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Tebentafusp is a bispecific molecule that recognizes CD3 and gp100. In a trial in patients with uveal melanoma, median survival at 3 years of follow-up was 21.6 months with tebentafusp and 16.9 months with standard therapy.

Two defined immune checkpoints have been exploited for cancer treatment. LAG-3 is a third immune checkpoint that blocks lymphocyte activation. Relatlimab, a monoclonal antibody against LAG-3, interferes with this block. Relatlimab plus nivolumab as compared with nivolumab alone in melanoma produced superior progression-free survival.

In long-term follow-up of more than 500 patients with melanoma containing a BRAF V600E or V600K mutation, a combination of dabrafenib plus trametinib was associated with progression-free survival in 19% of the patients and overall survival in 34% at 5 years. A complete response to dabrafenib plus trametinib was the strongest predictor of long-term survival.

Previous results from this trial showed longer overall survival after treatment with nivolumab plus ipilimumab or with nivolumab monotherapy than with ipilimumab monotherapy in patients with advanced melanoma. Given that patients with advanced melanoma are living longer than 7.5 years, longer-term data were needed to address new clinically relevant questions. We randomly assigned patients with previously untreated advanced melanoma, in a 1:1:1 ratio, to one of the following regimens: nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks; nivolumab (3 mg per kilogram) every 2 weeks plus placebo; or ipilimumab (3 mg per kilogram) every 3 weeks for four doses plus placebo. Treatment was continued until the occurrence of disease progression, unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to mutation status, metastasis stage, and programmed death ligand 1 expression. Here, we report the final, 10-year results of this trial, including results for overall survival and melanoma-specific survival, as well as durability of response. With a minimum follow-up of 10 years, median overall survival was 71.9 months with nivolumab plus ipilimumab, 36.9 months with nivolumab, and 19.9 months with ipilimumab. The hazard ratio for death was 0.53 (95% confidence interval [CI], 0.44 to 0.65) for nivolumab plus ipilimumab as compared with ipilimumab and was 0.63 (95% CI, 0.52 to 0.76) for nivolumab as compared with ipilimumab. Median melanoma-specific survival was more than 120 months with nivolumab plus ipilimumab (not reached, with 37% of the patients alive at the end of the trial), 49.4 months with nivolumab, and 21.9 months with ipilimumab. Among patients who had been alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with nivolumab plus ipilimumab, 97% with nivolumab, and 88% with ipilimumab. The final trial results showed a continued, ongoing survival benefit with nivolumab plus ipilimumab and with nivolumab monotherapy, as compared with ipilimumab monotherapy, in patients with advanced melanoma. (Funded by Bristol Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).

Metastatic uveal melanoma is an aggressive disease without an established standard treatment. In a randomized trial that evaluated tebentafusp, a soluble T-cell receptor bispecific protein, overall survival at 1 year was 73% among patients who received tebentafusp, as compared with 59% among those who received the investigator’s choice of therapy.

Patients with melanoma and positive sentinel nodes were randomly assigned to completion lymph-node dissection or observation. Melanoma-specific survival did not differ significantly between the groups. Sentinel-lymph-node biopsy is a standard procedure in the care of appropriately selected patients with melanoma. The first Multicenter Selective Lymphadenectomy Trial (MSLT-I) confirmed the value of early nodal evaluation and treatment. 1 – 3 This prospective, international, randomized trial showed that the pathologic status of the sentinel node or nodes was the most important prognostic factor and that patients who underwent sentinel-node biopsy had fewer recurrences of melanoma than patients who underwent wide excision and nodal observation. Among patients with intermediate-thickness melanomas (defined as 1.2 to 3.5 mm) and nodal metastases, early surgical treatment, guided by sentinel-node biopsy, was associated with increased . . .

In this trial, the anti–programmed death 1 antibody nivolumab was associated with a significantly higher response rate and longer survival than standard dacarbazine chemotherapy in previously untreated patients with metastatic melanoma without a BRAF mutation. The global incidence of melanoma continues to rise, and the mortality associated with unresectable or metastatic melanoma remains high. 1 Globally, 132,000 new cases of melanoma are diagnosed and an estimated 48,000 persons die from advanced melanoma each year. 2 , 3 Ipilimumab has been shown to improve the rate of survival at 2 years, as compared with a vaccine control, among previously treated patients with metastatic melanoma as well as among previously untreated patients who also received dacarbazine. 4 , 5 BRAF and MEK inhibitors are approved agents that, as monotherapy, have been associated with a survival advantage as compared with chemotherapy, with a . . .

The combination of inhibitors to BRAF and MEK improved response rates and progression-free survival among patients with metastatic melanoma. Some toxicity was increased, but the incidence of second skin cancers was drastically reduced by the combination therapy. Approximately 50% of metastatic cutaneous melanomas harbor a BRAF V600 mutation, resulting in constitutive activation of the mitogen-activated protein kinase (MAPK) pathway. 1 , 2 These discoveries led to the development of agents that specifically target this driver mutation. The BRAF inhibitor vemurafenib (Zelboraf, Genentech) was approved worldwide on the basis of results from a phase 3 trial showing improved progression-free survival and overall survival, as compared with chemotherapy alone; the relative reduction in the risk of death was 63% and in the risk of disease progression was 74%. 3 Similar results were also reported for another BRAF inhibitor, dabrafenib, 4 which has also . . .

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. 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. 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). 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. Merck & Co, Inc.

The authors treated 676 patients with metastatic melanoma with an antibody to CTLA-4 (ipilimumab), the antibody plus a gp100 vaccine, or the vaccine alone. Patients who received ipilimumab with or without gp100 vaccine survived nearly 4 months longer than did those who received the gp100 vaccine alone. Adverse immune-related events were noted and some were severe, but most were reversible with appropriate treatment. The incidence of metastatic melanoma has increased over the past three decades, 1 , 2 and the death rate continues to rise faster than the rate with most cancers. 3 The World Health Organization (WHO) estimates that worldwide there are 66,000 deaths annually from skin cancer, with approximately 80% due to melanoma. 4 In the United States alone, an estimated 8600 persons died from melanoma in 2009. 1 The median survival of patients with melanoma who have distant metastases (American Joint Committee on Cancer stage IV) is less than 1 year. 5 , 6 No therapy is approved beyond the first-line therapy for metastatic melanoma, and enrollment . . .