Dose expansion data from iintune-1, a phase 1/2 study of the STING agonist dazostinag plus pembrolizumab as first-line (1L), in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (RM-SCCHN).
Notice bibliographique
Résumé
6020 Background: Checkpoint inhibitors (CPIs) such as pembrolizumab (pembro) can lead to improved outcomes and durable responses in patients (pts) with RM-SCCHN. However, only a subset of pts with RM-SCCHN experience this benefit, and an unmet need for better treatments remains. STimulator of INterferon Genes (STING) agonism enhanced the response to CPIs preclinically. Dazostinag (dazo) is a small molecule STING agonist that has shown antitumor activity and activation of innate and adaptive immune responses in pts with solid tumors in the dose escalation part of iintune-1, with a recommended dose for expansion of 5 mg in combination with pembro. We report data from the ongoing dose expansion cohort 2A of iintune-1 in the first 30 pts with incurable 1L RM-SCCHN with a PD-L1 combined positive score (CPS) ≥1, treated with dazo in combination with pembro (NCT04420884). Methods: Pts receive dazo 5 mg IV on Days 1, 8, 15 plus pembro 200 mg IV on Day 1, in 21-day cycles. Primary endpoints are safety and tolerability. Secondary endpoints include investigator-assessed overall response rate (ORR) per RECIST 1.1 and duration of response (DOR). Dose optimization is planned as part of expansion. Results: As of Dec 16, 2024, 30 pts had been enrolled and received treatment. Median age was 64 years and 73% of pts were male. The most common primary tumor locations were oral cavity (n=10, 33%), oropharynx (n=8, 27%), and larynx (n=6, 20%). Median CPS score was 13.5 (range, 1–101). A median of 4.5 treatment cycles (range 1–15) were received. Treatment-emergent adverse events (TEAEs) occurred in all pts (grade ≥3 in 37%); the most common were fatigue (40%), nausea (27%), cough (23%), and headache (20%). Dazo-related TEAEs occurred in 80% of pts (grade ≥3 in 13%); the most common was fatigue (30%). Cytokine release syndrome was reported in 4 pts (13%; all dazo-related and grade 1–2). TEAEs led to dazo discontinuation in 1 pt. No treatment-related deaths were reported. Among 29 response-evaluable pts, 1 had a confirmed complete response and 7 had confirmed partial responses (+2 unconfirmed), for an ORR of 34%. Median DOR was not reached. Pharmacodynamic analyses revealed biomarker changes consistent with the expected mechanism of action and dose escalation data, including induction of a STING gene signature, cytokine induction, peripheral immune cell activation and CD8+ T cell recruitment to the tumor. Analyses of changes in peripheral ctDNA pre- and post-treatment are ongoing. Conclusions: This early study of dazo 5 mg IV in combination with pembro showed a manageable safety profile with an encouraging ORR in pts with RM-SCCHN. Pharmacodynamic findings demonstrate peripheral and intratumor changes consistent with STING agonism. Clinical trial information: NCT04420884 .
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,003 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».