Trabectedin/Durvalumab Shows Early Activity, Demonstrates Feasibility for Soft Tissue Sarcoma

The feasibility of treatment with trabectedin (Yondelis) in combination with durvalumab (Imfinzi) as treatment of patients with advanced or metastatic pretreated soft tissue sarcoma (STS) was demonstrated in the phase 1b TRAMUNE trial (NCT03085225). The combination demonstrated preliminary activity in an unselected group of patients with miscellaneous STS, as reported in a presentation during the 2020 European Society of Medical Oncology (ESMO) Virtual Congress.

Maud Toulmonde, MD, PhD, of the Insitut Bergonie in Bordeaux, France, who presented the data, explained that preclinical research suggested that trabectedin activity may be mediated in part by targeting tumor-associated macrophages. In addition, immune checkpoint inhibitors, namely anti–PD-1/PD-L1 agents, have already demonstrated activity in patients with STS, as well as in ovarian cancer. These preclinical findings served as rationale for using the chemotherapy agent trabectedin in combination with the PD-L1 inhibitor, durvalumab.

A total of 40 patients were enrolled in the study between the dose-escalation and expansion phases and assessed for the coprimary end points of safety, defined by the number of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD), as well as preliminary efficacy, defined by objective response to treatment. The secondary end points included objective response rate (ORR), the 6-month progression-free survival (PFS) rate, PFS per RECIST v1.1 criteria, and overall survival. An exploratory analysis of immune biomarker activity with the combination on serial liquid biopsies metabolomics on plasma sample were also evaluated.

In the dose-escalation phase of the study, 9 patients were included in the cohort and assessed for safety. Dosing for trabectedin started at 1 mg/m² and was elevated to 1.2 mg/m² and then 1.5 mg/m². The expansion cohorts of TRAMUNE were comprised of 16 patients with STS and 15 with ovarian cancer. Thirty of these patients were evaluated for safety, and 14 patients from each cohort were evaluated for preliminary efficacy.

Baseline characteristics showed a median patient age of 55 years (range, 40-70) in the dose-escalation cohort and 57 years (range, 25-75) in the STS expansion cohort. The patient population was predominantly female (68%), including 7 women in the dose-escalation cohort and 10 in the dose-expansion cohort. The majority of patients had an ECOG performance status of 0 (68%). In terms of histology among the patients with STS, the dose-escalation cohort had an even number of patients from each histology, but in the dose-expansion cohort, 6 patients had leiomyosarcoma, 8 were identified as having other STS tumor types, and 2 had dedifferentiated liposarcoma. Patients in the dose-escalation phase had received a median of 3 prior lines of therapy and 1 prior line in the dose-expansion cohort.

Only 1 DLT was observed at the level 2 dose from the dose-escalation phase of the study. The DLT was grade 4 hepatic cytolysis and was observed on day 8 of cycle 1, but the toxicity was

resolved to grade 2 after 7 days and grade 1 after 9 days. The dose-expansion phase identified the MTD of trabectedin to be 1.2 mg/m² given over 3 hours on day 1 of each cycle plus 1120 mg of durvalumab on day 2 every 3 weeks.

Most of the adverse events (AEs) that patients experienced in the dose-escalation phase were grade 1 or 2 in severity. The most common were fatigue, gastrointestinal disorder, and biological toxicities like cytopenia and hepatic cytolysis. Five serious AEs were also observed in this cohort, which included grade 3 infusion device infection in 1 patient, grade 3 heart dysfunction in 1, grade 4 neutropenia in 1, and grade 4 hepatic cytolysis in 2 patients.

“Of note, patients with cardiac dysfunction had STS with 3 prior lines [of therapy] on anthracyclines and antiandrogens,” Toulmonde stated in explanation of the dose-escalation safety results.

In terms of efficacy assessed in the STS dose-expansion cohort, tumor shrinkage occurred in 6 patients (43%), which resulted in 1 partial response to treatment. The ORR was 7.1% (95% CI, 0.2%-33.9%). Fifty-seven percent of patients had stable disease on treatment with trabectedin plus durvalumab, and 29% had progressive disease. Only 1 patient was not evaluable for response.

At a median follow-up of 10.7 months (95% CI, 3.1-13.5), the 6-month PFS rate was 28.6% (95% CI, 8.4%-58.1%). The median PFS was 2.3 months (95% CI, 0.8-10.8).

Grade 1/2 AEs in the dose-expansion cohorts were consistent with those observed in the dose-escalation phase. Serious AEs, however, occurred in 37% of patients in the cohorts, including grade 3 pneumonitis in 1 patient, grade 2/3 heart dysfunctions in 2, grade 4 neutropenia in 5, grade 4 hepatic cytolysis in 1, and grade 5 febrile aplasia in 2 patients.

“[Notably], 1 grade 3 heart dysfunction in a patient who was pretreated with anthracyclines and antiandrogens had stabilized pre-existing cardiac avulsion,” Toulmonde added.

Twenty patients with STS were included in the exploratory analysis of expression of immune markers on baseline biopsies. The results showed that 3 of the patients had PD-L1 expression greater than 0%. When co-staining of CD163 and CD8 was carried out, investigators noticed 3 clusters of markers, including immune desert tumors, those high in CD163, and those high in CD8. The clusters identified did not correlate with tumor shrinkage, though. Notably, 2 patients whose tumors were CD163-high showed the most progression of disease.

Toulmonde et al did find that CD8 and CD163 correlated with cell density as well as PFS. In tumors with CD8 <13 cells/mm², the PFS was 1.7 months (95% CI, 0.0-5.0), and in tumors with CD8 ≥13 cells/mm2, the PFS was 5.2 months (95% CI, 0.8-20.2; log-rank P = .183). In terms of CD163 tumors, those with <442 cells/mm² had a PFS of 4.9 months (95% CI, 0.0-NA), and those with ≥442 cells/mm² had a PFS of 2.3 months (95% CI, 0.0-7.7; log-rank P = .289).

TRAMUNE is an ongoing study but is no longer accruing patients. Those enrolled were required to be 18 years of age or older with histologically confirmed unresectable or metastatic STS or ovarian cancer with a BRCA wild-type mutation. Patients were also required to have had at least 1 prior line of therapy in the metastatic setting, and these prior therapies must have been platinum-based chemotherapy for the ovarian cancer group and anthracyclines for the STS group. Finally, patients were required to have had measurable and progressive disease per RECIST v1.1 and adequate hematological, renal, metabolic, and hepatic function.

Considering the design of the study, which required at least 1 objective response to trabectedin plus durvalumab for the regimen to be deemed active in patients with STS or ovarian cancer, the study was overall positive.

Reference:

Toulmonde, M, Brahmi M, Giraud A, et al. TRAMUNE, a phase Ib study combining trabectedin and durvalumab, results of the expansion cohort in patients with advanced pretreated soft tissue sarcomas. Presented at: Presented at: 2020 ESMO Congress; September 19-21, 2020; Virtual. Abstract LBA67.