First line immunotherapy extends brain metastasis free survival, improves overall survival, and reduces the incidence of brain metastasis in patients with advanced melanoma.

Recent advances in targeted therapy and immunotherapy have improved the prognosis of melanoma patients but brain metastasis remains a major challenge. Currently, it is unclear how existing therapies can be best used to prevent or treat brain metastasis in melanoma patients. We aimed to assess brain metastasis free survival (BMFS), overall survival (OS), incidence of brain metastases, and sequencing strategies of immunotherapy and targeted therapy in patients with BRAF-mutated advanced melanoma. We retrospectively analyzed 683 patients with BRAF-mutated advanced melanoma treated with first line (1L) immunotherapy (N = 266) or targeted therapy (N = 417). The primary outcome was BMFS. Secondary outcomes included OS of all patients and incidence of brain metastases in patients without documented brain metastases prior to 1L therapy. The median BMFS was 13.7 months [95% confidence interval (CI): 12.4-16.0] among all patients. The median BMFS for patients receiving 1L immunotherapy was 41.9 months [95% CI: 22.8-not reached (NR)] and targeted therapy was 11.0 months (95% CI: 8.8-12.5). Median OS results were qualitatively similar to BMFS results. The cumulative incidence of brain metastases for patients receiving 1L targeted therapy was higher than for patients receiving 1L immunotherapy (P < .001). Patients receiving 1L anti-CTLA4 plus anti-PD1 combination immunotherapy only or followed by second line (2L) targeted therapy had better BMFS (HR 0.40, 95% CI: 0.24-0.67, P = .001), improved OS (HR 0.49, 95% CI: 0.30-0.81, P = .005), and reduced incidence of brain metastases (HR 0.47, 95% CI: 0.24-0.67, P = .047) than patients receiving 1L combination BRAF and MEK targeted therapy followed by 2L immunotherapy. Patients with advanced BRAF mutant melanoma treated with 1L immunotherapy have significantly longer BMFS and OS, and reduced incidence of brain metastases, compared with those treated with 1L targeted therapy. Further studies evaluating the ability of immunotherapy and targeted therapy to improve OS and prevent brain metastases are warranted.

Wang X ，Haaland B ，Hu-Lieskovan S ，Colman H ，Holmen SL ... -  《Cancer Reports》

Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG.

Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy. Patients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC-V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS). Of 1704 patients, 916 were BRAF wild-type (BRAFwt) and 788 were BRAF V600 mutant (BRAFmut). Median follow-up time after start of 1L-therapy was 40.4 months. BRAFwt patients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAFmut patients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAFmut patients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAFmut patients. In BRAFwt patients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAFwt patients. For BRAFmut patients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK. In BRAFmut patients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAFwt patients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1.

Franklin C ，Mohr P ，Bluhm L ，Meier F ，Garzarolli M ，Weichenthal M ，Kähler K ，Grimmelmann I ，Gutzmer R ，Utikal J ，Terheyden P ，Herbst R ，Haferkamp S ，Pfoehler C ，Forschner A ，Leiter U ，Ziller F ，Meiss F ，Ulrich J ，Kreuter A ，Gebhardt C ，Welzel J ，Schilling B ，Kaatz M ，Scharfetter-Kochanek K ，Dippel E ，Nashan D ，Sachse M ，Weishaupt C ，Löffler H ，Gambichler T ，Loquai C ，Heinzerling L ，Grabbe S ，Debus D ，Schley G ，Hassel JC ，Weyandt G ，Trommer M ，Lodde G ，Placke JM ，Zimmer L ，Livingstone E ，Becker JC ，Horn S ，Schadendorf D ，Ugurel S ... -  《Journal for ImmunoTherapy of Cancer》

The combination of stereotactic radiosurgery with immune checkpoint inhibition or targeted therapy in melanoma patients with brain metastases: a retrospective study.

Martins F ，Schiappacasse L ，Levivier M ，Tuleasca C ，Cuendet MA ，Aedo-Lopez V ，Gautron Moura B ，Homicsko K ，Bettini A ，Berthod G ，Gérard CL ，Wicky A ，Bourhis J ，Michielin O ... -  《-》

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.

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. 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). 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. 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.

Cowey CL ，Boyd M ，Aguilar KM ，Beeks A ，Krepler C ，Scherrer E ... -  《Cancer Medicine》

PD-1 inhibitors might limit the development of brain metastases in patients with advanced melanoma.

Marcaillou M ，Linder C ，Chaltiel L ，Sibaud V ，Pagès C ，Modesto A ，Chira C ，Dalmasso C ，Boulinguez S ，Bedane C ，Meyer N ... -  《-》