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Abstract: Objective. : The ABC transporter MRP2 (ABCC2) can mediate cisplatin efflux, and over-expression of MRP2 has been associated with cisplatin resistance in cancer cell lines. The aim of this study was to determine the role of MRP2 in modulating cisplatin cytotoxicity in normal cells as well as the relationship between MRP2 expression and clinical response to platinum-based agents in ovarian cancer. Methods. : The effect of absence of MRP2 expression on cisplatin sensitivity was investigated using primary hepatocyte cultures from the TR− rat strain, which is deficient in Mrp2. We also examined MRP2 expression immunohistochemically in human ovarian tumors exhibiting extremes of clinical response to platinum-based chemotherapy, either absolute platin resistance or patients with residual disease after surgery who experienced extremely long complete response to primary platinum-based chemotherapy. Results. : Primary hepatocyte cultures from Mrp2-deficient TR− rats were over threefold more sensitive to cisplatin and accumulated a twofold greater amount of platinum on DNA that wild-type rat hepatocytes. In human ovarian carcinomas, MRP2 was detected by immunohistochemistry in 3/13 (23%) tumors from patients with absolute platin resistance compared with 5/9 (56%) tumors from patients with prolonged survival following treatment including a platinum-based agent. Conclusion. : These studies indicate that MRP2 may play an important role in modulating normal tissue response to cisplatin. However, MRP2 expression occurred only in a subset of primary ovarian cancers, was frequently aberrant in location and was not correlated with clinical response to platinum-based chemotherapy. [Copyright &y& Elsevier]

After more than two decades of extensive use, drugs based on platinum continue to have a major role in cancer treatment. Although systematic approaches to the development of new analogues have produced agents with less toxicity and novel mechanisms of action, to date such approaches have not achieved more cures than can be achieved with the parent compound, cisplatin. Greater gains might be expected from accumulating knowledge about what makes cancer cells sensitive or resistant to platinum-based chemotherapy. Recent information on drug-efflux pathways, including expression of multidrug-resistance protein 2, and on how tumour cells behave when their DNA is distorted by a platinum adduct, suggests new avenues for translational research. The prospects include modulation of cellular handling of platinum compounds and individualised therapy based on expression of molecules that determine platinum sensitivity. [Copyright &y& Elsevier]

Background: The outcome of patients with macroscopic stage III melanoma is poor. Neoadjuvant treatment with ipilimumab plus nivolumab at the standard dosing schedule induced pathological responses in a high proportion of patients in two small independent early-phase trials, and no patients with a pathological response have relapsed after a median follow up of 32 months. However, toxicity of the standard ipilimumab plus nivolumab dosing schedule was high, preventing its broader clinical use. The aim of the OpACIN-neo trial was to identify a dosing schedule of ipilimumab plus nivolumab that is less toxic but equally effective.Methods: OpACIN-neo is a multicentre, open-label, phase 2, randomised, controlled trial. Eligible patients were aged at least 18 years, had a WHO performance status of 0-1, had resectable stage III melanoma involving lymph nodes only, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1. Patients were enrolled from three medical centres in Australia, Sweden, and the Netherlands, and were randomly assigned (1:1:1), stratified by site, to one of three neoadjuvant dosing schedules: group A, two cycles of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg once every 3 weeks intravenously; group B, two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every 3 weeks intravenously; or group C, two cycles of ipilimumab 3 mg/kg once every 3 weeks directly followed by two cycles of nivolumab 3 mg/kg once every 2 weeks intravenously. The investigators, site staff, and patients were aware of the treatment assignment during the study participation. Pathologists were masked to treatment allocation and all other data. The primary endpoints were the proportion of patients with grade 3-4 immune-related toxicity within the first 12 weeks and the proportion of patients achieving a radiological objective response and pathological response at 6 weeks. Analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02977052, and is ongoing with an additional extension cohort and to complete survival analysis.Findings: Between Nov 24, 2016 and June 28, 2018, 105 patients were screened for eligibility, of whom 89 (85%) eligible patients were enrolled and randomly assigned to one of the three groups. Three patients were excluded after randomisation because they were found to be ineligible, and 86 received at least one dose of study drug; 30 patients in group A, 30 in group B, and 26 in group C (accrual to this group was closed early upon advice of the Data Safety Monitoring Board on June 4, 2018 because of severe adverse events). Within the first 12 weeks, grade 3-4 immune-related adverse events were observed in 12 (40%) of 30 patients in group A, six (20%) of 30 in group B, and 13 (50%) of 26 in group C. The difference in grade 3-4 toxicity between group B and A was -20% (95% CI -46 to 6; p=0·158) and between group C and group A was 10% (-20 to 40; p=0·591). The most common grade 3-4 adverse events were elevated liver enzymes in group A (six [20%)]) and colitis in group C (five [19%]); in group B, none of the grade 3-4 adverse events were seen in more than one patient. One patient (in group A) died 9·5 months after the start of treatment due to the consequences of late-onset immune-related encephalitis, which was possibly treatment-related. 19 (63% [95% CI 44-80]) of 30 patients in group A, 17 (57% [37-75]) of 30 in group B, and nine (35% [17-56]) of 26 in group C achieved a radiological objective response, while pathological responses occurred in 24 (80% [61-92]) patients in group A, 23 (77% [58-90]) in group B, and 17 (65% [44-83]) in group C.Interpretation: OpACIN-neo identified a tolerable neoadjuvant dosing schedule (group B: two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg) that induces a pathological response in a high proportion of patients and might be suitable for broader clinical use. When more mature data confirm these early observations, this schedule should be tested in randomised phase 3 studies versus adjuvant therapies, which are the current standard-of-care systemic therapy for patients with stage III melanoma.Funding: Bristol-Myers Squibb. [ABSTRACT FROM AUTHOR]

Background: Patients with advanced malignancies have historically been considered poor candidates for admission to the intensive care unit (ICU); however, prognosis is continually improving, and requirements for ICU access are increasing. Aim: To understand the characteristics and outcomes of oncology unit patients admitted to an Australian ICU and identify potential prognostic factors. Methods: A single‐centre, retrospective, cohort study conducted at a tertiary public hospital with a quaternary ICU in Sydney, Australia. All patients admitted under the medical oncology team requiring ICU admission between June 2014 and June 2016 were evaluated. Clinical outcomes were determined including mortality, ICU requirements (ventilation, dialysis, vasopressors, infection) and prognostic scores (Acute Physiologic and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) score). Results: There were 96 patients with mean age 61 years, 58% were male and 76% had metastatic disease. Most were receiving palliative treatment (89%), with recent chemotherapy (43%), immunotherapy (10%) and other therapies (5%). Of the 10 patients with recent immunotherapy, three (all with melanoma) required ICU admission due to immunotoxicity; 13% were admitted due to an oncological emergency. Mean APACHE II score was 17 (standard deviation (SD) 5.33), mean SOFA score was 3.99 (SD 2.70), ICU mortality was 5% and hospital mortality was 22%. Using multivariate logistic regression analysis, cancer stage, infection during ICU admission, intracranial mass effect on ICU admission and SOFA score were associated with 30‐day mortality. Conclusion: Our patient population had good short‐term survival outcomes despite most receiving palliative treatment. Cancer patients can achieve positive outcomes after ICU admission, and appropriate selection of patients is crucial. [ABSTRACT FROM AUTHOR]

Summary: Historically, the prognosis of patients with melanoma brain metastases is poor, with median overall survival (OS) of 4‐6 months. Little is known of OS in the era of modern systemic therapies and local therapy with stereotactic radiosurgery (SRS) or surgery. Patients diagnosed with melanoma brain metastases at Melanoma Institute Australia from January 2011 to December 2014 were included. OS and prognostic factors were analysed using Cox regression and Kaplan‐Meier survival analyses.355 patients were included. The median OS was 7.1 months (95% confidence interval [CI] 6.0‐8.1). Median OS differed by treatment modality: systemic therapy and SRS and/or surgery 14.9 months (95% CI 10.7‐19.0), SRS and/or surgery with or without whole brain radiotherapy (WBRT) 6.4 months (95% CI 5.4‐7.5), systemic therapy 5.4 months (95% CI 3.1‐7.7), systemic therapy and WBRT 5.2 months (95% CI 4.1‐6.4), WBRT 4.4 months (95% CI 2.4‐6.3), and best supportive care 1.8 months (95% CI 1.2‐2.3). OS for patients with melanoma brain metastases appears improved in the modern era, particularly for patients who are candidates for systemic therapy with SRS and/or surgery. [ABSTRACT FROM AUTHOR]

Background: Nivolumab monotherapy and combination nivolumab plus ipilimumab increase proportions of patients achieving a response and survival versus ipilimumab in patients with metastatic melanoma; however, efficacy in active brain metastases is unknown. We aimed to establish the efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with active melanoma brain metastases.Methods: This multicentre open-label randomised phase 2 trial was done at four sites in Australia, in three cohorts of immunotherapy-naive patients aged 18 years or older with melanoma brain metastases. Patients with asymptomatic brain metastases with no previous local brain therapy were randomly assigned using the biased coin minimisation method, stratified by site, in a 30:24 ratio (after a safety run-in of six patients) to cohort A (nivolumab plus ipilimumab) or cohort B (nivolumab). Patients with brain metastases in whom local therapy had failed, or who had neurological symptoms, or leptomeningeal disease were enrolled in non-randomised cohort C (nivolumab). Patients in cohort A received intravenous nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg every 3 weeks for four doses, then nivolumab 3 mg/kg every 2 weeks; patients in cohort B or cohort C received intravenous nivolumab 3 mg/kg every 2 weeks. The primary endpoint was intracranial response from week 12. Primary and safety analyses were done on an intention-to-treat basis in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02374242, and is ongoing for the final survival analysis.Findings: Between Nov 4, 2014, and April 21, 2017, 79 patients were enrolled; 36 in cohort A, 27 in cohort B, and 16 in cohort C. One patient in cohort A and two in cohort B were found to be ineligible and excluded from the study before receiving the study drug. At the data cutoff (Aug 28, 2017), with a median follow up of 17 months (IQR 8-25), intracranial responses were achieved by 16 (46%; 95% CI 29-63) of 35 patients in cohort A, five (20%; 7-41) of 25 in cohort B, and one (6%; 0-30) of 16 in cohort C. Intracranial complete responses occurred in six (17%) patients in cohort A, three (12%) in cohort B, and none in cohort C. Treatment-related adverse events occurred in 34 (97%) of 35 patients in cohort A, 17 (68%) of 25 in cohort B, and eight (50%) of 16 in cohort C. Grade 3 or 4 treatment-related adverse events occurred in 19 (54%) patients in cohort A, four (16%) in cohort B, and two (13%) in cohort C. No treatment-related deaths occurred.Interpretation: Nivolumab combined with ipilimumab and nivolumab monotherapy are active in melanoma brain metastases. A high proportion of patients achieved an intracranial response with the combination. Thus, nivolumab combined with ipilimumab should be considered as a first-line therapy for patients with asymptomatic untreated brain metastases.Funding: Melanoma Institute Australia and Bristol-Myers Squibb. [ABSTRACT FROM AUTHOR]

Background: Reduced-dose nivolumab in combination with standard-dose ipilimumab improves objective response and progression-free survival compared with standard-dose ipilimumab alone, but increases toxicity. We assessed the safety and anti-tumour activity of standard-dose pembrolizumab in combination with reduced-dose ipilimumab.Methods: In this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA. Eligible patients were aged at least 18 years, had advanced melanoma, had an Eastern Coooperative Oncology Group performance status of 0 or 1, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, had adequate organ function, had resolution of toxic effects of the most recent previous chemotherapy to grade 1 or less, had no active autoimmune disease requiring systemic steroids or immunosuppressive agents, had no active non-infectious pneumonitis, had no uncontrolled thyroid dysfunction or diabetes, had no active brain metastases, and had not received previous immune checkpoint inhibitor therapy. Patients received intravenous pembrolizumab 2 mg/kg plus intravenous ipilimumab 1 mg/kg every 3 weeks for four doses, followed by intravenous pembrolizumab 2 mg/kg every 3 weeks for up to 2 years or disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was safety and tolerability. The proportion of patients achieving an objective response assessed per RECIST version 1.1 by independent central review and overall survival were secondary endpoints. We also assessed progression-free survival. The primary endpoint was assessed in all patients who received at least one dose of combination therapy. Activity was assessed in all enrolled patients. This trial is registered with ClinicalTrials.gov, number NCT02089685. Enrolment into this cohort is closed, but patients are still being monitored for safety and anti-tumour activity.Findings: Between Jan 13, 2015, and Sept 17, 2015, we enrolled and treated 153 patients. As of the Oct 17, 2016, cutoff date, median follow-up was 17·0 months (IQR 14·8-18·8). 110 (72%) of 153 patients received all four pembrolizumab plus ipilimumab doses; 64 (42%) remained on pembrolizumab monotherapy. 110 grade 3-4 treatment-related adverse events occurred in 69 (45%) patients. No treatment-related deaths occurred. Treatment-related adverse events led to discontinuation of pembrolizumab and ipilimumab in 22 (14%) patients, including 17 (11%) who discontinued both treatments for the same event and five (3%) who discontinued ipilimumab for one event and later discontinued pembrolizumab for another. 12 (8%) patients discontinued ipilimumab only and 14 (9%) discontinued pembrolizumab only because of treatment-related adverse events. 158 immune-mediated adverse events of any grade occurred in 92 (60%) patients, and 50 immune-mediated adverse events of grade 3-4 occurred in 42 (27%) patients; the most common immune-mediated adverse events were hypothyroidism (25 [16%]) and hyperthyroidism (17 [11%]). 93 (61% [95% CI 53-69]) patients achieved an objective response. Estimated 1 year progression-free survival was 69% (95% CI 60-75), and estimated 1 year overall survival was 89% (95% CI 83-93).Interpretation: Standard-dose pembrolizumab given in combination with four doses of reduced-dose ipilimumab followed by standard-dose pembrolizumab has a manageable toxicity profile and provides robust anti-tumour activity in patients with advanced melanoma. These data suggest that standard-dose pembrolizumab plus reduced-dose ipilimumab might be a tolerable, efficacious treatment option for patients with advanced melanoma. A randomised phase 2 trial of alternative dosing strategies of this combination is underway.Funding: Merck & Co, Inc. [ABSTRACT FROM AUTHOR]

After more than two decades of extensive use, drugs based on platinum continue to have a major role in cancer treatment. Although systematic approaches to the development of new analogues have produced agents with less toxicity and novel mechanisms of action, to date such approaches have not achieved more cures than can be achieved with the parent compound, cisplatin. Greater gains might be expected from accumulating knowledge about what makes cancer cells sensitive or resistant to platinum-based chemotherapy. Recent information on drug-efflux pathways, including expression of multidrug-resistance protein 2, and on how tumour cells behave when their DNA is distorted by a platinum adduct, suggests new avenues for translational research. The prospects include modulation of cellular handling of platinum compounds and individualised therapy based on expression of molecules that determine platinum sensitivity. [ABSTRACT FROM AUTHOR]