Safety and preliminary clinical activity of NVL-520, a highly selective ROS1 inhibitor, in patients with advanced ROS1 fusion-positive solid tumors

Background: Oncogenic ROS1 fusions drive various malignancies, including 1–3% of non-small cell lung cancers (NSCLC). Rationally designed ROS1 tyrosine kinase inhibitors (TKIs) that surpass the limitations of FDA/ EMA-approved (crizotinib/entrectinib) or other investigational agents are a medical need. The novel ROS1 TKI NVL-520 is highly selective and designed to avoid the neurologic toxicities associated with ROS1 TKIs that concurrently inhibit TRK (entrectinib/repotrectinib/taletrectinib). Furthermore, NVL-520 is brain-penetrant and targets a diverse array of ROS1 fusions and recalcitrant resistance mutations, including the ROS1 G2032R solvent-front mutation.

Materials and Methods: ARROS-1 (NCT05118789) is a global, tumor-agnostic, phase 1/2 trial of NVL-520. In the ongoing phase 1 dose escalation, patients are required to have a previously treated ROS1 fusion-positive solid tumor, including NSCLC treated with ≥1 prior ROS1 TKI. Primary objectives are to determine the recommended phase 2 dose (RP2D) and, if applicable, the maximum tolerated dose. Additional objectives include safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity. Response (RECIST v1.1) was investigator assessed. Data cut: June 13, 2022.

Results: Twenty patients (19 NSCLC, 1 pancreatic cancer) have received NVL-520 orally at dose levels of 25–100 mg once daily. Patients received a median of 3 (range: 1–9) prior anticancer therapies, including any ROS1 TKI (100%); investigational ROS1 TKI (85%, including lorlatinib in 55%, repotrectinib in 40%); ≥2 ROS1 TKIs (75%); any chemotherapy (80%); ≥2 lines of chemotherapy (50%). At baseline, 55% had CNS metastases and 45% had ROS1 G2032R. No dose-limiting toxicities (DLTs), dose reductions, or drug-related treatment discontinuations have been reported. All treatment-related adverse events (TRAEs) were grade 1. The only TRAE in >1 patient was nausea (n = 2). NVL-520 PK analyses demonstrated dose-dependent exposure. Among 12 efficacy-evaluable patients with ROS1 + NSCLC treated at 25–75 mg QD, 6 confirmed partial responses (PRs) were achieved. Shrinkage or resolution of intracranial metastases were observed; no patients had intracranial progression. A PR was achieved in most (n = 5/7) ROS1 G2032R-mutant cancers, including lorlatinib or repotrectinib pretreated tumors. Circulating tumor DNA analyses showed reductions of ROS1 variant allele frequency. The RP2D has not been identified and dose escalation continues.

Conclusions: NVL-520 has been well-tolerated up to 100 mg daily with favorable pharmacokinetics. Activity has been demonstrated in heavily pretreated patients (of whom 70% received ≥2 prior ROS1 TKIs plus chemotherapy), including those with brain metastases and the G2032R mutation.

Ownership: Treeline Bio (AD) Nuvalent (JG, JS, YS, VZ) Turning Point Therapeutics, Elevation Oncology (SO).

Advisory Board: Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/ Millenium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, Abbvie, 14ner/Elevation Oncology, ArcherDX, Monopteros, Novartis, EMD Serono, Medendi, Repare RX, Nuvalent, Merus, Chugai Pharmaceutical, Remedica Ltd, mBrace, AXIS, EPG Health, Harborside Nexus, Liberum, RV More, Ology, Amgen, TouchIME, Janssen, Entos, Treeline Bio, Prelude, Applied Pharmaceutical Science, Inc, AiCME, i3 Health, MonteRosa (AD).

Amgen, Astra Zeneca, Bayer, Bristol-Myers Squibb, Daichii Sankyo, Eli Lilly, F. Hoffmann-La Roche, Glaxo Smith Kline, Janssen, Merck Sharp & Dohme, Merck Serono, Novartis, Peptomyc, Pfizer, Sanofi, Takeda (EF) Genentech/ Roche, Pfizer (SG) AbbVie, Amgen, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Checkpoint Therapeutics, CytomX Therapeutics, Daiichi Sankyo, EcoR1, Editas Medicine, Eisai, EMD Serono, G1 Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Ideaya Biosciences, iTeos, Janssen, Lilly, Merck, Mirati Therapeutics, Novartis, Oncorus, Regeneron Pharmaceuticals, Revolution Medicines, Ribon Therapeutics, Sanofi-Aventis, Turning Point Therapeutics, VBL Therapeutics, WindMIL (MJ) Pfizer, Nuvalent, C4 Therapeutics, Turning Point Therapeutics, Elevation Oncology, Novartis, Mirati Therapeutics, Bayer, Genentech, Blueprint Medicines (JL) Syneos health, cell therapy program (MM) Elevation Oncology (SO).

Board of Directors: Grífols (EF).

Corporate-sponsored Research: Pfizer, Exelixis, GlaxoSmithKlein, Teva, Taiho, PharmaMar (AD) 4D Pharma, Abbvie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Chugai p harmaceutical, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, EISAI, Genzyme Corporation, GSK, Inivata, IPSEN, Janssen, Onxeo, OSE immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals, Turning Point Therapeutics (BB) Nuvalent (RC, GL, AS) Merck Healthcare KGAa, Fundación Merck Salud (EF) AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Boehringer Ingelheim, Calithera Biosciences, Checkpoint Therapeutics, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Pfizer, PMV Pharmaceuticals, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL, Y-mAbs Therapeutics (MJ) Hengrui Therapeutics, Turning Point Therapeutics, Novartis, Neon Therapeutics, Bayer, Roche/Genentech, Pfizer, Elevation Oncology, Relay Therapeutics, Linnaeus Therapeutics, Nuvalent (JL) Roche, Novartis, MSD, Pharmamar, Cytomex, Abbvie, Achilles, Astra Zeneca, Basilea, Bayer, Biontech, Catalym, Dizal, Fameway, Genentech, Janssen, Menarini, Regeneron and Seattle (MM) Pfizer, Daiichi Sankyo, Revolution Medicine, Merus, Roche, Mirati, BluePrint Medicines, JNJ/Jassen (SO).

Other Substantive Relationships: Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis, Peerview Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences, Med Learning, Imedex, Answers in CME, Clinical Care Options, EPG Health, JNCC/Harborside, Liberum, Remedica Ltd., Wolters Kluwer, Merck, Puma, Merus, Boehringer Ingelheim, Astra Zeneca, Eli Lilly (AD).

Amgen, Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Janssen, Medscape, Merck Sharp & Dohme, PeerVoice, Pfizer, Medical

Trends, Merck Serono, Sanofi, Takeda, TouchONCOLOGY (EF) Pfizer, OncLive, Northwell Health, Medstar Health (JL) JNJ/Jassen, BeiGene, Pfizer, Lilly, DAVA Oncology LLP, Caris Life Science (SO).