ABSTRACT
BACKGROUND: The combination of nivolumab + relatlimab is superior to nivolumab alone in the treatment of naive patients and has activity in PD-1 refractory melanoma. We had previously observed a reduced expression of LAG3 in melanoma tissue from patients with type 2 diabetes. METHOD: To evaluate the impact of diabetes on oncological outcomes of patients with advanced melanoma treated with nivolumab plus the LAG3 inhibitor relatlimab we performed a retrospective multicenter study. RESULTS: Overall, 129 patients were included: 88 without diabetes before the treatment, 37 who were diagnosed with type 2 diabetes before the start of treatment, and 4 without diabetes before treatment who developed immune checkpoint inhibitor-induced diabetes (ICI-DM). PFS was 21.71 months (95% CI: 15.61-27.81) in patients without diabetes, 10.23 months (95% CI: 5.81-14.66) in patients with type 2 diabetes, and 50.85 months (95% CI: 23.04-78.65) in patients who developed ICI-DM. OS was 37.94 months (95% CI: 31.02-44.85) in patients without diabetes, 22.12 months (95% CI: 14.41-29.85) in those with type 2 diabetes and 57.64 months (95% CI: 42.29-72.99) in those who developed ICI-DM. Multivariate analysis showed that the presence of diabetes and LDH was correlated with OS and PFS. The mean OS was 64.63 months in subjects with low levels of glucose (< 137 mg/dl) and 36.27 months in those with high levels (hazard ratio 0.16, 95% CI: 0.04-0.58; p = 0.005). The patients whose glucose blood level increased after 3 months of treatment with nivolumab + relatinib compared to baseline (ratio of blood level at baseline/after 3 months > 1.5) had a worse prognosis than those whose glucose level had not increased. This result was observed also in subgroups treated either in first line or further lines. Patients who developed ICI-DM during the study period had better outcomes than the overall population and patients without diabetes. CONCLUSIONS: LAG3 inhibition for treating metastatic or unresectable melanoma has a reduced efficacy in patients with type 2 diabetes, possibly due to a low expression of LAG3 in tumor tissue. Higher level evidence should be obtained.
Subject(s)
Diabetes Mellitus, Type 2 , Melanoma , Humans , Nivolumab/therapeutic use , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Melanoma/complications , Melanoma/drug therapy , Melanoma/pathology , Glucose , Ipilimumab/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of melanoma and other cancers. However, no reliable biomarker of survival or response has entered the clinic to identify those patients with melanoma who are most likely to benefit from ICIs. Glycosylation affects proteins and lipids' structure and functions. Tumours are characterized by aberrant glycosylation which may contribute to their progression and hinder an effective antitumour immune response. METHODS: We aim at identifying novel glyco-markers of response and survival by leveraging the N-glycome of total serum proteins collected in 88 ICI-naive patients with advanced melanoma from two European countries. Samples were collected before and during ICI treatment. RESULTS: We observe that responders to ICIs present with a pre-treatment N-glycome profile significantly shifted towards higher abundancy of low-branched structures containing lower abundances of antennary fucose, and that this profile is positively associated with survival and a better predictor of response than clinical variables alone. CONCLUSION: While changes in serum protein glycosylation have been previously implicated in a pro-metastatic melanoma behaviour, we show here that they are also associated with response to ICI, opening new avenues for the stratification of patients and the design of adjunct therapies aiming at improving immune response.
Subject(s)
Immune Checkpoint Inhibitors , Melanoma , Humans , Melanoma/drug therapy , Ambulatory Care Facilities , Europe , PolysaccharidesABSTRACT
Stage IIB/IIC melanoma has a high risk of recurrence after surgical resection. While, for decades, surgery was the only option for high-risk stage II disease in most countries, adjuvant therapies now exist. Anti-programmed cell death protein 1 (PD-1) antibodies significantly improve recurrence-free survival versus placebo in patients with fully resected stage IIB/IIC melanoma. Combined BRAF MEK inhibitor therapy showed benefits in high-risk stage III and advanced disease; however, its role in patients with fully resected stage BRAF-mutated IIB/IIC melanoma is still unknown. Here we describe the rationale and design of the ongoing randomized, placebo-controlled COLUMBUS-AD trial, the first study of a BRAF-MEK inhibitor combination therapy (encorafenib + binimetinib) in patients with BRAF V600-mutated stage IIB/IIC melanoma.
Melanoma is a type of skin cancer. Although most stage II melanomas (cancer affecting the first two layers of skin) can be cured with surgery, the risk of the cancer returning and spreading to other areas of the body is high in some patients with stage IIB/IIC melanoma. Furthermore, once the melanoma has spread, it is much more difficult to treat successfully and remove all the cancer cells from the body. Some melanomas have a DNA alteration (or mutation) in what is known as the BRAF gene. This mutation can be identified by testing a sample of the tumor tissue removed during a biopsy or surgery. Testing for BRAF mutations at diagnosis can help ensure that patients receive the most appropriate treatment for their cancer. In some countries, surgery is the only option for patients with stage II melanoma, while in other countries, patients may be offered additional (adjuvant) anticancer treatment with immunotherapy (agents that work with the immune system to kill cancer cells). While immunotherapy can reduce the risk of melanoma recurrence, persistent, long-term toxicities are common and the use of this treatment in all stage IIB/IIC melanoma patients is not always possible. Here, we describe the rationale and design of an ongoing clinical trial (COLUMBUS-AD), which will be the first study (to our knowledge) to investigate the efficacy and safety of a treatment that specifically targets cancers with BRAF mutations (i.e., the BRAF-MEK inhibitor combination of the drugs encorafenib and binimetinib) in patients with BRAF-mutated stage IIB/IIC melanoma. Clinical Trial Registration: NCT05270044 (ClinicalTrials.gov).
Subject(s)
Melanoma , Skin Neoplasms , Humans , Proto-Oncogene Proteins B-raf/genetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Melanoma/drug therapy , Melanoma/genetics , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Mitogen-Activated Protein Kinase Kinases , Mutation , Protein Kinase Inhibitors/adverse effects , Clinical Trials, Phase III as Topic , Melanoma, Cutaneous MalignantABSTRACT
PURPOSE: Myasthenia gravis (MG) is a rare but life-threatening complication of immune-checkpoint inhibitor (ICI) therapy and often co-presents with myositis and myocarditis. Previous case series of ICI-related MG have reported high mortality rates. We present a series of ten patients from a tertiary oncology centre outlining outcomes of an early multi-modal immunosuppression strategy. METHODS: We reviewed The Christie Hospital database of immunotherapy-related toxicity from 2017 to 2020. Symptom severity was assessed using the Myasthenia Gravis Foundation of America (MGFA) classification. RESULTS: Ten patients with ICI-related MG were identified. All patients presented following 1 (n = 4) or 2 (n = 6) cycles of ICI. Symptom progression was rapid with a median of 3 days from onset of symptoms to admission. Concomitant myositis and myocarditis were observed in nine patients. AChR or MuSK autoantibodies were positive in six patients. All patients received urgent treatment with intravenous methylprednisolone (IVMP) and eight received intravenous immunoglobulin (IVIG). A single patient died from myasthenia-related symptoms; the remaining 9 patients were successfully discharged. CONCLUSION: In our cohort, we demonstrate good outcomes associated with early intensive immunosuppressive treatment with IVIG and IVMP. An agreed national treatment protocol or clinical discussion forum would be beneficial.
Subject(s)
Myasthenia Gravis , Myocarditis , Myositis , Humans , Immune Checkpoint Inhibitors/adverse effects , Immunoglobulins, Intravenous/therapeutic use , Immunosuppression Therapy , Myasthenia Gravis/chemically induced , Myasthenia Gravis/drug therapy , Myasthenia Gravis/complications , Myocarditis/chemically induced , Myocarditis/drug therapy , Myocarditis/complications , Myositis/chemically induced , Myositis/drug therapy , Myositis/complicationsABSTRACT
BACKGROUND: Circulating tumour DNA (ctDNA) monitoring is a new technology that detects cancer DNA fragments in blood circulation. Regular monitoring with ctDNA has the potential to detect and treat cancer relapse earlier, but there is little evidence on patient acceptability. This study examines the views of patients with early-stage melanoma on the acceptability of the test and early treatment. METHODS: A qualitative cross-sectional design using one-to-one semi-structured telephone interviews was employed. Twenty-five patients diagnosed with early-stage melanoma (Stage IA-IIC) were asked for their views on ctDNA monitoring and early treatment for relapse. Interviews were analysed using reflexive thematic analysis. RESULTS: Two themes were generated: ctDNA monitoring would add service value where participants described regular ctDNA monitoring in follow-up care as more reassuring, more "scientific" than skin checks and preferable to scans. Test results provide opportunity and knowledge focuses on how participants wanted to know when to expect results to manage anxiety, with a positive result seen as an opportunity to receive treatment early. CONCLUSIONS: Participants were positive about ctDNA monitoring and early treatment and would welcome extra surveillance, as well as trust ctDNA tests. This indicates the feasibility of the wider implementation of ctDNA tests, which have applicability for many tumour types and disease stages.
Subject(s)
Circulating Tumor DNA , Melanoma , Biomarkers, Tumor/genetics , Circulating Tumor DNA/genetics , Cross-Sectional Studies , Humans , Melanoma/pathology , Neoplasm Recurrence, Local/pathologyABSTRACT
BACKGROUND: The use of indoor tanning devices causes melanoma and other skin cancers with resulting morbidity, mortality and increased healthcare costs. Policymakers require robust economic evidence to inform decisions about a possible ban of such devices to mitigate these burdens. OBJECTIVES: To assess the health costs and consequences of introducing a policy-based intervention across England to ban commercial indoor tanning with an accompanying public information campaign. METHODS: A cost-effectiveness analysis, adopting a healthcare system perspective, was conducted using a decision model to track a national cohort of 18-year-olds over a lifetime time horizon. A nationwide ban on commercial indoor tanning combined with a public information campaign (the policy-based intervention) was compared with the status quo of availability of commercial indoor tanning. The expected costs (currency, GBP; price year, 2019) and quality-adjusted life-years (QALYs) were calculated. Net monetary benefit (NMB) (net benefit measured in cost compared with an accepted threshold) and net health benefit (NHB) (net gain in QALYs compared with an accepted threshold) of implementation were calculated. A probabilistic sensitivity analysis was used to calculate the probability that the intervention was cost-effective. RESULTS: Compared with the current situation, a ban on commercial indoor tanning combined with a public information campaign would result in 1206 avoided cases of melanoma, 207 fewer melanoma deaths and 3987 averted cases of keratinocyte cancers over the lifetime of all 18-year-olds (n = 618 873) living in England in 2019. An additional 497 QALYs would be realized along with healthcare cost-savings of £697 858. This intervention would result in an NMB of £10.6m and an NHB of 530 QALYS. Multiple sensitivity analyses confirmed the robustness of the findings. At a cost-effectiveness threshold of £20 000, there is a 99% likelihood of this policy-based intervention being cost-effective. CONCLUSIONS: The implementation of a ban on commercial indoor tanning across England with an accompanying public information campaign would be an effective use of healthcare resources.
Subject(s)
Melanoma , Skin Neoplasms , Sunbathing , Cost-Benefit Analysis , Humans , Melanoma/epidemiology , Melanoma/etiology , Melanoma/prevention & control , Policy , Skin Neoplasms/epidemiology , Skin Neoplasms/etiology , Skin Neoplasms/prevention & control , SyndromeABSTRACT
BACKGROUND: Checkpoint inhibitor (CPI) therapy has significantly improved overall survival in several cancers including metastatic melanoma (MM) and in the adjuvant setting. Cutaneous immune-related adverse events (irAEs) secondary to CPIs are commonly observed; however, autoimmune blistering disorders such as bullous pemphigoid (BP) are rare. OBJECTIVES: To review the prevalence, incidence risk, clinicopathological features and management of toxicity in bullous cutaneous irAEs associated with CPI therapy. METHODS: A multicentre, retrospective, observational study of CPI-associated bullous irAEs in adults with all cancers across four UK specialist centres between 2006 and 2019. RESULTS: In total, 7391 patients were identified. CPI-associated bullous irAEs including BP (n = 16) occurred in 0·3% (n = 22). The median age of onset was 76 years, and there was a male predominance. Most patients had cutaneous melanoma (73%, n = 16), of which 81% (13 of 16) were BRAF wildtype. Grade 1, 2, 3 and 4 skin toxicity occurred in 9%, 45%, 41% and 5%, respectively. The mucosae were involved in 27%, and 25% of confirmed cases of BP did not present with bullae. The median time to onset of bullous irAEs was 12 months, with a median total symptom duration of 6 months. Single PD-1/PD-L1 agents had a longer time to onset of symptoms than combination therapy (median 12 vs. 7 months, respectively). Overall, 91%, 64% and 9% of patients required one, two or three lines of treatment, respectively. Two cases occurred after completion of CPIs (1 and 3 months). Of the 20 cases that presented while on CPIs this was permanently discontinued in 55% (11 of 20) and temporarily held in 20% (four of 20). In the four held cases of CPI, bullous eruption reflared in 50%. CONCLUSIONS: CPI-associated bullous skin toxicity is a rare cutaneous irAE occurring in approximately 0·3% of cases over 13 years of treated patients in this series. Not all cases are diagnostic of BP, but management remains the same. There is a prolonged latency of onset compared with other cutaneous irAEs, with a median time of 12 months, and they can occur after cessation of therapy. Discontinuation of CPIs may be required. Recognizing bullous irAEs promptly and referral to dermatology are essential to optimize management and improve patient outcomes and tumour responses. What is already known about this topic? Checkpoint inhibitor (CPI)-associated bullous pemphigoid is a rare dermatological immune-related adverse event (irAE) that has been reported in small case series and reports. What does this study add? This is the largest multicentre, observational study conducted in the UK over the longest period of 13 years, which demonstrates an overall incidence of bullous cutaneous irAEs secondary to CPIs of 0·3%. Clinical presentation is variable, with one-quarter of patients with bullous pemphigoid presenting without bullae, and mucosal involvement was noted in 27%. Prolonged pruritus is frequently a prodromal symptom. The median time to diagnosis is 12 months and irAEs rarely present after cessation of treatment. Time to onset of symptoms is longer with a single CPI, but with a shorter duration of symptoms compared with combination CPI therapy. Most patients had cutaneous melanoma, of which 81% were BRAF wildtype.
Subject(s)
Immune Checkpoint Inhibitors , Melanoma , Pemphigoid, Bullous , Skin Neoplasms , Aged , Female , Humans , Male , Blister/drug therapy , Immune Checkpoint Inhibitors/adverse effects , Melanoma/drug therapy , Pemphigoid, Bullous/chemically induced , Pemphigoid, Bullous/diagnosis , Programmed Cell Death 1 Receptor , Proto-Oncogene Proteins B-raf , Retrospective Studies , Skin Neoplasms/drug therapy , Melanoma, Cutaneous MalignantABSTRACT
PURPOSE OF REVIEW: Liquid biopsies, including circulating tumour DNA (ctDNA), can inform a variety of clinical questions. This review examines the potential role of ctDNA as a clinical tool to inform clinical decision-making from early to late stage cutaneous melanoma. RECENT FINDINGS: In pre-clinical studies, ctDNA has been shown to detect minimal residual disease and molecular relapse; predict and monitor response to therapy; and identify key resistance mechanisms. Here, we examine the potential utility of ctDNA and discuss its limitations for use in patients with melanoma. We present novel clinical trials, which are testing its value as a tool to augment clinical decision-making. Finally, we discuss the steps that are needed to ensure that ctDNA is used optimally in order to improve outcomes for patients with melanoma. Preclinical studies have shown that ctDNA has huge potential to provide real-time information about disease status in patients with melanoma. It is now time to test it rigorously within clinical trials to assess how it can be optimally used to benefit patients in the clinic.
Subject(s)
Circulating Tumor DNA , Melanoma , Skin Neoplasms , Biomarkers, Tumor/genetics , Circulating Tumor DNA/genetics , Humans , Melanoma/pathology , Neoplasm Recurrence, Local , Skin Neoplasms/genetics , Skin Neoplasms/pathologyABSTRACT
BACKGROUND: Anti-PD-1 therapy (hereafter referred to as anti-PD-1) induces long-term disease control in approximately 30% of patients with metastatic melanoma; however, two-thirds of patients are resistant and will require further treatment. We aimed to determine the efficacy and safety of ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab) compared with ipilimumab monotherapy in patients who are resistant to anti-PD-(L)1 therapy (hereafter referred to as anti-PD-[L]1). METHODS: This multicentre, retrospective, cohort study, was done at 15 melanoma centres in Australia, Europe, and the USA. We included adult patients (aged ≥18 years) with metastatic melanoma (unresectable stage III and IV), who were resistant to anti-PD-(L)1 (innate or acquired resistance) and who then received either ipilimumab monotherapy or ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab), based on availability of therapies or clinical factors determined by the physician, or both. Tumour response was assessed as per standard of care (CT or PET-CT scans every 3 months). The study endpoints were objective response rate, progression-free survival, overall survival, and safety of ipilimumab compared with ipilimumab plus anti-PD-1. FINDINGS: We included 355 patients with metastatic melanoma, resistant to anti-PD-(L)1 (nivolumab, pembrolizumab, or atezolizumab), who had been treated with ipilimumab monotherapy (n=162 [46%]) or ipilimumab plus anti-PD-1 (n=193 [54%]) between Feb 1, 2011, and Feb 6, 2020. At a median follow-up of 22·1 months (IQR 9·5-30·9), the objective response rate was higher with ipilimumab plus anti-PD-1 (60 [31%] of 193 patients) than with ipilimumab monotherapy (21 [13%] of 162 patients; p<0·0001). Overall survival was longer in the ipilimumab plus anti-PD-1 group (median overall survival 20·4 months [95% CI 12·7-34·8]) than with ipilimumab monotherapy (8·8 months [6·1-11·3]; hazard ratio [HR] 0·50, 95% CI 0·38-0·66; p<0·0001). Progression-free survival was also longer with ipilimumab plus anti-PD-1 (median 3·0 months [95% CI 2·6-3·6]) than with ipilimumab (2·6 months [2·4-2·9]; HR 0·69, 95% CI 0·55-0·87; p=0·0019). Similar proportions of patients reported grade 3-5 adverse events in both groups (59 [31%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 54 [33%] of 162 patients in the ipilimumab group). The most common grade 3-5 adverse events were diarrhoea or colitis (23 [12%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 33 [20%] of 162 patients in the ipilimumab group) and increased alanine aminotransferase or aspartate aminotransferase (24 [12%] vs 15 [9%]). One death occurred with ipilimumab 26 days after the last treatment: a colon perforation due to immune-related pancolitis. INTERPRETATION: In patients who are resistant to anti-PD-(L)1, ipilimumab plus anti-PD-1 seemed to yield higher efficacy than ipilimumab with a higher objective response rate, longer progression-free, and longer overall survival, with a similar rate of grade 3-5 toxicity. Ipilimumab plus anti-PD-1 should be favoured over ipilimumab alone as a second-line immunotherapy for these patients with advanced melanoma. FUNDING: None.
Subject(s)
Immune Checkpoint Inhibitors/administration & dosage , Ipilimumab/administration & dosage , Melanoma/drug therapy , Programmed Cell Death 1 Receptor/genetics , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Cohort Studies , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/immunology , Female , Humans , Immune Checkpoint Inhibitors/adverse effects , Ipilimumab/adverse effects , Male , Melanoma/genetics , Melanoma/immunology , Melanoma/pathology , Middle Aged , Neoplasm Metastasis , Nivolumab/administration & dosage , Nivolumab/adverse effects , Positron Emission Tomography Computed Tomography , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Progression-Free Survival , Retrospective StudiesABSTRACT
BACKGROUND: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43-0·74], p<0·0001) compared with placebo, leading to its approval in the USA and Europe. This report provides the final results for the secondary efficacy endpoint, distant metastasis-free survival and an update of the recurrence-free survival results. METHODS: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with complete resection of cutaneous melanoma metastatic to lymph node, classified as American Joint Committee on Cancer staging system, seventh edition (AJCC-7) stage IIIA (at least one lymph node metastasis >1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37. FINDINGS: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5-45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9-69·5] in the pembrolizumab group vs 49·4% [44·8-53·8] in the placebo group; HR 0·60 [95% CI 0·49-0·73]; p<0·0001). In the 853 patients with PD-L1-positive tumours, 3·5-year distant metastasis-free survival was 66·7% (95% CI 61·8-71·2) in the pembrolizumab group and 51·6% (46·6-56·4) in the placebo group (HR 0·61 [95% CI 0·49-0·76]; p<0·0001). Recurrence-free survival remained longer in the pembrolizumab group 59·8% (95% CI 55·3-64·1) than the placebo group 41·4% (37·0-45·8) at this 3·5-year follow-up in the ITT population (HR 0·59 [95% CI 0·49-0·70]) and in those with PD-L1-positive tumours 61·4% (56·3-66·1) in the pembrolizumab group and 44·1% (39·2-48·8) in the placebo group (HR 0·59 [95% CI 0·49-0·73]). INTERPRETATION: Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median follow-up, which was consistent with the improvement in recurrence-free survival. Therefore, the results of this trial support the indication to use adjuvant pembrolizumab therapy in patients with resected high risk stage III cutaneous melanoma. FUNDING: Merck Sharp & Dohme.
Subject(s)
Melanoma/drug therapy , Skin Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized , Double-Blind Method , Female , Humans , Male , Melanoma/mortality , Melanoma/pathology , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Skin Neoplasms/mortality , Skin Neoplasms/pathologyABSTRACT
BACKGROUND: The European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 trial in patients with resected, high-risk stage III melanoma demonstrated improved recurrence-free survival with adjuvant pembrolizumab compared with placebo (hazard ratio 0·57 [98·4% CI 0·43-0·74]; p<0·0001). This study reports the results from the health-related quality-of-life (HRQOL) exploratory endpoint. METHODS: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with previously untreated histologically confirmed stage IIIA, IIIB, or IIIC resected cutaneous melanoma, and an Eastern Cooperative Oncology Group performance status score of 1 or 0 were eligible. Patients were randomly assigned (1:1) using a central interactive voice-response system on the basis of a minimisation technique stratified for stage and geographic region to receive intravenously 200 mg pembrolizumab or placebo. Treatment was administered every 3 weeks for 1 year, or until disease recurrence, unacceptable toxicity, or death. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, with global health/quality of life (GHQ) over 2 years measured by the EORTC QLQ-C30 as the primary analysis. Analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37, and long-term follow-up is ongoing. FINDINGS: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to pembrolizumab (n=514) or placebo (n=505). Median follow-up was 15·1 months (IQR 12·8-16·9) at the time of this analysis. HRQOL compliance was greater than 90% at baseline, greater than 70% during the first year, and greater than 60% thereafter for both groups. Because of low absolute compliance numbers at later follow-up, the analysis was truncated to week 84. Baseline GHQ scores were similar between groups (77·55 [SD 18·20] in the pembrolizumab group and 76·54 [17·81] in the placebo group) and remained stable over time. The difference in average GHQ score between the two groups over the 2 years was -2·2 points (95% CI -4·3 to -0·2). The difference in average score during treatment was -1·1 points (95% CI -3·2 to 0·9) and the difference in average score after treatment was -2·2 points (-4·8 to 0·4). These differences are within the 5-point clinical relevance threshold for the QLQ-C30 and are therefore clinically non-significant. INTERPRETATION: Pembrolizumab does not result in a clinically significant decrease in HRQOL compared with placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting. FUNDING: Merck Sharp & Dohme.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Melanoma/drug therapy , Quality of Life , Skin Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Double-Blind Method , Female , Humans , Male , Melanoma/mortality , Melanoma/pathology , Melanoma/psychology , Middle Aged , Neoplasm Staging , Skin Neoplasms/mortality , Skin Neoplasms/pathology , Skin Neoplasms/psychologyABSTRACT
Incidence rates of Merkel cell carcinoma (MCC), an uncommon skin cancer with an aggressive disease course, have increased in recent decades. Limited treatment options are available for patients with metastatic MCC (mMCC). Avelumab, an anti-programmed cell death-ligand 1 monoclonal antibody, became the first approved treatment for mMCC after the results of the phase 2 JAVELIN Merkel 200 study. Prior to its regulatory approval, an expanded access program (EAP) enabled compassionate use of avelumab in patients with mMCC. Here we report findings from patients enrolled in the EAP in Europe and the Middle East. Efficacy and safety data were provided at the discretion of treating physicians. Between March 2, 2016, and December 22, 2018, 403 requests for avelumab were received from 21 countries, and avelumab was supplied to 335 patients. Most patients (96.7%) received avelumab as second-line or later treatment. In 150 patients for whom response data were available, the objective response rate was 48.0%, and in responding patients, median duration of treatment was 7.4 months (range, 1.0-41.7 months). The most common treatment-related adverse events were infusion-related reaction (2.4%) and pyrexia (2.1%), and no new safety signals were observed. Overall, results from European and Middle Eastern patients enrolled in this EAP confirm the efficacy and safety of avelumab treatment observed in previous studies in patients with mMCC.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Carcinoma, Merkel Cell/drug therapy , Skin Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Carcinoma, Merkel Cell/pathology , Compassionate Use Trials , Europe , Female , Humans , Male , Middle Aged , Middle East , Skin Neoplasms/pathology , Treatment OutcomeABSTRACT
BACKGROUND: The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma. METHODS: Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated. RESULTS: At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group. CONCLUSIONS: As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .).
Subject(s)
Adjuvants, Immunologic/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , Melanoma/drug therapy , Skin Neoplasms/drug therapy , Adjuvants, Immunologic/adverse effects , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , B7-H1 Antigen/analysis , Disease-Free Survival , Double-Blind Method , Female , Humans , Infusions, Intravenous , Intention to Treat Analysis , Kaplan-Meier Estimate , Male , Melanoma/mortality , Melanoma/surgery , Middle Aged , Neoplasm Recurrence, Local , Neoplasm Staging , Quality of Life , Skin Neoplasms/mortality , Skin Neoplasms/surgery , Survival RateABSTRACT
Advances in research have transformed the management of melanoma in the past decade. In parallel, patient advocacy has gained traction, and funders are increasingly prioritizing patient and public involvement. Here we discuss the ways in which patients and the public can be engaged in different stages of the research process, from developing, prioritizing and refining the research question to preclinical studies and clinical trials, then finally to ongoing research in the clinic. We discuss the challenges and opportunities that exist at each stage in order to ensure that a representative population of patients and the public contribute to melanoma research both now and in the future.
Subject(s)
Biomedical Research , Melanoma/therapy , Patient Participation , Clinical Trials as Topic , Humans , Information Dissemination , Informed Consent , Patient Advocacy , Patient Selection , Research DesignABSTRACT
BACKGROUND: With the advent of immunotherapy, substantial progress has been made in improving outcomes for patients with advanced cancer. However, not all patients benefit equally from treatment, and confounding immune-related issues may have an impact. Several studies suggest that antibiotic use (which alters the gut microbiome) may result in poorer outcomes for patients treated with immune checkpoint inhibitors (ICI). MATERIALS AND METHODS: This is a large, single-site retrospective review of n = 291 patients with advanced cancer treated with ICI (n = 179 melanoma, n = 64 non-small cell lung cancer, and n = 48 renal cell carcinoma). Antibiotic use (both single and multiple courses/prolonged use) during the periods 2 weeks before and 6 weeks after ICI treatment was investigated. RESULTS: Within this cohort, 92 patients (32%) received antibiotics. Patients who did not require antibiotics had the longest median progression-free survival (PFS), of 6.3 months, and longest median overall survival (OS), of 21.7 months. With other clinically relevant factors controlled, patients who received a single course of antibiotics had a shorter median OS (median OS, 17.7 months; p = .294), and patients who received multiple courses or prolonged antibiotic treatment had the worst outcomes overall (median OS, 6.3 months; p = .009). Progression-free survival times were similarly affected. CONCLUSION: This large, multivariate analysis demonstrated that antibiotic use is an independent negative predictor of PFS and OS in patients with advanced cancer treated with ICIs. This study highlighted worse treatment outcomes from patients with cumulative (multiple or prolonged courses) antibiotic use, which warrants further investigation and may subsequently inform clinical practice guidelines advocating careful use of antibiotics. IMPLICATIONS FOR PRACTICE: Antibiotic use is negatively associated with treatment outcomes of immune checkpoint inhibitors (ICI) in advanced cancer. Cumulative antibiotic use is associated with a marked negative survival outcome. Judicious antibiotic prescribing is warranted in patients receiving treatment with ICI for treatment of advanced malignancy.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Antibodies, Monoclonal/therapeutic use , Immunotherapy/methods , Aged , Anti-Bacterial Agents/pharmacology , Antibodies, Monoclonal/pharmacology , Female , Humans , Male , Middle Aged , Retrospective Studies , Treatment OutcomeABSTRACT
PURPOSE: Immune-mediated hypophysitis is an important toxicity related to immune checkpoint inhibitors (ICI). Optimal management is associated with improved outcomes. It represents a wide spectrum of clinical presentations, and a proportion may be suitable for emergency ambulatory management. METHODS: Emergency ambulatory management of patients presenting with clinical features and findings consistent with ICI-induced hypophysitis was considered at a tertiary cancer/endocrinology hospital. Suitable patients were initially investigated and treated in accordance with the UK emergency management guidelines for ICI induced hypophysitis. After an initial observation period of 4 h, patients were discharged with oral hydrocortisone (20, 10, 10 mg). RESULTS: An initial cohort of 4 patients with emergency presentations of ICI-induced hypophysitis has been managed in an ambulatory fashion in the first 3 months. There were no 30-day readmissions. CONCLUSION: Carefully selected emergency presentations with immune-mediated hypophysitis may be suitable for ambulatory management.
Subject(s)
Hypophysitis/therapy , Aged , Female , Humans , Hypophysitis/physiopathology , Male , Middle Aged , OutpatientsABSTRACT
BACKGROUND: Pembrolizumab improved progression-free survival and overall survival versus ipilimumab in patients with advanced melanoma and is now a standard of care in the first-line setting. However, the optimal duration of anti-PD-1 administration is unknown. We present results from 5 years of follow-up of patients in KEYNOTE-006. METHODS: KEYNOTE-006 was an open-label, multicentre, randomised, controlled, phase 3 study done at 87 academic institutions, hospitals, and cancer centres in 16 countries. Patients aged at least 18 years with Eastern Cooperative Oncology Group performance status of 0 or 1, ipilimumab-naive histologically confirmed advanced melanoma with known BRAFV600 status and up to one previous systemic therapy were randomly assigned (1:1:1) to intravenous pembrolizumab 10 mg/kg every 2 weeks or every 3 weeks or four doses of intravenous ipilimumab 3 mg/kg every 3 weeks. Treatments were assigned using a centralised, computer-generated allocation schedule with blocked randomisation within strata. Exploratory combination of data from the two pembrolizumab dosing regimen groups was not protocol-specified. Pembrolizumab treatment continued for up to 24 months. Eligible patients who discontinued pembrolizumab with stable disease or better after receiving at least 24 months of pembrolizumab or discontinued with complete response after at least 6 months of pembrolizumab and then progressed could receive an additional 17 cycles of pembrolizumab. Co-primary endpoints were overall survival and progression-free survival. Efficacy was analysed in all randomly assigned patients, and safety was analysed in all randomly assigned patients who received at least one dose of study treatment. Exploratory assessment of efficacy and safety at 5 years' follow-up was not specified in the protocol. Data cutoff for this analysis was Dec 3, 2018. Recruitment is closed; the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT01866319. FINDINGS: Between Sept 18, 2013, and March 3, 2014, 834 patients were enrolled and randomly assigned to receive pembrolizumab (every 2 weeks, n=279; every 3 weeks, n=277), or ipilimumab (n=278). After a median follow-up of 57·7 months (IQR 56·7-59·2) in surviving patients, median overall survival was 32·7 months (95% CI 24·5-41·6) in the combined pembrolizumab groups and 15·9 months (13·3-22·0) in the ipilimumab group (hazard ratio [HR] 0·73, 95% CI 0·61-0·88, p=0·00049). Median progression-free survival was 8·4 months (95% CI 6·6-11·3) in the combined pembrolizumab groups versus 3·4 months (2·9-4·2) in the ipilimumab group (HR 0·57, 95% CI 0·48-0·67, p<0·0001). Grade 3-4 treatment-related adverse events occurred in 96 (17%) of 555 patients in the combined pembrolizumab groups and in 50 (20%) of 256 patients in the ipilimumab group; the most common of these events were colitis (11 [2%] vs 16 [6%]), diarrhoea (ten [2%] vs seven [3%]), and fatigue (four [<1%] vs three [1%]). Any-grade serious treatment-related adverse events occurred in 75 (14%) patients in the combined pembrolizumab groups and in 45 (18%) patients in the ipilimumab group. One patient assigned to pembrolizumab died from treatment-related sepsis. INTERPRETATION: Pembrolizumab continued to show superiority over ipilimumab after almost 5 years of follow-up. These results provide further support for use of pembrolizumab in patients with advanced melanoma. FUNDING: Merck Sharp & Dohme.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Ipilimumab/administration & dosage , Melanoma/drug therapy , Adult , Aged , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Drug Administration Schedule , Female , Humans , Ipilimumab/adverse effects , Male , Melanoma/pathology , Middle Aged , Neoplasm Staging , Progression-Free Survival , Proportional Hazards ModelsABSTRACT
BACKGROUND: Studies evaluating a relationship of vitamin D in patients with primary melanoma have consistently identified an inverse correlation with Breslow thickness, but an inconsistent impact on survival. Vitamin D in later stages of melanoma has been less studied. METHODS: Vitamin D was measured in serum from 341 patients with resected stage IIB-IIIC melanoma recruited to the AVAST-M adjuvant melanoma randomised trial, collected prior to randomisation, then at 3 and 12 months. Vitamin D levels were compared with patient demographics, known melanoma prognostic factors, disease-free interval (DFI) and overall survival (OS). RESULTS: A total of 73% patients had stage III melanoma, 32% were enroled (and therefore tested) >1 year after primary melanoma diagnosis. Median pre-randomisation vitamin D level was 56.5 (range 12.6-189.0 nmol/L). Vitamin D levels did not significantly vary over 12 months (p = 0.24). Individual pre-randomisation vitamin D levels did not differ significantly for Breslow thickness, tumour ulceration, or disease stage. Neither did pre-randomisation vitamin D predict for DFI (HR = 0.98 per 10 nmol/L increase; 95% confidence interval (CI) 0.93-1.04, p = 0.59) or OS (HR = 0.96 per 10 nmol/L increase, 95% CI 0.90-1.03, p = 0.31). For stage II patients, DFI improved with higher pre-randomisation vitamin D levels for those on bevacizumab (HR = 0.74 per 10 nmol nmol/L increase; 95% CI 0.56-0.97), but not for the observation arm (HR = 1.07 per 10 nmol/L increase; 95% CI 0.85-1.34). CONCLUSIONS: In this stage II/III melanoma cohort, vitamin D did not correlate with known prognostic markers, nor predict for DFI or OS, but there was some evidence of benefit for patients with stage II disease treated with bevacizumab.
Subject(s)
Antineoplastic Agents, Immunological/administration & dosage , Bevacizumab/administration & dosage , Melanoma/drug therapy , Melanoma/surgery , Vitamin D/analogs & derivatives , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Immunological/therapeutic use , Bevacizumab/therapeutic use , Chemotherapy, Adjuvant , Female , Humans , Male , Melanoma/metabolism , Melanoma/pathology , Middle Aged , Neoplasm Staging , Survival Analysis , Treatment Outcome , United Kingdom , Vitamin D/blood , Young AdultABSTRACT
BACKGROUND: Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis. METHODS: In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of pembrolizumab, or one regimen of ipilimumab, using a centralised, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3, 2015. This study was registered with ClinicalTrials.gov, number NCT01866319. FINDINGS: Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous pembrolizumab every 2 weeks (n=279), intravenous pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either pembrolizumab group and was 16·0 months with ipilimumab (hazard ratio [HR] 0·68, 95% CI 0·53-0·87 for pembrolizumab every 2 weeks vs ipilimumab; p=0·0009 and 0·68, 0·53-0·86 for pembrolizumab every 3 weeks vs ipilimumab; p=0·0008). 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group. INTERPRETATION: Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between pembrolizumab dosing schedules. These conclusions further support the use of pembrolizumab as a standard of care for advanced melanoma. FUNDING: Merck & Co.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Agents, Immunological/administration & dosage , Ipilimumab/administration & dosage , Melanoma/drug therapy , Melanoma/mortality , Skin Neoplasms/drug therapy , Skin Neoplasms/mortality , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Chemical and Drug Induced Liver Injury/epidemiology , Colitis/chemically induced , Colitis/epidemiology , Drug Administration Schedule , Endocrine System Diseases/chemically induced , Endocrine System Diseases/epidemiology , Female , Humans , Ipilimumab/adverse effects , Male , Melanoma/pathology , Middle Aged , Skin Neoplasms/pathology , Young AdultABSTRACT
BACKGROUND: The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma. METHODS: In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival. RESULTS: The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%). CONCLUSIONS: The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.).