance cases. ALK G1202R tumors treated with lorlatinib have relapsed by acquiring compound mutations such as G1202R/L1196M and G1202R/T1151M, which confer resistance to all approved ALK TKIs. To address this medical need, we reported the discovery of NVL-655: a brain-penetrant TKI that selectively inhibits ALK and ALK resistance mutants over TRKB. Avoiding TRKB is advantageous as its inhibition has been linked to neurological adverse events and dose-limiting toxicities. Here we demonstrate the preclinical activity of NVL-655 in patient-derived models, including from patients who progressed on prior ALK TKIs. Methods: EML4-ALK fusion cell lines were established from NSCLC patients: MGH026-1, MGH048-1, and MGH064-1 (treatment-naïve); MGH045-1 (L1196M post-crizotinib); MGH953-4 and YU-1077 (G1202R post-alectinib); MGH9037-2 (G1202R post-brigatinib); MGH953-7 (G1202R/ L1196M post-lorlatinib); and MR448re (G1202R/T1151M post-lorlatinib). Murine xenografts were generated from YU-1077 tumors, MR619 cholangiocarcinoma tumors (STRN-ALK G1202R post-alectinib); MGH953-7 tumors; and MR448re cell line. Results: NVL-655 and lorlatinib had similar potency against cancer cell lines derived from treatment-naïve ALK patients (IC50 <5 nM). However, only NVL-655 retained high activity (IC50 ∼1 nM) against ALK G1202R cell lines derived from alectinib- or brigatinib-relapsed patients, showing substantially improved potency compared to second-generation ALK TKIs or lorlatinib (IC50 ∼35 nM–1.5 μM). ALK G1202R/L1196M and ALK G1202R/T1151M cell lines derived from lorlatinib-relapsed patients were indeed resistant to lorlatinib (IC50 >400 nM) but highly sensitive to NVL-655 (IC50 <5 nM). Western blot analysis confirmed on-target engagement and inhibition of pathway signaling. Consistent with in vitro results, NVL-655 induced regression in ALK G1202R, G1202R/L1196M, and G1202R/T1151M xenografts derived from patient tumors. Conclusion: Patient-derived cells and xenografts are among the most disease-relevant preclinical models for evaluating new therapies and drug resistance. NVL-655 showed activity in diverse patient-derived models of ALK-positive cancers, including ones that exhibited clinical resistance to prior-generation ALK TKIs. The broad preclinical activity of NVL-655 suggests potential utility as a best-in-class therapy for ALK-positive cancer patients.

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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
Drug Name Trade Name Synonyms Drug Classes Drug Description
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 G1202R lung non-small cell carcinoma predicted - sensitive NUV-655 Preclinical - Pdx & cell culture Actionable In a preclinical study, NUV-655 demonstrated activity in a patient-derived non-small cell lung cancer cell line harboring EML4-ALK with ALK G1202R in culture and induced tumor regression in a patient-derived xenograft (PDX) model (Eur J Cancer 2022 Vol 174, Supp 1:S78-S79). detail...
EML4 - ALK ALK T1151M ALK G1202R lung non-small cell carcinoma predicted - sensitive NUV-655 Preclinical - Pdx & cell culture Actionable In a preclinical study, NUV-655 demonstrated activity in a patient-derived non-small cell lung cancer cell line harboring EML4-ALK with ALK G1202R and ALK T1151M in culture and induced tumor regression in a patient-derived xenograft (PDX) model (Eur J Cancer 2022 Vol 174, Supp 1:S78-S79). detail...
EML4 - ALK ALK L1196M ALK G1202R lung non-small cell carcinoma predicted - sensitive NUV-655 Preclinical - Pdx & cell culture Actionable In a preclinical study, NUV-655 demonstrated activity in a patient-derived non-small cell lung cancer cell line harboring EML4-ALK with ALK G1202R and ALK L1196M in culture and induced tumor regression in a patient-derived xenograft (PDX) model (Eur J Cancer 2022 Vol 174, Supp 1:S78-S79). detail...