Tremelimumab Prompts Durable Responses in Metastatic Urothelial Cancer

Tremelimumab monotherapy showed clinical activity with durable responses in patients with metastatic urothelial carcinoma and documented transitional cell carcinoma of the urothelium who failed first-line platinum-based chemotherapy, according to results from a phase II study, which is evaluating the drug in solid tumors.

Padmanee Sharma, MD, PhD

Tremelimumab monotherapy showed clinical activity with durable responses in patients with metastatic urothelial carcinoma and documented transitional cell carcinoma of the urothelium who failed first-line platinum-based chemotherapy, according to results from a phase II study, which is evaluating the drug in solid tumors.

Results published inClinical Cancer Researchshowed that in 32 evaluable patients, the objective response rate (ORR) was 18.8% (95% CI, 7.2%-36.4%), which include complete responses (CRs) in 6.3% of patients (n = 2) , and partial responses (PRs) in 12.5% of patients (n = 4). The median duration of response (DOR) was not reached in this study. There was one case of stable disease (SD) which lasted more than 12 months. A disease control rate (DCR) of 21.9% was achieved at 12 months.

The median overall survival (OS) was 10.3 months (range, 9.5-not evaluable), which was estimated to be a 36.0% OS rate at 12 months. A progression-free survival event occurred in 62.5% of patients (n = 20), with the median PFS being 2.63 months. Patients who had a response to tremelimumab monotherapy also showed a 30% to 100% decreased in target lesion size and had durable changes in a period of 24 months. But there was a 20% to 150% increase in target lesion size among patients with progressive disease, which were recorded over 13 months.

A group of patients continued to show response to tremelimumab after the primary data cutoff date. One patient demonstrated a 35-month DOR and had been in CR for 30 months, as of May 2019. Another patient demonstrated a 13-month DOR before death, which was not considered to be treatment related. A third patient showed a 26-month clinical benefit.

All-grade adverse events (AEs) were observed in 93.8% of patients (n = 30). Of these AEs, 59.4% (n = 19) were grade 3 or 4. The most common grade 3/4 AEs were colitis and anemia, which both occurred in 9.4% of patients each. There were 31.3% of patients who discontinued treatment due to an AE.

Treatment-related adverse events (TRAEs) were observed in 56.3% of patients (n = 18), and of them the most common were fatigue (28.1%), colitis (25.1%), pruritis (21.9), diarrhea (18.8%), and nausea (18.8%). TRAEs were grade 3 or higher in 28.1% of patients (n = 9). The most common grade ≥3 TRAEs were colitis (12.5%), diarrhea (9.4%), and anemia (9.4%). TRAEs were considered serious TRAEs in 28.1% of patients, and 28.1% of patients (n = 9) discontinued treatment with tremelimumab because of a TRAEs. Of the patients who discontinued treatment, 21.9% had colitis (n = 7), 3.1% experienced hepatoxicity (n = 1), and 3.1% had pruritis (n = 1).

Immune-mediated AEs (imAE) were all observed in this study and occurred in 34.4% of patients (n = 11), and of these imAEs, 15.6% were grade 3 or higher (n = 5) and 18.8% were serious imAEs. Most of these toxicities required treatment with high-dose steroid/systemic corticosteroid, endocrine therapy, or other immunosuppressive therapy, which were administered to 65.7%, 12.5%, and 9.4% patients, respectively. In 15.6% of patients, the imAEs were resolved, but 18.8% of patients still suffered from imAEs.

There were no treatment-related deaths observed in this study. The deaths that occurred in 34.4% of patients were related to disease.

In the open-label, multicenter study of patients with solid tumors (NCT02527434), tremelimumab 750mg was administered intravenously every 4 weeks for 7 cycles. Then, the monotherapy was given every 12 weeks for 2 additional cycles. Treatment continued for up to 12 months or until disease progression, initiation of other anticancer therapy, unacceptable toxicity, or patient consent withdrawal. The primary end point of the study was the percentage of patients with a confirmed overall response. The secondary end points included DOR, DCR, PFS, best objective response, and OS.

Any patient with a histologically or cytologically documented solid tumor malignancy who had no previous radiation therapy was eligible to enroll in the study. Patients who had any concurrent chemotherapy, biologic, or hormonal therapy for the treatment of cancer were excluded.

Sharma et al. concluded that single-agent tremelimumab showed favorable and durable clinical activity, which provides a rationale to evaluate the drug in combination with an anti—PD-1/PD-L1 agent. Based on these findings, the phase III DANUBE trial (NCT02516241) and NILE trial (NCT03682068) were launched to investigate the safety and efficacy of tremelimumab plus durvalumab (Opdivo) versus the standard of care in patients with unresectable stage IV urothelial carcinoma.

“I’m very excited that the anti—CTLA-4 agent tremelimumab represents another immunotherapy strategy that may provide clinical benefit for patients with metastatic bladder cancer. We conducted the first neoadjuvant treatment with ipilimumab [Yervoy] in patients with bladder cancer and published 2 papers in 2008 and 2010, prior to any FDA-approvals for any immune checkpoint therapy agents. It’s exciting to see the field moving forward to further develop anti–CTLA-4 therapy for treatment of [patients with bladder cancer],” Padmanee Sharma, MD, PhD, the scientific director of the Immunotherapy Platform, professor of the Departments of Genitourinary Medical Oncology and Immunology T. C. and the Jeanette D. Hsu Endowed Chair in Cell Biology, co-director of the Parker Institute for Cancer Immunotherapy at M. D. Anderson Cancer Center, and lead author of the study toldTargeted Oncology.

Reference:

Sharma P, Sohn J, Shin SJ, et al. Efficacy and Tolerability of Tremelimumab in Locally Advanced or Metastatic Urothelial Carcinoma Patients Who Have Failed First-Line Platinum-Based Chemotherapy.Clin Can Res. [Published online January 2020]. DOI: 10.1158/1078-0432.CCR-19-1635