Abstract P239: Safety and efficacy of copanlisib in combination with nivolumab: A phase Ib study in patients with advanced solid tumors
Notice bibliographique
Résumé
Abstract Introduction: Copanlisib (C) is a pan-class I PI3K inhibitor, with predominant activity against the PI3K-α and -δ isoforms, approved for patients (pts) with relapsed follicular lymphoma. The PD-1 inhibitor nivolumab (N) is approved for several advanced or metastatic solid tumors. Following preclinical demonstration of the immunomodulatory activity of C (Glaeske et al. AACR 2018), we report Phase Ib results evaluating the safety and efficacy of C+N in pts with advanced solid tumors (NCT03735628). Methods: PD-1 inhibitor-naive adult pts with advanced solid tumors received C 45 mg or 60 mg i.v. (days 1, 8, and 15; 28-day cycle) and N 240 mg (day 15 of cycle 1 and days 1 and 15 of subsequent cycles). The primary objective was determination of the recommended Phase II dose (RP2D) of C in combination with N. Secondary endpoints were safety/tolerability, pharmacokinetics (PK), and efficacy. Exploratory real-time evaluation of 77 pharmacodynamic and predictive immune cell biomarkers by flow cytometry on whole blood was performed. Results: 16 pts were treated (C 45 mg + N 240 mg, n=5; C 60 mg + N 240 mg, n=11). Median age was 65 years (range 37–89), 12 pts (75%) were male, and 8 pts (50%) had stage IV disease at diagnosis; the most common tumor types were head and neck squamous cell carcinoma (HNSCC; 7 pts) and bladder cancer (BC; 4 pts). No dose-limiting toxicities were reported. The RP2D of C+N 240 mg was 60 mg. As of 13 May 2020, 4 pts remain on treatment. The most common treatment-emergent adverse events (TEAEs) of any grade were hypertension and diarrhea (7 pts [44%] each, ≤ grade [G] 3) and maculo-papular rash and fatigue (6 pts [38%] each, ≤G3). C-related TEAEs were reported in 88% of pts, all ≤G3. AEs leading to C dose interruption/reduction were reported in 31%/19% of pts; TEAEs led to C discontinuation in 1 pt (60 mg; hematuria). Serious AEs occurred in 5 pts (31%). One G5 TEAE occurred (45 mg; general physical health deterioration, unrelated to C or N). No PK interactions were observed between C and N. Two pts had a partial response: 1 in the C 45 mg group (HNSCC) and 1 in the 60 mg group (BC; benefit sustained after 19 cycles). Stable disease was seen in 10 pts and disease progression in 3 pts; disease control rate (DCR) was 75%. Maximum decrease in circulating monocytic myeloid-derived suppressor cells (M-MDSCs; p<0.05) from baseline occurred on day 2 after C, returning to baseline on day 8. A significant increase in activated (HLA-DR+ and CD38+) natural killer and CD8+ T cells was seen 2 weeks post-treatment with C+N. Lower baseline levels of CD8+ Teffector memory (TEM) subset CD45RA-/CCR7- (CD3+/CD8+) seemed to associate with higher DCR. Conclusions: C+N showed acceptable safety and preliminary efficacy in pts with advanced solid tumors. The immunomodulatory effect of C on M-MDSCs was seen 2 days post-treatment, and lower TEM subset levels seemed to associate with better disease control. These results support further investigation of C+N in pts with advanced solid tumors. Funding: Bayer AG. Writing support: Complete HealthVizion. Citation Format: Benedito A. Carneiro, Robert Jotte, Nashat Gabrail, Omid Hamid, Funan Huang, Shalini Chaturvedi, Matthias Herpers, Lidia Mongay Soler, Barrett H. Childs, Aaron Hansen. Safety and efficacy of copanlisib in combination with nivolumab: A phase Ib study in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P239.
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 | 0,001 |
| 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 ».