Abstract B154: Safety and preliminary activity of the selective ALK inhibitor NVL-655 in patients with ALK fusion-positive solid tumors
Notice bibliographique
Résumé
Abstract Background: Oncogenic ALK alterations drive diverse tumor types, including ALK fusions in 3-5% of non-small cell lung cancers (NSCLCs). While 3 generations (1G, 2G, 3G) of ALK tyrosine kinase inhibitors (TKIs) are approved globally for ALK fusion-positive (ALK+) NSCLC, they are limited by acquired ALK resistance mutations, CNS relapses, and for the 3G TKI lorlatinib, neurologic adverse events attributed to off-target TRK inhibition. A rationally designed ALK TKI that overcomes these limitations is needed. Preclinically, NVL-655 is a brain-penetrant, ALK-selective, and TRK-sparing TKI that exhibits activity against diverse ALK fusions and resistance mutations, including lorlatinib-refractory compound mutations. Materials and Methods: ALKOVE-1 (NCT05384626) is a global phase 1/2 trial of NVL-655. The ongoing phase 1 dose escalation enrolls patients (pts) with a previously treated ALK+ solid tumor, including NSCLC treated with ≥1 prior 2G or 3G ALK TKI. Primary objectives are to determine the safety/tolerability, recommended phase 2 dose (RP2D), and if applicable, the maximum tolerated dose (MTD). Additional objectives include assessments of pharmacokinetics (PK), pharmacodynamics, and preliminary activity by investigator-assessed tumor response (RECIST v1.1). Data cut: June 12, 2023. Results: 57 pts (54 NSCLC, 3 other solid tumors) received NVL-655 orally at 15-200 mg once daily (QD). Pts previously received a median of 4 (range: 1-8) prior anticancer therapies, including a 2G or 3G ALK TKI (100%); ≥1 2G ALK TKI + lorlatinib (77%); ≥3 ALK TKIs (53%); and chemotherapy (60%). At baseline, 51% had a history of CNS metastases. 47% had known ALK resistance mutations and 32% had compound ALK mutations, as per available local testing or central analyses of baseline circulating tumor DNA (ctDNA). Treatment-related adverse events (TRAEs) were generally mild; most frequent were nausea (12%), transaminase elevation (12%), fatigue (9%), and constipation (7%). Grade ≥3 TRAEs were transaminase elevation (n=2), CPK elevation (n=1), and fatigue (n=1). NVL-655 PK analyses demonstrated dose-proportional exposure. Partial responses (PR) were observed in 45% (15/33; 8 pending confirmation) of efficacy-evaluable pts with ALK+ NSCLC (15-150 mg QD), in 65% (11/17) with baseline ALK resistance mutations, and in 41% (12/29) post-lorlatinib, including cases with compound resistance mutations. CNS activity, including complete resolution of CNS metastases, has been observed. ctDNA analyses showed reductions, including clearance, of ALK fusion and mutation variants. Neither the MTD nor RP2D has been identified; phase 1 continues. Conclusions: NVL-655 has been well-tolerated up to 200 mg daily with favorable PK. Preliminary activity has been demonstrated in heavily pretreated pts with ALK+ NSCLC, including those who previously received 2G ALK TKI(s) + lorlatinib, with brain metastases, or with single/compound ALK resistance mutations. Citation Format: Jessica J Lin, Melissa Johnson, Enriqueta Felip, Sai-Hong Ignatius Ou, Benjamin Besse, Christina Baik, Julien Mazieres, Yasir Elamin, Joshua E. Reuss, Anna Minchom, Aurelie Swalduz, Nick Pavlakis, Geoffrey Liu, Shirish Gadgeel, D. Ross Camidge, Jennifer A Green, Junwu Shen, John Soglia, Yuting Sun, Viola W Zhu, Alexander Drilon. Safety and preliminary activity of the selective ALK inhibitor NVL-655 in patients with ALK fusion-positive solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B154.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».