Original ResearchLong term survival with cytotoxic T lymphocyte-associated antigen 4 blockade using tremelimumab
Introduction
A well-recognised hallmark of cancer immunotherapy is the long duration of responses, lasting even decades, as evidenced with the use of high dose interleukin-2 or certain cancer vaccines [1], [2]. Only a minority of patients with advanced melanoma attain objective responses with these therapies; however, when reached, the nature of these responses is usually sustained over several years.
Anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibodies such as ipilimumab and tremelimumab bind to the inhibitory CTLA-4 receptor on T cells; by blocking the inhibition of co-stimulatory B7 ligands by CTLA-4, they increase immune stimulation and drive T cell activity [3]. Both drugs are fully human monoclonal antibodies directed against CTLA-4; there are minimal differences between them as ipilimumab is an immunoglobulin G1 (IgG1) isotype and tremelimumab is a non-complement-fixing immunoglobulin G2 (IgG2) isotype [4]. Ipilimumab was approved by the FDA in 2011 for the treatment of patients with unresectable metastatic melanoma based on improvement in overall survival (OS) in two randomised trials [5], [6]. While response rates for ipilimumab in patients with advanced melanoma have ranged from only 10–15% [6], the demonstration of long-lasting responses with ipilimumab has stimulated further interest in use of these therapies, with a plateau in the survival curve of 21% beginning at 3 years [7].
As the other anti-CTLA-4 antibody in clinical trials, tremelimumab has also been studied in patients with advanced melanoma and other tumour types [10]. A phase 2 trial of tremelimumab in melanoma compared two dosing regimens at 10 mg/kg once per month and 15 mg/kg once every 3 months [11]. While no difference was seen in the response rate or survival, a dose of 15 mg/kg every 3 month dosing was selected for phase 3 trial testing due to a better toxicity profile. In the phase 3 trial, 655 patients with Stage IIIC or IV and measurable disease were enrolled and randomised to either tremelimumab at 15 mg/kg every three months or chemotherapy with dacarbazine or temozolamide. While no significant statistical differences were observed in the overall response rates (11% with tremelimumab and 10% with chemotherapy; p = 0.618) or median OS (12.6 months for tremelimumab and 10.7 months with chemotherapy; p = 0.127) between arms, the duration of the anti-tumour responses was significantly different (tremelimumab 35.8 months versus chemotherapy 13.7 months (p = 0.0011) [12]. The study design did not allow crossover for patients who progressed to chemotherapy. However, patients in the chemotherapy arm were exposed to ipilimumab (up to 34% of patients who were alive or censored at time of study closure) and the cross-over therapy with the frequent use of a different anti-CTLA-4 antibody in the chemotherapy control arm may have explained the lack of a survival impact [13].
Newer immune checkpoint inhibitors such anti-PD-1 and PD-L1 antibodies have shown response rates ranging between 30% and 40%, higher than either of the two anti-CTLA-4 antibodies, although long term follow up of patients treated with anti-PD-1/PD-L1 therapies is not yet available [14], [15]. As both ipilimumab and tremelimumab have moved towards combination regimens in clinical trials with other checkpoint inhibitors or immune agonists in advanced melanoma and other tumours [16], [17], we wanted to evaluate the long-term survival in patients with advanced melanoma treated with tremelimumab. We retrospectively reviewed the records of 143 patients enrolled in four different phase 1 and 2 tremelimumab trials and report on the outcome and follow up of those patients during the past decade.
Section snippets
Patients
The data presented in this retrospective analysis were obtained from patients enrolled in four clinical trials conducted at University of California, Los Angeles (UCLA) and MD Anderson Cancer Center since these two sites were the initial and highest accruing sites for the early tremelimumab clinical trials. All patients with confirmed stage IIIC or IV melanoma were included. Further details can be found in the original publications of each of the studies [11], [18], [19], [20]. The
Patient characteristics
A total of 143 patients enrolled between January 2002 and May 2008 were included in this analysis (Table 1). Eighteen patients (12.6%) had stage IIIC disease, while the remainder had stage IV disease. Approximately 80% of patients received tremelimumab at either 10 mg/kg every month or 15 mg/kg every 3 months. All others received lower doses.
Response rate
One hundred-forty-one patients (98%) were assessed for response and 22 patients achieved objective responses (15.6%, 95% Clopper–Pearson CI of 10–22.7%).
Discussion
Our data suggest that CTLA-4 blockade with tremelimumab induces durable responses in patients with advanced melanoma, with a plateau of the survival curve observed. The combined long term follow up data with ipilimumab and tremelimumab provide compelling evidence that CTLA-4 blockade therapy can lead to very long duration of responses, which most likely represent cures from their advanced melanoma in a small subset of patients. Long term follow up with ipilimumab treatment has been provided
Conflict of interest statement
Antoni Ribas: Consultant or advisory role with Merck Sharp & Dohme Corp., Amgen, Astellas, Daiichi-Sankyo, GlaxoSmithKline, Genentech-Roche, Novartis, Pierre Fabre. DSMB member for MedImmune/AstraZeneca and Novartis. Stock or ownership interests from Kite Pharma, Compugen.
Bartosz Chmielowski: Consulting or advisory role with Genentech, Merck, Amgen, Astellas Pharma, Lilly, Served as speaker for Bristol-Myers Squibb, Genentech/Roche, Honororia from Merck, Amgen.
Kevin B. Kim: Received research
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