Ipilimumab experience in heavily pretreated patients with melanoma in an expanded access program at the University Hospital of Siena (Italy)

Abstract

Aim of study: To evaluate the feasibility of ipilimumab treatment for metastatic melanoma outside the boundaries of clinical trials, in a setting similar to that of daily practice.

Methods: Ipilimumab was available upon physician request in the Expanded Access Programme for patients with life-threatening, unresectable stage III/IV melanoma who failed or did not tolerate previous treatments and for whom no therapeutic option was available. Induction treatment with ipilimumab 10 mg/kg was administered intravenously every 3 weeks, for a total of 4 doses, with maintenance doses every 12 weeks based on physicians' discretion and clinical judgment. Tumors were assessed at baseline, Week 12, and every 12 weeks thereafter per mWHO response criteria, and clinical response was scored as complete response (CR), partial response (PR), stable disease (SD), or progressive disease. Durable disease control (DC) was defined as SD at least 24 weeks from the first dose, CR, or PR.

Results: Disease control rate at 24 and 60 weeks was 29.6% and 15%, respectively. Median overall survival at a median follow-up of 8.5 months was 9 months. The 1- and 2-year survival rates were 34.8% and 23.5%, respectively. Changes in lymphocyte count slope and absolute number during ipilimumab treatment appear to correlate with clinical response and survival, respectively. Adverse events were predominantly immune related, manageable, and generally reversible. One patient died from pancytopenia, considered possibly treatment related.

Conclusion: Ipilimumab was a feasible treatment for malignant melanoma in heavily pretreated, progressing patients. A sizeable proportion of patients experienced durable DC, including benefits to long-term survival.

Fig. 1

Treatment design. ID identification, W week

Fig. 2

Case study 1. a CT scans of patient’s liver at baseline and at Week 12, Week 24, and Week 60 after the initiation of ipilimumab therapy. The patient developed liver metastases at Week 12. At Weeks 24 and 60, whereas these lesions persisted, no new metastases developed and the patient achieved stable disease. b Photographs of melanoma lesions on patient’s torso at baseline and at Week 12, Week 24, and Week 60 after the initiation of ipilimumab therapy document the slow progressive decline in melanoma tumor volume. c Histopathology of cutaneous biopsy at Week 56 confirms the observed progressive decline in tumor burden as a result of ipilimumab therapy. (I) Nodular, hyperpigmented component of the lesion surrounded by pigmented flat areas (original magnification 25×). (II) Detail of the flat area, showing regressive changes with mild fibrosis, melanophages, and blood vessels (original magnification 100×). (III) and (IV) Bland nuclei of mostly melanin-laden macrophages and lymphocytes are detectable both in the upper. (III) and lower (IV) more fibrotic areas of the nodular lesion (original magnification 400×). Histologic examination of liver melanoma metastases at Week 102 showed massive necrosis of melanocytes. On left, well-preserved fibroblasts with rare lymphocytes inside of a fibrotic septum, and melanophages are recognizable (original magnification 200×) (V)

Fig. 3

Case study 2. CT scans of 2 distinct foci of lung metastasis (a and b) at baseline and Weeks 12, 24, and 48 after initiation of ipilimumab therapy. The patient achieved PR at Week 24 followed by SD beginning at Week 24 and lasting through Week 48