Nivolumab In Advanced Melanoma Research Articles

Real-world outcomes with ipilimumab and nivolumab in advanced melanoma: a multicentre retrospective study

PurposeTo assess efficacy and toxicity of combination immunotherapy with ipilimumab plus nivolumab in routine practice in a retrospective multicentre cohort of patients with advanced melanoma. Patients and methodsThis retrospective analysis included patients with advanced melanoma treated with ipilimumab and nivolumab between October 2015 and January 2020 at six centres in Australia, Europe and the United States of America. We describe efficacy outcomes (overall survival [OS], progression-free survival [PFS] and objective response rate [ORR]) in treatment-naïve and pre-treated patients, with and without brain metastases, plus treatment-related adverse events (trAEs) in all patients treated. ResultsA total of 697 patients were identified; 472 were treatment-naïve of which 138 (29.2%) had brain metastases, and 225 were previously treated of which 102 (45.3%) had brain metastases. At baseline, 32.3% had stage M1c and 34.4% stage M1d disease. Lactate dehydrogenase was high in 280 patients (40.2%). With a median follow-up of 25.9 months, median OS in the 334 treatment-naïve patients without brain metastases was 53.7 months (95% confidence interval [CI] 40.8-NR) and 38.7 months (95% CI 18.6-NR) for the 138 treatment-naïve patients with brain metastases. For the entire cohort the ORR was 48%, for treatment-naïve patients without brain metastases ORR was 56.6% with a median PFS of was 13.7 months (95% CI 9.6–26.5). Median PFS was 7.9 months (95% CI 5.8–10.4) and OS 38 months (95% CI 31-NR) for the entire cohort. Grade 3–4 trAE were reported in 44% of patients, and 4 (0.7%) treatment-related deaths (1 pneumonitis, 2 myocarditis and 1 colitis) were recorded. ConclusionThe outcome and toxicity of combination immunotherapy with ipilimumab and nivolumab in a real-world patient population are similar to those reported in pivotal trials.

Real-World Outcomes with Ipilimumab and Nivolumab in Advanced Melanoma: A Multicentre Retrospective Study

Real-World Outcomes with Ipilimumab and Nivolumab in Advanced Melanoma: A Multicentre Retrospective Study

Time to Treatment With Nivolumab or Pembrolizumab for Patients With Advanced Melanoma in Everyday Practice.

BackgroundThe anti-programmed cell death one antibodies (Anti-PD-1 Ab) pembrolizumab or nivolumab are commonly prescribed to patients with advanced melanoma. The purpose of the current study is to identify baseline clinical characteristics associated with time to treatment initiation (TTI) of pembrolizumab or nivolumab for advanced melanoma and whether treatment delays are associated with differences in survival outcomes.MethodsAll patients receiving Anti-PD-1 Ab as a first-line treatment for advanced melanoma outside of clinical trials at British Columbia Cancer Agency between 10/2015 and 10/2019 were identified retrospectively. TTI was defined as the interval from pathologic diagnosis of advanced melanoma to first Anti-PD-1 Ab treatment. To determine the association between TTI and baseline characteristics, multivariable Cox proportional hazard regression analyses provided an estimate of the instantaneous relative risk of starting treatment at any time point (hazard ratio [HR] >1 indicates shorter TTI). To describe changes in overall survival (OS) observed for each four-week delay in treatment initiation, multivariable cox proportional hazard regression modelling was also performed.ResultsIn a cohort of 302 patients, the median TTI was 52 days (interquartile range 30.2-99.0). Pulmonary metastases (M1b)/non-central nervous system visceral metastases (M1c) vs. metastases to skin or non-regional lymph nodes (M1a)(HR=1.50, 95% CI=1.12-2.02; p=0.007) and pre-treatment Eastern Cooperative Oncology Group Performance Status (ECOG PS) >1 (vs 0/1, HR=1.50, 95% CI= 1.11-2.01; p=0.008) were associated with earlier TTI. An association between treatment delay and improved OS was observed.ConclusionPatients having visceral metastases and poor baseline ECOG PS were more likely to initiate Anti-PD-1 Ab sooner. The association of shorter TTI with worse OS likely represents confounding by indication (urgent treatment offered to patients with aggressive disease).

Survival Outcomes Following Discontinuation of Ipilimumab and Nivolumab for Advanced Melanoma in a Population-based Cohort

AimsInduction ipilimumab and nivolumab followed by maintenance nivolumab improve overall survival compared with ipilimumab alone in patients with advanced melanoma, but immune-related adverse events (irAE) occur commonly. The need for induction discontinuation because of irAE and the relationship between irAE and survival in non-trials patients are unclear. Materials and methodsPatients with unresectable stage III–IV melanoma receiving first-line combination immunotherapy at one of six centres between December 2017 and February 2020 outside of trials were identified retrospectively. Landmark 12-week Kaplan–Meier analyses and log-rank tests were used to evaluate associations between discontinuation of induction therapy on overall survival and time to treatment failure (TTF). Multivariable analysis of factors influencing overall survival and TTF was undertaken. ResultsAmong 95 patients, the median age was 62 years, 38.9% had Eastern Cooperative Oncology Group performance status ≥1 and 22.1% had brain metastases. The median follow-up for the whole cohort was 19.8 months by the reverse Kaplan–Meier method. Any grade and grade 3–4 irAE were noted in 78.9% and 44.2% of the cohort, respectively. 44.2% of patients completed induction immunotherapy, whereas 41.1% did not due to irAE. Twelve-week landmark overall survival and TTF were similar in patients who completed induction versus those who did not due to irAE. On multivariable analysis, any grade irAE (versus none) was associated with longer overall survival (hazard ratio = 0.35, 95% confidence interval 0.15–0.82, P = 0.02) and TTF (hazard ratio = 0.38, 95% confidence interval = 0.17–0.81, P = 0.01). Grade 3–4 irAE correlated with longer TTF (hazard ratio = 0.45, 95% confidence interval = 0.20–1.01, P = 0.05). ConclusionIn this population-based cohort, discontinuation of induction immunotherapy as a result of irAE did not adversely affect overall survival or TTF. irAE observed during ipilimumab and nivolumab induction were associated with improved survival outcomes.

Cost-effectiveness of nivolumab in advanced melanoma: a drug review

ABSTRACT Introduction: The immune checkpoint inhibitors, including nivolumab, and targeted agents have dramatically improved the outcome for patients with unresectable advanced melanoma. Areas covered: This is a narrative review of the published evidence on nivolumab in metastatic melanoma. Expert opinion: In ipilimumab pre-treated patients (CheckMate 037), nivolumab was associated with a higher response rate and a longer duration of response when compared to chemotherapy. In previously untreated patients, nivolumab improves survival when compared to chemotherapy (CheckMate 066) or to ipilimumab (CheckMate 067). The combination of nivolumab and ipilimumab also improves survival when compared to ipilimumab (CheckMate 067). CheckMate 067 was not designed to compare the nivolumab–ipilimumab combination to nivolumab alone. A modified regimen using a lower dose of ipilimumab in combination with standard dose nivolumab is better tolerated than nivolumab in combination with standard dose ipilimumab (CheckMate 511). In patients with previously untreated metastatic melanoma, the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab improve survival when compared to ipilimumab. Nivolumab is equally active in BRAF mutated and BRAF wild type melanoma. The optimal sequence of checkpoint inhibitors and BRAF/MEK inhibitors in BRAF mutated patients has not been established.

Predicting development of ipilimumab-induced hypophysitis: utility of T4 and TSH index but not TSH

PurposeIpilimumab, a monoclonal antibody inhibiting CLTA-4, is an established treatment in metastatic melanoma, either alone or in combination with nivolumab, and results in immune mediated adverse events, including endocrinopathy. Hypophysitis is one of the most common endocrine abnormalities. An early recognition of hypophysitis may prevent life threatening consequences of hypopituitarism; therefore, biomarkers to predict which patients will develop hypophysitis would have clinical utility. Recent studies suggested that a decline in TSH may serve as an early marker of IH. This study was aimed at assessing the utility of thyroid function tests in predicting development of hypophysitis.MethodsA retrospective cohort study was performed for all patients (n = 308) treated with ipilimumab either as a monotherapy or in combination with nivolumab for advanced melanoma at the Royal Marsden Hospital from 2010 to 2016. Thyroid function tests, other pituitary function tests and Pituitary MRIs were used to identify those with hypophysitis.Results and conclusionsIpilimumab-induced hypophysitis (IH) was diagnosed in 25 patients (8.15%). A decline in TSH was observed in hypophysitis cohort during the first three cycles but it did not reach statistical significance (P = 0.053). A significant fall in FT4 (P < 0.001), TSH index (P < 0.001) and standardised TSH index (P < 0.001) prior to cycles 3 and 4 in hypophysitis cohort was observed. TSH is not useful in predicting development of IH. FT4, TSH index and standardised TSH index may be valuable but a high index of clinical suspicion remains paramount in early detection of hypophysitis.

1353P - Real-world outcomes of ipilimumab plus nivolumab for advanced melanoma in the Netherlands

BackgroundIn phase III trials, the results of ipilimumab plus nivolumab combination therapy (IPI+NIVO) are promising for metastatic melanoma (MM), despite many treatment-related grade 3-4 adverse events (AEs). Here, we report real-world outcomes of IPI+NIVO for MM. MethodsPatients with (non-uveal) MM who received 1st-line IPI+NIVO between 2015 and 2017 were selected from the Dutch Melanoma Treatment Registry, a nation-wide population based registry. Probability of 2nd-line treatment was estimated with competing risk analysis and overall survival (OS) with Kaplan-Meier method and Cox regression analysis. ResultsIn total, 2116 pts with MM were treated with systemic therapy of which 151 pts with 1st-line IPI+NIVO. Median age was 58yrs versus 64yrs for pts treated with other systemic therapy in 1st-line. Half of the pts treated with 1st-line IPI+NIVO had elevated LDH, 90% an ECOG PS of≤1, 32% brain metastases (21% symptomatic), 87% stage IV-M1c and 42% had BRAF-mutated melanoma. Grade 3-4 AEs occurred in 90 pts (60%); 39 (26%) had colitis, 37 (25%) hepatitis and 22 (13%) endocrine insufficiency. No deaths due to AEs were reported. For 66 pts who stopped IPI+NIVO because of AEs, 1-yr survival probability was 76% (95%CI: 66-87) compared to 57% (95%CI: 47-69) for the remaining 85 (56%) patients treated with 1st-line IPI+NIVO. A total of 50 (33%) pts completed all 4 courses of IPI+NIVO and 44 (29%) pts received maintenance with NIVO. The 1- and 2-yr OS probabilities (95%CI) were 66% (58-74%) and 55% (46-65%). Probability of still being in 1st-line IPI+NIVO at 1- and 2-yrs was 50% (95%CI; 42-59) and 34% (95%CI; 25-45). Cumulative incidence for 2nd-line treatment and death at 1yr were respectively 24% (95%CI: 18-33) and 27% (95%CI: 20-34). Adjusted HR for ECOG PS of≥2, symptomatic brain metastases, liver metastases were respectively 3.1 (95%CI; 1.2-8.3), 2.0 (95%CI; 1.0-3.8), 2.2 (95%CI; 1.2-4.2). HR for BRAF-wildtype status was 0.5 (95%CI; 0.2-0.9). ConclusionsHalf of pts receiving 1st-line IPI+NIVO for MM had elevated LDH, one third brain metastases and a majority ECOG PS≤1. Nevertheless, OS is encouraging especially in pts who stopped treatment due to AEs. With appropriate patient selection in real-world, promising results can be achieved with 1st-line IPI+NIVO. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureA.J.M. van den Eertwegh: Advisory / Consultancy: BMS; Advisory / Consultancy: Merck; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Amgen. A.C.J. van Akkooi: Advisory / Consultancy: Amgen; Advisory / Consultancy: BMS; Advisory / Consultancy: Novartis; Advisory / Consultancy: MSD - Merck; Advisory / Consultancy: MSD - Pfizer; Advisory / Consultancy: 4SC. J.W. de Groot: Advisory / Consultancy: BMS; Advisory / Consultancy: Merck. G.A.P. Hospers: Advisory / Consultancy: BMS; Advisory / Consultancy: Merck. E. Kapiteijn: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck. K.P.M. Suijkerbuijk: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Honoraria (institution), Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Honoraria (institution): Roche. A.A.M. Van der Veldt: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Ipsen. J.B.A.G. Haanen: Advisory / Consultancy: Amgen; Advisory / Consultancy: AZ; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Bayer; Advisory / Consultancy: Celsius Therapeutics; Advisory / Consultancy: GSK; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution): Neon Therapeutics; Advisory / Consultancy: AIMM; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Immunocore. All other authors have declared no conflicts of interest.

Abstract 2273: A machine learning approach to identify a peripheral prognostic cytokine signature via nivolumab clearance in patients with advanced melanoma

Abstract Background: Data suggest that peripheral factors such as circulating cytokines could function as predictive indicators of clinical response to specific therapies or as general prognostic indicators of outcome in patients with cancer. Previous studies have focused on evaluating the association between individual cytokines and clinical outcome. There is no clear consensus on how or which of these cytokines should be selected for prediction of treatment outcome. Clearance of immunotherapeutic agents such as the anti-PD-1 nivolumab (NIVO) has been shown to be a predictor of best overall response and overall survival (OS) across multiple indications. Determination of clearance requires post-treatment pharmacokinetic (PK) samples which negates its utility as a baseline prognostic factor. We investigated a novel machine learning approach to identify a baseline composite cytokine signature that correlates with the established efficacy response relationship for NIVO clearance in advanced melanoma. This approach, which is capable of integrating multivariate factors into a composite feature, may provide a more accurate reflection of underlying biologic factors that contribute to outcome following treatment. Methods: Peripheral serum PK (NIVO clearance) and pharmacodynamic (Myriad Rules Based Medicine-customized inflammatory cytokine panel) data from 2 phase 3 studies (NCT01721772; NCT01844505) of NIVO monotherapy in patients with melanoma (n = 471) were used for machine learning model development (training data set). A third phase 3 study of NIVO in advanced melanoma (NCT01721746) was included in model application (test data set; n = 158). Random forest, a tree-based ensemble learning method, was used for feature selection and classification (low vs high) of NIVO clearance. Kaplan-Meier analyses and log-rank p values were used to assess statistical difference in long-term OS between predicted high- vs low-clearance groups. Results: A panel of ~20 baseline inflammatory cytokines related to immune cell modulation were selected by the machine learning model to predict clearance of NIVO monotherapy in patients with advanced melanoma (area under the curve of receiver operating characteristic: 0.79). The predicted clearance value from the cytokine signature was significantly associated with OS across all 3 studies, including patients treated with NIVO or dacarbazine (control) (p&amp;lt;0.01). Conclusions: We developed a machine learning approach to identify a serum prognostic cytokine signature based on the relationship between NIVO clearance and response. The strong association of the defined cytokine signature with OS from NIVO and dacarbazine suggests a prognostic role for drug clearance. This cytokine signature has the potential to be a prognostic biomarker in melanoma and may be used for balancing and randomization of patients in clinical studies. Citation Format: Rui Wang, Xiao Shao, Junying Zheng, Abdel Saci, Max Qian, Irene Pak, Amit Roy, Akintunde Bello, Jasmine Rizzo, Fareeda Hosein, Rebecca A. Moss, Megan Wind-Rotolo, Yan Feng. A machine learning approach to identify a peripheral prognostic cytokine signature via nivolumab clearance in patients with advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2273.

Association of Baseline Serum Levels of CXCL5 With the Efficacy of Nivolumab in Advanced Melanoma.

Anti-programmed cell death protein 1 (PD1) antibodies are in wide use for the treatment of various cancers. PD1 antibody-based immunotherapy, co-administration of nivolumab and ipilimumab, is one of the optimal immunotherapies, especially in advanced melanoma with high tumor mutation burden. Since this combined therapy leads to a high frequency of serious immune-related adverse events (irAEs) in patients with advanced melanoma, biomarkers are needed to evaluate nivolumab efficacy to avoid serious irAEs caused by ipilimumab. This study analyzed baseline serum levels of CXCL5, CXCL10, and CCL22 in 46 cases of advanced cutaneous melanoma treated with nivolumab. Baseline serum levels of CXCL5 were significantly higher in responders than in non-responders. In contrast, there were no significant differences in baseline serum levels of CXCL10 and CCL22 between responders and non-responders. These results suggest that baseline serum levels of CXCL5 may be useful as a biomarker for identifying patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy.

Tinostamustine and Nivolumab in Advanced Melanoma

Tinostamustine and Nivolumab in Advanced Melanoma

Real-world experience of combined ipilimumab and nivolumab for advanced melanoma in a single UK institution

Real-world experience of combined ipilimumab and nivolumab for advanced melanoma in a single UK institution

Epacadostat plus nivolumab for advanced melanoma: Updated phase 2 results of the ECHO-204 study.

9511Background: Indoleamine 2,3-dioxygenase 1 (IDO1) enzyme-induced immunosuppression in the tumor microenvironment supports tumor cell evasion of immune surveillance. Epacadostat (E) is a potent a...

A multicenter retrospective analysis of nivolumab in advanced melanoma during the French Temporary Authorization Use.

e21598Background: Nivolumab was the first anti-PD1 therapy to receive a European marketed authorization for the treatment of advanced (unresectable or metastatic) melanoma. To collect and evaluate ...

Nivolumab for advanced melanoma: pretreatment prognostic factors and early outcome markers during therapy.

BackgroundAn anti-programmed cell death protein 1 monoclonal antibody, nivolumab, is one of the most effective drugs for advanced melanoma. Tumor cell-derived or immune cell-derived markers and clinical predictors such as serum lactate dehydrogenase (LDH) and cutaneous adverse events, have already been described as prognostic factors for advanced melanoma treated with nivolumab. We sought to identify further clinical predictors that can be determined in routine clinical practice.MethodsWe retrospectively analyzed clinical findings of 98 consecutive patients with unresectable stage III or IV melanoma treated with nivolumab, at the National Cancer Center Hospital or at Keio University Hospital, in Tokyo, Japan, between July 2014 and July 2016. These patients had been administered nivolumab at a dose of 2mg/kg every 3 weeks.ResultsAs for pretreatment prognostic factors, ECOG performance status (PS) ≥1, maximum tumor diameters of ≥30mm, elevated LDH and elevated C-reactive protein were significantly associated with poor overall survival (OS) (hazard ratio [HR] 0.29 [P<0.001], HR 0.40 [p=0.003], HR 0.29 [P<0.001], HR 0.42 [P=0.004], respectively) on univariate analysis. Among these factors, PS and LDH were identified as independent variables by multivariate analysis. As for early markers examined during therapy, patients with absolute lymphocyte count (ALC) ≥ 1000/μl (Week3: HR 0.40 [P=0.004], Week6: HR 0.33 [P=0.001]) and absolute neutrophil count (ANC) <4000/μl (Week3: HR 0.46 [P=0.014], Week6: HR 0.51 [P=0.046]) had significantly better OS.ConclusionALC≥1000/μl and ANC<4000/μl during treatment appear to be early markers associated with OS. Nivolumab might have minimal efficacy in patients with a massive tumor burden.

Partitioned Survival Versus State Transition Modeling in Oncology: a Case Study with Nivolumab in Advanced Melanoma

Partitioned Survival Versus State Transition Modeling in Oncology: a Case Study with Nivolumab in Advanced Melanoma

An exploratory study of the biologic effects of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) treatment in patients (pts) with advanced (unresectable or metastatic) melanoma (MEL).

TPS3114 Background: Programmed death-1 (PD-1) is an immune checkpoint receptor expressed by T cells that negatively regulates T-cell activity and may promote tumor immune evasion by binding to its ligands (PD-L1/L2) on tumor cells and/or antigen-presenting cells. Nivolumab is a fully human IgG4 PD-1 receptor blocking monoclonal antibody that has shown antitumor activity in phase I trials in pts with solid tumors, including advanced MEL. Objective responses were observed in pts whose diseases were refractory to multiple prior therapies. We describe an ongoing exploratory, open-label, multicenter translational study designed to further investigate the immunoregulatory activity and mechanisms of action of nivolumab in advanced MEL, including ipilimumab (anti-CTLA-4) naïve and refractory pts. Methods: This study is enrolling advanced MEL pts who are either ipilimumab naive (n=40) or refractory (n=40). Eligible pts must not have received &gt;3 prior therapies for metastatic disease and must consent to pre-and on-treatment biopsy (after 2 doses of nivolumab [Day 28]) of an accessible tumor. Nivolumab will be administered IV every 2 weeks (wks) at a dose of 3mg/kg and may continue for up to 13 cycles (104 wks) until clinically significant progression or treatment discontinuation criteria are met. Tumor responses will be assessed every 8 wks using RECIST 1.1 criteria. The primary objective is to investigate the pharmacodynamic (immunoregulatory) activity of nivolumab in the peripheral blood (PB), tumor, and tumor microenvironment. Secondary objectives include evaluation of safety and tolerability, preliminary antitumor activity, and immunogenicity of nivolumab, as well as the association between tumor PD-L1 expression and clinical efficacy. Exploratory objectives include characterization of pharmacokinetics (PK) and evaluation of the potential association between selected PB and/or tumor biomarkers and PK, clinical safety, and efficacy (eg, progression-free and overall survival). Clinical trial information: NCT01621490.