Reference Detail

Ref Type

Journal Article

PMID

(34965951)

Authors

Toulmonde M, Brahmi M, Giraud A, Chakiba C, Bessede A, Kind M, Toulza E, Pulido M, Albert S, Guégan JP, Cousin S, Mathoulin-Pelissier S, Perret R, Croce S, Blay JY, Ray-Coquard I, Floquet A, Italiano A

Title

Trabectedin plus Durvalumab in Patients with Advanced Pretreated Soft Tissue Sarcoma and Ovarian Carcinoma (TRAMUNE): An Open-Label, Multicenter Phase Ib Study.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	28	9	2022 05 02	1765-1772	Clin Cancer Res

URL

Abstract Text

Trabectedin has shown preclinical synergy with immune checkpoint inhibitors in preclinical models.TRAMUNE is a phase Ib study investigating the combination of trabectedin with durvalumab through a dose escalation phase and two expansion cohorts, soft tissue sarcoma (STS) and ovarian carcinoma. Trabectedin was given at three dose levels (1 mg/m2, 1.2 mg/m2, and 1.5 mg/m2) on day 1, in combination with durvalumab, 1,120 mg on day 2, every 3 weeks. The primary endpoints were the recommended phase II dose (RP2D) of trabectedin combined with durvalumab and the objective response rate (ORR) as per RECIST 1.1. The secondary endpoints included safety, 6-month progression-free rate (PFR), progression-free survival (PFS), overall survival, and biomarker analyses.A total of 40 patients were included (dose escalation, n = 9; STS cohort, n = 16; ovarian carcinoma cohort, n = 15, 80% platinum resistant/refractory). The most frequent toxicities were grade 1-2 fatigue, nausea, neutropenia, and alanine/aspartate aminotransferase increase. One patient experienced a dose-limiting toxicity at dose level 2. Trabectedin at 1.2 mg/m2 was selected as the RP2D. In the STS cohort, 43% of patients experienced tumor shrinkage, the ORR was 7% [95% confidence interval (CI), 0.2-33.9], and the 6-month PFR was 28.6% (95% CI, 8.4-58.1). In the ovarian carcinoma cohort, 43% of patients experienced tumor shrinkage, the ORR was 21.4% (95% CI, 4.7-50.8), and the 6-month PFR was 42.9% (95% CI, 17.7-71.1). Baseline levels of programmed death-ligand 1 expression and CD8-positive T-cell infiltrates were associated with PFS in patients with ovarian carcinoma.Combining trabectedin and durvalumab is manageable. Promising activity is observed in patients with platinum-refractory ovarian carcinoma. See related commentary by Digklia et al., p. 1745.

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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
CD274 positive	ovarian carcinoma	predicted - sensitive	Durvalumab + Trabectedin	Case Reports/Case Series	Actionable	In a Phase Ib trial (TRAMUNE), Yondelis (trabectedin) plus Imfinzi (durvalumab) demonstrated safety and resulted in an objective response rate of 21.4% (3/14, all partial responses), 3- and 6-month progression-free rates of 42.9% and 42.9%, a 1-year progression-free survival (PFS) rate of 7.1%, and a 1-year overall survival rate of 57.1% in patients with ovarian carcinoma, with an improved PFS for patients with CD274 (PD-L1) expression (6.8 mo vs 1.3 mo) (PMID: 34965951; NCT03085225).	34965951