Italian nivolumab Expanded Access Programme in melanoma adjuvant setting: patient outcomes and safety profile.

INTRODUCTION: The CheckMate 238 randomised study demonstrated the relevant benefit in terms of recurrence-free survival (RFS) of nivolumab versus ipilimumab in resected stage IIIB-C or IV melanoma patients with a tolerable safety profile. MATERIALS AND METHODS: From November 2018 to June 2019, 611 patients with stage III and IV resected melanoma were enroled to receive nivolumab as part of an Italian Expanded Access Programme (EAP). According to stages, 77% were stage III while 141 (23%) were stage IV with no evidence of disease (NED). Among stage III, 121 patients had IIIA (19.8%). RESULTS: After a median follow-up of 23 months, the RFS in the Intention-to-Treat (ITT) population was 76.6% at 1 year and 59.6% at 2 years; 1- and 2-year distant metastasis-free survival were 83.7% and 71.2%, respectively. The overall survival rate in the ITT population was 93.8% at 1 year and 85.5% at 2 years. No significant differences in RFS were observed according to BRAF status. Treatment-related adverse events of grades 3-4 occurred in 11.5% of patients. CONCLUSION: This paper reports the results of the Italian Nivolumab EAP in the adjuvant setting of stage III and IV NED melanoma patients. Our results confirm in a real-life setting the clinical activity and safety of nivolumab reported in the CheckMate238 registrative/pivotal. The enroled cohort of 611 patients highlights the relevant clinical need in this setting, also confirmed by the very short accrual time, representing one of the largest series reported as adjuvant EAP with the longest follow-up.

Dabrafenib plus trametinib is effective in the treatment of BRAF V600-mutated metastatic melanoma patients: analysis of patients from the dabrafenib plus trametinib Named Patient Program (DESCRIBE II).

In clinical trials, dabrafenib plus trametinib improved overall survival (OS) compared with single-agent BRAF inhibitors (BRAFi) in patients with BRAF V600-mutant unresectable or metastatic melanoma. We investigated dabrafenib plus trametinib therapy in a compassionate-use setting [Named Patient Program (NPP); DESCRIBE II]. A retrospective chart review of patients with BRAF V600-mutated unresectable stage III/IV melanoma receiving dabrafenib plus trametinib as compassionate use was conducted. Treatment patterns and duration, clinical outcomes, and tolerability were evaluated. Of 271 patients, 92.6% had stage IV melanoma, including 36.5% with brain metastases. Overall, 162 patients (59.8%) were BRAFi naive and 171 (63.1%) received first-line dabrafenib plus trametinib. Among BRAFi-naive patients, the overall response rate (ORR) was 67.3%, median OS (mOS) was 20.0 months, and median progression-free survival (mPFS) was 7.5 months. In BRAFi-naive patients with known brain metastases (n = 62), ORR was 61.3%, mOS was 15.5 months, and mPFS was 6.2 months. Eighty-four patients received BRAFi monotherapy for >30 days and switched to dabrafenib plus trametinib prior to progression. Of these 84 patients, 63 had known disease status at the time of switch, and 22 improved with the combination therapy. No new safety signals were identified, and dabrafenib plus trametinib was well tolerated. Dabrafenib plus trametinib showed substantial clinical activity in NPP patients with BRAF V600-mutated unresectable or metastatic melanoma. Analysis of treatment patterns demonstrated the effectiveness of the combination in patients with brain metastases and across lines of therapy with a well tolerated and manageable safety profile.

A meta-analysis of melanoma risk in industrial workers.

Industrial workers are exposed to occupational pollutants, which may cause diseases such as cancer, but links to melanoma are not established. The identification of industry-related risk factors for melanoma incidence and mortality might be of importance for workers, health providers, and insurance companies. To assess melanoma incidence and mortality among oil/petroleum, chemical, and electrical industry workers. All studies reporting standardized mortality ratios (SMR) and/or standardized incidence ratios (SIR) of melanoma in workers employed in oil/petroleum, chemical, and electrical industries were included. Random-effect meta-analyses were carried out to summarize SIR and SMR for melanoma among oil/petroleum, chemical, and electrical industry workers. Heterogeneity was assessed using χ and I statistics. Possible source bias and quality were assessed using the Strengthening the Reporting of Observational Studies in Epidemiology checklist and a modified version of the Newcastle-Ottawa scale. Of 1878 citations retrieved, we meta-analyzed 21, 6, and 9 studies for the oil/petroleum, electrical, and chemical industry, respectively. Oil/petroleum industry: summary standardized incidence ratio (SSIR) = 1.23 [95% confidence interval (CI): 1.11-1.36, I = 45%]; summary standardized mortality ratio (SSMR) = 1.02 (95% CI: 0.81-1.28, I = 48%); subgroups: SSIR = 1.16 (95% CI: 1.01-1.32, I = 15%), SSMR = 1.19 (95% CI: 1.00-1.42, I = 20%). Electrical industry: SSIR = 1.00 (95% CI: 0.93-1.11, I = 72%); SSMR = 1.16 (95% CI: 0.74-1.81, I = 11%). Chemical industry: SSIR = 2.08 (95% CI: 0.47-9.24, I = 73%); SSMR = 2.01 (95% CI: 1.09-3.72, I = 33%). Our meta-analysis suggests a slightly increased risk of developing melanoma among oil/petroleum industry workers and an increased melanoma mortality among oil/petroleum and chemical industry workers. No increased risks were found among electrical industry workers.

Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.

BACKGROUND: Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial. METHODS: We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 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 ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group. RESULTS: At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted. CONCLUSIONS: Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).

The impact of patient characteristics and disease-specific factors on first-line treatment decisions for BRAF-mutated melanoma: results from a European expert panel study.

Treatment decisions for advanced melanoma are increasingly complex and guidelines provide limited advice on how to choose between immunotherapy and targeted therapy for first-line treatment. A Delphi study was carried out to understand which patient characteristics and disease-related factors inform clinicians' choices of first-line treatment for BRAF-mutated melanoma. Twelve European melanoma specialists experienced in using immunotherapies and targeted agents participated in a double-blind two-phase Delphi study. In phase 1, participants completed a questionnaire developed after reviewing patient characteristics and disease-related factors reported in trials, clinical guidelines, and health technology assessments. Phase 2 was an expert panel meeting to explore outstanding issues from phase 1 and seek consensus, defined as 80% agreement. Twenty patient-related and disease-related characteristics were considered. There was consensus that tumor burden (83% of clinicians) and disease tempo (83%) are very or extremely important factors when selecting first-line treatment. Several components were deemed important when assessing tumor burden: brain metastases (82% of clinicians) and location of metastases (89%). There was consensus that disease tempo can be quantified in clinical practice, but not on a formal classification applicable to all patients. Lactate dehydrogenase level is a component of both tumor burden and disease tempo; all clinicians considered lactate dehydrogenase important when choosing first-line treatment. The majority (92%) did not routinely test programmed death ligand-1 status in patients with melanoma. Clinicians agreed that choosing a first-line treatment for advanced melanoma is a complex, multifactorial process and that clinical judgment remains the most important element of decision-making until research can provide clinicians with better scientific parameters and tools for first-line decision-making.

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.

BACKGROUND: Nivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial. METHODS: We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group versus the ipilimumab group. RESULTS: At a minimum follow-up of 36 months, the median overall survival had not been reached in the nivolumab-plus-ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group. CONCLUSIONS: Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505 .).

Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.

BACKGROUND: Nivolumab (a programmed death 1 [PD-1] checkpoint inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] checkpoint inhibitor) have been shown to have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab plus ipilimumab was compared with ipilimumab alone in patients with metastatic melanoma. METHODS: We assigned, in a 1:1:1 ratio, 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone. Progression-free survival and overall survival were coprimary end points. Results regarding progression-free survival are presented here. RESULTS: The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group. CONCLUSIONS: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).

Dacarbazine in combination with bevacizumab for the treatment of unresectable/metastatic melanoma: a phase II study.

The combined treatment of dacarbazine with an antiangiogenic drug such as bevacizumab may potentiate the therapeutic effects of dacarbazine in metastatic melanoma (MM). Preliminary antitumour activity of dacarbazine plus bevacizumab is evaluated, together with the toxicity and safety profile, in MM patients. This prospective, open-label, phase II study included patients with previously untreated MM or unresectable melanoma. Patients received dacarbazine and bevacizumab until progressive disease or unacceptable toxicity. The primary efficacy variable was the overall response rate. The secondary efficacy parameters included duration of response, duration of stable disease, time to progression/progression-free survival, time to treatment failure and overall survival. The safety analysis included recordings of adverse events and exposure to study treatment. The intention-to-treat population included 37 patients (24 men and 13 women, mean age 54.2±13.1 years). Overall response rate was 18.9% (seven patients achieved a response) and clinical benefit was 48.6%. In patients who achieved a response, the median duration of response was 16.9 months and the median duration of stable disease was 12.5 months. The median time to progression/progression-free survival and time to treatment failure were 5.5 and 3.1 months, respectively. The median overall survival was 11.4 months. Almost all patients (94.6%) experienced at least one adverse event; however, no new area of toxicity of bevacizumab emerged. The dacarbazine/bevacizumab combination provides benefits compared with dacarbazine monotherapy in historical controls, with an acceptable safety profile. This combination appears to be a valid option in specific subgroups of patients, namely, those triple negative (BRAF, C-KIT and NRAS wild type) or with a BRAF mutation who have already received, or are not eligible for, immunomodulating or targeted agents.

Efficacy and safety of ipilimumab 3mg/kg in patients with pretreated, metastatic, mucosal melanoma.

BACKGROUND: Mucosal melanoma is an extremely rare and aggressive malignancy that often remains undetected until it reaches an advanced stage, when effective treatment options are limited. The activity and safety of ipilimumab were assessed in an Expanded Access Programme (EAP) that included patients with metastatic, mucosal melanoma. METHODS: Ipilimumab was available upon physician request for patients aged ⩾16years with stage III (unresectable) or IV skin, ocular or mucosal melanoma, who had failed or did not tolerate previous treatments and had no other therapeutic option available. Patients received ipilimumab 3mg/kg every 3weeks for four doses. Patients with stable disease or an objective response to ipilimumab were eligible for retreatment upon disease progression. Tumour assessments were conducted at baseline and week 12 using immune-related response criteria. Patients were monitored for adverse events (AEs), including immune-related AEs, within 3 to 4days of each scheduled visit. RESULTS: Of 855 patients participating in the EAP in Italy, 71 (8%) had metastatic, mucosal melanoma. With a median follow-up of 21.8months, the response rate was 12% and the immune-related disease control rate was 36%. Median progression-free survival and overall survival were 4.3 and 6.4months, respectively. In total, 34% of patients reported treatment-related AEs of any grade, which were grade 3 or 4 in 9% of patients. AEs were generally manageable as per protocol-specific guidelines. CONCLUSION/INTERPRETATION: Ipilimumab may be a feasible treatment option in pretreated patients with metastatic mucosal melanoma, and warrants further investigation in prospective clinical trials.

Oncophage: step to the future for vaccine therapy in melanoma.

Heat-shock proteins (HSPs) are a group of proteins whose expression is increased when the cells are exposed to elevated temperatures or other stressful conditions. This increase in expression is transcriptionally regulated. The function of HSPs is similar in virtually all living organisms, from bacteria to humans. Their expression also occur under non-stressful conditions, simply 'monitoring' the cell's proteins, i.e., they carry old proteins to the cell's 'recycling bin' and they help newly synthesized proteins fold properly. These activities are part of a cell's own repair system. HSPs are molecular chaperones for protein molecules. They are usually cytoplasmic proteins and they perform functions in various intracellular processes. Tumour-derived HSP-peptide complexes (HSPPCs) can be used for vaccination against malignancies. In particular, HSPPC-96 complex, called Vitespen (formerly Oncophage) is a HSPs-based vaccine made from individual patients' tumours with a promising role in cancer management. This vaccine has been extensively studied in Phase I and II clinical trials, showing activity on different malignancies, including gastric cancer, colorectal cancer, pancreatic cancer, non-Hodgkin's lymphoma and chronic myelogenous leukaemia. The vaccine has also been studied in Phase III clinical trials in melanoma and kidney cancer, showing an excellent safety profile with essentially no toxicity. Thus, HSP-based vaccines are a novel therapeutic approach with a promising role in cancer management.

Anti-CTLA4 monoclonal antibody Ipilimumab in the treatment of metastatic melanoma: recent findings.

Use of monoclonal anti-CTLA4 antibodies represents a new promising strategy to block the activation of immunosuppressive CTLA-4 and thus induce tumour regression. This review is mainly focused on the report of existing data on the clinical use of Ipilimumab (formerly MDX-010) in the treatment of metastatic melanoma. Several phase I and II trials have been conducted to evaluate safety and efficacy of this form of immunotherapy either alone or in combination with vaccines or chemotherapy in patients with stage III or stage IV melanoma. Results from these studies are presented, patented and discussed. The mechanism of ipilimumab action may take time to induce an anti-tumour immune response and thus it is recommended that ipilimumab therapy should be carried out for at least 12 weeks, even in the presence of early progressive disease. Objective response of around 15% has been reported in patients treated with ipilimumab. However, ipilimumab-mediated objective response and stable disease tend to be durable. The therapy with ipilimumab is associated with different side effects classified as immune-related adverse events (IRAEs). The most common IRAEs are enterocolitis and dermatitis. Majority of IRAEs disappear with the discontinuation of ipilimumab anti-CTLA-4 therapy. Several phase II/III trials are ongoing to evaluate ipilimumab alone or in combination with other therapeutic modalities. Results from these trials are awaited.

High activity 90Y-ibritumomab tiuxetan (Zevalin) with peripheral blood progenitor cells support in patients with refractory/resistant B-cell non-Hodgkin lymphomas.

Radioimmunotherapy (RIT) is an alternative approach in the treatment of resistant/refractory B-cell non-Hodgkin lymphoma (NHL). We performed a feasibility and toxicity pilot study of escalating activity of 90Y-ibritumomab tiuxetan followed by autologous stem cell transplantation (ASCT). Three activity levels were fixed--30 MBq/kg (0.8 mCi/kg), 45 MBq/kg (1.2 mCi/kg) and 56 MBq/kg (1.5 mCi/kg)--and 13 patients enrolled. One week before treatment all patients underwent dosimetry. ASCT was performed 13 d after Zevalin administration. Treatment was well tolerated and all patients engrafted promptly. No differences in terms of haematological toxicities were observed among the three levels, apart from a delayed platelet recovery in heavily pretreated patients receiving 56 MBq/kg. Non-haematologic toxicity was mainly related to infections and liver toxicity. One patient died 4 months after treatment because of hepatitis C virus reactivation. One patient developed a myelodysplastic syndrome 2 years after treatment. In conclusion, high-activity Zevalin with ASCT is feasible and could be safely delivered in elderly and heavily pretreated NHL patients, including those who previously received high-dose chemotherapy and ASCT. Maximum tolerated dose was not clearly defined according to dosimetry and clinical toxicities, and further studies are needed to confirm the toxicity profile and evaluate efficacy.