Ipilimumab, an anticytotoxic T-lymphocyte–associated protein (CTLA)-4 antibody, was approved in 2011 by the FDA for the treatment of advanced melanoma (1, 2). Our study aimed to evaluate the impact of immunosuppressants used for the treatment of immune-related adverse events (irAE) on outcome of patients treated with ipilimumab.
We retrospectively evaluated 113 patients with advanced melanoma after treatment at 3 mg/kg. Median age was 58 years (19–81). The majority of patients had cutaneous melanomas (75%), BRAF wild type (55%), M1c (69%), and PS = 0 (62%) and were treated in second line (67%).
Two patients (2%) achieved complete responses, 8 (8%) partial responses, 16 (15%) stable disease (SD), and 71 (68%) patients progressed through ipilimumab.
Skin toxicity (31%) and diarrhea (28%) were the most common irAEs. Nineteen (65%) patients developed G2-4 diarrhea. The median time to diarrhea onset from first ipilimumab was 59 days (7–123). The presence or absence of irAEs was not associated with response or SD (P = 0.3).
IrAEs were treated according to published guidelines. Twenty-nine of the 32 (90%) patients with diarrhea received oral steroids; in 13 of 32 cases, treatment was escalated to intravenous steroids. Seven patients received infliximab after 2 (N = 3), 3 (N = 3), or 4 (N = 1) doses of ipilimumab. One dose of infliximab 5 mg/kg in 4 patients, 2 in 2 patients, and 3 in 1 patient were administered before resolution of the diarrhea. The median time to use of infliximab from ipilimumab first infusion was 65 days (32–113).
Patients suffering any irAEs showed better outcomes, with a median OS (mOS): 10.7 months [95% confidence interval (CI), 3.2–18.3), versus patients with no irAEs, mOS: 4.3 months (95% CI, 3.4–5.2; P = 0.019; Fig. 1A).
A, Kaplan–Meier overall survival curve for patients showing any type or grade of toxicity comparing with those without any recorded toxicity. B, Kaplan–Meier overall survival curve for patients with diarrhea comparing those treated with infliximab with those who did not receive infliximab.
The outcome in patients treated with infliximab was not significantly worse (mOS: not reached) compared with those treated with steroids only (mOS: 7 months; 95% CI, 3–11) but rather showed a trend to increased OS (P = 0.2; Fig. 1B). No differences were observed comparing patients treated with oral versus intravenous steroids.
It has been hypothesized that the use of immunosuppressants for management of irAEs would be detrimental by counteracting the beneficial effects of immunostimulatory drugs. However, recent data show that steroids do not adversely impact patient outcome (3–5), although their use, usually prolonged, causes toxicity in its own right. Importantly for clinical management, we identify here that ipilimumab-derived colitis can be safely treated with infliximab without adversely affecting outcome. This argues for an early administration of infliximab, both for irAE control and reduction of steroid toxicity.
Disclosure of Potential Conflicts of Interest
C.H. Ottensmeier reports receiving a commercial research grant from Bristol-Myers Squibb, speakers bureau honoraria from Bristol-Myers Squibb and MSD, and is a consultant/advisory board member for Bristol-Myers Squibb and MSD. No potential conflicts of interest were disclosed by the other authors.
Grant Support
This study was supported by Experimental Cancer Medicine Centre, UK.
- Received October 14, 2015.
- Accepted October 14, 2015.
- ©2015 American Association for Cancer Research.
Volume 21, Issue 24
