Systemic therapy for Asian patients with advanced BRAF V600-mutant melanoma in a real-world setting: A multi-center retrospective study in Japan (B-CHECK-RWD study).

Anti-PD-1-based immunotherapy is considered a preferred first-line treatment for advanced BRAF V600-mutant melanoma. However, a recent international multi-center study suggested that the efficacy of immunotherapy is poorer in Asian patients in the non-acral cutaneous subtype. We hypothesized that the optimal first-line treatment for Asian patients may be different. We retrospectively collected data of Asian patients with advanced BRAF V600-mutant melanoma treated with first-line BRAF/MEK inhibitors (BRAF/MEKi), anti-PD-1 monotherapy (Anti-PD-1), and nivolumab plus ipilimumab (PD-1/CTLA-4) between 2016 and 2021 from 28 institutions in Japan. We identified 336 patients treated with BRAF/MEKi (n = 236), Anti-PD-1 (n = 64) and PD-1/CTLA-4 (n = 36). The median follow-up duration was 19.9 months for all patients and 28.6 months for the 184 pa tients who were alive at their last follow-up. For patients treated with BRAF/MEKi, anti-PD-1, PD-1/CTLA-4, the median ages at baseline were 62, 62, and 53 years (p = 0.03); objective response rates were 69%, 27%, and 28% (p < 0.001); median progression-free survival (PFS) was 14.7, 5.4, and 5.8 months (p = 0.003), and median overall survival (OS) was 34.6, 37.0 months, and not reached, respectively (p = 0.535). In multivariable analysis, hazard ratios (HRs) for PFS of Anti-PD-1 and PD-1/CTLA-4 compared with BRAF/MEKi were 2.30 (p < 0.001) and 1.38 (p = 0.147), and for OS, HRs were 1.37 (p = 0.111) and 0.56 (p = 0.075), respectively. In propensity-score matching, BRAF/MEKi showed a tendency for longer PFS and equivalent OS with PD-1/CTLA-4 (HRs for PD-1/CTLA-4 were 1.78 [p = 0.149]) and 1.03 [p = 0.953], respectively). For patients who received second-line treatment, BRAF/MEKi followed by PD-1/CTLA-4 showed poor survival outcomes. The superiority of PD-1/CTLA-4 over BRAF/MEKi appears modest in Asian patients. First-line BRAF/MEKi remains feasible, but it is difficult to salvage at progression. Ethnicity should be considered when selecting systemic therapies until personalized biomarkers are available in daily practice. Further studies are needed to establish the optimal treatment sequence for Asian patients.

Namikawa K ，Ito T ，Yoshikawa S ，Yoshino K ，Kiniwa Y ，Ohe S ，Isei T ，Takenouchi T ，Kato H ，Mizuhashi S ，Fukushima S ，Yamamoto Y ，Inozume T ，Fujisawa Y ，Yamasaki O ，Nakamura Y ，Asai J ，Maekawa T ，Funakoshi T ，Matsushita S ，Nakano E ，Oashi K ，Kato J ，Uhara H ，Miyagawa T ，Uchi H ，Hatta N ，Tsutsui K ，Maeda T ，Matsuya T ，Yanagisawa H ，Muto I ，Okumura M ，Ogata D ，Yamazaki N ... -  《Cancer Medicine》

Real-world survival of patients with advanced BRAF V600 mutated melanoma treated with front-line BRAF/MEK inhibitors, anti-PD-1 antibodies, or nivolumab/ipilimumab.

The optimal treatment sequence for patients with advanced BRAF V600 mutant melanoma is unknown. BRAF/MEK inhibition (BRAF/MEKi), single agent anti-PD-1 (aPD-1) antibodies and combination immune checkpoint inhibition with nivolumab and ipilimumab (niv/ipi) are all approved; however, they have not been prospectively compared. Therefore, we sought to compare overall survival of patients with advanced BRAF mutant melanoma treated with either front-line BRAF/MEKi, aPD-1, or niv/ipi. Patients with advanced BRAF mutant melanoma who had received BRAF/MEKi, niv/ipi, or aPD-1 in the front-line setting were identified from a nationwide database comprising de-identified patient-level structured and unstructured data derived from electronic health records. Survival was compared using Kaplan-Meier curves and log-rank analysis. Univariate and multivariate Cox regression models were used to measure the effect of front-line treatment, age (>64 or not), LDH (elevated or not), and Eastern Cooperative Oncology Group (ECOG) performance status (>1 or not) on survival. Five hundred and sixty seven patients with advanced disease and treated with front-line aPD-1 (n = 162), BRAF/MEKi (n = 297) or niv/ipi (n = 108) were identified. With a median follow-up of 22.4 months, median overall survival (OS) for patients treated with front-line niv/ipi was not reached (NR) while median OS for patients treated with aPD-1 or BRAF/MEKi was 39.5 months and 13.2 months, respectively. Front-line treatment with PD-1 and niv/ipi were associated with statistically longer survival than BRAF/MEKi in multivariate analyses. In our real-world retrospective analysis, patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.

Moser JC ，Chen D ，Hu-Lieskovan S ，Grossmann KF ，Patel S ，Colonna SV ，Ying J ，Hyngstrom JR ... -  《Cancer Medicine》

Melanoma brain metastases that progress on BRAF-MEK inhibitors demonstrate resistance to ipilimumab-nivolumab that is associated with the Innate PD-1 Resistance Signature (IPRES).

Melanoma brain metastases (MBMs) are a challenging clinical problem with high morbidity and mortality. Although first-line dabrafenib-trametinib and ipilimumab-nivolumab have similar intracranial response rates (50%-55%), central nervous system (CNS) resistance to BRAF-MEK inhibitors (BRAF-MEKi) usually occurs around 6 months, and durable responses are only seen with combination immunotherapy. We sought to investigate the utility of ipilimumab-nivolumab after MBM progression on BRAF-MEKi and identify mechanisms of resistance. Patients who received first-line ipilimumab-nivolumab for MBMs or second/third line ipilimumab-nivolumab for intracranial metastases with BRAFV600 mutations with prior progression on BRAF-MEKi and MRI brain staging from March 1, 2015 to June 30, 2018 were included. Modified intracranial RECIST was used to assess response. Formalin-fixed paraffin-embedded samples of BRAFV600 mutant MBMs that were naïve to systemic treatment (n=18) or excised after progression on BRAF-MEKi (n=14) underwent whole transcriptome sequencing. Comparative analyses of MBMs naïve to systemic treatment versus BRAF-MEKi progression were performed. Twenty-five and 30 patients who received first and second/third line ipilimumab-nivolumab, were included respectively. Median sum of MBM diameters was 13 and 20.5 mm for the first and second/third line ipilimumab-nivolumab groups, respectively. Intracranial response rate was 75.0% (12/16), and median progression-free survival (PFS) was 41.6 months for first-line ipilimumab-nivolumab. Efficacy of second/third line ipilimumab-nivolumab after BRAF-MEKi progression was poor with an intracranial response rate of 4.8% (1/21) and median PFS of 1.3 months. Given the poor activity of ipilimumab-nivolumab after BRAF-MEKi MBM progression, we performed whole transcriptome sequencing to identify mechanisms of drug resistance. We identified a set of 178 differentially expressed genes (DEGs) between naïve and MBMs with progression on BRAF-MEKi treatment (p value <0.05, false discovery rate (FDR) <0.1). No distinct pathways were identified from gene set enrichment analyses using Kyoto Encyclopedia of Genes and Genomes, Gene Ontogeny or Hallmark libraries; however, enrichment of DEG from the Innate Anti-PD1 Resistance Signature (IPRES) was identified (p value=0.007, FDR=0.03). Second-line ipilimumab-nivolumab for MBMs after BRAF-MEKi progression has poor activity. MBMs that are resistant to BRAF-MEKi that also conferred resistance to second-line ipilimumab-nivolumab showed enrichment of the IPRES gene signature.

Lau PKH ，Feran B ，Smith L ，Lasocki A ，Molania R ，Smith K ，Weppler A ，Angel C ，Kee D ，Bhave P ，Lee B ，Young RJ ，Iravani A ，Yeang HA ，Vergara IA ，Kok D ，Drummond K ，Neeson PJ ，Sheppard KE ，Papenfuss T ，Solomon BJ ，Sandhu S ，McArthur GA ... -  《Journal for ImmunoTherapy of Cancer》

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》

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》