Phase I/II Study of Metastatic Melanoma Patients Treated with Nivolumab Who Had Progressed after Ipilimumab

Abstract

The checkpoint inhibitor nivolumab is active in metastatic melanoma patients who have failed ipilimumab. In this phase I/II study, we assessed nivolumab's safety in 92 ipilimumab refractory patients with unresectable stage III or IV melanoma, including those who experienced grade 3-4 drug related toxicity to ipilimumab. We report long-term survival, response duration, and biomarkers in these patients after nivolumab treatment (3 mg/kg) every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. Response rate for ipilimumab-refractory patients was 30% (95%CI: 21% - 41%). Median duration of response was 14.6 months, median progression-free survival was 5.3 months, and median overall survival was 20.6 months, when followed up a median of 16 months. One and two year survivals were 68.4% and 31.2%, respectively. Ipilimumab-naïve and -refractory patients showed no significant difference in survival. The 21 patients with prior grade 3–4 toxicity to ipilimumab that was managed with steroids, tolerated nivolumab well, with 62% (95%CI: 38% - 82%) having complete or partial remissions or stabilized disease at 24 weeks. High numbers of myeloid-derived suppressor cells (MDSCs) were associated with poor survival. Thus, survival and long-term safety were excellent in ipilimumab-refractory patients treated with nivolumab. Prior grade 3-4 immune-related adverse effects from ipilimumab were not indicative of nivolumab toxicities, and patients had a high overall rate of remission or stability at 24 weeks. Prospectively evaluating MDSC numbers before treatment could help assess the expected benefit of nivolumab.

Risk of Liver Toxicity with Nivolumab Immunotherapy in Cancer Patients

“…Incidence of allgrade ALT elevations ranged from 0.9 to 35.3%. The highest incidence was seen in a stage III trial of advanced melanoma [29], and the lowest incidence in a phase I trial in patients with non-small cell lung cancer [25]. Amongst all the patients who received nivolumab, the summary incidence of all-grade ALT elevations was 4.9% (95% CI 2.9-8.2) based on a random-effects model (heterogeneity test: Q = 215.46, I 2 = 89.325, p < 0.001) (Fig.…”

“…All patients were ≥18 years of age with histologically or cytologically confirmed malignancy. From these patients, nivolumab was administered with ipilimumab in 4 trials accounting for 309 patients [29,[34][35][36]. Nivolumab was administered with platinum agents in one trial which had 59 patients [33].…”

“…Patients with ovarian cancer exhibited the highest incidence of AST and ALT elevations, with incidence rates of 40 and 25%, respectively [21]. The group with the second highest incidence was that consisting of patients with advanced melanoma who had incidence rates of AST and ALT elevations of 9.1 and 9.0%, respectively [22,23,26,[28][29][30][34][35][36]. Interestingly, the RCC patient cohort which constituted 611 patients exhibited a lower incidence rate than other tumors, with AST and ALT incidence rates of 2.6 and 3.2%, respectively [3,6,24].…”

Thyroid dysfunctions secondary to cancer immunotherapy

“…The same group analyzed the safety and efficacy of nivolumab (3 mg/kg) with or without a multi-peptide vaccine in 92 ipilimumab-refractory melanoma patients. They reported thyroid dysfunctions (hypothyroidism and hyperthyroidism) in 8 of 61 (13%) patients in the nivolumab only arm and in 9 of 31 (29%) patients in the nivolumab plus cancer vaccine arm [106]. Recently, Freeman-Keller et al [59] analyzed data from two melanoma trials using nivolumab with or without a multi-peptide cancer vaccine.…”

Immune Checkpoint Inhibitors in the Treatment of Melanoma: From Basic Science to Clinical Application

“…MDSCs are immunosuppressive and contribute to angiogenesis, tumor invasion, and metastasis (93,94). In addition, pretreatment MDSC frequencies are inversely correlated with clinical responses to ipilimumab and nivolumab in melanoma patients (95,96).…”