Subset analysis of the safety and efficacy of nivolumab in elderly patients with metastatic melanoma
Creators: name: Morganna Freeman
name: Youngchul Kim
name: Weber, Jeffrey
Publisher: name: F1000Research
Year: 2015

description: Cancer immunotherapy has generated significant response rates and prolonged survival, particularly in melanoma, where sustained clinical responses can be seen even after cessation of therapy. Inhibition of critical immune checkpoints, while clinically effective, also carry the risk of immune-related adverse events (irAEs) which have been well-described in the literature [Topalian 2012]. The treatment of elderly patients with checkpoint inhibition presents a unique challenge, as nearly half of all malignancies are diagnosed in patients &gt;65 [Jemal 2011; Bray 2006; Berger 2006], and the clinical indications for immunotherapy continue to increase [Robert 2013; Robert 2015; BMS 2015]. Furthermore the characteristic side effect profiles (GI and pulmonary toxicity, endocrinopathies) seen with these agents [Gangadhar 2014; Gedye 2014] warrant prompt evaluation, and may be more challenging in older patients, given the association of age with greater comorbidties and a reduction in functional reserve [Theou 2014]. The efficacy of such therapies is also worth exploring, as “immunosenescence,” age-related impairment of adaptive and innate immunity, could potentially impair the effectiveness of checkpoint inhibition [Sanchez-Correa 2014].<br><br>We performed a retrospective analysis of irAEs and survival outcomes in melanoma patients treated with nivolumab, with a subset analysis of patients age 65 or younger compared to those over age 65. Data were pooled from 148 patients (33 resected, 115 unresectable) treated with nivolumab plus peptide vaccine or nivolumab alone every 2 weeks for 12 weeks. Patients with stable disease or regression received an additional 12-week cycle, then nivolumab alone every 12 weeks for up to 2 additional years. Frequency, grade, and characteristics of irAEs were analyzed among patients &lt;65 and &gt;65 years of age. Additionally, a 12-week landmark survival analysis using a multivariate time-dependent Cox proportional hazard model assessed difference in OS in the presence or absence of irAEs, and survival was compared in each age group.<br><br>Of the 148 patients profiled, 52 (35%) were age &gt;65. The most commonly occurring irAEs amongst patients aged 65 and younger included rash (38.5%), diarrhea/colitis (30.2%), and vitiligo (10.4%). These were also the most common irAEs seen in patients 65 and older (40.4%, 21.2% and 7.7%, respectively). No statistically significant difference in irAE incidence was seen between these subgroups (p=0.966, 0.322, and 0.805, respectively) and there was no statistically significant OS difference seen between patients &gt;65 and &lt;65 (p=0.113). There was a statistically significant OS benefit in patients &lt;65 experiencing any grade of irAE (p=&lt;0.001); this was also seen in patients &gt;65 (p=0.033).<br><br>Nivolumab may be an effective therapeutic option for patients 65 and older, as the irAE profile seen below and above this age cutoff was similar, and showed no statistically significant difference in incidence among older patients. Additionally the presence of irAEs in patients &gt;65 was still associated with a survival benefit, thus demonstrating that older patients may still respond appropriately to immune checkpoint inhibition. This encouraging data should be validated in larger patient cohorts, with specifically targeted age ranges (i.e age 65-70, 70-75) to further investigate tolerance and response.<br>