Toripalimab (anti-PD-1) versus high-dose interferon-α2b as adjuvant therapy in resected mucosal melanoma: a phase II randomized trial.

BACKGROUND: No standard of care for mucosal melanoma (MM) in the adjuvant setting has been established. Meanwhile, relapse-free survival (RFS) is only ∼5 months after surgery alone. This phase II trial aimed to compare toripalimab versus high-dose interferon-α2b (HDI) as an adjuvant therapy for resected MM. PATIENTS AND METHODS: From July 2017 to May 2019, 145 patients with resected MM were randomized (1 : 1) to receive HDI (n = 72) or toripalimab (n = 73) for 1 year until disease relapse/distant metastasis, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS. The secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS), and safety. RESULTS: After a median follow-up of 26.3 months, the number of RFS, OS, and DMFS events was 51 versus 46, 33 versus 29, and 49 versus 44 in the toripalimab arm and the HDI arm, respectively. The median RFS was 13.6 [95% confidence interval (CI) 8.31-19.02] months and 13.9 (95% CI 8.28-19.61) months in the toripalimab arm and the HDI arm, respectively. The DMFS was not significantly different between the two arms [hazard ratio (HR) 1.00; 95% CI 0.65-1.54]. The median OS was 35.1 months (95% CI 27.93 months-not reached) in the toripalimab arm, with no significant difference in all-cause death (HR 1.11, 95% CI 0.66-1.84) for the two arms. The median sums of the patients' actual infusion doses were 3672 mg and 1054.5 MIU in the toripalimab arm and the HDI arm, respectively. The incidence of treatment-emergent adverse events with a grade ≥3 was much higher in the HDI arm than in the toripalimab arm (87.5% versus 27.4%). CONCLUSIONS: Toripalimab showed a similar RFS and a more favorable safety profile than HDI, both better than historical data, suggesting that toripalimab might be the better treatment option. However, additional translational studies and better treatment regimens are still warranted to improve the clinical outcome of MM.

An updated analysis of 4 randomized ECOG trials of high-dose interferon in the adjuvant treatment of melanoma.

BACKGROUND: The pivotal E1684, E1690, E1694, and E2696 trials of adjuvant high-dose interferon-α (HDI) enrolled nearly 2000 patients, and established HDI as the standard of care in adjuvant therapy for patients with resected high-risk melanoma. Herein, the authors present an updated analysis of these 4 trials. METHODS: Survival and disease status were updated in September 2016. These data represent a median follow-up of 17.9 years for the E1684 trial, 12.2 years for the E1690 trial, 16.0 years for the E1694 trial, and 16.5 years for the E2696 trial. RESULTS: The current analysis confirmed the benefit to recurrence-free survival (RFS) of HDI in the E1684 trial at a median follow-up of 17.9 years. The RFS benefit in the E1694 trial remained evident at a median follow-up of 16 years. Furthermore, the results of the current study confirmed the RFS benefit of adjuvant HDI compared with observation in a pooled analysis of the E1684 and E1690 trials. No overall survival benefit was apparent in this pooled analysis. Updated results for the E1690 and E2696 trials did not differ from those previously reported. In addition, to the authors' knowledge, the current study is the first to report a significant difference in melanoma-specific survival (MSS) between patients treated with HDI compared with the ganglioside GM2/keyhole limpet hemocyanin (GMK) vaccine in the E1694 trial. CONCLUSIONS: In patients with resected high-risk melanoma, adjuvant HDI demonstrated improved RFS in the E1684 and E1694 trials, and improved MSS in a pooled analysis of HDI in the E1694 trial. To the authors' knowledge, these findings represent the most mature level of evidence for the benefit of HDI with respect to RFS and MSS. HDI is the only approved adjuvant treatment for which there are data available in patients with resected stage IIB/IIC melanoma, and remains a reasonable treatment option in this population.

Assessment of Incidence and Character of Neurologic/ Neuropsychiatric Complications in a Group of Patients with Malignant Melanoma Treated with Adjuvant High Dose Interferon.

BACKGROUND: Authors describe the incidence and character of neurologic and neuropsychiatric complications - particularly depression and parkinsonism - during adjuvant treatment of malignant melanoma (MM) with high dose interferon (HDI). Among the most frequently observed side effects are fatigue, hematotoxicity, and hepatotoxicity. Most research has been directed at depression and parkinsonism because of the lack of literature concerning these complications. Interferon induced parkinsonism has only been described rarely and only in case reports. PATIENTS AND METHODS: Twenty-nine patients with MM, treated from January 2010 to January 2014 with adjuvant high dose interferon alfa-2b intravenous (HDI 20MIU/sqm for 5 days per week during the first 4 weeks, and then maintenance subcutaneous 10MIU/sqm up to a total time of 1 year) were retrospectively evaluated and the incidence and character of neurologic and neuropsychiatric complications were determined. RESULTS: Significant neurologic and neuropsychiatric complications were observed in 3 of the 29 patients. Dose modifications were required in 2 cases. One case developed parkinsonism and treatment had to be stopped after 10 applications of intravenous interferon. CONCLUSION: High dose interferon can cause depression and parkinsonism. Prophylaxis with antidepressant medication can keep the incidence of depression as low as 10% or lower. Development of parkinsonism during HDI is rare. According to available reports, this is the first description of parkinsonism development related to HDI in MM. Key words malignant melanoma - high dose interferon - neurologic and neuropsychiatric complication - drug-induced depression - drug-induced  parkinsonism The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 7. 4. 2018 Accepted: 16. 8. 2018.

Mental health services use by melanoma patients receiving adjuvant interferon: association of pre-treatment mental health care with early discontinuation.

BACKGROUND: Although high-dose interferon (hd-ifn) is the sole approved adjuvant systemic treatment for melanoma in many jurisdictions, it is toxic. We sought to assess the population-level effects of hd-ifn toxicity, particularly neuropsychiatric toxicity, hypothesizing that such toxicity would have the greatest effect on mental health services use in advanced resected melanoma. METHODS: This retrospective population-based registry study considered all melanoma patients receiving adjuvant hd-ifn in Ontario during 2008-2012. Toxicity was investigated through health services use compatible with hd-ifn toxicity (for example, mental health physician billings). Using stage data reported from cancer centres about a subset of patients (stages iib-iiic), a propensity-matched analysis compared such service use in patients who did and did not receive hd-ifn. Associations between early hd-ifn discontinuation and health services use were examined. RESULTS: Of 718 melanoma patients who received hd-ifn, 12% were 65 years of age and older, and 83% had few or no comorbidities. One third of the patients experienced 1 or more toxicity-associated health care utilization events within 1 year of starting hd-ifn. Of 420 utilization events, 364 (87%) were mental health-related, with 54% being family practitioner visits, and 39% being psychiatrist visits. In the propensity-matched analysis, patients receiving hd-ifn were more likely than untreated matched controls to use a mental health service (p = 0.01), with 42% of the control group and 51% of the hd-ifn group using a mental health service in the period spanning the 12 months before to the 24 months after diagnosis. In the multivariable analysis, early drug discontinuation was more likely in the presence of pre-existing mental health issues (odds ratio: 2.0; 95% confidence limits: 1.1, 3.4). CONCLUSIONS: Stage iib-iiic melanoma patients carry a substantial burden of mental health services use whether or not receiving hd-ifn, highlighting an important survivorship issue for these patients. High-dose interferon is associated with more use of mental health services, and pre-treatment use of mental health services is associated with treatment discontinuation. That association should be kept in mind when hd-ifn is being considered.

Adjuvant Therapy in Acral Melanoma: A Systematic Review.

Background: Acral melanoma presents distinct biological characteristics compared to cutaneous melanoma. While adjuvant therapeutic strategies for high-risk resected acral melanoma closely resemble those for cutaneous melanoma, the evidence supporting the clinical application of adjuvant therapy for acral melanoma remains inadequate. Our aim was to systematically analyze the efficacy and safety profile of adjuvant therapy in acral melanoma. Methods: This systematic review adhered to a pre-registered protocol. We comprehensively searched four electronic databases and reference lists of included articles to identify eligible studies. The primary outcome was therapeutic efficacy, and the secondary outcome was adverse events (AEs). Results: This systematic review included 11 studies with 758 acral melanoma patients undergoing adjuvant therapy. High-dose interferon α-2b (IFN) regimens showed no significant difference in recurrence-free survival (RFS), though the longer regimen was linked to increased hepatotoxicity. Adjuvant anti-PD-1 therapy demonstrated varying efficacy, with improved RFS in patients who experienced immune-related AEs. Targeted therapy with dabrafenib plus trametinib achieved high 12-month RFS in patients with BRAF-mutated acral melanoma. Comparative studies suggested that adjuvant anti-PD-1 therapy is similarly effective to IFN in prolonging survival for high-risk acral melanoma patients. Additionally, prior treatment with pegylated IFN enhanced RFS in patients receiving adjuvant pembrolizumab. Conclusion: High-dose IFN was widely used as adjuvant therapy for acral melanoma, but serious AEs prompted the search for alternatives. Adjuvant anti-PD-1 therapy shows promise, though it may be less effective than in non-acral melanoma. Further prospective studies are needed to determine the optimal adjuvant treatment for acral melanoma.

Chemotherapy in combination with anti-PD-1 agents as adjuvant therapy for high-risk oral mucosal melanoma.

BACKGROUND: Adjuvant therapy plays a critical role in the treatment of oral mucosal melanoma (OMM). Anti-programmed cell death-1 (PD-1) agents are recommended as front-line therapy for metastatic melanoma, but their efficacy as adjuvant therapy for high-risk OMM remains unclear. PATIENTS AND METHODS: A single-center, retrospective cohort study was conducted in 193 nodular-type oral mucosal melanoma (NOMM) patients who received chemotherapy alone or in combination with high-dose interferon-α2b (HDI) or anti-PD-1 agents as adjuvant therapy. Multivariate analysis was performed to identify significant prognostic factors for the 2-year overall survival (OS) and progression-free survival (PFS). RESULTS: Tumor thickness, ulceration and invasion level were found to be independent prognostic factors for both 2-year OS and PFS, while T-stage was only associated with OS. The 2-year OS and PFS were 43.5% and 10.9% in patients who received only chemotherapy. In comparison, the 2-year OS was improved, albeit not significantly (47.4%; p > 0.05), and PFS was significantly improved (43.6%; p = 0.0028) in patients who received chemotherapy plus HDI; and both 2-year OS (71.0%; p = 0.0118) and PFS (53.6%; p = 0.0001) were significantly improved in patients received chemotherapy plus anti-PD-1. The serious adverse event (SAE) (p < 0.0001) and discontinued treatment due to SAE (p < 0.0001) were significantly lower in patients who received anti-PD-1 than in patients who received HDI. CONCLUSIONS: Invasion level and tumor thickness are independent prognostic factors for NOMM. Chemotherapy plus anti-PD-1 agents seem to be the adjuvant therapy of choice for NOMM, as it is safer and more tolerable than HDI and, more importantly, it can significantly improve the OS and PFS.

The pharmacotherapeutic management of nail unit and acral melanomas.

INTRODUCTION: Acral and nail unit melanomas are rare subtypes of melanoma, which have poor prognoses. Current guidelines for optimal treatment are lacking. Recent clinical trials have evaluated new pharmacotherapeutic agents for melanoma treatment, with dramatically improved survival rates; however, studies on acral and nail unit melanomas are limited in comparison to trials on cutaneous melanoma. AREAS COVERED: This is a comprehensive review of the literature regarding the available treatment options for acral and nail unit melanomas, with consideration of safety and tolerability. EXPERT OPINION: Programmed cell death protein 1 inhibitors are more efficacious than cytotoxic T lymphocyte-associated antigen-4 blockers in acral and nail unit melanomas, although both are well-tolerated. Tyrosine kinase inhibitors have good clinical activity, however, data on safety is relatively limited. There is minimal data on high dose interferon α-2b and cyclin-dependent kinase 4 and 6 inhibitors, and efficacy and safety must be evaluated in future trials before they can be recommended for use in this patient population. Prospective clinical trials on acral and nail unit melanomas are lacking, and must be performed in large patient populations, with international collaboration likely necessary in order to enroll adequate participants.

Cost-effectiveness of ipilimumab versus high-dose interferon as an adjuvant therapy in resected high-risk melanoma.

BACKGROUND: Adjuvant ipilimumab was found to improve the overall survival and reduce toxicity compared to high-dose interferon (HDI) in patients with resected, high-risk melanoma. However, the cost of ipilimumab is substantially higher than HDI. This study evaluates the cost-effectiveness of ipilimumab as an adjuvant treatment in melanoma from a healthcare perspective. METHODS: We designed a Markov model simulating resected, high-risk melanoma patients receiving either ipilimumab or HDI. Transition probabilities, including risks of survival, disease progression, and toxicity, were ascertained from clinical trial data. Costs and quality of life measurements (health utilities) were extracted from the literature. Incremental cost-effectiveness ratios (ICERs), defined as incremental costs divided by incremental quality-adjusted life-years (QALYs), assessed cost-effectiveness. ICERs <$100,000/QALY were deemed cost-effective. We measured model uncertainty with one-way and probabilistic sensitivity analyses. RESULTS: In our base case model, ipilimumab increased costs by $107,100 and increased effectiveness by 0.43 QALY, yielding an ICER of $392,600/QALY. Our model was moderately sensitive to the costs of ipilimumab, though the cost of ipilimumab would need to decrease by 44% for ipilimumab to become cost-effective compared to HDI. The model was not sensitive to survival, toxicity, or other costs. Probabilistic sensitivity analysis showed that HDI would remain the cost-effective treatment option 96.2% of the time at a willingness-to-pay threshold of $100,000/QALY. CONCLUSIONS: Adjuvant ipilimumab increases the survival and decreases the toxicity compared to HDI in resected, high-risk melanoma patients, though this would not be considered cost-effective due to the high price of ipilimumab.

Comparison of the effects of low dose interferon and high dose interferon on reduction of the number and size of plaques in patients with Multiple Sclerosis: A historical cohort.

Background: This study was performed to compare the effects of low dose interferon beta-1 (IFN-ß-1) (CinnoVex, 30 mcg) and high dose IFN-ß-1 (REBIF, 44 mcg) on the reduction of the number and size of plaques in magnetic resonance imaging (MRI) in patients with multiple sclerosis (MS). Methods: This historical cohort study, which was performed in 2014 in Sanandaj (western part of Iran). 43 MS patients in two groups were investigated. The first group, which included 19 patients, was treated using high dose IFN (44 mcg) and the second group, which was consisted of 24 patients, was treated using low dose IFN (30 mcg). Patients' data were collected and analyzed by the Stata version 11 software; the analyses were performed using statistical t-test, chi-square test, Fisher test, and logistic regression. Results: Both drugs were effective in controlling active demyelinating plaque and in preventing plaque activation (P = 0.633). The impact of both drugs in the reduction of the number and size of plaques was evaluated. Based on the results of the MRI, high dose IFN therapy was more effective than the low dose IFN drugs and had a better performance in terms of reducing the number of plaques and in stop-and-recovery (P = 0.039), as well as in reducing the plaque size (P = 0.050). Conclusion: The high dose IFN therapy was more effective than the low dose IFN therapy in reducing the number and size of brain plaques in patients with relapsing-remitting MS (RRMS).

Efficacy and tolerability of combination therapy with interferon-alfa plus ribavirin in patients with chronic hepatitis C virus infection: a single-center study in relapsers and nonresponders to previous treatment with high-dose interferon-alfa monotherapy.

BACKGROUND: In chronic hepatitis C virus (HCV) infection, interferon (IFN) monotherapy usually is carried out at doses of 3 to 6 million units (MU) 3 times per week, but treatment efficacy is low. OBJECTIVE: The aim of our study was to assess the efficacy and tolerability of IFN-alfa2b in combination with ribavirin in relapsers and nonresponders to high-dose IFN treatment (5 to 6 MU 3 times per week). We measured the biochemical and virologic responses to treatment and the risk for relapse during the 24 weeks following the end of treatment. METHODS: Patients with chronic HCV infection (relapsers and nonresponders to a previous treatment with high-dose IFN) received IFN-alfa2b, 3 MU 3 times per week, and ribavirin, 1000 or 1200 mg/d for 24 or 48 weeks. The patients were then followed up for an additional 24 weeks. Sustained response was defined as normal serum alanine aminotransferase (ALT) level and undetectable HCV RNA 24 weeks after treatment was stopped. RESULTS: Forty-three patients (32 men, 11 women; mean [SD] age, 45 [2] years; 10 relapsers, 33 nonresponders) were included in the study. Four patients were withdrawn from the study at week 4 of treatment because of treatment-related adverse events, and 1 dropped out. At the end of the treatment period, normalization of serum ALT levels and undetectable HCV RNA levels were seen in 58.1% and 30.2% of patients, respectively. No significant difference in virologic response at the end of treatment was found between nonresponders (10/33 [30.3%]) to previous IFN therapy and relapsers (3/10 [30.0%]). At the end of follow-up, 3 (7.0%) treated patients had sustained response (2 nonresponders to the first IFN course and 1 relapser). All of the patients with sustained response were treated for 24 weeks. CONCLUSION: Based on the results of our study, combination therapy with IFN-alfa and ribavirin may be of value in a limited number of patients with chronic HCV infection who do not respond to, or relapse after, a first course of treatment with high-dose IFN monotherapy.