Ipilimumab For Metastatic Melanoma Research Articles

Nivolumab plus ipilimumab in metastatic melanoma: a critical appraisal focused on specific subpopulations.

The development of immune checkpoint inhibitors has revolutionized the landscape of treatment of advanced melanoma in recent years. Based on the efficacy results of the phase III CheckMate 067 trial, nivolumab in combination with ipilimumab is one of the first-line standard options for advanced melanoma along with pembrolizumab, nivolumab, and, recently, nivolumab plus relatlimab. Counterbalancing its efficacy, nivolumab plus ipilimumab is associated with severe immune-related toxicity. This article will review the efficacy and safety of the nivolumab plus ipilimumab combination in advanced melanoma across phase I, II, and III clinical trials that evaluated this approach. We also explore the benefit of the combination schedule across different subgroups of patients and possible predictive biomarkers for efficacy outcomes in order to elucidate which patients could be the best candidates for combination or single-agent therapy. Patients with BRAF-mutant tumours, asymptomatic brain metastases, or PD-L1-negative status appear to reach better survival outcomes with the combination relative to single-agent immunotherapy.

Efficacy of ipilimumab 3 mg/kg following progression on low-dose ipilimumab in metastatic melanoma

BackgroundDiffering doses of ipilimumab (IPI) are used in combination with an anti-PD1 antibody in advanced melanoma. There is no data on the outcomes of patients who progress following low-dose IPI (< 3 mg/kg) and are subsequently treated with IPI 3 mg/kg (IPI3). We conducted a multicentre retrospective survey to assess the efficacy of this strategy. MethodsPatients with resected stage III, unresectable stage III or IV melanoma who received low dose IPI (< 3 mg/kg) with an anti-PD1 antibody with recurrence (neo/adjuvant) or progressive disease (metastatic), who then received IPI3± anti-PD1 antibody were eligible. Best investigator-determined Response Evaluation Criteria in Solid Tumours response, progression-free survival (PFS) and overall survival (OS) were analysed. ResultsTotal 36 patients received low-dose IPI with an anti-PD1 antibody, 18 (50%) in the neo/adjuvant and 18 (50%) in the metastatic setting. Of which, 20 (56%) had primary resistance and 16 (44%) had acquired resistance. All patients received IPI3 for unresectable stage III or IV melanoma; median age 60 (29–78), 18 (50%) M1d disease, 32 (89%) Eastern Cooperative Oncology Group performance status 0–1. Around 35 (97%) received IPI3 with nivolumab and 1 received IPI3 alone. The response rate to IPI3 was 9/36 (25%). In patients with primary resistance, the response rate was 6/20 (30%). After a median follow-up of 22 months (95% CI: 15–27 months), the median PFS and OS were not reached in patients who responded; 1-year PFS and OS were 73% and 100%, respectively. ConclusionsIPI3 following recurrence/progression on low dose IPI has clinical activity, including in primary resistance. IPI dosing is therefore critical in a subset of patients.

Abstract A09: Immune checkpoint inhibitor-induced polyarthritis: a case series

Abstract Background. Immune checkpoint inhibitors (ICIs) have revolutionized cancer care. However, their mechanism of action also results in the uncontrolled collateral of ICI-related adverse events (ICI-AEs). Polyarthritis is a rare ICI-AE. Here we describe two cases of ICI-induced polyarthritis, induced by nivolumab/ipilimumab and sasanlimab for melanoma and urothelial cancer, respectively. Methods/Results. A 64-year-old male received combination immunotherapy with nivolumab and ipilimumab for metastatic melanoma. Within one month of his second cycle of nivolumab alone, he developed polyarthritis of the small joints of the hands bilaterally, as well as the shoulders and knees; active synovitis; and erosive arthropathy on radiographic findings. He was successfully treated with prednisone at 20mg daily, gradually tapered over several months. A 43-year-old male with high-grade non-invasive urothelial cell carcinoma received two cycles of adjuvant sasanlimab. Within two months of his second treatment, he developed a large-joint polyarthritis involving the bilateral knees, ankles, elbows, and the cervical spine. His symptoms resolved with prednisone, initiated at 50mg daily with a recommended slow taper, however resurfaced five days after he abruptly ceased treatment. He was subsequently started on methotrexate in combination with prednisone. Both patients had a past medical history of non-rheumatological autoimmune disease, developed symptoms within 8 weeks of ICI, had elevated inflammatory markers and negative autoantibodies. Neither had to discontinue their cancer therapy and indeed both had a good tumour responses to their ICI. Both of our patients were initially well-managed prednisone. However, our second patient relapsed after abrupt cessation of his prednisone and required a combination of methotrexate with prednisone to control his symptoms. Conclusions. These cases add to the literature on ICI-induced polyarthritis, a rare ICI-AE. Clinical manifestations most commonly resemble rheumatoid arthritis, with bilateral inflammation of the small joints. Time to onset tends to be &amp;lt;12 weeks after ICI exposure, and repeated ICI exposure is a risk factor. Most patients have no personal or family history of autoimmune disease, negative autoantibodies, and can be managed well with glucocorticoids. As ICIs become more widely used, rheumatologists and oncologists alike should familiarise themselves with their adverse effects. More research is needed to understand the epidemiology, clinical presentation, and treatment of these adverse events. Citation Format: Megan Smith-Uffen, Konstantinos Tselios. Immune checkpoint inhibitor-induced polyarthritis: a case series [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A09.

Efficacy of ipilimumab 3mg/kg following progression on low dose ipilimumab in metastatic melanoma.

e21533 Background: Anti-cytotoxic T lymphocyte-associated antigen 4 inhibitors, such as ipilimumab (IPI), are commonly used in melanoma management. Whilst a clear dose-toxicity relationship exists, and a dose-response relationship is seen with monotherapy in people with anti PD-1 antibody-naïve melanoma, there is no data on the outcomes of patients who progress following low dose IPI and are subsequently treated with standard dose IPI. We conducted a multicentre, retrospective review to assess the efficacy of this strategy. Methods: Patients with resected stage III, unresectable stage III or IV melanoma who received low dose IPI (&lt; 3mg/kg) with an anti-PD1 antibody in the neoadjuvant, adjuvant or metastatic setting with recurrence (neo/adjuvant) or progressive disease (metastatic) as best response, who then received standard dose IPI (3mg/kg, IPI3) alone or in combination with an anti-PD1 antibody were eligible. IPI dose, frequency and best investigator-assessed RECIST response were collected. Progression free survival (PFS) and overall survival (OS) were analysed using the Kaplan Meier method. Results: 36 patients from 8 centres; 27 (75%) male, BRAF V600 mutant (18, 50%). All patients received low dose IPI with an anti-PD1 antibody, 18 (50%) in the neo/adjuvant and 18 (50%) in the metastatic setting; 15 (42%) received IPI 1mg/kg every 6 weeks, 13 (36%) IPI 1mg/kg every 3 weeks, 3 (8%) IPI 50mg every 6 weeks or 100mg every 12 weeks respectively, and 2 (6%) IPI 1mg/kg every 8 weeks. 23 (64%) received &gt;1 intervening line of systemic therapy prior to IPI3. The most common intervening therapy was BRAF/MEK inhibitors; 14/23 (61%) as 2nd line treatment, 4/8 (50%) as 3rd line treatment, and all progressed. All patients received standard dose IPI3 for unresectable stage III or stage IV melanoma; median age 60 (29-78), 18 (50%) had M1d disease, 32 (89%) ECOG 0-1, 18 (50%) normal lactate dehydrogenase. 35 (97%) received IPI3 with nivolumab and 1 received single agent IPI3. 15 (42%) received 4 cycles of IPI3. The most common reason for IPI3 cessation was progressive disease (16, 44%). The response rate to IPI3 following progression on low dose IPI was 9/36 (25%); the disease control rate was 12/36 (33%). After a median follow up of 22 months (95% CI: 15-27 months), the median PFS and OS were not reached in patients who responded;1-year PFS and OS were 73% and 100% respectively. 13/36 (36%) had grade 3-4 immune-related adverse events (irAE). In 3/36 (8%), the same irAE was observed at low dose IPI and IPI3, and 1 patient had the same irAE (rash) at a higher grade with IPI3 compared to low dose IPI. Conclusions: Standard dose IPI3 following progression on low dose IPI has clinical activity.This is a reasonable treatment strategy for patients who progress on low dose IPI and provides further evidence of a dose-response relationship for IPI. Further research is needed to manage resistance to IPI with anti-PD1.

Clinical Models to Define Response and Survival With Anti-PD-1 Antibodies Alone or Combined With Ipilimumab in Metastatic Melanoma.

Currently, there are no robust biomarkers that predict immunotherapy outcomes in metastatic melanoma. We sought to build multivariable predictive models for response and survival to anti-programmed cell death protein 1 (anti-PD-1) monotherapy or in combination with anticytotoxic T-cell lymphocyte-4 (ipilimumab [IPI]; anti-PD-1 ± IPI) by including routine clinical data available at the point of treatment initiation. One thousand six hundred forty-four patients with metastatic melanoma treated with anti-PD-1 ± IPI at 16 centers from Australia, the United States, and Europe were included. Demographics, disease characteristics, and baseline blood parameters were analyzed. The end points of this study were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The final predictive models for ORR, PFS, and OS were determined through penalized regression methodology (least absolute shrinkage and selection operator method) to select the most significant predictors for all three outcomes (discovery cohort, N = 633). Each model was validated internally and externally in two independent cohorts (validation-1 [N = 419] and validation-2 [N = 592]) and nomograms were created. The final model for predicting ORR (area under the curve [AUC] = 0.71) in immunotherapy-treated patients included the following clinical parameters: Eastern Cooperative Oncology Group Performance Status, presence/absence of liver and lung metastases, serum lactate dehydrogenase, blood neutrophil-lymphocyte ratio, therapy (monotherapy/combination), and line of treatment. The final predictive models for PFS (AUC = 0.68) and OS (AUC = 0.77) included the same variables as those in the ORR model (except for presence/absence of lung metastases), and included presence/absence of brain metastases and blood hemoglobin. Nomogram calculators were developed from the clinical models to predict outcomes for patients with metastatic melanoma treated with anti-PD-1 ± IPI. Newly developed combinations of routinely collected baseline clinical factors predict the response and survival outcomes of patients with metastatic melanoma treated with immunotherapy and may serve as valuable tools for clinical decision making.

Analysis of top-cited articles on melanoma

This bibliometric analysis evaluates the most influential studies in clinical research on melanoma. Based on the bibliometric theory, articles in the Thomson Reuters Web of Science database were analyzed. Full English-language articles were searched for using the terms melanoma, superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma. The 100 most-cited articles were analyzed by topic, author, journal of publication, year of publication, institution, and country of origin. The search returned 243,109 articles, with the majority from the past 3 decades: 1991-2000 (n = 29), 2001-2010 (n = 28), and 2011-2020 (n = 30). The top 100 cited articles had mean and median citations of 2,159 and 1,793, respectively. An article on the use of ipilimumab in metastatic melanoma, by Hodi et al., was most cited (8,150). The New England Journal of Medicine had the most citations (58,489), and Nature published the most articles (n = 21). The United States published the most articles (n = 81), led by the National Cancer Institute (n = 16). The majority of articles explored management (n = 68), prognosis (n = 57), and immunotherapy (n = 27). This analysis serves as a guide for future research and highlights key areas of research, particularly in genetics and immunotherapy, that have influenced current knowledge of melanoma.

Modeling the Ex Post Real Option Value in Metastatic Melanoma Using Real-World Data

ObjectivesReal option value (ROV) is created when a drug enables a patient to live long enough to benefit from a future innovation. Few studies have quantified ROV in the real world. We aimed to estimate the ex post ROV for ipilimumab in metastatic melanoma using real-world data (RWD). MethodsWe developed a framework for calculating ROV using RWD, accounting for the health gain in the standard therapy arm and the uptake of future innovations. A Markov model was developed to estimate the quality-adjusted life-years (QALYs) gained with ipilimumab compared with chemotherapy for patients with or without subsequent cancer immunotherapy (CIT). A nationwide electronic health record-derived, deidentified database was used to estimate survival and uptake of CIT. ResultsThe incremental QALYs gained for ipilimumab compared with chemotherapy without subsequent CIT were 1.74. With subsequent CIT, the incremental QALYs compared with chemotherapy increased by 0.92, 0.60, 0.33, 0.18, 0.10, and 0.02 when CIT became available 0, 3, 6, 9, 12, and 24 months after the initiation of first-line treatment, respectively. The results were most sensitive to the survival benefit of ipilimumab, the survival benefit of subsequent CIT, and the uptake of CIT. ConclusionsThis is the first study to estimate ex post ROV using RWD. The ex post ROV was between 1% and 54% of conventional value for patients who received a diagnosis within 2 years before CIT availability. Further studies are needed to understand ROV in other disease areas, particularly those with longer survival times.

RW2 Real-World Evidence of Option Value in Metastatic Melanoma

There is little real-world evidence of realized real option value (ROV) - the value a drug provides by extending survival to receive benefits from future innovations. This analysis aims to measure ROV with real-world clinical outcomes data, using ipilimumab in metastatic melanoma (mM). We conducted a retrospective analysis using the nationwide Flatiron Health electronic health record-derived de-identified database. Patients with mM initiating treatment before 4/19/15 (1st line (1L) pembrolizumab data available) were included in the study. The next innovation date was defined as 9/4/2014 (the FDA approval date for 2nd line (2L) pembrolizumab). We estimated proportions of patients surviving to the next innovation date and receiving a cancer immunotherapy (CIT). Inverse probability of treatment weighted Kaplan-Meier estimates for real-world overall survival (OS) were estimated by treatment cohorts (Ipilimumab followed by CIT or no CIT) and line of therapy. Observed ROV was estimated using truncated mean OS and proportions in each treatment cohort. Among 721 mM patients, 50% of 1L ipilimumab users and 18% of 1L chemotherapy users survived to the next innovation date. Among survivors to the next innovation date, 45% (1L Ipilimumab), 26% (1L chemotherapy), 52% (2L Ipilimumab), and 50% (2L Chemotherapy) received CITs. Mean OS for ipilimumab followed by a CIT was 38.3 months (1L) and 38.9 months (2L), while those who didn’t receive a CIT was 21.7 months (1L) and 13.9 months (2L). Estimated ROV for ipilimumab was an additional 3.7 months survival (32.2% of conventional value) in 1L, and 5.1 months (60% of conventional value) in 2L ipilimumab, and 4.0 months across lines of therapy. This study provides real-world evidence of clinically meaningful ROV and may support consideration of ROV when assessing the value of life-extending drugs in areas with likely future innovation.

A stratified phase I dose escalation trial of hypofractionated radiotherapy followed by ipilimumab in metastatic melanoma: long-term follow-up and final outcomes

ABSTRACT We conducted a phase I dose-escalation trial of radiation with ipilimumab in patients with melanoma with ≥2 metastatic lesions. Here, we report the final full clinical analysis. Patients received RT (6 or 8 Gy x 2 or 3 doses) to a single lesion followed by 4 cycles of ipilimumab. The primary endpoint was maximum tolerated dose of RT, and secondary endpoint was response at non-radiated sites. Twenty-two patients with treatment-naïve (n = 11) or treatment-refractory (n = 11) Stage IV melanoma were enrolled. There were 31 treatment-related adverse events (AEs), of which 16 were deemed immune-related. Eleven patients had grade 3 AEs (no grade 4/5). There were no dose-limiting toxicities related to the radiation/ipilimumab combination. Five of 22 patients (22.7%, 95% CI 7.8–45.4%) had partial response as best response and three (13.6%) had stable disease. Median overall survival was 10.7 months (95% CI, 4.9 months to not-estimable) and median progression-free survival 3.6 months (95% CI, 2.9 months to 7.8 months). Seven patients were still alive at the time of last follow-up (median follow-up 89.2 months), most of whom received pembrolizumab after progression. Radiotherapy followed by ipilimumab was well tolerated and yielded a response rate that compares favorably to the objective response rate with ipilimumab alone. Furthermore, 32% of patients are long-term survivors, most of whom received pembrolizumab. Based on these results, the recommended dose that was used in subsequent Phase 2 trials was 8 Gy x 3 doses. Clinical Trial Registration: NCT01497808 (www.clinicaltrials.gov)

Real-world, population-based cohort study of toxicity and resource utilization of second-line ipilimumab for metastatic melanoma in Ontario, Canada.

Second-line ipilimumab has been publicly funded in Ontario for metastatic melanoma (MM) since September 2012. We examined real-world toxicity of second-line ipilimumab compared to standard second-line treatments prior to funding. MM patients who received systemic treatment from April 2005 to March 2015 were included. Patients receiving second-line ipilimumab after September 2012 were considered as cases, and those who received second-line treatment prior to the funding date were included as historical controls. Outcomes assessed include treatment-related mortality, any-cause hospital visits, ipilimumab-related hospital visits and specialist visits (eg, endocrinologists, ophthalmologists, gastroenterologists, rheumatologists and respirologists), which were captured from up to 30 and/or 90 days after end of second-line treatment. Inverse probability of treatment weighting was used to adjust for baseline differences between groups. Odds ratios (ORs) from logistic regressions and rate ratios (RRs) from rate regressions were used to assess differences between groups. We identified 329 MM patients who received second-line treatments (ipilimumab: 189; controls: 140). Ipilimumab was associated greater any-cause (60.1% vs 45.7%; OR = 1.81; P value = .019) and ipilimumab-related (47.2% vs 31.9%; OR = 1.91; P value = .011) hospital visits. Adjusting for different follow-up days, ipilimumab was associated with higher rates of all-cause (RR = 1.56 [95%CI: 1.12-2.16]), and ipilimumab-related (RR = 2.18 [95% CI: 1.45-3.27]) hospital visits. Patients receiving ipilimumab were more likely to visit specialist involved in immunotherapy toxicity management (23.5% vs 13.7%; P value = .04). Compared to historical second-line treatments, second-line ipilimumab was associated with more health service utilization (specifically hospital visits and specialist visits), suggestive of potentially increased toxicity in the real world.

PO-1227: A dose escalation phase 1 study of radiotherapy combined with ipilimumab in metastatic melanoma.

PO-1227: A dose escalation phase 1 study of radiotherapy combined with ipilimumab in metastatic melanoma.

Autoimmune myositis and myasthenia gravis resulting from a combination therapy with nivolumab and ipilimumab for metastatic melanoma.

Checkpoint inhibitors are a novel option in the management of metastatic melanomas and many other malignancies. They are used to promote the activation of cytotoxic T-lymphocytes by inhibiting deactivation signals, enabling the immune response to the tumor. Numerous Immune-related adverse effects caused by checkpoint inhibitors have been reported in the literature. They are diverse in nature, and many are life threatening. We report a case of autoimmune myositis and myasthenia gravis following treatment with a combination of ipilimumab and nivolumab for metastatic melanoma.

A phase I study (E011-MEL) of a TriMix-based mRNA immunotherapy (ECI-006) in resected melanoma patients: Analysis of safety and immunogenicity.

2641 Background: ECI-006 is a combination of TriMix (mRNAs encoding for dendritic cell [DC] activating molecules [CD40L, CD70 and caTLR4]), and mRNAs encoding for melanoma-specific tumor-associated antigens (TAAs): tyrosinase, gp100, MAGE-A3, MAGE-C2, and PRAME. DCs transfected ex vivo with TriMix and TAAs mRNAs showed significant clinical activity in combination with ipilimumab in metastatic melanoma without increasing toxicity. This study aims to assess the safety and immunogenicity of ECI-006 vaccine administered intranodally (i.n.) in an adjuvant setting for patients with resected melanoma. Methods: Twenty patients who underwent resection of stage IIc/III/IV cutaneous melanoma received 5 administrations of ECI-006 (either 600 µg or 1800 µg [n = 10, each]) injected i.n. on Day 1 and after 2, 4, 6 and 14 weeks. Treatment-emergent adverse events (TEAEs) were graded using CTCAE version 4.0.3. Blood samples for immune monitoring (ELISPOT and intracellular cytokine staining [ICS]) were collected pre-dose and at weeks 4, 7, 14 and 15. Results: Nineteen patients completed the treatment. One patient in the low dose group discontinued the study after 4 doses due to disease relapse. Administration of ECI-006 was well tolerated. No serious adverse events or TEAEs Grade 3 or higher were reported. Of all TEAEs, myalgia and fatigue were the most reported in 3 (15%) and 5 (25%) patients, respectively. ELISPOT and ICS were performed on T cells pre-stimulated in vitro for 10-12 days, using a previously in-house validated protocol. Vaccine-induced immune responses according to predefined criteria were detected in 4/10 and 3/9 patients treated with the low and high dose, respectively. Samples from these patients are currently being subjected to T-cell receptor repertoire analysis. Conclusions: Among patients undergoing resection of stage IIc/III/IV melanoma, i.n. administration of ECI-006 at 600 or 1800 µg was generally well tolerated. ECI-006 demonstrated to be immunogenic in a proportion of patients. These results warrant further development of ECI-006 in combination with anti-PD-1 therapy in melanoma patients. Clinical trial information: NCT03394937.

Characteristics of patients receiving immune checkpoint inhibitors (ICI) in ASCO’s CancerLinQ.

2566 Background: ICI’s have demonstrated significant clinical benefit since the first FDA approval in 2011 of ipilimumab for metastatic melanoma. Five additional ICI therapies have since been approved across several indications. The objectives of this study were to describe the clinical and demographic features of patients receiving ICI treatment along with utilization patterns in real-world settings. Methods: We conducted a retrospective, observational cohort study using statistically de-identified data from January 2011 to November 2018 in CancerLinQ, ASCO’s real-world oncology database, which now contains EHR data from 49 diverse oncology practices in the U.S. Adult patients diagnosed with any cancer type who received ≥1 dose of an ICI (see Table) and had ≥2 clinical visits were eligible for inclusion. Patients were excluded if they received an ICI prior to its first FDA approval date to avoid inclusion of clinical trial patients. Descriptive statistics were used to examine treatment patterns and clinical characteristics of patients receiving ICIs. Results: This analysis included 12,712 patients who received an ICI. Median patient age was 67.4 years [IQR 59.3, 75.3]; 58% were male. White race made up the highest percent (83%) of ICI patients, followed by Black race (9%) and Other (8%). The most common primary cancers at the start of treatment were lung cancer (36%), melanoma (8%), urothelial cancer (2%) and renal cell carcinoma (2%). Of the 8,444 patients with known disease stage, 5,446 (64%) had Stage IV cancer. Breakdown of ICI treatment patterns can be found in the accompanying table. Uptake of ICIs was the most rapid for nivolumab, which had the highest use (49%), followed by pembrolizumab for rapid adoption and use (30%). Conclusions: This analysis gives insights into patient characteristics and real-world treatment patterns for ICIs. ICIs were used most widely in males, lung cancer patients and patients with advanced disease. These baseline characteristics inform our analyses of ICI use in patients with autoimmune disease, also reported herein.[Table: see text]

Response rate and safety of standard-dose nivolumab with reduced-dose ipilimumab in metastatic melanoma.

140 Background: Reduced-dose nivolumab in combination with standard-dose ipilimumab was shown to improve overall response rate (58%), progression free survival (11.5 months), and overall survival compared to ipilimumab alone in Checkmate 067. Improved outcomes were accompanied by an increased risk of toxicities with a 59% rate of grade 3-4 toxicities for the combination. Keynote 029 evaluated standard-dose pembrolizumab with reduced-dose ipilimumab with a slightly lower risk of grade 3-4 toxicities at 45%. Here we report outcomes for standard-dose nivolumab combined with reduced-dose ipilimumab in metastatic melanoma. Methods: We conducted a retrospective review of metastatic melanoma patients that received standard-dose nivolumab with reduced-dose ipilimumab at West Virginia University Cancer Institute. Response to therapy and incidence of immune-related adverse events were assessed. Results: From February 2017 to October 2018, 11 patients received the alternative dosing regimen. Only 1 (9%) patient experienced a grade 3-4 toxicity, and 3 (27%) additional patients experienced a grade 1-2 toxicity. The overall response rate was 54%. Conclusions: Standard-dose nivolumab in combination with reduced-dose ipilimumab is better tolerated than reduced-dose nivolumab with standard-dose ipilimumab without a loss in overall response rate.

Assessing Long-Term Survival Benefits of Immune Checkpoint Inhibitors Using the Net Survival Benefit.

The treatment effect in survival analysis is commonly quantified as the hazard ratio, and tested statistically using the standard log-rank test. Modern anticancer immunotherapies are successful in a proportion of patients who remain alive even after a long-term follow-up. This new phenomenon induces a nonproportionality of the underlying hazards of death. The properties of the net survival benefit were illustrated using the dataset from a trial evaluating ipilimumab in metastatic melanoma. The net survival benefit was then investigated through simulated datasets under typical scenarios of proportional hazards, delayed treatment effect, and cure rate. The net survival benefit test was computed according to the value of the minimal survival difference considered clinically relevant. As comparators, the standard and the weighted log-rank tests were also performed. In the illustrative dataset, the net survival benefit favored ipilimumab [Δ(0) = 15.8%, 95% confidence interval = 4.6% to 27.3%, P = .006]. This favorable effect was maintained when the analysis was focused on long-term survival differences (eg, >12 months, Δ(12) = 12.5% (95% confidence interval = 4.4% to 20.6%, P = .002). Under the scenarios of a delayed treatment effect and cure rate, the power of the net survival benefit test compared favorably to the standard log-rank test power and was comparable to the power of the weighted log-rank test for large values of the threshold of clinical relevance. The net long-term survival benefit is a measure of treatment effect that is meaningful whether or not hazards are proportional. The associated statistical test is more powerful than the standard log-rank test when a delayed treatment effect is anticipated.

Adverse events need for hospitalization and systemic immunosuppression in very elderly patients (over 80years) treated with ipilimumab for metastatic melanoma.

Checkpoint inhibitors are first-line therapies in melanoma, but safety in older adults has not yet been assessed. Ipilimumab improves survival, but immunologic-related adverse events (AEs) can be threatening, and its use in elderly people raises questions. To assess safety in a cohort of very elderly patients treated with ipilimumab. All patients over 80years treated with ipilimumab for melanoma were retrospectively included. AE occurrence, management, and outcome, as well as response rate at week 16 and overall survival were recorded, and compared to data for a group of younger patients treated in our institution during the same period. In the elderly group, 23 patients were included with a median age of 82years [80-90]. AEs amounting to 23 occurred in 15 patients (65%) with 5 grade 3 (22%) and 1 grade 5 (opportunistic infection) AEs. Corticosteroids were required for five (22%) patients, additive immunosuppressive therapy for two, hospitalization for four, and definitive interruption of ipilimumab for three. Median overall survival was 14months. In the younger group, 29 patients were included with a median age of 58years. AEs occurred in 15/29 (52%) with 4 grade 3 (19%) and 1 grade 4 (7%). Median OS was 17months. Serious AEs occurred in 80 + adults at the same rate as observed in our younger patients and as previously reported in younger populations. Ipilimumab can be an option in elderly patients, as patients may benefit from therapy and safety seems to be manageable.

Nivolumab monotherapy or in combination with ipilimumab for metastatic melanoma: systematic review and meta-analysis of randomized-controlled trials.

Nivolumab, a completely human programmed death-1 inhibitor antibody, was first approved by the Food and Drug Administration for patients with advanced malignant melanoma resistant to other modalities of treatment. In 2015, it received approval as the first line of treatment for malignant melanoma. We aimed to synthesize evidence from published randomized-controlled trials on the safety and efficacy of nivolumab, either alone or in combination with ipilimumab, in the management of advanced unresectable melanoma. We searched the following electronic databases: PubMed, Scopus, Web of Science, and Cochrane Central. The records retrieved were screened for eligibility. Time-to-event data were pooled as Hazard ratio using the generic inverse variance method and dichotomous data were pooled as relative risk (RR) in a random-effects model. We used Review Manager 5.3 software for windows. Four unique randomized-controlled trials (five reports) with a total of 1910 patients (nivolumab group, n=1207 and control group, n=703) were included. The overall effect estimate favored nivolumab plus ipilimumab versus ipilimumab alone in terms of the objective response rate [RR: 3.58, 95% confidence interval (CI): 2.08-6.14], the complete response rate (RR: 5.93, 95% CI: 2.45-14.37), the partial response rate (RR: 2.80, 95% CI: 2.16-3.64), the stable disease rate (RR: 0.56, 95% CI: 0.41-0.76), and progression-free survival (hazard ratio: 0.67, 95% CI: 0.60-0.74). The pooled studies were homogenous. Similar results were obtained for nivolumab monotherapy versus chemotherapy comparison. Nivolumab alone or combined with ipilimumab significantly improved the overall and complete response rates compared with ipilimumab alone. In addition, nivolumab resulted in longer progression-free survival with a comparable safety profile.

Body mass index may predict the response to ipilimumab in metastatic melanoma: An observational multi-centre study.

IntroductionImmunotherapy is a well-established treatment option in patients with metastatic melanoma. However, biomarkers that can be used to predict a response in these patients have not yet been found, putting patients at risk of severe side effects.MethodsIn this retrospective analysis, we investigated the association between the body mass index and ipilimumab treatment response in patients with metastatic melanoma. Patients with metastatic melanoma who received a monotherapy of up to 4 doses of ipilimumab (3 mg/kg) every 3 weeks from 2011 to 2014 in three major hospitals in Austria were included. Patients were classified into two groups: normal group (BMI<25) and overweight group (BMI≥25).Results40 patients had a normal BMI, and 36 had a BMI above normal. Patients with a BMI that was above normal showed significantly higher response rates (p = 0.024, χ2), and lower likelihood of brain metastases (p = 0.012, χ2). No differences were found between both groups with respect to gender (p = 0.324, χ2), T-stage (p = 0.197, χ2), or the occurrence of side effects (p = 0.646, χ2). Patients with a BMI above normal showed a trend towards longer overall survival (p = 0.056, Log-Rank), but no difference was found regarding progression-free survival (p = 0.924, Log-Rank).ConclusionsThe BMI correlated with the response to ipilimumab treatment in a cohort of metastatic melanoma patients.

Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain

BackgroundBrain metastases are a common cause of disabling neurologic complications and death in patients with metastatic melanoma. Previous studies of nivolumab combined with ipilimumab in metastatic melanoma have excluded patients with untreated brain metastases. We evaluated the efficacy and safety of nivolumab plus ipilimumab in patients with melanoma who had untreated brain metastases.MethodsIn this open-label, multicenter, phase 2 study, patients with metastatic melanoma and at least one measurable, nonirradiated brain metastasis (tumor diameter, 0.5 to 3 cm) and no neurologic symptoms received nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for up to four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks until progression or unacceptable toxic effects. The primary end point was the rate of intracranial clinical benefit, defined as the percentage of patients who had stable disease for at least 6 months, complete response, or partial response.ResultsAmong 94 patients with a median follow-up of 14.0 months, the rate of intracranial clinical benefit was 57% (95% confidence interval [CI], 47 to 68); the rate of complete response was 26%, the rate of partial response was 30%, and the rate of stable disease for at least 6 months was 2%. The rate of extracranial clinical benefit was 56% (95% CI, 46 to 67). Treatment-related grade 3 or 4 adverse events were reported in 55% of patients, including events involving the central nervous system in 7%. One patient died from immune-related myocarditis. The safety profile of the regimen was similar to that reported in patients with melanoma who do not have brain metastases.ConclusionsNivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases. (Funded by Bristol-Myers Squibb and the National Cancer Institute; CheckMate 204 ClinicalTrials.gov number, NCT02320058.)