BRAF with or Without MEK Inhibition Plus PD-1 Checkpoint Blockade for the Treatment of Metastatic Melanoma.

Michelle Rohlfs,Roland L. Bassett,Carol Lacey,Natalie McQuail,Urvi Mehta,Ida John,Rinata Simien,Stephanie Tupue,Tina Karin Dett,Isabella Claudia Glitza,Adi Diab,Rodabe Navroze Amaria,Hussein Abdul-Hassan Tawbi,Michael A. Davies,Wen-Jen Hwu,Patrick Hwu,Sapna Pradyuman Patel

Environment International（2016）SCI 1区

Univ Texas MD Anderson Canc Ctr

Cited 2|Views53

Abstract

9548 Background: The treatment (tx) of metastatic melanoma (MM) has met with considerable advances with the use of targeted therapy such as BRAF and MEK inhibitors (BRAFi, MEKi) and anti-PD1 (aPD1) checkpoint agents, pembrolizumab (PEMBRO) and nivolumab (NIVO). The combination (combo) of these two therapeutic classes has previously been studied with ipilimumab and is currently being studied with PEMBRO (KEYNOTE-022). Given the commercial availability of these agents, many providers have begun combining these agents for clinical use. Thus, we evaluated our use of combo BRAFi +/- MEKi with aPD1 agents PEMBRO or NIVO to determine the tolerability and efficacy of these combined tx. Methods: We performed a single-center IRB-approved retrospective review of patients (pts) with BRAF-positive mm who received tx with the combo of BRAFi +/- MEKi plus PEMBRO or NIVO. Pts could have received prior tx with either class of agents, and have a run-in with BRAFi +/- MEKi or with aPD1 drugs of any duration before concurrent combo tx. Toxicity via adverse event (AE) documentation and efficacy via PFS were captured. Results: Between June 2014 and December 2015, 38 pts were treated with the combo BRAFi +/- MEKi plus aPD1. The median age was 54, 52% were male, 68% had M1c disease and 24% had elevated LDH at the time of combo tx. Run-in consisted of BRAFi +/- MEKi in 63%, 34% had a run-in with aPD1; one pt started the combo tx concurrently. Eight pts (21%) had a run-in period of 4 wks or less, 12 pts (32%) of 6 wks or less. 58% received BRAFi + aPD1 while 42% received BRAFi + MEKi + aPD1. Mean number of doses of aPD1 was 10, with majority of pts (79%) receiving PEMBRO. Median follow-up was 4.9 mos and median PFS from start of combo tx was 7.6 mos (doublet tx 8.5 mos and triplet tx 7.2 mos). AEs were noted in 28 pts (74%). The majority were Grade (G) 1-2, commonly fatigue. G3-4 AEs were seen in 4 pts (11%) as a result of rash, nausea/vomiting, fever and chills. No pts had tx held for hepatotoxicity; there have been no G5 AEs with this combo, and all pts remain alive at last follow-up. Conclusions: The addition of aPD1 to a targeted therapy regimen of BRAFi +/- MEKi appears safe and well-tolerated in BRAF-positive MM. Results of the prospective KEYNOTE-022 will further our understanding of this combo.

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Pretraining has recently greatly promoted the development of natural language processing (NLP)
We show that M6 outperforms the baselines in multimodal downstream tasks, and the large M6 with 10 parameters can reach a better performance
We propose a method called M6 that is able to process information of multiple modalities and perform both single-modal and cross-modal understanding and generation
The model is scaled to large model with 10 billion parameters with sophisticated deployment, and the 10 -parameter M6-large is the largest pretrained model in Chinese
Experimental results show that our proposed M6 outperforms the baseline in a number of downstream tasks concerning both single modality and multiple modalities We will continue the pretraining of extremely large models by increasing data to explore the limit of its performance

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