Time and productivity loss associated with immunotherapy infusions for the treatment of melanoma in the United States: a survey of health care professionals and patients.

INTRODUCTION: A new dosing schedule for the oncology immunotherapy pembrolizumab, every 6 weeks (Q6W), has been approved by the U.S. FDA, reducing the frequency of visits to infusion centers. We quantified the time spent by oncologists, nurses, patients, and caregivers per melanoma-related immunotherapy infusion visit to evaluate its potential impact. METHODS: Surveys were self-completed by 100 oncologists, 101 oncology nurses, and 100 patients with melanoma across the U.S. to quantify the time spent per infusion visit with pembrolizumab (Q3W or Q6W), nivolumab (Q2W or Q4W), or nivolumab+ipilimumab (nivolumab in combination: Q3W; nivolumab maintenance: Q2W or Q4W). Time measures included traveling, waiting, consultation, infusion, post-treatment observation, and caregiving. Respondents were also surveyed regarding the impact of the COVID-19 pandemic on infusion treatments. RESULTS: Responses deemed valid were provided by 89 oncologists, 93 nurses, and 100 patients. For each new [returning] patient treated with pembrolizumab, nivolumab or nivolumab+ipilimumab, oncologists reported to spend an average of 90 [64], 87 [60] and 101 [69] minutes per infusion visit (p-value for between-group difference = 0.300 [0.627]). For first [subsequent] treatment cycles, nurses reported spending 160 [145] average minutes per visit for nivolumab+ipilimumab, versus roughly 120 [110] for the single agents (p-value for between-group difference = 0.018 [0.022]). Patients reported to spend an average of 263, 382, and 224 minutes per visit at the center for pembrolizumab (N = 47), nivolumab (n = 34), and nivolumab+ipilimumab (n = 15) respectively (p-value for between-group difference = 0.0002). Patients also reported that their unpaid (N = 20) and paid caregivers (N = 41) spent with them an average of 966 and 333 minutes, respectively, from the day before to the day after the infusion visit. CONCLUSION: Less frequent immunotherapy infusion visits may result in substantial time savings for oncologists, nurses, patients, and caregivers.

Systematic literature review and meta-analysis of clinical outcomes and prognostic factors for melanoma brain metastases.

Background: More than 60% of all stage IV melanoma patients develop brain metastases, while melanoma brain metastases (MBM) is historically difficult to treat with poor prognosis. Objectives: To summarize clinical outcomes and prognostic factors in MBM patients. Methods: A systematic review with meta-analysis was conducted, and a literature search for relevant studies was performed on November 1, 2020. Weighted average of median overall survival (OS) was calculated by treatments. The random-effects model in conducting meta-analyses was applied. Results: A total of 41 observational studies and 12 clinical trials with our clinical outcomes of interest, and 31 observational studies addressing prognostic factors were selected. The most common treatments for MBM were immunotherapy (IO), MAP kinase inhibitor (MAPKi), stereotactic radiosurgery (SRS), SRS+MAPKi, and SRS+IO, with median OS from treatment start of 7.2, 8.6, 7.3, 7.3, and 14.1 months, respectively. Improved OS was observed for IO and SRS with the addition of IO and/or MAPKi, compared to no IO and SRS alone, respectively. Several prognostic factors were found to be significantly associated with OS in MBM. Conclusion: This study summarizes pertinent information regarding clinical outcomes and the association between patient characteristics and MBM prognosis.

Burden and Risk Factors of Brain Metastases in Melanoma: A Systematic Literature Review.

Melanoma can frequently metastasize to the brain with severe consequences. However, variation of melanoma brain metastases (MBM) development among populations is not well studied, and underlying mechanisms and risk factors for MBM development are not consistently documented. We conducted a systematic literature review (SLR) including a total of 39 articles to evaluate the proportion of melanoma patients who are diagnosed with, or develop, brain metastases, and summarize the risk factors of MBM. The average proportion of MBM was calculated and weighted by the sample size of each study. Meta-analyses were conducted for the selected risk factors using a random-effects model. The proportion of MBM at diagnosis was 33% (975 with MBM out of 2948 patients) among patients with cutaneous melanoma (excluding acral) and 23% (651/2875) among patients with cutaneous mixed with other types of melanoma. The proportion at diagnosis was lower among populations with mucosal (9/96, 9%) or uveal (4/184, 2%) melanoma and among populations outside the United States and Europe. Meta-analysis demonstrated that male vs. female gender and left-sided tumors vs. right-sided were significantly associated with increased risk of melanoma brain metastases. These data may help clinicians to assess an individual patient's risk of developing melanoma brain metastases.

HER2 expression in urothelial carcinoma, a systematic literature review.

Background: Urothelial carcinoma (UC) is a common malignancy with significant associated mortality. Recent clinical trials suggest an emerging role for HER2-targeted therapy. Testing for HER2 expression in UC is not part of current routine clinical practice. In consequence, the prevalence of HER2 expression in UC is not well defined. Methods: A systematic literature review (SLR) was conducted to characterize HER2 expression in both locally advanced unresectable or metastatic (LA/mUC) and earlier stage UC, classified as HER2+, HER2-low, HER2-. HER2+ was defined as an immunohistochemistry (IHC) score of 3+ or IHC 2+ and ISH/FISH+. HER2-low was defined as an IHC score of 2+ and ISH/FISH- or IHC 1+. HER2- was defined as an IHC score of 0. Weighted averages were calculated to generate an estimate of the population prevalence. Results: A total of 88 studies were identified, with 45, 30, and 13 studies investigating LA/mUC, earlier stage UC, and mixed stage/unspecified, respectively. The most common assays used were Dako HercepTest and Ventana Pathway anti-HER2/neu (4B5) for IHC to assess HER2 protein expression; Abbott PathVysion HER-2 DNA Probe Kit, FoundationOne CDx, and Guardant360 CDx for assessing HER2 gene amplification. The most frequently cited scoring guidelines were ASCO/CAP guidelines for breast cancer and gastric cancer, though most studies defined their own criteria for HER2 expression. Using the pre-specified definition, HER2+ prevalence ranged from 6.7% to 37.5% with a weighted average of 13.0% in LA/mUC. Only 1 study presented data that could be classified as HER2+ based on pre-specified criteria in earlier stage UC patients, and this study represented a likely outlier, at 76.0%. Conclusion: The results from this SLR help to shed light on HER2 expression in UC, a potentially clinically relevant biomarker-driven subpopulation for emerging HER2-directed regimens. Results of this SLR illuminate the variability in how HER2+ status expression levels are being assessed and how HER2+ is defined. Consensus on standardized HER2 testing and scoring criteria is paramount to better understand the clinical relevance in patients with UC.

Real-world clinical outcomes of patients with stage IIB or IIC cutaneous melanoma treated at US community oncology clinics.

Aim: To describe clinical outcomes after complete surgical resection of stage IIB and IIC melanoma. Methods: Adult patients (n = 567) with stage IIB or IIC cutaneous melanoma initially diagnosed and completely resected from 2008-2017 were identified using data from a US community-based oncology network. Results: Median patient follow-up was 38.8 months from melanoma resection to death, last visit or data cut-off (31 December 2020). For stage IIB (n = 375; 66%), Kaplan-Meier median real-world recurrence-free survival (rwRFS) was 58.6 months (95% CI, 48.6-69.5). For stage IIC (n = 192; 34%), median rwRFS was 29.9 months (24.9-45.5). Overall, 44% of patients had melanoma recurrence or died; 30% developed distant metastases. Conclusion: Melanoma recurrence was common, highlighting the need for effective adjuvant therapy for stage IIB and IIC melanoma.

New treatments are now available that decrease tumor recurrence when administered after surgery to remove melanoma skin tumors that are graded as stage IIB or IIC (i.e., with no cancer spread to the local lymph nodes). We studied 567 'real-world' patients at clinics in the USA who had stage IIB or IIC melanoma tumors removed in 2008­2017, before these new postsurgical treatments were widely available, to evaluate their survival and tumor recurrence. We found that almost half of these patients (44%) had melanoma recurrence or had died, and a third (30%) had tumor spread beyond the original site, by the end of 2020. These findings highlight the need for more effective treatments after surgical removal of stage IIB and IIC melanoma.

Resistance to anti-PD1 therapies in patients with advanced melanoma: systematic literature review and application of the Society for Immunotherapy of Cancer Immunotherapy Resistance Taskforce anti-PD1 resistance definitions.

Nearly half of advanced melanoma patients do not achieve a clinical response with anti-programmed cell death 1 protein (PD1) therapy (i.e. primary resistance) or initially achieve a clinical response but eventually progress during or following further treatment (i.e. secondary resistance). A consensus definition for tumor resistance to anti-PD1 monotherapy was published by Society for Immunotherapy of Cancer Immunotherapy Resistance Taskforce (SITC) in 2020. A systematic literature review (SLR) of clinical trials and observational studies was conducted to characterize the proportions of advanced melanoma patients who have progressed on anti-PD1 therapies. The SLR included 55 unique studies and the SITC definition of primary resistance was applied to 37 studies that specified disease progression by best overall response. Median and range of patients with primary resistance in studies that specified first-line and second-line or higher anti-PD1 monotherapy was 35.50% (21.19-39.13%; n = 4 studies) and 41.54% (30.00-56.41%, n = 3 studies); median and range of patients with primary resistance in studies that specified first-line and second-line or higher combination therapy was 30.23% (15.79-33.33%; n = 6 studies), and 70.00% (61.10-73.33%; n = 3 studies). Primary resistance to anti-PD1 monotherapies and when in combination with ipilimumab are higher in patients receiving second-line or higher therapies, in patients with acral, mucosal, and uveal melanoma, and in patients with active brain metastases. The percentage of patients with primary resistance was generally consistent across clinical trials, with variability in resistance noted for observational studies. Limitations include applying the SITC definitions to combination therapies, where consensus definitions are not yet available. Future studies should highly consider utilizing the SITC definitions to harmonize how resistance is classified and facilitate meaningful context for clinical activity.

Current Treatment Approaches and Global Consensus Guidelines for Brain Metastases in Melanoma.

Background: Up to 60% of melanoma patients develop melanoma brain metastases (MBM), which traditionally have a poor diagnosis. Current treatment strategies include immunotherapies (IO), targeted therapies (TT), and stereotactic radiosurgery (SRS), but there is considerable heterogeneity across worldwide consensus guidelines. Objective: To summarize current treatments and compare worldwide guidelines for the treatment of MBM. Methods: Review of global consensus treatment guidelines for MBM patients. Results: Substantial evidence supported that concurrent IO or TT plus SRS improves progression-free survival (PFS) and overall survival (OS). Guidelines are inconsistent with regards to recommendations for surgical resection of MBM, since surgical resection of symptomatic lesions alleviates neurological symptoms but does not improve OS. Whole-brain radiation therapy is not recommended by all guidelines due to negative effects on neurocognition but can be offered in rare palliative scenarios. Conclusion: Worldwide consensus guidelines consistently recommend up-front combination IO or TT with or without SRS for the treatment of MBM.

Real-World Therapy with Pembrolizumab: Outcomes and Surrogate Endpoints for Predicting Survival in Advanced Melanoma Patients in Germany.

Knowledge on the real-world characteristics and outcomes of pembrolizumab-treated advanced melanoma patients in Germany and on the value of different real-world endpoints as surrogates for overall survival (OS) is limited. A sample of 664 pembrolizumab-treated patients with advanced melanoma from the German registry ADOReg was used. We examined OS, real-world progression-free survival (rwPFS), real-world time to next treatment (rwTtNT), and real-world time on treatment (rwToT). Spearman's rank and iterative multiple imputation (IMI)-based correlation coefficients were computed between the OS and the rwPFS, rwTtNT, and rwToT and reported for the first line of therapy and the overall sample. The median OS was 30.5 (95%CI 25.0-35.4) months, the rwPFS was 3.9 months (95%CI 3.5-4.9), the rwTtNT was 10.7 months (95%CI 9.0-12.9), and the rwToT was 6.2 months (95%CI 5.1-6.8). The rwTtNT showed the highest correlation with the OS based on the IMI (rIMI = 0.83), Spearman rank correlations (rs = 0.74), followed by the rwToT (rIMI = 0.74 and rs = 0.65) and rwPFS (rIMI = 0.69 and rs = 0.56). The estimates for the outcomes and correlations were similar for the overall sample and those in first-line therapy. The median OS was higher compared to recent real-world studies, supporting the effectiveness of pembrolizumab in regular clinical practice. The rwTtNT may be a valuable OS surrogate, considering the highest correlation was observed with the OS among the investigated real-world endpoints.

Treatment and overall survival among anti-PD-1-exposed advanced melanoma patients with evidence of disease progression.

Background: Little is known regarding treatment patterns and overall survival (OS) for patients with advanced melanoma who progress after anti-PD-1 exposure. Methods: The Kaplan-Meier method was used to evaluate OS from electronic health records for patients with advanced melanoma who progressed on anti-PD-1 therapy and received subsequent therapy. Descriptive statistics were used to summarize treatment. Results: A total of 304 patients who progressed after anti-PD-1 therapy received subsequent therapy: 50% immunotherapy, 36% BRAF and/or MEK inhibitors, 14% other therapies. Median OS was 7.2 months (95% CI: 6.4-8.8), with an association (p < 0.01) with best response to baseline anti-PD-1 therapy and further associations with Eastern Co-operative Oncology Group (ECOG) performance status ≤1 (p < 0.001 compared with ECOG ≥2), normal LDH (p < 0.001 compared with elevated levels) and treatment with BRAF and/or MEK inhibitors (p = 0.02 compared with other treatment). There was an association (p < 0.01) of survival with best response to baseline anti-PD-1 therapy. Conclusions: OS for advanced melanoma patients who progress on anti-PD-1 therapy is suboptimal, which highlights the need for further research to develop new medications and optimize treatment strategies.

Cost-Effectiveness of Pembrolizumab Versus Carboplatin and Paclitaxel in Patients With Unresectable or Metastatic Melanoma After First-Line Treatment in China.

OBJECTIVE: This study aimed to evaluate the cost-effectiveness of pembrolizumab compared with standard-of-care chemotherapy (paclitaxel + carboplatin [PC]) in patients with unresectable or metastatic melanoma after first-line treatment from a Chinese healthcare system perspective. METHODS: We conducted a partitioned-survival model with a 1-week cycle length and a 20-year base-case time horizon. Piecewise parametric models were fitted to KEYNOTE-006 trial data to estimate progression-free survival and overall survival for pembrolizumab, and a network meta-analysis was used to estimate the clinical outcomes for standard of care. Quality-adjusted life-years (QALYs) were calculated using EQ-5D data from KEYNOTE-006, applying Chinese-specific utility tariffs. Costs included drug acquisition, administration, adverse events, and disease management, reflecting the Chinese pricing system. Chinese-specific disease management costs were estimated based on clinical opinion on health state resource use and chemotherapy-related adverse events. Costs and outcomes were discounted at 5% annually. Multiple deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results. RESULTS: In the base-case analysis, the treatment of pembrolizumab is estimated to yield 2.63 life-years (LYs) and 2.24 QALYs at an incremental cost of ¥372 316.46 versus PC. The incremental costs per LY and per QALY were ¥141 771.00 and ¥165 865.69, respectively, the latter being below a threshold of 3 times the per capita gross domestic product (ï¿¥193 932) in China, deemed as cost-effective according to the World Health Organization threshold. These findings were robust against a wide range of sensitivity analyses. CONCLUSIONS: Pembrolizumab is projected as cost-effective compared with PC in patients with unresectable or metastatic melanoma after first-line treatment in China.

Real-world effectiveness of pembrolizumab in advanced melanoma: analysis of a French national clinicobiological database.

Aim: To describe real-world pembrolizumab administration and outcomes for advanced melanoma in France. Materials & methods: Using the MelBase longitudinal database, this multicenter historical-prospective study examined treatment and outcomes of patients with nonuveal, unresectable stage III/IV melanoma initiating pembrolizumab from April 2016 to September 2017, with follow-up to September 2019. Kaplan-Meier time-to-event analyses were conducted. Results: Of 223 patients (median age 67; 51% men), 134 (60%), 36 (16%) and 53 (24%) initiated pembrolizumab in first-, second- and third-line, respectively. Median overall survival (months) was 32.6 (95% CI: 20.3-not reached [NR]), 14.4 (8.6-NR) and 9.3 (6.4-NR), respectively. Best real-world tumor response of complete or partial response was recorded for 49, 39 and 26% of patients, respectively. Conclusion: Study results support benefits of pembrolizumab therapy for advanced melanoma.

Systematic literature review for the association of biomarkers with efficacy of anti-PD-1 inhibitors in advanced melanoma.

Aim: Summarize the literature assessing biomarkers in predicting efficacy of anti-PD-1 therapy for patients with high-risk unresectable or metastatic melanoma. Materials & methods: Relevant studies were identified via a systematic literature review. Results: About 334 unique biomarkers or biomarker combinations were identified from 121 citations. Neutrophil-to-lymphocyte ratio was the most frequently studied biomarker, followed by C-reactive protein. Fifty-nine biomarkers were significantly associated with overall survival (OS), 51 with progression-free survival (PFS) and 44 with response. Twenty biomarkers were associated with both OS and PFS; two were associated with OS, PFS and response (MHC-II and tumor mutational burden). Conclusion: Numerous biomarkers could potentially predict the efficacy of anti-PD-1-based therapy for melanoma patients. However, confirmatory studies are needed as well as determination of implications for clinical decision-making.

Pembrolizumab Utilization and Clinical Outcomes Among Patients With Advanced Melanoma in the US Community Oncology Setting: An Updated Analysis.

Favorable outcomes have been observed with pembrolizumab among patients with advanced melanoma in clinical trials; however, limited evidence exists on the long-term efficacy in the real-world setting. This was an updated, retrospective observational study of adult patients with advanced (unresectable or metastatic) melanoma who initiated pembrolizumab (in any line of therapy) between January 1, 2014, and December 31, 2016, in The US Oncology Network and were followed through December 31, 2019 [median follow-up: 18.2 mo (range: 0.1-63.1 mo)]. Study data were sourced from electronic health records. Patient demographic, clinical, and treatment characteristics were assessed descriptively. Kaplan-Meier methods were used to evaluate overall survival (OS), time to treatment discontinuation, time to next treatment, physician-assessed time to tumor progression, and physician-assessed progression-free survival (rwPFS). Independent risk factors for OS and rwPFS were identified with multivariable Cox regression models. Of the 303 study-eligible patients, 119, 131, and 53 received pembrolizumab in the first-line, second-line, and third-line or beyond setting, respectively. Median OS across the study population was 29.3 months [95% confidence interval (CI): 20.3-49.7] and was the longest among those who received first-line pembrolizumab [42.8 mo (95% CI: 24.8-not reached)]. Median rwPFS across the study population was 5.1 months (95% CI: 4.0-7.6) and 8.1 months (95% CI: 4.6-14.4) among those who received first-line pembrolizumab. In the multivariable analyses for OS, increased age, worsening performance status, elevated lactate dehydrogenase, brain metastases, and pembrolizumab use in later lines were significantly associated a worse prognosis.

Cost-Effectiveness of Pembrolizumab for the Adjuvant Treatment of Melanoma Patients with Lymph Node Involvement Who Have Undergone Complete Resection in Argentina.

INTRODUCTION: The KEYNOTE-054 trial demonstrated that adjuvant pembrolizumab improves recurrence-free survival in completely resected stage III melanoma versus watchful waiting (hazard ratio [HR] = 0.57; 98.4% confidence interval [CI], 0.43-0.74). We evaluated the cost-effectiveness of pembrolizumab in Argentina, where watchful waiting is still widely used among these patients despite the high risk of recurrence with surgery alone. METHODS: A four-health state model was used (recurrence-free, locoregional recurrence [LR], distant metastases [DM], death). Lifetime medical costs to payers (72.08 Argentine pesos [AR$] = 1.00 U.S. dollar [USD]) and outcomes (3% annual discount) were assessed, together with incremental cost-effectiveness ratios (ICERs). First and LR→DM recurrences were modeled using KEYNOTE-054 and real-world data, respectively. No benefits of adjuvant treatment were assumed post-progression. Pre-DM and post-DM mortality was based on KEYNOTE-054 and on a network meta-analysis of advanced treatments expected in each arm, respectively. Utilities were derived from KEYNOTE-054 Euro-QoL data using an Argentinian algorithm, and from the literature. Public ex-factory drug prices were used. RESULTS: Patients in the pembrolizumab and the watchful waiting arms accrued 8.78 and 5.83 quality-adjusted life-years (QALYs), 9.91 and 6.98 life-years, and costs of AR$12,698,595 (176,174 USD) and AR$11,967,717 (166,034 USD), respectively. The proportion of life-years accrued that were recurrence-free was 80.8% and 56.9% in the pembrolizumab and the watchful waiting arms, respectively. Pembrolizumab patients gained 2.94 life-years and 2.96 QALYs versus watchful waiting; the ICER per QALY was AR$247,094 (3428 USD). Recurrence rates and advanced melanoma treatments were the key drivers of the ICER. At a threshold of AR$1,445,325 (29,935 USD) per QALY, pembrolizumab had an 83.5% probability of being cost-effective versus watchful waiting. CONCLUSIONS: Adjuvant pembrolizumab after complete resection of melanoma with node involvement is highly cost-effective relative to watchful waiting in Argentina, across disease stage subgroups and BRAF mutational status. This strongly supports its coverage and reimbursement across the entire health system.

An observational study of drug utilization and associated outcomes among adult patients diagnosed with BRAF-mutant advanced melanoma treated with first-line anti-PD-1 monotherapies or BRAF/MEK inhibitors in a community-based oncology setting.

INTRODUCTION: Anti-PD-1 monotherapies (aPD-1) and BRAF/MEK inhibitors (BRAF/MEKi) changed the BRAF-mutant advanced melanoma treatment landscape. This study aimed to improve the understanding of real-world treatment patterns and optimal treatment sequence. METHODS: This was a retrospective study of BRAF-mutant advanced melanoma patients who initiated 1L aPD-1 or BRAF/MEKi in the US Oncology Network between 1 January 2014 and 31 December 2017, followed through 31 December 2018. Patient and treatment characteristics were assessed descriptively, with Kaplan-Meier methods used for time-to-event endpoints. As the primary analysis, overall survival (OS) and physician-assessed progression-free survival (rwPFS) were evaluated with Cox proportional hazard regression models and propensity score matching (n = 49). RESULTS: A total of 224 patients were included (median age 61 years, 62.9% male, 89.7% white): 36.2% received aPD-1 and 63.8% BRAF/MEKi. Median OS and rwPFS were longer among aPD-1 vs BRAF/MEKi patients (OS: not reached vs 13.9 months, log-rank P = .0169; rwPFS: 7.6 vs 6.5 months, log-rank P = .0144). Receipt of aPD-1 was associated with improved OS (HR = 0.602 vs BRAF/MEKi [95%CI 0.382-0.949]; P = .0287). Among patients without an event within 6 months of 1L initiation, receipt of aPD-1 was associated with a decreased risk of progression or death from 6 months onwards (HR = 0.228 [95%CI 0.106-0.493]; P = .0002). This association was not observed among patients within 6 months of 1L initiation (HR = 1.146; 95% CI 0.755-1.738). Results from the propensity score-matched pairs were consistent with these trends. CONCLUSION: These results suggest a clinical benefit of 1L aPD-1 compared to BRAF/MEKi after 6 months of treatment for BRAF-mutant advanced melanoma. Future research should explore factors associated with early progression and their relationship with clinical outcomes.

An Economic Evaluation of Pembrolizumab Versus Other Adjuvant Treatment Strategies for Resected High-Risk Stage III Melanoma in the USA.

BACKGROUND AND OBJECTIVE: Over the past 5 years, adjuvant treatment options for surgically resected stage III melanoma have expanded with the introduction of several novel immune checkpoint inhibitors and targeted therapies. Pembrolizumab, a programmed cell death protein 1 inhibitor, received US Food and Drug Administration approval in 2019 for resected high-risk stage III melanoma based on significantly longer recurrence-free survival versus placebo. This study evaluated the cost-effectiveness of pembrolizumab versus other adjuvant treatment strategies for resected high-risk stage III melanoma from a US health system perspective. METHODS: A Markov cohort-level model with four states (recurrence-free, locoregional recurrence, distant metastases, death) estimated costs and quality-adjusted life-years (QALYs) for pembrolizumab versus routine observation and other adjuvant comparators: ipilimumab in the overall population; and dabrafenib + trametinib in the BRAF-mutation positive (BRAF+) subgroup. Transition probabilities starting from recurrence-free were estimated through parametric multi-state modeling based on phase 3 KEYNOTE-054 (NCT02362594) trial data for pembrolizumab and observation, and network meta-analyses for other comparators. Post-recurrence transitions were modeled based on electronic medical records data and trials in advanced/metastatic melanoma. Utilities were derived using quality-of-life data from KEYNOTE-054 and literature. Costs of treatment, adverse events, disease management, and terminal care were included. RESULTS: Over a lifetime, pembrolizumab, ipilimumab, and observation were associated with QALYs of 9.24, 7.09, and 5.95 and total costs of $511,290, $992,721, and $461,422, respectively (2019 US dollars). Pembrolizumab was thus dominant (less costly, more effective) versus ipilimumab, with an incremental cost-effectiveness ratio of $15,155/QALY versus observation. In the BRAF+ subgroup, pembrolizumab dominated dabrafenib + trametinib and observation, decreasing costs by $62,776 and $11,250 and increasing QALYs by 0.93 and 3.10 versus these comparators, respectively. Results were robust in deterministic and probabilistic sensitivity analyses. CONCLUSIONS: As adjuvant treatment for resected stage III melanoma, pembrolizumab was found to be dominant and therefore cost-effective compared with the active comparators ipilimumab and dabrafenib + trametinib. Pembrolizumab increased costs relative to observation in the overall population, with sufficient incremental benefit to be considered cost-effective based on typical willingness-to-pay thresholds.

Outcomes of retreatment with anti-PD-1 monotherapy after response to first course in patients with cutaneous melanoma.

Aim: To determine outcomes of retreatment with anti-PD-1 monotherapy for melanoma. Materials & methods: This retrospective study included adults with unresectable cutaneous melanoma who achieved stable disease (SD) or better after anti-PD-1 monotherapy and were retreated with anti-PD-1 monotherapy after ≥90-day gap. We determined overall survival and real-world tumor response. Results: For 21 eligible patients, from retreatment initiation, median follow-up was 14.4 months (range, 2.6-34.5); median overall survival was 30.0 months (95% CI: 14.4-not reached); 1-year survival was 100% (95% CI: 100-100%); 2-year survival was 83% (48-96%). Of 16 patients with recorded best real-world tumor response, ten (63%) responded (complete/partial response); three achieved SD; three had progressive disease. Conclusion: Patients with advanced melanoma achieving SD/better after first-course anti-PD-1 monotherapy may benefit from retreatment.

Epidemiology and survival outcomes in stages II and III cutaneous melanoma: a systematic review.

AIM: Management of cutaneous melanoma (CM) is continually evolving with adjuvant treatment of earlier stage disease. The aim of this review was to identify published epidemiological data for stages II-III CM. MATERIALS & METHODS: Systematic searches of Medline and Embase were conducted to identify literature reporting country/region-specific incidence, prevalence, survival or mortality outcomes in stage II and/or III CM. Screening was carried out by two independent reviewers. RESULTS & CONCLUSION: Of 41 publications, 14 described incidence outcomes (incidence rates per stage were only reported for US and Swedish studies), 33 reported survival or mortality outcomes and none reported prevalence data. This review summarizes relevant data from published literature and highlights an overall paucity of epidemiological data in stages II and III CM.

Hospitalization and emergency department utilization in patients with advanced melanoma receiving pembrolizumab versus ipilimumab plus nivolumab in US academic centers.

Background: Both pembrolizumab (PEMBRO) and ipilimumab + nivolumab (IPI + NIVO) are FDA-approved immunotherapy regimens for advanced melanoma (AM). Each regimen has different toxicity profiles potentially impacting healthcare resource utilization (HCRU). This study compared real-world hospitalization and emergency department (ED) utilization within 12 months of therapy initiation of each regimen.Methods: A retrospective cohort study was conducted in AM patients ≥18 years old initiating PEMBRO or IPI + NIVO between January 1, 2016-December 30, 2017. Patients were identified from 12 US-based academic and satellite centers. All-cause hospitalization ED visits were identified. These events were used to calculate rates per 1,000 patient months. Utilization between groups was compared using multivariate logistic regression.Results: In total, 400 patients were included (200 PEMBRO, 200 IPI + NIVO). PEMBRO vs IPI + NIVO patients had poorer Eastern Cooperative Group (ECOG) performance status, 29% 2-4, vs 12% (p < .001); more diabetes, 21% vs 13% (p = .045); were more often PD-L1 expression positive, 77% vs 63% (p = .011); and less likely BRAF mutant, 35% vs 50% (p = .003). The proportion with more than one hospitalization over 12 months was 17% PEMBRO vs 24% IPI + NIVO. Less than 2% had more than one admission and none had more than two. Unadjusted mean (SD) hospitalizations per 1,000 patient-months were 16 (37) and 20 (38), PEMBRO and IPI + NIVO, respectively. Adjusted odds ratio for hospitalization was 0.6 (95% CI = 0.3-0.9; p = .027) for PEMBRO vs IPI + NIVO. ED visits occurred in 18% vs 21%, PEMBRO and IPI + NIVO, respectively, 0.7 (p = .186).Conclusions: PEMBRO patients had a significantly lower probability of hospitalization through 12 months vs IPI + NIVO. The probability of ED visits did not differ.

An indirect treatment comparison of the efficacy of pembrolizumab versus competing regimens for the adjuvant treatment of stage III melanoma.

Objective: To determine the efficacy of pembrolizumab relative to other treatments used in stage III melanoma by conducting a systematic literature review (SLR) and network meta-analysis (NMA). Methods: A SLR was conducted to identify randomized clinical trials (RCTs) evaluating approved adjuvant treatments including interferon-containing regimens, BRAF-inhibitors, and PD-L1 inhibitors in stage III melanoma patients. Relative treatment effects for recurrence-free survival (RFS) were synthesized with Bayesian NMA models that allowed for hazard ratios (HRs) to vary over time. Results: Included studies formed a connected network of evidence composed of eight trials. In high-risk stage III patients, the HR for pembrolizumab vs observation decreased significantly over time with the superiority of pembrolizumab over observation becoming statistically meaningful before 3 months. By 9 months, the HR for pembrolizumab vs observation was statistically significantly lower than the HR for most other treatments vs observation, with the exception of ipilimumab and biochemotherapy due to overlapping 95% credible intervals. In BRAF + patients, pembrolizumab was statistically significantly better than observation after 3 months. The HR for both BRAF-inhibitors vs observation increased significantly over time and pembrolizumab was statistically superior to both BRAF-inhibitors after 15 months. Conclusions: Pembrolizumab results in statistically significantly improved RFS compared to all competing regimens after 9 months, except ipilimumab and biochemotherapy, for the adjuvant treatment of stage III melanoma. However, point estimate HRs vs observation for pembrolizumab are much lower than those for ipilimumab. In BRAF + patients, the advantage of pembrolizumab versus competing interventions increases over time with respect to RFS.