Retrospective study of advanced melanoma patients treated with ipilimumab after nivolumab: Analysis of 60 Japanese patients
Introduction
Immune checkpoint inhibitors play an important role in the current management of advanced melanoma [1], [2], [3]. Ipilimumab, a monoclonal antibody that binds the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) molecule on the surface of T cells and blocks CTLA-4 mediated signaling, was the first checkpoint inhibitor approved for melanoma treatment [1]. However, anti-programmed death-1 (PD-1) monoclonal antibodies (αPD-1mAbs: nivolumab [4], [5] and pembrolizumab [6], [7]) were shown to be more effective than αCTLA-4mAb, and the current melanoma guideline recommends αPD-1mAbs as the first-line treatment for patients without BRAF mutation (NCCN melanoma guideline, version 1.2017). Combination therapy using ipilimumab and nivolumab could achieve a greater response than nivolumab monotherapy and is also recommended as the first-line treatment. However, αPD-1mAb monotherapy remains an attractive treatment option because the combination therapy carries a high risk of severe immune-related adverse event (irAE) occurrence [8], [9], [10]. A recent study revealed that combination therapy was superior to nivolumab monotherapy only when the tumors are negative for PD-L1 expression [8], indicating that combination therapy should be considered only in selected patients.
Sequential use of these antibodies was also evaluated in the clinical study and revealed that starting with nivolumab and switching to ipilimumab (and switching back to nivolumab) showed better response than starting with ipilimumab and switching to nivolumab [11], with a response ratio similar to that of combination therapy. However, the frequency of severe irAEs was also similar to that of combination therapy [12].
In Japan, nivolumab was first approved in July 2014 followed by ipilimumab in 2015, but the combination therapy is still not approved. Therefore, in the clinic, although we can initiate monotherapy with either ipilimumab or αPD-1mAb, αPD-1mAb is the first-line treatment for patient without BRAF mutation. Several reports from other countries have indicated that ipilimumab is still effective when initiated for a αPD-1mAb-refractory patient and could be considered as a second-line therapy [13], [14], [15]. However, to the best of our knowledge, there is no study that has evaluated second-line ipilimumab after αPD-1mAb in a Japanese population. In this multicenter, retrospective study, we evaluate the role of ipilimumab after αPD-1mAb in a Japanese population.
Section snippets
Patients
Data from melanoma patients who received ipilimumab treatment following nivolumab treatment from August 2015 to April 2017 were retrospectively collected from 9 clinical sites in Japan. Inclusion criteria were unresectable or stage IV melanoma treated with nivolumab followed by ipilimumab. Patients received nivolumab at either 2 mg/kg followed by a 3-week rest or 3 mg/kg followed by a 2-week rest. All patients received ipilimumab at 3 mg/kg followed by 3-week rest. Clinical data including primary
Patients (supplementary Table 1)
We collected data for 67 patients treated with ipilimumab after nivolumab. Of those, 60 patients were included in the analysis; 4 patients were omitted from the analysis due to treatment using BRAF inhibitor (and MEK inhibitor) in between nivolumab and ipilimumab (which might influence further analyses), 2 patients switched to ipilimumab as part of a treatment plan (not due to the progression of disease or intolerable irAEs), and another patient lacked clinical data.
The mean age was 63.3 years
Discussion
Our study showed that ipilimumab treatment after progression or occurrence of intolerable irAE with nivolumab treatment could achieve only a 3.6% response ratio, which was lower than that reported in previous studies (10% to 16% [13], [15]). This could perhaps be accounted for by the difference in patient population compared to previous reports, which have consisted mainly by Caucasian populations. Furthermore, over half of the patients in our study were being treated for acral lentiginous and
Conclusion
In our cohort, the response to ipilimumab treatment after nivolumab in advanced Japanese melanoma patients was only 3.6% and associated with a high rate of G3/4 irAEs. The interval between initial ipilimumab and last nivolumab administration within 28 days possibly correlates with a higher rate of severe irAE occurrence. Endocrine irAE and skin irAE could be correlated with survival, but this needs to be confirmed with a larger data set. Frequent occurrence of irAE clearly shows that ipilimumab
Funding source
None.
Conflict of interest
The authors declare no potential conflicts of interest.
Acknowledgement
We would like to thank Thomas Mayers of the Medical English Communication Center of the University of Tsukuba, for his excellent English revisions.
References (38)
- et al.
Immune checkpoint protein inhibition for cancer: preclinical justification for CTLA-4 and PD-1 blockade and new combinations
Semin. Oncol.
(2015) - et al.
Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial
Lancet Oncol.
(2016) - et al.
Ipilimumab alone or in combination with nivolumab after progression on anti-PD-1 therapy in advanced melanoma
Eur. J. Cancer
(2017) - et al.
Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor
Eur. J. Cancer
(2016) - et al.
Ipilimumab in patients with cancer and the management of dermatologic adverse events
J. Am. Acad. Dermatol.
(2014) - et al.
Immune dysregulation underlies a subset of patients with chronic idiopathic pruritus
J. Am. Acad. Dermatol.
(2016) - et al.
Novel opportunities to use radiation therapy with immune checkpoint inhibitors for melanoma management
Surg. Oncol. Clin. N. Am.
(2017) - et al.
Improved survival with ipilimumab in patients with metastatic melanoma
N. Engl. J. Med.
(2010) - et al.
Checkpoint inhibitors in advanced melanoma: effect on the field of immunotherapy
Exp. Rev. Anticancer Ther.
(2017) - et al.
Nivolumab in previously untreated melanoma without BRAF mutation
N. Engl. J. Med.
(2015)
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer
N. Engl. J. Med.
Pembrolizumab versus ipilimumab in advanced melanoma
N. Engl. J. Med.
Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma
N. Engl. J. Med.
Combined nivolumab and ipilimumab or monotherapy in untreated melanoma
N. Engl. J. Med.
Nivolumab and ipilimumab versus ipilimumab in untreated melanoma
N. Engl. J. Med.
Nivolumab plus ipilimumab in advanced melanoma
N. Engl. J. Med.
Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial
Lancet Oncol.
Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy
Br. J. Cancer
Anti-programmed cell death protein 1 tolerance and efficacy after ipilimumab immunotherapy: observational study of 39 patients
Melanoma Res.
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