First-Line Immunotherapy Versus Targeted Therapy in Patients With BRAF -Mutant Advanced Melanoma: A Real-World Analysis

Abstract

Aim: To compare effectiveness of nivolumab + ipilimumab (NIVO + IPI) versus BRAF + MEK inhibitors (BRAFi + MEKi) in patients with BRAF-mutant advanced melanoma in the real-world setting. Materials & methods: This study used the Flatiron Health electronic medical record database. Results: After adjusting for differences in baseline characteristics, NIVO + IPI was associated with a 32% reduction in risk of death versus BRAFi + MEKi. At a mean follow-up of 15–16 months, 64% of NIVO + IPI patients and 43% of BRAFi + MEKi patients were alive; subsequent therapy was administered to 33 and 41% of patients, respectively. After first-line NIVO + IPI, 20% of patients died before subsequent therapy, whereas 32% died after first-line BRAFi + MEKi. Conclusion: In this real-world study, patients treated with first-line NIVO + IPI showed significant survival benefit versus those receiving first-line BRAFi + MEKi.

Real World Outcomes in Patients with Advanced Melanoma Treated in Alberta, Canada: A Time-Era Based Analysis

“…were preferentially started on targeted treatment. Lastly, upfront immunotherapy may indeed be superior to targeted agents in the first line setting and another real-world analysis has demonstrated similar trends in this scenario [18].…”

Real-World Evidence of Systemic Therapy Sequencing on Overall Survival for Patients with Metastatic BRAF-Mutated Cutaneous Melanoma

“…Pavlick et al [18] also reported similar findings with a 32% mortality risk reduction favouring first-line dual IO over BRAK + MEK inhibitors in patients with BRAF-mutant advanced melanoma. Both author groups utilized the same Flatiron health database, and it was unclear if the data captured were within the same time frame [15,19]. Taking these into account, the differences in our study compared to others were likely due to the relatively smaller proportion of patients receiving 1L-dual ICI, as most patients in this study were treated before dual-IO became widely available in Canada.…”

“…Additional evidence in support of sequencing these therapies comes from the real-world data available from electronic health records and single-institution case series. To date, the published data from such analyses are predominantly retrospective assessments [15][16][17][18][19]. In general, most studies included small numbers of patients and although some included patients from multiple centres, many were limited to a single-centre dataset.…”

Managing Metastatic Melanoma in 2022: A Clinical Review

“…This approach has been previously founded on currently available long-term durable response and survival rates of ICI, even when prematurely discontinued, in addition to retrospectively observed improvements in patient outcomes and OS when initially treated with ICI before exposure of targeted agents. [102][103][104][105][106] However, updates of two prospective studies (SECOMBIT and DREAMseq) presented in late 2021 have now further supported the use of combination ICI over targeted therapies in the frontline setting for patients with untreated, metastatic BRAFV600-mutated melanoma. The SECOMBIT trial has observed that patients treated with ICI combination (ipilimumab plus nivolumab) before BRAF and MEK inhibition (encorafenib plus binimetinib) exhibited 3-year PFS (53% v 41%) and OS (62% v 54%) benefits when compared with the reverse sequence of those regimens, along with additional PFS (54%) and OS (60%) benefits through a sandwich approach of BRAF and MEK inhibition both before and after combination ICI.…”

“…102,103,107 The recommended sequence of these agents and the utility of ICI monotherapy remain major topics of interest currently under prospective investigation (Clinical-Trials.gov identifier: NCT02224781 and NCT02631447) with further exploration of predictive biomarkers and patterns of therapeutic resistance as additional fields of clinical necessity in guiding the optimal management of this cohort. 102,103 In regard to the duration of systemic therapy, encouraging observations of continuous durable responses have been observed after early discontinuation of single-agent and combination ICI therapy and relatively low rates of disease progression in those discontinuing targeted therapy. 114,115 However, the most durable responses after treatment discontinuation appear to be limited to patients who have achieved a CR during their initial treatment, and therefore, a much more extensive understanding of the clinical characteristics and biomarkers associated with continuous responses after the discontinuation of systemic therapies is required before safely endorsing the discontinuation of these life-prolonging agents.…”