Cost-effectiveness of Response-Adapted De-escalation of Immunotherapy in Advanced Melanoma.

Importance: Combination immunotherapy with nivolumab and ipilimumab has markedly improved outcomes for patients with advanced melanoma. However, these therapies pose a considerable financial burden to both patients and the health care system. The ADAPT-IT trial demonstrated comparable progression-free and overall survival for patients with response-adapted ipilimumab discontinuation compared with standard of care (SOC). Objective: To determine the cost-effectiveness of ipilimumab discontinuation for patients with interim imaging-confirmed tumor response in the treatment of advanced melanoma. Design, Setting, and Participants: This cost-effectiveness analysis was performed using data from the ADAPT-IT (follow-up of 33 months) and CheckMate 067 (follow-up of 6.5 years) trials, as well as published literature over the ADAPT-IT trial duration of 33 months. The analysis was performed in a US setting from a US-payer perspective, and the willingness-to-pay (WTP) threshold was set at $100 000/quality-adjusted life-year (QALY). A total of 355 patients with previously untreated melanoma (unresectable stage III or IV metastatic melanoma) were included. Exposure: Response-adapted ipilimumab discontinuation compared with SOC therapy. Main Outcomes and Measures: The primary outcomes of the CheckMate trial were overall survival and progression-free survival, while that of ADAPT-IT was objective response. This informed a decision model to estimate lifetime costs and QALYs associated with both strategies. Incremental cost, effectiveness, and cost-effectiveness ratio were assessed. Sensitivity and scenario analyses were performed to account for variability in trials and input parameters. Results: Of the 355 patients included in the analysis, 41 patients were from the ADAPT-IT trial (median age, 65 years; 28 [68%] male) and 314 patients from the CheckMate 067 trial (median age, 61 years; 206 [66%] male). Response-adapted treatment was the cost-effective option in 94.0% of scenarios based on Monte Carlo simulations, with a dominant incremental cost-effectiveness ratio and an incremental net monetary benefit of $28 849 compared with SOC therapy. Cost savings were estimated at $19 891 per patient compared with SOC. In scenario analyses, current SOC was only considered as a cost-effective option under best survival assumptions and if the willingness-to-pay threshold exceeded $630 000/QALY. Conclusions and Relevance: This economic evaluation demonstrated that response-adapted treatment de-escalation in patients with advanced melanoma may lead to considerable savings in health care costs and could represent the most cost-effective strategy across various resource settings. Future trials should aim to provide further evidence on noninferiority.

Assessment of sorafenib induced changes in tumor perfusion of uveal melanoma metastases with dynamic contrast-enhanced ultrasound (DCE-US).

PURPOSE: Dynamic contrast-enhanced ultrasound (DCE-US) was used to monitor early response to sorafenib therapy in patients with liver metastases from uveal melanoma. METHODS: In total, 21 patients with liver metastases were recruited within a prospective trial and underwent daily sorafenib therapy. DCE-US of a target lesion was performed before initiation of treatment, on day 15 and 56. Two independent blinded investigators performed software analysis for DCE-US parameters and inter-observer-correlation was calculated. Response to treatment was evaluated on day 56. DCE-US parameters were correlated with clinical response and RECIST1.1 criteria. RESULTS: Inter-observer-correlation (r) of DCE-US parameters [time-to-peak (TTP), mean-transit-time (MTT), peak intensity (PI), regional blood volume (RBV), regional blood flow (RBF)] at baseline, day 15, and day 56 was highly significant (r-range 0.73-0.97, all p < 0.001). Out of 17 evaluable patients, 12 patients survived day 56 (clinical responders, cRE), whereas, five patients died before day 56 and were classified as non-responders (cNR). TTP values significantly increased in the cRE group 15 days after initiation of treatment for investigator 1 (p = 0.034) and at day 56 for both investigators (p = 0.028/0.028). MTT had increased significantly in the cRE group on day 56 (p = 0.037/0.022). In the cNR group changes for TTP and MTT remained insignificant. Thus, increase of the DCE-US parameters TTP and MTT are associated with response to treatment and prognosis. CONCLUSION: An increase of TTP and MTT at frequent intervals could serve as a surrogate marker for early response evaluation to anti-angiogenic treatment of metastatic uveal melanoma.

Patterns of care and follow-up care of patients with uveal melanoma in German-speaking countries: a multinational survey of the German Dermatologic Cooperative Oncology Group (DeCOG).

PURPOSE: Uveal melanoma (UM) is an orphan cancer of high unmet medical need. Current patterns of care and surveillance remain unclear as they are situated in an interdisciplinary setting. METHODS: A questionnaire addressing the patterns of care and surveillance in the management of patients with uveal melanoma was distributed to 70 skin cancer centers in Austria, Germany and Switzerland. Frequency distributions of responses for each item of the questionnaire were calculated. RESULTS: 44 of 70 (62.9%) skin cancer centers completed the questionnaire. Thirty-nine hospitals were located in Germany (88.6%), three in Switzerland (6.8%) and two in Austria (4.5%). The majority (68.2%) represented university hospitals. Most patients with metastatic disease were treated in certified skin cancer centers (70.7%, 29/41). Besides, the majority of patients with UM were referred to the respective skin cancer center by ophthalmologists (87.2%, 34/39). Treatment and organization of follow-up of patients varied across the different centers. 35.1% (14/37) of the centers stated to not perform any screening measures. CONCLUSION: Treatment patterns of patients with uveal melanoma in Germany, Austria and Switzerland remain extremely heterogeneous. A guideline for the treatment and surveillance is urgently needed.

Therapy preferences in melanoma treatment-Willingness to pay and preference of quality versus length of life of patients, physicians, healthy individuals and physicians with oncological disease.

BACKGROUND: In recent years, monoclonal antibodies such as ipilimumab, nivolumab, and pembrolizumab have made a significant impact on the treatment of advanced melanoma. Combination of immune checkpoint inhibitors leads to improved survival and response rates of 58%-61% as compared to monotherapy (36%-44%). However, the price for the better response rates is also a higher frequency of severe adverse events (59%) as compared to monotherapy (17%-21%). This study examines attitudes towards melanoma therapy options of physicians, healthy individuals, melanoma patients, and physicians with oncological disease, their willingness to pay, and preference of quality versus length of life. METHODS: After obtaining ethical approval and informed consent surveys were conducted in 111 participants divided into four groups: melanoma patients (n = 30), healthy individuals as controls (n = 30), physicians (n = 27), and physicians with oncological disease (n = 24). Statistical analyses were conducted using SPSS statistics (version 25, IBM), applying the Pearson´s chi-squared test, Spearman correlation coefficient, Wilcoxon-Mann-Whitney test, and Kruskal-Wallis test. RESULTS: Life prolongation is more valued by melanoma patients and physicians with oncological disease compared to healthy controls and healthy physicians. In total, 30% of melanoma patients opt for a life prolonging therapy in all cases, even if this life prolongation is only marginal. Physicians are the strongest proponents of combination immunotherapy.    CONCLUSION: The valuation of the different treatment options differs in the four study groups with affected people valuing life prolongation much more. The individual value of cancer therapies is high, but differs from the societal standpoint.

Willingness to pay for a cure of low-risk melanoma patients in Germany.

Malignant melanoma is potentially life-threatening but in most cases curable if detected early. Willingness to pay (WTP) is a preference-based construct that reflects burden of disease by assessment of the monetary value for a hypothetical cure from disease. Since WTP (directly as total amount of money) has not been assessed so far in patients with low risk melanoma, it was interesting to gain insights in this patient population and then, in a second step, compare it directly with the WTP of their treating dermato-oncologists. WTP was assessed in 125 patients with low-risk melanoma and additionally in 105 treating physicians, asking for the one-time and continuous payments they would be willing to make for a sustainable cure, both as absolute sums and as percentages of monthly income. The median WTP based on one-time payment was €10,000 for patients and €100,000 for physicians; relative numbers were 100% versus 300% of monthly income. For continuous monthly payments, WTP was €500 for patients and €1000 for physicians, relative numbers 25% and 50% of income, respectively. Even after controlling for income differences, there was a significantly higher WTP in physicians for all four questions. Compared to patients with chronic skin diseases such as vitiligo, rosacea, atopic eczema and psoriasis, patients with low-risk melanoma showed a significantly higher WTP. Our data suggest that there is a relevant burden of disease even in patients with low-risk tumors. Higher WTP of physicians underlines the prevalence of differences in disease perception.

Therapy preferences in melanoma treatment--willingness to pay and preference of quality versus length of life of patients, physicians and healthy controls.

BACKGROUND: New melanoma therapies, like e.g. ipilimumab, improve survival. However, only a small subset of patients benefits while 60% encounter side effects. Furthermore, these marginal benefits come at a very high price of €110'000 per treatment. This study examines attitudes towards melanoma therapy options of physicians, healthy individuals and patients, their willingness to pay and preference of quality versus length of life. METHODS: Based on findings from a focus group questionnaires were developed and pretested. After obtaining ethical approval and informed consent surveys were conducted in a total of 90 participants (n = 30 for each group). Statistical analyses were conducted using R. FINDINGS: Attitudes vastly differed between healthy participants, physicians and melanoma patients. Whereas melanoma patients show a high willingness to endure side effects despite very small survival gains (down to 1 extra week) or even only hope with no survival benefit, healthy controls are more critical, while physicians are the most therapy adverse. Consequently, if given €100'000 and the free decision what to spend the money on the willingness to pay for therapy was much higher in the patient group (68%) compared to 28% of healthy controls and only 43% of the physicians, respectively. When lowering the amount of cash that could be received instead of ipilimumab to €50'000 or €10'000 to test price sensitivity 69% (+1%) and 76% (+8%) of melanoma patients, respectively, preferred ipilimumab over cash. When judging on societal spending even melanoma patients opted for spending on ipilimumab in only 21%. CONCLUSION: The judgment about the benefits of new treatment options largely differs between groups, physicians being the most critical against therapy. Price elasticity was low.

The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network.

BACKGROUND: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. METHODS AND FINDINGS: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patients delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. CONCLUSION: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.

Sarcoidosis induced by interferon-α in melanoma patients: incidence, clinical manifestations, and management strategies.

Treatment with interferon-α has been recommended for patients with melanoma in case of micrometastases, or high risk melanoma, for example, ulcerated melanoma. Furthermore, regular dermatologic examination and regular imaging to detect recurrence or progression of disease is part of the management of melanoma patients. Sarcoidosis has been described as an adverse effect of treatment with interferon-α. Especially in hepatitis C patients, there is a series of case reports on sarcoidosis induced by interferon treatment whereas in melanoma this has rarely been reported. In a retrospective study, all melanoma patients treated with interferon-α at our hospital between 2007 and 2009 were screened for occurrence of sarcoidosis. Three of 16 melanoma patients treated with interferon-α (19%) presented with sarcoidosis. All 3 patients showed lesions with higher uptake in the positron emission tomography-computed tomography scan leading to the differential diagnosis of melanoma metastases or inflammation. Skin lesions were present in 1 patient. Diagnosis was confirmed by histologic assessment of lesions showing epithelioid granuloma-negative on Ziehl Neelson. Additional work-up included blood and urinalysis, electrocardiography, and ophthalmologic examination. Cessation of interferon-α led to regression of granulomas. Sarcoidosis induced by interferon-α in melanoma patients could be more common than previously thought. This is an important complication to be aware of as it can be mistaken for metastatic spread of melanoma and thus lead to incorrect therapy.