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First-line Advanced Cutaneous Melanoma Treatments: Where Do We Stand?

ABSTRACT: Cutaneous melanoma has always been a dreaded diagnosis because of its high mortality rate and its proclivity for invasiveness and metastasis. Historically, advanced melanoma treatment has been limited to chemotherapy and nonspecific immunotherapy agents that display poor curative potential and high toxicity. However, during the last decade, the evolving understanding of the mutational burden of melanoma and immune system evasion mechanisms has led to the development of targeted therapy and specific immunotherapy agents that have transformed the landscape of advanced melanoma treatment. Despite the considerable strides in understanding the clinical implications of these agents, there is a scarcity of randomized clinical trials that directly compare the efficacy of the aforementioned agents; hence, there are no clear preferences among the available first-line options. In addition, the introduction of these agents was associated with a variety of dermatologic adverse events, some of which have shown a detrimental effect on the continuity of treatment. This holds especially true in light of the current fragmentation of care provided by the managing health care professionals. In this study, we attempt to summarize the current understanding of first-line treatments. In addition, the paper describes the indirect comparative evidence that aids in bridging the gap in the literature. Furthermore, this paper sheds light on the impact of the scarcity of dermatology specialist input in the management of dermatologic adverse events associated with advanced melanoma treatment. It also looks into the potential avenues where dermatologic input can bridge the gap in the care provided by oncologists, thus standardizing the care provided to patients with melanoma presenting with dermatologic adverse events.

SUBMITTER: Abdulkarim LS

PROVIDER: S-EPMC8717133 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:For unresectable or metastatic melanoma, first-line ipilimumab has demonstrated long-term survival benefits over a 7-year period. First-line treatment with BRAF inhibitors has demonstrated efficacy in clinical trials with up to 3 years of follow-up. The long-term comparative efficacy and costs of ipilimumab and BRAF inhibitors are unknown.Patient-level data from 12 clinical studies for ipilimumab were used. Survival data were extracted from included clinical trials for BRAF inhibitors based on a systematic literature review. Different parametric survival models, including exponential, Gompertz, log-normal, and Weibull models, were used to fit reported overall survival (OS) data and to project long-term survival for BRAF inhibitors. Survival benefits were measured in terms of total life-months gained as calculated by the area under the curve of OS Kaplan-Meier curves for the observed ipilimumab data and projected BRAF inhibitor data. Total life-months gained and cumulative costs per life-month gained were compared between ipilimumab and BRAF inhibitors.The systematic literature review identified six randomized-controlled trials of BRAF inhibitors for subsequent analyses. With 7-year follow-up, ipilimumab was associated with a total of 28.5 life-months gained. Based on the Weibull model, the extrapolated total life-months gained for BRAF inhibitors were 26.5 months for dabrafenib, 21.3 months for trametinib, 14.3 months for vemurafenib, and 24.6 months for dabrafenib + trametinib. In sensitivity analyses, extrapolated total life-months gained varied across the three other models, ranging from 13.7 to 36.8 months across therapies. Cumulative costs per life-month gained with ipilimumab decreased steadily over time, while the costs remained constant for BRAF inhibitors due to continuous dosing. By year 3, cumulative costs per life-month gained were the lowest with ipilimumab; by year 7, the costs were $4281 for ipilimumab, compared with $8920 for dabrafenib, $10,211 for trametinib, $11,002 for vemurafenib, and $19,132 for the dabrafenib + trametinib combination therapy.Ipilimumab was associated with a better long-term cost-per-life month compared to BRAF agents. Long-term extrapolation of survival with BRAF agents was uncertain, and showed no evidence of prolonged survival compared to ipilimumab.

Project description:BackgroundMalignancies are molecularly complex and become more resistant with each line of therapy. We hypothesized that offering matched, individualized combination therapies to patients with treatment-naïve, advanced cancers would be feasible and efficacious. Patients with newly diagnosed unresectable/metastatic, poor-prognosis cancers were enrolled in a cross-institutional prospective study.MethodsA total of 145 patients were included in the study. Genomic profiling (tissue and/or circulating tumor DNA) was performed in all patients, and PD-L1 immunohistochemistry, tumor mutational burden, and microsatellite status assessment were performed in a subset of patients. We evaluated safety and outcomes: disease-control rate (stable disease for ≥ 6 months or partial or complete response), progression-free survival (PFS), and overall survival (OS).ResultsSeventy-six of 145 patients (52%) were treated, most commonly for non-colorectal gastrointestinal cancers, carcinomas of unknown primary, and hepatobiliary malignancies (53% women; median age, 63 years). The median number of deleterious genomic alterations per patient was 5 (range, 0-15). Fifty-four treated patients (71%) received ≥ 1 molecularly matched therapy, demonstrating the feasibility of administering molecularly matched therapy. The Matching Score, which reflects the percentage of targeted alterations, correlated linearly with progression-free survival (R2 = 0.92; P = 0.01), and high (≥ 60%) Matching Score was an independent predictor of improved disease control rate [OR 3.31 (95% CI 1.01-10.83), P = 0.048], PFS [HR 0.55 (0.28-1.07), P = 0.08], and OS [HR 0.42 (0.21-0.85), P = 0.02]. Serious adverse event rates were similar in the unmatched and matched groups.ConclusionsPersonalized combination therapies targeting a majority of a patient's molecular alterations have antitumor activity as first-line treatment. These findings underscore the feasibility and importance of using tailored N-of-1 combination therapies early in the course of lethal malignancies.Trial registrationI-PREDICT ( NCT02534675 ) was registered on August 25, 2015.

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First-line Advanced Cutaneous Melanoma Treatments: Where Do We Stand?

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