Patient responses to ipilimumab, a novel immunopotentiator for metastatic melanoma: how different are these from conventional treatment responses?

Advanced melanoma has defied treatment advances for several decades. Immunotherapy with high-dose interleukin-2 or interferon-α has been beneficial in some cases, but significant toxicities limit its use. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) signaling switches off T-cell activation and induces immune tolerance. Inhibiting CTLA-4 prolongs the antitumor T-cell response, reversing tolerance. Ipilimumab is a first-in-class anti-CTLA-4 monoclonal antibody, currently under review by the Food and Drug Administration for pretreated melanoma. Ipilimumab has shown durable responses and manageable toxicities in a large phase 3 clinical trial in patients with advanced melanoma. Variable response patterns have been observed, including: (1) response in baseline lesions; (2) a slow, steady decline in tumor burden; (3) response after an increase in tumor burden; and (4) response in index and new lesions accompanied by the appearance of other new lesions. Although responses (1) and (2) may be captured using standard methods, atypical responses (3) and (4) would be classified as progressive disease using conventional assessments. Patients on ipilimumab may have delayed responses or durable stable disease even after apparent disease progression, therefore using new immune-related response criteria is recommended to avoid premature treatment withdrawal. This review compares and contrasts responses to ipilimumab with those after chemotherapy, and discusses treatment implications.

Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study.

BACKGROUND: Ipilimumab is a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 and has shown promising activity in advanced melanoma. We aimed to ascertain the antitumour efficacy of ipilimumab in patients with advanced melanoma. METHODS: We undertook a randomised, double-blind, phase 2 trial in 66 centres from 12 countries. 217 patients with previously treated stage III (unresectable) or stage IV melanoma were randomly assigned a fixed dose of ipilimumab of either 10 mg/kg (n=73), 3 mg/kg (n=72), or 0.3 mg/kg (n=72) every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. Randomisation was done with a permuted block procedure, stratified on the basis of type of previous treatment. The primary endpoint was best overall response rate (the proportion of patients with a complete or partial response, according to modified WHO criteria). Efficacy analyses were done by intention to treat, whereas safety analyses included patients who received at least one dose of ipilimumab. This study is registered with ClinicalTrials.gov, number NCT00289640. FINDINGS: The best overall response rate was 11.1% (95% CI 4.9-20.7) for 10 mg/kg, 4.2% (0.9-11.7) for 3 mg/kg, and 0% (0.0-4.9) for 0.3 mg/kg (p=0.0015; trend test). Immune-related adverse events of any grade arose in 50 of 71, 46 of 71, and 19 of 72 patients at doses of 10 mg/kg, 3 mg/kg, and 0.3 mg/kg, respectively; the most common grade 3-4 adverse events were gastrointestinal immune-related events (11 in the 10 mg/kg group, two in the 3 mg/kg group, none in the 0.3 mg/kg group) and diarrhoea (ten in the 10 mg/kg group, one in the 3 mg/kg group, none in the 0.3 mg/kg group). INTERPRETATION: Ipilimumab elicited a dose-dependent effect on efficacy and safety measures in pretreated patients with advanced melanoma, lending support to further studies at a dose of 10 mg/kg. FUNDING: Bristol-Myers Squibb.

Results of curative therapy for esophageal cancer in a community training hospital.

A 12-year experience of therapy for esophageal carcinoma in a community-based cancer center was reviewed retrospectively. Of a total of 88 patients with histologically proven carcinoma of the esophagus 30 (34.1%) underwent curative esophagectomy. Twelve patients received preoperative chemoradiotherapy. Fourteen esophagectomies were performed transhiatally and 16 via the thoracolaparotomy approach. The average distance from incisors was 32.2 and 32.1 cm, respectively. Overall morbidity was 36.7%, with major complications in 30% of patients. Mortality was 3.3%. A comparison of patients treated with preoperative chemoradiotherapy (12 patients) and surgery alone (18 patients) showed no statistical difference in morbidity, mortality, or length of hospital stay. Analysis of these parameters in groups of patients operated via the transhiatal versus thoracolaparotomy approach demonstrated statistically lower morbidity (14.3% versus 56.3%, respectively), with no difference in mortality and a trend toward a shorter hospital stay in the former group. Overall survival at 3 years was 63.9%. In the combined therapy group, 90.9% of patients survived 3 years compared to 40.4% in the surgery only group (P = 0.0177). There was a trend toward better survival in the group of patients treated via the transhiatal approach. This study demonstrated that curative therapy for esophageal carcinoma can be performed with acceptable morbidity and mortality in a community teaching hospital.