Pembrolizumab in the adjuvant treatment of melanoma: efficacy and safety.
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ABSTRACT:
SUBMITTER: Nebhan CA
PROVIDER: S-EPMC8238788 | biostudies-literature | 2021 Jun
REPOSITORIES: biostudies-literature
Publications
Pembrolizumab in the adjuvant treatment of melanoma: efficacy and safety.
Nebhan Caroline A CA Johnson Douglas B DB
Expert review of anticancer therapy 20210214 6
<b>Introduction</b>: Regional or distant metastases from melanoma may be surgically resected but remain at high-risk of recurrence. Over the last few years, several treatments have been approved to mitigate this risk. These include anti-PD-1 agents, specifically pembrolizumab and nivolumab.<b>Areas covered</b>: Herein, we will discuss the landscape of pembrolizumab safety and efficacy used in the adjuvant setting for high-risk, resected melanoma. We place this in context with other available adj ...[more]
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Project description: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.
| S-EPMC6713115 | biostudies-literature
Project description:BackgroundWhether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown.MethodsIn a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated.ResultsAt a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group.ConclusionsAmong patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).
| S-EPMC10410527 | biostudies-literature
Project description:Combination immunotherapy can overcome the limited objective response rates of PD-1 blockade. Interferon alpha (IFN-α) has been proven to be effective in modulating immune responses and may enhance the clinical responses to PD-1 blockade. According to clinical practice guidelines, IFN-α was recommended as adjuvant therapy for stage IIB/C melanoma patients. However, the impact of prior IFN-α therapy on the efficacy of subsequent PD-1 blockade in melanoma has not been previously reported. Therefore, we performed a retrospective analysis for melanoma patients and addressed whether prior IFN-α therapy enhanced adjuvant pembrolizumab as later-line treatment. Fifty-six patients with resectable stage III/IV melanoma who received adjuvant therapy with pembrolizumab were retrospectively enrolled in this study. Notably, 25 patients received adjuvant pegylated IFN-α (PEG-IFN-α) in the prior line of treatment while 31 patients did not receive prior PEG-IFN-α therapy. Cox regression analysis showed that prior PEG-IFN-α therapy was associated with the efficacy of later-line adjuvant pembrolizumab (hazard ratio=0.37, 95% CI 0.16-0.89; P = 0.026). The recurrence rates after treatment with adjuvant pembrolizumab were significantly reduced in the prior PEG-IFN-α group (P < 0.001). The Kaplan-Meier analysis also showed that recurrence-free survival (RFS) after adjuvant pembrolizumab therapy was prolonged by prior PEG-IFN-α treatment (median RFSPem 8.5 months vs. 4.5 months; P = 0.0372). These findings indicated that prior PEG-IFN-α could enhance the efficacy of adjuvant pembrolizumab. The long-lasting effects of PEG-IFN-α provide a new rationale for designing combination or sequential immunotherapy.
| S-EPMC8243982 | biostudies-literature
Project description:We conducted a randomized phase III trial to evaluate whether adjuvant pembrolizumab for one year (647 patients) improved recurrence-free survival (RFS) or overall survival (OS) in comparison with high-dose IFNα-2b for one year or ipilimumab for up to three years (654 patients), the approved standard-of-care adjuvant immunotherapies at the time of enrollment for patients with high-risk resected melanoma. At a median follow-up of 47.5 months, pembrolizumab was associated with significantly longer RFS than prior standard-of-care adjuvant immunotherapies [HR, 0.77; 99.62% confidence interval (CI), 0.59-0.99; P = 0.002]. There was no statistically significant association with OS among all patients (HR, 0.82; 96.3% CI, 0.61-1.09; P = 0.15). Proportions of treatment-related adverse events of grades 3 to 5 were 19.5% with pembrolizumab, 71.2% with IFNα-2b, and 49.2% with ipilimumab. Therefore, adjuvant pembrolizumab significantly improved RFS but not OS compared with the prior standard-of-care immunotherapies for patients with high-risk resected melanoma.SignificanceAdjuvant PD-1 blockade therapy decreases the rates of recurrence, but not survival, in patients with surgically resectable melanoma, substituting the prior standard-of-care immunotherapies for this cancer. See related commentary by Smithy and Shoushtari, p. 599. This article is highlighted in the In This Issue feature, p. 587.
| S-EPMC8904282 | biostudies-literature
Project description:IntroductionSince 2010 multiple targeted therapies and immunotherapies have been approved for the treatment of advanced melanoma. Pembrolizumab, a humanized monoclonal antibody directed against programed death receptor 1 has shown significant activity in advanced melanoma resulting in its approval first as post-ipilimumab and subsequently as frontline treatment.Areas coveredThis article reviews the approved agents for the treatment of advanced melanoma with a focus on the preclinical and clinical evidence for the use of pembrolizumab in this setting. Primary emphasis is given to the clinical development of pembrolizumab, including phase I-III trials. Finally, we explore the role of pembrolizumab in combination with other therapies and ongoing investigations into its effectiveness in expanded patient populations.Expert opinionPembrolizumab provides durable responses and represents a major advancement in the treatment options for patients with advanced melanoma. Early studies of pembrolizumab in combination with other therapeutic agents have generated significant interest and further investigations including advanced clinical trials are warranted to evaluate safety and potential improved outcomes. Pembrolizumab and other immune checkpoint inhibitors are likely to play an expanded role in the treatment of advanced melanoma and other solid tumors over the next decade.
| S-EPMC5010088 | biostudies-literature
Project description:The role of immunotherapy in treatment of brain metastases is unknown because most trials exclude patients with active brain lesions. As new immunomodulating agents gain approval for many malignancies, it is important to know if they have unique effects in the central nervous system (CNS). Here, we present a case of a patient with progressing brain metastases treated with a single cycle of pembrolizumab, who presented with mental status changes 11 days thereafter. MRI of the brain showed enlargement of CNS lesions with intense central enhancement and diffuse perilesional edema. Histologic evaluation of a resected lesion revealed isolated clusters of tumor cells surrounded by reactive astrocytosis, scattered inflammatory cells, and an abundance of microglial cells. Given the increasing use of immune checkpoint inhibitors in patients with brain metastases from melanoma and other diseases, recognition of pseudoprogression and management with immune suppression are essential.
| S-EPMC4881844 | biostudies-literature
Project description:Background and objectiveOver 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.MethodsA 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.ResultsOver 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.ConclusionsAs 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.
| S-EPMC7311503 | biostudies-literature
Project description:IntroductionPembrolizumab was approved in the US as adjuvant treatment of patients with stage IIB or IIC melanoma post-complete resection, based on prolonged recurrence-free survival vs. placebo in the Phase 3 KEYNOTE-716 trial. This study aimed to evaluate the cost-effectiveness of pembrolizumab vs. observation as adjuvant treatment of stage IIB or IIC melanoma from a US health sector perspective.MethodsA Markov cohort model was constructed to simulate patient transitions among recurrence-free, locoregional recurrence, distant metastasis, and death. Transition probabilities from recurrence-free and locoregional recurrence were estimated via multistate parametric modeling based on patient-level data from an interim analysis (data cutoff date: 04-Jan-2022). Transition probabilities from distant metastasis were based on KEYNOTE-006 data and network meta-analysis. Costs were estimated in 2022 US dollars. Utilities were based on applying US value set to EQ-5D-5L data collected in trial and literature.ResultsCompared to observation, pembrolizumab increased total costs by $80,423 and provided gains of 1.17 quality-adjusted life years (QALYs) and 1.24 life years (LYs) over lifetime, resulting in incremental cost-effectiveness ratios of $68,736/QALY and $65,059/LY. The higher upfront costs of adjuvant treatment were largely offset by reductions in costs of subsequent treatment, downstream disease management, and terminal care, reflecting the lower risk of recurrence with pembrolizumab. Results were robust in one-way sensitivity and scenario analyses. At a $150,000/QALY threshold, pembrolizumab was cost-effective vs. observation in 73.9% of probabilistic simulations that considered parameter uncertainty.ConclusionAs an adjuvant treatment of stage IIB or IIC melanoma, pembrolizumab was estimated to reduce recurrence, extend patients' life and QALYs, and be cost-effective versus observation at a US willingness-to-pay threshold.
| S-EPMC10271902 | biostudies-literature
Project description:IntroductionThe KEYNOTE-054 trial found that adjuvant treatment with pembrolizumab improved recurrence-free survival versus placebo in completely resected high-risk stage III melanoma patients. We assessed the cost-effectiveness of adjuvant pembrolizumab in Colombia compared with watchful waiting, a widely used strategy despite the high risk of recurrence with surgery alone.MethodsA four-health state [recurrence-free (RF), locoregional recurrence (LR), distant metastases (DM), and death) Markov model was developed to assess the lifetime medical costs and outcomes (3% annual discount), along with cost-effectiveness ratios (ICERs). The transitions from the RF and LR states were modeled using KEYNOTE-054 data, and those from the DM state were modeled using data from the KEYNOTE-006 trial and a network meta-analysis of advanced treatments received after adjuvant pembrolizumab and watchful waiting. The health state utilities were derived from KEYNOTE-054 Euro-QoL data and literature. Costs are expressed in 2021 Colombian pesos (COP).ResultsOver a 46-year time horizon, patients on adjuvant pembrolizumab and watchful waiting were estimated to gain 9.69 and 7.56 quality-adjusted life-years (QALYs), 10.83 and 8.65 life-years (LYs), and incur costs of COP 663,595,726 and COP 563,237,206, respectively. The proportion of LYs spent in RF state was 84.63% for pembrolizumab and 72.13% for watchful waiting, yielding lower subsequent treatment, disease management, and terminal care costs for pembrolizumab. Adjuvant pembrolizumab improved survival by 2.18 LYs and 2.13 QALYs versus watchful waiting. The ICER per QALY was COP 47,081,917, primarily driven by recurrence rates and advanced melanoma treatments. The deterministic sensitivity analysis results were robust and consistent across various reasonable inputs and alternative scenarios. At a willingness-to-pay threshold of COP 69,150,201 per QALY, the probability of pembrolizumab being cost-effective was 65.70%.ConclusionPembrolizumab is cost-effective as an adjuvant treatment compared to watchful waiting among patients with high-risk stage III melanoma after complete resection in Colombia.
| S-EPMC10219874 | biostudies-literature
Project description:Introduction: Nivolumab (N), pembrolizumab (P), and dabrafenib plus trametinib (D + T) have been registered as adjuvant treatments for resected stage III and IV melanoma since 2018. Electronic health records (EHRs) are a real-world data source that can be used to review treatments in clinical practice. In this study, we applied EHR text-mining software to evaluate the real-world tolerability, safety, and efficacy of adjuvant melanoma treatments. Methods: Adult melanoma patients receiving adjuvant treatment between January 2019 and October 2021 at the Leiden University Medical Center, the Netherlands, were included. CTcue text-mining software (v3.1.0, CTcue B.V., Amsterdam, The Netherlands) was used to construct rule-based queries and perform context analysis for patient inclusion and data collection from structured and unstructured EHR data. Results: In total, 122 patients were included: 54 patients treated with nivolumab, 48 with pembrolizumab, and 20 with D + T. Significantly more patients discontinued treatment due to toxicity on D + T (N: 16%, P: 6%, D + T: 40%), and X2 (6, n = 122) = 14.6 and p = 0.024. Immune checkpoint inhibitors (ICIs) mainly showed immune-related treatment-limiting adverse events (AEs), and chronic thyroid-related AE occurred frequently (hyperthyroidism: N: 15%, P: 13%, hypothyroidism: N: 20%, P: 19%). Treatment-limiting toxicity from D + T was primarily a combination of reversible AEs, including pyrexia and fatigue. The 1-year recurrence-free survival was 70.3% after nivolumab, 72.4% after pembrolizumab, and 83.0% after D + T. Conclusions: Text-mining EHR is a valuable method to collect real-world data to evaluate adjuvant melanoma treatments. ICIs were better tolerated than D + T, in line with RCT results. For BRAF+ patients, physicians must weigh the higher risk of reversible treatment-limiting AEs of D + T against the risk of long-term immune-related AEs.
| S-EPMC9657798 | biostudies-literature