Avelumab in Combination with Eribulin Mesylate in Metastatic Urothelial Carcinoma: BTCRC GU-051, a Phase 1b Study

Monika Joshi, Sheldon L Holder, Junjia Zhu, Hong Zheng, Shraddha Komanduri, Joshua Warrick, Hesham Yasin, Rohan Garje, Bei Jia, Joseph J Drabick, David J DeGraff, Yousef Zakharia, Monika Joshi, Sheldon L Holder, Junjia Zhu, Hong Zheng, Shraddha Komanduri, Joshua Warrick, Hesham Yasin, Rohan Garje, Bei Jia, Joseph J Drabick, David J DeGraff, Yousef Zakharia

Abstract

Background: Patients with metastatic urothelial carcinoma (mUC) have poor prognosis, so further development of novel combinations for these patients is needed.

Objective: To assess the safety and efficacy of eribulin mesylate (eribulin) with avelumab in mUC.

Design, setting, and participants: This was an open-label, phase 1b study in which patients with mUC who were cisplatin-ineligible and treatment-naïve or platinum-resistant were treated with eribulin and avelumab. A 3 + 3 design was used. The study was prematurely terminated because the free study drug became unavailable, but we performed extended follow-up for patients enrolled in the study.

Intervention: Patients received eribulin 1.1 mg/m2 plus avelumab 10 mg/kg on days 1 and 15 in every 28-d cycle in cohort 0, or eribulin 1.4 mg/m2 plus avelumab 10 mg/kg on days 1 and 15 in every 28-d cycle in cohort +1.

Outcome measurements and statistical analysis: The primary objectives were to determine the maximum tolerated dose (MTD) of eribulin with avelumab and assess the objective response rate. A key secondary endpoint was to assess efficacy by evaluating the disease control rate. Exploratory endpoints included PD-1 expression on T cells in peripheral blood and in tumor cells, and tumor DNA sequencing.

Results and limitations: A total of six patients were enrolled in the MTD group (n = 3 in cohort 0 and n = 3 in cohort +1). No dose-limiting toxicity (DLT) was observed in cohort 0, whereas two DLT events were observed in cohort +1. Two patients in cohort 0 had a partial response that was durable, with one patient having a durable response for 7.8 mo. Disease control was observed in 4/6 patients (66.7%). Owing to the early termination, MTD could not be determined.

Conclusions: While early termination of this trial precludes any definitive conclusions, the combination of eribulin and avelumab shows promise in mUC. We observed that treatment was better tolerated and efficacious at lower doses of eribulin. Further research is warranted for this combination in mUC.

Patient summary: We evaluated different doses of eribulin (a chemotherapy drug) in combination with a fixed dose of avelumab (an antibody used to treat several different cancers) in a small group of patients with metastatic cancer of the urinary tract. The lower dose of eribulin was easier to tolerate and the combination had an anti-cancer effect. This trial is registered at ClinicalTrials.gov as NCT03502681.

Keywords: Avelumab; Eribulin; Urothelial carcinoma.

Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1 –
Fig. 1 –
(A) Schema and (B) CONSORT diagram for the planned study. MTD = maximum tolerated dose; ORR = objective response rate; CT = computed tomography.
Fig. 2 –
Fig. 2 –
Efficacy of avelumab and eribulin mesylate (eribulin) among all patients. (A) Swimmer plot for all six patients (time period on initial study + additional follow-up study). PR = partial response; SD = stable disease. (B) Number (#) of cycles of each drug during the study. The median number of cycles was 4.25 for avelumab and 4 for eribulin. Each 28-d cycle consisted of drug administration on days 1 and 15. (C) Best outcome overall and by dose cohort. RECIST = Response Evaluation Criteria in Solid Tumors; DCR = disease control rate. (D) Disease course for subject 2, who experienced a durable partial response during the study. Dx = diagnosis; Rt = right side; NAC 4XGC = neoadjuvant chemotherapy, 4 cycles of gemcitabine-cisplatin; ChemoRT = chemoradiation therapy; UTUC = upper tract urothelial carcinoma; BUC = bladder urothelial carcinoma; TURBT = transurethral resection of bladder tumor; PET/CT = positron emission tomography/computed tomography; FDG = fluorodeoxyglucose; C1D1 = cycle 1, day 1; C11D15 = cycle 11, day 15; LN = lymph node; Bx = biopsy; RPLN = retroperitoneal LN. FGFR3 = fibroblast growth factor receptor 3 (E) Chest computed tomography scans before and after 8 wk of treatment with avelumab plus eribulin mesylate in subjects 2 and 3, who experienced partial responses. Arrows depict areas of disease.
Fig. 3 –
Fig. 3 –
Representative flow cytometry data for expression of (A) PD-1 on CD8+ T cells and (B) TIGIT on CD4+ T cells in peripheral blood from subjects 1–6. (C) Statistical summary plots of the frequency of PD-1 and TIGIT on CD4+ and CD8+ T cells. Time points: baseline, before treatment on day 1 in cycle 1 (C1D1) and cycle 2 (C2D1); and after drug administration (Rx) or 2 wk after completion of treatment. The p values are for paired Student’s t tests.

Source: PubMed

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