Outcome of combination therapy using BRAF and MEK inhibitors among Asian patients with advanced melanoma: An analysis of 112 cases

2021 ◽  
Vol 145 ◽  
pp. 210-220
Author(s):  
Yasuhiro Fujisawa ◽  
Takamichi Ito ◽  
Hiroshi Kato ◽  
Hiroyuki Irie ◽  
Tatsuya Kaji ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Advanced Melanoma ◽  
Mek Inhibitors ◽  
Asian Patients

scholarly journals MEK inhibitors and their potential in the treatment of advanced melanoma: the advantages of combination therapy

2015 ◽  
pp. 43 ◽  
Author(s):  
Emanual Maverakis ◽  
Khiem Tran ◽  
Michelle Cheng ◽  
Anupam Mitra ◽  
Hiromi Ogawa ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Advanced Melanoma ◽  
Mek Inhibitors

Prolonged survival of a patient with brain melanoma metastasis treated with BRAF and MEK inhibitors combination therapy

2020 ◽  
Vol 155 (2) ◽  
Author(s):  
Giulia Spallone ◽  
Virginia Garofalo ◽  
Eliseo Picchi ◽  
Rossella Pitocco ◽  
Federico Bianchi ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Prolonged Survival ◽  
Melanoma Metastasis ◽  
Mek Inhibitors

Clinical activity of fianlimab (REGN3767), a human anti-LAG-3 monoclonal antibody, combined with cemiplimab (anti-PD-1) in patients (pts) with advanced melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9515-9515
Author(s):  
Omid Hamid ◽  
Ding Wang ◽  
Tae Min Kim ◽  
Sang-We Kim ◽  
Nehal J. Lakhani ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Adrenal Insufficiency ◽  
Safety Profile ◽  
Phase 1 ◽  
Objective Response ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Treatment Naïve ◽  
Grade 3

9515 Background: Fianlimab and cemiplimab are two high-affinity, fully human, hinge-stabilized IgG4 monoclonal antibodies. In a Phase 1 dose escalation study, fianlimab combined with cemiplimab showed an acceptable safety profile and some clinical activity in pts with advanced malignancies. Here, we present safety and clinical activity data from two expansion cohorts of pts with advanced melanoma (anti–programmed cell death/ligand-1 [anti–PD-(L)1] naïve or experienced) who were treated with fianlimab + cemiplimab and had an opportunity for first on-treatment tumor assessment (cut-off date: Jan 4, 2021). Methods: Pts with advanced melanoma who had no prior anti–PD-(L)1 treatment (naïve) or prior anti–PD-(L)1 treatment within 3 months of screening (experienced) received fianlimab 1600 mg + cemiplimab 350 mg by IV infusion every 3 weeks. Tumor measurements were performed every 6 weeks for the first 24 weeks and subsequently every 9 weeks per RECIST v1.1. Results: 48 pts with advanced melanoma were treated with the combination therapy: 33 were anti–PD-(L)1 naïve and 15 were anti–PD-(L)1 experienced (median age: 69 years vs 59 years; male: 66.7% vs 46.7%; Caucasian: 87.9% vs 60%). The safety profile (including immune-related adverse events [AEs]) of fianlimab + cemiplimab combination therapy was similar to that of anti–PD-1 monotherapy with one exception. The rate of adrenal insufficiency, 8.3% (4/48) of pts, is similar to the rate previously observed with anti–PD-1 + anti–cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) combination therapy but higher than that observed with anti–PD-1 monotherapy. Grade ≥3 treatment-emergent AEs (TEAEs) occurred in 35.4% (17/48) of patients; Grade ≥3 serious TEAEs occurred in 22.9% (11/48) of patients; 8.3% (4/48) of patients discontinued treatment due to a TEAE. The most common TEAEs were fatigue (n = 15, 31.3%) and rash (n = 11, 22.9%). By investigator assessment, objective response rate (includes unconfirmed complete [CR] and partial responses [PR]) was 63.6% (3 CRs and 18 PRs) for anti–PD-(L)1 naïve pts and 13.3% (1 CR and 1 PR) for anti–PD-(L)1 experienced pts. Median progression-free survival and median duration of response for the anti–PD-(L)1 treatment naïve cohort have not been reached. Prognostic clinical markers and tumor biomarkers such as expression of LAG-3, PD-L1, and major histocompatibility complex II are being evaluated. Recruitment is ongoing. Conclusions: The safety profile of fianlimab + cemiplimab is similar to that observed with cemiplimab monotherapy and other anti–PD-1s, with the exception of higher rate of adrenal insufficiency. Fianlimab + cemiplimab combination has shown clinical activity for pts with advanced melanoma that is similar to anti–PD-1 + CTLA-4 combination therapy, but with lower demonstrated rates of TEAEs. Clinical trial information: NCT03005782.

scholarly journals Safety profile of nivolumab (NIVO) and ipilimumab (IPI) combination therapy in patients (pts) with advanced melanoma (MEL)

2016 ◽  
Vol 27 ◽  
pp. vi385 ◽  
Author(s):  
M. Sznol ◽  
P.F. Ferrucci ◽  
D. Hogg ◽  
M. Atkins ◽  
P. Wolter ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Safety Profile ◽  
Advanced Melanoma

scholarly journals P865 Safety & efficacy of lifileucel (LN-144) tumor infiltrating lymphocyte therapy in metastatic melanoma patients after progression on multiple therapies – independent review committee data update

2020 ◽  
Vol 8 (Suppl 1) ◽  
pp. A12-A12
Author(s):  
Amod Sarnaik ◽  
Nikhil Khushalani ◽  
Jason Chesney ◽  
Harriet Kluger ◽  
Brendan Curti ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Advanced Melanoma ◽  
Review Committee ◽  
Safety And Efficacy ◽  
Mek Inhibitors ◽  
Tumor Infiltrating Lymphocyte ◽  
Heavily Pretreated ◽  
Independent Review ◽  
Melanoma Patients

BackgroundTreatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel, a centrally manufactured cryopreserved autologous TIL therapy assessed by both investigator and an independent review committee (IRC), are presented.MethodsC-144-01 is a global Phase 2 open-label, multicenter study of the safety and efficacy of lifileucel in patients with unresectable metastatic melanoma. We report on Cohort 2 (N = 66) patients with Stage IIIC/IV unresectable melanoma who received lifileucel. Tumors resected at local institutions were processed in central GMP facilities for TIL production in a 22-day process. Final TIL infusion product was cryopreserved and shipped to sites. Patients received one week of cyclophosphamide/fludarabine preconditioning lymphodepletion, a single lifileucel infusion, followed by up to 6 doses of IL-2. All responses were assessed by RECIST 1.1.Results66 patients had the following baseline characteristics: 3.3 mean prior therapies (anti-PD1 100%; anti-CTLA-4 80%; BRAF/MEK inhibitor 23%), relatively high tumor burden (106 mm mean target lesion sum of diameters), 44% with liver and/or brain lesions, median LDH 244 U/L. Objective Response Rate (ORR) by investigator was 36.4% (2 CR, 22 PR, 1 previously confirmed PR is now changed to SD) and Disease Control Rate (DCR) of 80.3%. At a median follow up of 9.7 months, median Duration of Response (DOR) has not been reached. The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens.The ORR per IRC was 34.8% (2 CR, 21 PR) and DCR was 72.7%. At a median follow up of 6.9 months, the median IRC DOR has not been reached. Overall concordance rate of investigator and IRC read of response was 89.4%. The concordance compares favorably with literature reports in a metastatic disease.1ConclusionsLifileucel treatment resulted in a 36.4% ORR in heavily pretreated metastatic melanoma patients with high baseline disease burden who had received prior anti-PD1 and BRAF/MEK inhibitors, if tumor BRAF mutated. The high concordance of 89.4% between investigator and IRC confirms the original assessment of lifileucel efficacy in metastatic melanoma.2AcknowledgementsThe authors would like to thank the patients and their families for participation in the study.The authors would also like to acknowledge the support and dedication of all investigators and site team members from all participating clinical trial institutions.Trial RegistrationClinicalTrials. gov Identifier: NCT02360579Ethics ApprovalEthics Approval This trial was approved by Western Institutional Review Board - IRB Tracking Number: 20160198.ReferencesGhiorghiu DC, et al. Comparison of central and site review of RECIST data in an open randomised phase II trial in advanced melanoma. 10.1594.ecr 2009/C-075.Sarnaik A, et al. Safety and efficacy of cryopreserved autologous tumor infiltrating lymphocyte therapy (LN-144, lifileucel) in advanced metastatic melanoma patients who progressed on multiple prior therapies including anti-PD-1. J Clin Oncol 2019;37:2518–2518.

Real‐world efficacy and safety data of nivolumab and ipilimumab combination therapy in Japanese patients with advanced melanoma

2020 ◽  
Vol 47 (11) ◽  
pp. 1267-1275
Author(s):  
Akira Takahashi ◽  
Kenjiro Namikawa ◽  
Dai Ogata ◽  
Eiji Nakano ◽  
Shunichi Jinnai ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Real World ◽  
Safety Data ◽  
Japanese Patients ◽  
Advanced Melanoma ◽  
Efficacy And Safety

scholarly journals O85 Durable responses in anti-PD-1 refractory melanoma following intratumoral injection of a toll-like receptor 9 (TLR9) agonist, CMP-001, in combination with pembrolizumab

2020 ◽  
Vol 8 (Suppl 1) ◽  
pp. A2.2-A3 ◽  
Author(s):  
Mohammed Milhem ◽  
Yousef Zakharia ◽  
Diwakar Davar ◽  
Elizabeth Buchbinder ◽  
Theresa Medina ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Confidence Interval ◽  
Initial Period ◽  
Objective Response ◽  
Intratumoral Injection ◽  
Advanced Melanoma ◽  
Low Grade ◽  
Tumor Biopsy ◽  
Tlr9 Agonist ◽  
Duration Of Response

BackgroundIntratumoral (IT) injection of CMP-001, a CpG-A TLR9 agonist packaged within a virus-like particle, is designed to activate tumor-associated plasmacytoid dendritic cells, inducing an interferon-rich tumor microenvironment and anti-tumor CD8+ T cell responses.MethodsCMP-001-001 is an ongoing Phase 1b trial evaluating the safety and efficacy of CMP-001 in combination with pembrolizumab (Part 1; N = 144) or alone (Part 2; N = 23) in patients with advanced melanoma resistant to prior anti-PD-1 therapy (Tables 1). CMP-001 is administered IT into accessible lesion(s) either with, or without on-site saline dilution (table 1), and response assessed by RECIST v1.1. Monotherapy patients who progress can be rolled over onto combination therapy and continue on study. Baseline and on-therapy serum is analyzed for cytokines, and immunohistochemistry and RNA-Seq are performed on available tumor biopsies.Abstract O85 Table 1Advanced anti-PD-1 Refractory melanoma patient population by treatment allocationResultsAdverse events (AEs) attributed to CMP-001 in combination with pembrolizumab or as monotherapy consisted predominately of transient low-Grade flu-like symptoms and injection site reactions: Grade 3+ related AEs were reported in 33% of patients treated with combination therapy and 22% of patients with monotherapy.The Objective Response Rate (ORR) with undiluted CMP-001 in combination with pembrolizumab was 24% (18/75; 95% confidence interval: 15%-35% (table 1); on-site dilution of CMP-001 was associated with a substantial decrease in ORR to 12% (7/61; 95% confidence interval: 5%-22% (table 1). Three additional patients had a delayed partial response after an initial period of disease progression. Anti-tumor response was comparable between injected and uninjected lesions. The median duration of response to combination therapy has not been reached. The ORR to CMP-001 monotherapy was 22% (5/23; 95% confidence interval: 7%-44% (table 1); time from last anti-PD-1 therapy before CMP-001 was 1.5 to >20 months in responders; 3 of the patients responding to CMP-001 monotherapy achieved PR at the first evaluation, but progressed by the second evaluation.Serum and tumor biopsy translational studies in the patients receiving combination therapy supported the proposed mechanism of TLR9 activation and identified a possible association between induction of serum CXCL10 and response.ConclusionsIT CMP-001 alone and in combination with pembrolizumab appears well tolerated, can reverse resistance to anti-PD-1 therapy, and can produce deep and durable clinical responses in patients with advanced melanoma.Ethics ApprovalCMP-001-001 was centrally approved by the WCG-WIRB, WIRB approval tracking number 20152597.

Salvage combination ipilimumab and nivolumab after failure of prior checkpoint inhibitor therapy in patients with advanced melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21009-e21009 ◽  
Author(s):  
Elizabeth Mary Gaughan ◽  
Gina R. Petroni ◽  
William W. Grosh ◽  
Craig L. Slingluff
Keyword(s):  
Combination Therapy ◽  
Small Sample Size ◽  
Objective Response ◽  
Initial Therapy ◽  
Subsequent Treatment ◽  
Advanced Melanoma ◽  
Small Sample ◽  
Treatment Naïve ◽  
Clinicopathologic Factors ◽  
Clinically Significant

e21009 Background: The combination of Ipilimumab and Nivolumab is standard initial therapy in patients with advanced melanoma based on trials involving treatment-naïve patients. The benefit in those previously managed with checkpoint monotherapy is not well defined. Methods: We identified metastatic melanoma patients from our Immunotherapy database managed with combination Ipilimumab/Nivolumab after progression on prior checkpoint monotherapy. Baseline clinical factors, treatment history, combination therapy outcome by RECIST v1.1 and toxicity data were collected. Descriptive statistics were used to summarize the data. Given the small sample size and limited numbers of deaths, it is too early to look for preliminary associations between outcomes and clinicopathologic factors. Results: We identified 19 patients treated with combination Ipilimumab/Nivolumab after progression on prior checkpoint monotherapy. The cohort included 15 men and 4 women with an average age of 63 years. Thirteen patients had M1c disease, and 7 had a BRAF mutation. Patients had received up to four lines of prior immunotherapy including 9 treated with both prior anti-PD1 and anti-CTLA4 monotherapy. Seven patients completed all four doses of combination therapy with 6 proceeding onto maintenance nivolumab. Eight patients stopped treatment due to toxicity and 4 due to progressive disease. Thirteen patients had clinically significant toxicity, with rash, colitis, hepatitis, and hypophysitis reported most frequently. There were no treatment-related deaths. Overall, 2/19 patients (10.5%, 95% CI [1.3% to 33.1%]) had an objective response (CR+PR) and 9/19 patients (47.4%, 95% CI [24.5% to 71.1%]) had disease control (CR+PR+SD). Four of the patients had stable disease for over 6 months. Six of the 19 patients went on to receive subsequent treatment. Median follow-up for patients still alive was 7 months (range 1 to 20 months) and median survival was not reached. Six-month survival was 68.5% (95% CI [39.3% to 85.8%]) Conclusions: The combination of Ipilimumab and Nivolumab can result in melanoma control in patients with progression on prior checkpoint monotherapy with an expected toxicity profile.

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