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

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.

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

Pooled Analysis Safety Profile of Nivolumab and Ipilimumab Combination Therapy in Patients With Advanced Melanoma

2017 ◽  
Vol 35 (34) ◽  
pp. 3815-3822 ◽  
Author(s):  
Mario Sznol ◽  
Pier Francesco Ferrucci ◽  
David Hogg ◽  
Michael B. Atkins ◽  
Pascal Wolter ◽  
...  
Keyword(s):  
Median Time ◽  
Safety Profile ◽  
Progression Free Survival ◽  
Pooled Analysis ◽  
Advanced Melanoma ◽  
Cytotoxic T Cell ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Grade 3 ◽  
Time To Onset

Purpose The addition of nivolumab (anti–programmed death-1 antibody) to ipilimumab (anti–cytotoxic T-cell lymphocyte–associated 4 antibody) in patients with advanced melanoma improves antitumor response and progression-free survival but with a higher frequency of adverse events (AEs). This cross-melanoma study describes the safety profile of the approved nivolumab plus ipilimumab regimen. Methods This retrospective safety review on data from three trials (phase I, II, and III) included patients with advanced melanoma who received at least one dose of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks × 4 and then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity while following established guidelines for AE management. Analyses were of all treatment-related AEs, select (immune-related) AEs, time to onset and resolution, and use of immune-modulating agents and their effects on outcome. Results Among 448 patients, median duration of follow-up was 13.2 months. Treatment-related grade 3/4 AEs occurred in 55.5% of patients; 35.7% had treatment-related AEs that led to discontinuation. The most frequent treatment-related select AEs of any grade were skin (64.3%) and GI (46.7%) and of grade 3/4, hepatic (17.0%) and GI (16.3%); 30.1% developed a grade 2 to 4 select AE in more than one organ category. Median time to onset of grade 3/4 treatment-related select AEs ranged from 3.1 (skin) to 16.3 (renal) weeks, and with the exclusion of endocrine AEs, median time to resolution from onset ranged from 1.9 (renal) to 4.5 (pulmonary) weeks, with resolution rates between 79% and 100% while using immune-modulating agents. Four (< 1%) on-study deaths were attributed to therapy. Conclusion Frequency of grade 3/4 treatment-related AEs was higher with nivolumab plus ipilimumab and occurred earlier than historical experience with either agent alone, but resolution rates were similar.

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.

Safety of ipilimumab in patients (pts) with untreated, advanced melanoma alive beyond 2 years: Results from a phase III study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8512-8512 ◽  
Author(s):  
Luc Thomas ◽  
Jedd D. Wolchok ◽  
Claus Garbe ◽  
Celeste Lebbe ◽  
Igor Bondarenko ◽  
...  
Keyword(s):  
Safety Profile ◽  
Human Monoclonal Antibody ◽  
Survival Rates ◽  
Safety Data ◽  
Advanced Melanoma ◽  
T Cell Response ◽  
Phase Iii ◽  
Low Grade ◽  
Grade 3 ◽  
The Impact

8512 Background: Ipilimumab (IPI), a fully human monoclonal antibody, blocks cytotoxic T-lymphocyte antigen-4 to potentiate an antitumor T-cell response. In a phase 3 study (CA184-024) of previously untreated pts with stage III or IV melanoma, IPI + dacarbazine (DTIC) significantly improved overall survival (OS) vs. DTIC alone (Robert et al. NEJM 2011). We now report safety data of IPI in pts from this study alive > 2 yrs from study initiation. Methods: Pts with untreated advanced melanoma, were randomized to IPI (10 mg/kg) + DTIC (850 mg/m2) or placebo + DTIC (850 mg/m2) given at Wks 1, 4, 7, 10 followed by DTIC q 3 wks through Wk 22. Eligible pts (stable disease or better) received IPI or placebo q 12 wks as maintenance. In the population of subjects alive >2 yrs, the appearance of immune-related adverse events (irAEs) occurring after 2 yrs was evaluated. Within this group was a subset of subjects still receiving IPI dosing after 2 yrs; safety for these pts was evaluated to assess the impact of prolonged IPI exposure. Results: In the IPI + DTIC group 68 (28%) pts survived > 2 yrs compared to 44 (18%) in the DTIC alone group; 11 of the 68 continued IPI dosing for ≥ 2 yrs. Safety assessment beyond 2 yrs showed 3 of the 11 pts had any grade irAEs; 1 pt had grade 3/4 rash, pruritus while low grade events included rash, pruritus (n=2) and elevated ALT / AST (n=1). Overall among all 68 pts in the Ipi + DTIC group, there were 5 pts (7.4%) with any grade irAEs including grade 3/4 rash, pruritus (n=1) and low grade rash (n=3), pruritus (n=2), skin hypopigmentation, and elevated ALT / AST (n=1). No gastrointestinal or endocrine events (any grade) were observed. Conclusions: In Study 024, IPI + DTIC treatment improved OS pts with untreated, advanced melanoma with higher survival rates in the IPI + DTIC group at 1 yr (47.3% vs. 36.3%), 2 yrs (28.5% vs. 17.9%), and 3 yrs (20.8% vs. 12.2%) (HR 0.72, p<0.001). The safety profile of pts alive after 2 yrs suggests that treatment with IPI + DTIC is associated with low rates of irAEs in these pts. Furthermore, in pts still receiving active IPI treatment beyond ≥ 2 yrs, the safety profile appears to be consistent and medically manageable using established safety guidelines (Weber, Oncologist 2007).

Safety profile of nivolumab (NIVO) in patients (pts) with advanced melanoma (MEL): A pooled analysis.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. 9018-9018 ◽  
Author(s):  
Jeffrey S. Weber ◽  
Scott Joseph Antonia ◽  
Suzanne Louise Topalian ◽  
Dirk Schadendorf ◽  
James M. G. Larkin ◽  
...  
Keyword(s):  
Safety Profile ◽  
Pooled Analysis ◽  
Advanced Melanoma

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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