Patterns of Response in Patients with Pretreated Metastatic Melanoma who Received Ipilimumab 3 mg/kg in a European Expanded Access Program: Five Illustrative Case Reports
A 44-year-old man (Patient B), who in September 2007 had undergone a successful resection of a primary melanoma lesion on his back with no evidence of metastatic spread and no adjuvant treatment, subsequently developed liver metastasis in June 2008. He achieved CR after two cycles of dacarbazine and radiofrequency ablation of the liver lesion. A further 9 months later, however, he was diagnosed with two subcortical brain metastases and multiple metastases localized in the para-aortic lymph nodes and the lungs. He received radiosurgery for the brain metastases (1 × 20 Gy per lesion), but systemic chemotherapy for the other lesions with two cycles of dacarbazine was unsuccessful, with PD comprising significant growth of baseline lesions and appearance of new gluteal and mesenteric lymph node metastases. Patient B underwent second-line therapy in a phase 2 trial of oral sunitinib malate (Sutent®, Pfizer) 50 mg four times daily during which time he had stabilization of his extracranial metastases (). Four months after starting sunitinib, however, he developed two new brain lesions; 2 months later these had grown and were treated with radiosurgery (1 × 20 Gy per lesion). Although there was no further CNS progression, 8 months after starting sunitinib Patient B had progression of his known visceral metastases and developed two new metastases—a lesion in the quadriceps muscle and a paravertebral lesion.\nAfter giving written informed consent, Patient B was entered into a European EAP and received third-line systemic therapy with intravenous infusion of ipilimumab 3 mg/kg every 3 weeks for a total of four doses. After the first ipilimumab administration, the patient received radiotherapy for his symptomatic paravertebral and muscular (quadriceps) lesion. At first evaluation 12 weeks after starting ipilimumab, a new 18FDG-PET/CT scan revealed normalization of 18FDG-uptake of most metastases and complete regression of muscle metastases (Figure ). A single duodenal metastasis was persistently 18FDG-avid without radiological evidence for growth but new metastatic localizations affecting the mediastinal lymph nodes and a peri-hepatic lymph node were found. According to conventional mWHO tumor response criteria or Response Evaluation Criteria in Solid Tumors (RECIST), Patient B had PD but qualified for SD according to irRC as his overall burden of disease had decreased. Given this patient's preserved general well-being, absence of biological evidence of endangered organ function and decrease in total tumor burden, we believed that an atypical response to ipilimumab was still possible and therefore, no alternative therapy was initiated. During ipilimumab treatment, patient B showed an initial decrease of his ALC (from 1,232 to 695/mm3). This was possibly influenced by the administered radiotherapy for the symptomatic paravertebral and quadriceps lesion between the first and second iplimumab dose. At Week 9, there was a partial recovery of the lymphodepletion and the ALC was 1044/mm3. On repeat assessment 24 weeks after he started ipilimumab, Patient B had complete regression of his 18FDG-avid mediastinal lymph node metastases and confirmed complete regression in all other baseline lesions except for the persistently 18FDG-avid duodenal lesion which remained stable (Figure ).\nA control 18FDG-PET/CT scan obtained 33 weeks after the start of ipilimumab treatment showed no residual 18FDG uptake at any metastases with the exception of a single lesion located in the duodenum (Figure ). The patient remained clinically stable except for an increase of frontal headaches. An MRI of the brain revealed the reappearance of a lesion anterior in the right frontal lobe (at the exact same anatomical localization where the irradiated frontal metastasis had been) with important surrounding edema. The additional lesions within the brain had remained stable and there was no evidence of new metastases within the CNS. A neurosurgical resection of that frontal lesion was performed and the histopathological examination revealed the presence of radiation necrosis (). Following this neurosurgical resection, Patient B's clinical course remained uneventful (WHO PS 0) and he required no further antimelanoma therapy up to latest follow-up 56 weeks after the initiation of ipilimumab. Following documented persistent nonprogressive 18FDG-uptake of the single duodenal lesion in August 2011, the patient requested not to undergo further endoscopic investigation of this asymptomatic lesion.