Tremelimumab Falls Short of OS Endpoint in Phase IIb Mesothelioma Trial

Data from the phase IIb DETERMINE trial, which enrolled 571 patients with unresectable pleural or peritoneal malignant mesothelioma, are being prepared for presentation at an upcoming medical meeting. AstraZeneca has not released data from the study. Prior to the analysis, tremelimumab had been granted an orphan drug designation for malignant mesothelioma.

“We are disappointed that tremelimumab monotherapy did not demonstrate a survival benefit in this patient population with no approved medicines beyond first-line treatment," Robert Iannone, Senior Vice President, Head of Immuno-Oncology, Global Medicines Development at AstraZeneca, said in a statement. "However, we remain confident in tremelimumab’s clinical activity in combination."

In the DETERMINE study, patients were randomized in a 2:1 ratio to tremelimumab or placebo. Intravenous tremelimumab was administered at 10 mg/kg. The primary endpoint of OS was assessed from the time of randomization to death for up to 3 years. The study consisted of four periods focused on screening, treatment, a 90-day follow up for safety, and an assessment of survival.

In a prior phase II study,1 29 patients with advanced chemotherapy-resistant malignant mesothelioma received tremelimumab at 10 mg/kg once every 4 weeks for six doses. The median age of patients in the study was 65 years. Most patients had stage IV disease (n = 18) and an ECOG PS between 0 and 1 (n = 23). Altogether, 6 patients had an ECOG PS of 2.

The objective response rate (ORR) was 3% and the disease control rate was 38% with tremelimumab. Responses consisted of 4 immune-related partial responses, which occurred between 12 and 24 weeks following treatment. Two responses were indicative of pseudoprogression, wherein the tumor progressed before a response was indicated. When including stable disease, the disease control rate was 52%.

A preceding phase II study had explored a larger 15 mg/kg dose of tremelimumab for patients with chemotherapy-resistant mesothelioma.2 This trial did not statistically meet its endpoint. The ORR was 6.9% and the duration of response was 12.4 months. When including stable disease, the disease control rate was 31%.

Median OS was 10.7 months with tremelimumab and the median progression-free survival was 6.2 months. The 1-year OS rate was 48.3% and the 2-year OS rate was 36.7%.

Grade 1/2 treatment-related adverse events occurred in 93% of patients treated with tremelimumab at 15 mg/kg, which mainly consisted of rash, pruritus, colitis, and diarrhea. Grade 3/4 events were experienced by 14% of patients. The most common adverse events were gastrointestinal, dermatological, and fever. In the lower dose trial, the rate of grade 1/2 events declined to 90% and the grade 3/4 events were cut in half, to 7%.

Despite the setback, studies continue to assess immune checkpoint inhibition in mesothelioma. The PD-1 inhibitor nivolumab (Opdivo) and pembrolizumab (Keytruda) have demonstrated promising results in early phase clinical trials. Additionally, the combination of tremelimumab and the PD-L1 inhibitor durvalumab is currently being assessed in a phase II study for patients with mesothelioma (NCT02592551).

References

1. Calabro L, Morra A, Fonsatti E, et al. Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study.Lancet Respir Med. 2015. 3(4):301-309.
2. Calabro L, Morra A, Fonsatti E, et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncology. 2013:14(11):1104—1111.