Sagun Parakh

Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy

Background:Recent phase III clinical trials have established the superiority of the anti-PD-1 antibodies pembrolizumab and nivolumab over the anti-CTLA-4 antibody ipilimumab in the first-line treatment of patients with advanced melanoma. Ipilimumab will be considered for second-line treatment after the failure of anti-PD-1 therapy.Methods:We retrospectively identified a cohort of 40 patients with metastatic melanoma who received single-agent anti-PD-1 therapy with pembrolizumab or nivolumab and were treated on progression with ipilimumab at a dose of 3u2009mgu2009kg−1 for a maximum of four doses.Results:Ten percent of patients achieved an objective response to ipilimumab, and an additional 8% experienced prolonged (>6 months) stable disease. Thirty-five percent of patients developed grade 3–5 immune-related toxicity associated with ipilimumab therapy. The most common high-grade immune-related toxicity was diarrhoea. Three patients (7%) developed grade 3–5 pneumonitis leading to death in one patient.Conclusions:Ipilimumab therapy can induce responses in patients who fail the anti-PD-1 therapy with response rates comparable to previous reports. There appears to be an increased frequency of high-grade immune-related adverse events including pneumonitis that warrants close surveillance.

Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases

Background:There is limited data on the efficacy of anti-programmed death 1 (PD-1) antibodies in patients (pts) with melanoma brain metastasis (BM), particularly those which are symptomatic.Method:We retrospectively assessed pts with melanoma BM treated with PD-1 antibodies, nivolumab and pembrolizumab. Clinicopathologic and treatment parameters were collected and outcomes determined for intracranial (IC) response rate (RR) using a modified RECIST criteria, with up to five IC target lesions used to determine IC response, disease control rate (DCR) and progression-free survival (PFS).Results:A total of 66 pts were identified with a median follow up of 7.0 months (range 0.8–24.5 months). A total of 68% were male and 45% BRAF V600 mutation positive. At PD-1 antibody commencement, 50% had an elevated LDH; 64% had local therapy to BM prior to commencing anti-PD1, of which 5% had surgical resection, 14% stereotactic radiosurgery (SRS), 18% whole-brain radiotherapy (WBRT), 27% had surgery and radiotherapy. Twenty-one per cent started anti-PD-1 as first line systemic therapy. No pt had prior anti-PD-1 treatment. The IC overall RR was 21 and DCR 56%. Responses occurred in 21% of pts with symptomatic BM. The median OS was 9.9 months (95% CI 6.93–17.74). Pts with symptomatic BM had shorter PFS than those without symptoms (2.7 vs 7.4 months, P=0.035) and numerically shorter OS (5.7 vs 13.0 months, P=0.068). Pts requiring corticosteroids also had a numerically shorter PFS (3.2 vs 7.4 months, P=0.081) and OS (4.8 vs 13.1 months, P=0.039).Conclusions:IC responses to anti-PD-1 antibodies occur in pts with BM, including those with symptomatic BM requiring corticosteroids. Prospective trials evaluating anti-PD-1 therapy in pts with BM are underway.

Patterns of care and outcomes for elderly patients with metastatic colorectal cancer in Australia

OBJECTIVESnThe elderly accounts for a large proportion of patients with metastatic colorectal cancer (mCRC). This study reviews patterns of care and outcomes for elderly patients with mCRC in the community setting.nnnMATERIALS AND METHODSnElderly patients (≥ 65 years) with mCRC on the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) registry were identified. Treatment, bevacizumab-related adverse events, and overall survival (OS) were analysed by age cohorts, comparing those aged 65-74 vs. 75-84 vs. ≥ 85 years and correlated with potential prognostic factors. Factors affecting chemotherapy and bevacizumab administration were analysed using logistic regression analysis.nnnRESULTSnOf 1439 patients, 363, 352, and 106 were aged 65-74, 75-84, and ≥ 85 years, respectively. 584 (71%) patients received first-line chemotherapy, with chemotherapy use declining with advancing age (84%, 69%, and 34% in 65-74-, 75-84- and ≥ 85-year-olds, respectively). Seven (10%) patients aged ≥ 85 years were not treated with chemotherapy on the basis of age alone. Only 10 of 36 very elderly patients who received chemotherapy also received bevacizumab. Factors affecting bevacizumab administration included age, treatment location, and comorbidities. There was no impact of age on bevacizumab-related adverse events. Resection of metastatic disease occurred in 173 (21%) patients overall, with rates declining with age (26% vs. 21% vs. 6%).nnnCONCLUSIONnChemotherapy usage and resection of metastatic disease decline with advancing age. A minority of patients are not treated with systemic therapy due to advanced age alone. Our cohort suggests underutilisation of bevacizumab in older patients, but where given, toxicity rates did not increase with age.

Regorafenib-induced hyperammonemic encephalopathy

Regorafenib improves progression‐free survival as a late‐line treatment for patients with metastatic gastrointestinal stromal tumour (GIST). As a multitargeted tyrosine kinase inhibitor (TKI), the expected adverse events of regorafenib are similar to those reported with imatinib, sunitinib or sorafenib. We report the first case of hyperammonemic encephalopathy related to regorafenib in a patient with metastatic GIST.

Cholecystitis after yttrium-90 resin microsphere radioembolization treatment: Clinical and pathologic findings.

BACKGROUNDnRadioembolization with yttrium microspheres is an established therapeutic modality for primary and secondary hepatic malignancies, with studies demonstrating improved overall survival. There remains a paucity of data on cholecystitis as a complication of radioembolization. We describe a small series of patients who developed cholecystitis as a result of radioembolization.nnnMETHODSnPatients who had developed cholecystitis as a complication of radioembolization in our institution between 2001 and 2012 were retrospectively reviewed. Patient demographics, cancer details including treatment history, and procedural details of radioembolization and complications of cholecystitis were collected.nnnRESULTSnOf 74 patients who underwent radioembolization using yttrium-90emitting microspheres, four (5.4%) presented with acute cholecystitis as a result of their treatment. All patients presented over 4 weeks following radioembolization and did not settle with conservative treatment. At surgery, the gallbladder was fibrotic and contracted in all cases making surgery difficult.nnnCONCLUSIONnThe incidence of symptomatic radiation cholecystitis after radioembolization is low, and prophylactic cholecystectomy is not routinely recommended for patients undergoing radioembolization. Radiation cholecystitis should be suspected in patients presenting with symptoms of biliary colic or cholecystitis following radioembolization. Early cholecystectomy can be considered in patients undergoing surgery for other indications, especially in high-risk surgical patients in whom there is a high likelihood of radioembolization in the future as they do not respond to conservative treatment.

Updated efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in metastatic melanoma patients previously treated with anti-PD-1 therapy

Meeting abstractsnnImmunotherapy with anti-CTLA-4 and anti-PD-1 antibodies has demonstrated overall survival benefits in patients (pts) with metastatic melanoma (MM) compared to previous standard therapy. Two randomised clinical trials indicate that combined anti-CTLA-4 and anti-PD-1 antibody

Delayed Autoimmune Toxicity Occurring Several Months After Cessation of Anti‐PD‐1 Therapy

Treatment with anti-programmed cell death protein 1 (PD-1) antibodies has demonstrated clinical efficacy in a whole range of malignancies including advanced melanoma, renal cell cancer, bladder cancer, and non-small cell lung cancer. Immune-related adverse events are a unique side effect of checkpoint regulator therapy including anti-PD-1 antibodies. Treatment-related autoimmunity can occur in any organ system, with the median onset usually within 5-15 weeks from the commencement of therapy, depending on the organ system involved. This study describes for the first time a case of delayed autoimmunity occurring 8 months after discontinuing treatment with the anti-PD-1 antibody nivolumab in a patient with metastatic melanoma. The case highlights the need for ongoing surveillance of patients treated with immune checkpoint inhibitors even after cessation of therapy, especially as patients increasingly stop treatment after achieving durable responses.

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