Cutaneous melanoma Eggermont, Alexander MM, Prof; Spatz, Alan, MD; Robert, Caroline, MD
The Lancet (British edition),
03/2014, Letnik:
383, Številka:
9919
Journal Article
Recenzirano
Summary In the past decade, major advances have been made in the understanding of melanoma. New predisposition genes have been reported and key somatic events, such as BRAF mutation, directly ...translated into therapeutic management. Surgery for localised melanoma and regional lymph node metastases is the standard of care. Sentinel-node biopsy provides precise staging, but has not been reported to affect survival. The effect of lymph-node dissection on survival is a topic of investigation. Two distinct approaches have emerged to try to extend survival in patients with metastatic melanoma: immunomodulation with anti-CTLA4 monoclonal antibodies, and targeted therapy with BRAF inhibitors or MEK inhibitors for BRAF -mutated melanoma. The combination of BRAF inhibitors and MEK inhibitors might improve progression-free survival further and, possibly, increase overall survival. Response patterns differ substantially—anti-CTLA4 immunotherapy can induce long-term responses, but only in a few patients, whereas targeted drugs induce responses in most patients, but nearly all of them relapse because of pre-existing or acquired resistance. Thus, the long-term prognosis of metastatic melanoma remains poor. Anti-PD1 and anti-PDL1 antibodies have emerged as breakthrough drugs for melanoma that have high response rates and long durability. Biomarkers that have predictive value remain elusive in melanoma, although emerging data for adjuvant therapy indicate that interferon sensitivity is associated with ulceration of the primary melanoma. Intense investigation continues for clinical and biological markers that predict clinical benefit of immunotherapeutic drugs, such as interferon alfa or anti-CTLA4 antibodies, and the mechanisms that lead to resistance of targeted drugs.
Abstract Cancer immunotherapy is now established as a powerful way to treat cancer. The recent clinical success of immune checkpoint blockade (antagonists of CTLA-4, PD-1 and PD-L1) highlights both ...the universal power of treating the immune system across tumour types and the unique features of cancer immunotherapy. Immune-related adverse events, atypical clinical response patterns, durable responses, and clear overall survival benefit distinguish cancer immunotherapy from cytotoxic cancer therapy. Combination immunotherapies that transform non-responders to responders are under rapid development. Current challenges facing the field include incorporating immunotherapy into adjuvant and neoadjuvant cancer therapy, refining dose, schedule and duration of treatment and developing novel surrogate endpoints that accurately capture overall survival benefit early in treatment. As the field rapidly evolves, we must prioritise the development of biomarkers to guide the use of immunotherapies in the most appropriate patients. Immunotherapy is already transforming cancer from a death sentence to a chronic disease for some patients. By making smart, evidence-based decisions in developing next generation immunotherapies, cancer should become an imminently treatable, curable and even preventable disease.
Inhibition of immune checkpoints using anti-programmed cell death-1 (PD-1) or anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibodies has revolutionized the management of ...patients with advanced-stage melanoma and is among the most promising treatment approaches for many other cancers. Use of CTLA-4 and PD-1 inhibitors, either as single agents, or in combination, has been approved by the US FDA for the treatment of metastatic melanoma. Treatment with these novel immunotherapies results in a unique and distinct spectrum of adverse events, which are mostly related to activation of the immune system and are, therefore, an unwanted consequence of their mechanisms of action. Adverse effects of CTLA-4 and/or PD-1 inhibition are most commonly observed in the skin, gastrointestinal tract, liver and endocrine systems and include pruritus, rash, nausea, diarrhoea and thyroid disorders. In this Review, the authors describe the adverse event profile of checkpoint inhibitors targeting CTLA-4 and PD-1, used both as monotherapies and in combination and aim to provide some general guidelines, based upon the mechanisms of action of these therapies and on the management of these immune-related adverse events.
A blinded trial involving patients with resected stage III melanoma showed that adjuvant pembrolizumab every 3 weeks for a year was associated with a 1-year recurrence-free survival rate of 75%, as ...compared with 61% for placebo.
Improved Endpoints for Cancer Immunotherapy Trials Hoos, Axel; Eggermont, Alexander M. M.; Janetzki, Sylvia ...
JNCI : Journal of the National Cancer Institute,
09/2010, Letnik:
102, Številka:
18
Journal Article
Recenzirano
Odprti dostop
Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, ...followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan–Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation.
In patients with advanced melanomas with the BRAF V600E mutation, vemurafenib produced a response in nearly half the patients; secondary skin tumors, arthralgia, rash, and fatigue were side effects. ...Dacarbazine produced a response in 6%.
Metastatic melanoma has a poor prognosis, with the median survival for patients with stage IV melanoma ranging from 8 to 18 months after diagnosis, depending on the substage.
1
In the United States last year, 8700 deaths from melanoma were projected, with an estimated rate of death of 2.6 in 100,000.
2
Rates of death from melanoma in Australia and New Zealand are slightly higher (3.5 in 100,000), whereas rates in Western Europe are slightly lower (1.8 in 100,000).
3
In phase 3 studies, dacarbazine, the only chemotherapeutic agent approved by the Food and Drug Administration for the treatment of metastatic melanoma, was . . .
Summary Background Ipilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma ...at high risk of recurrence. Methods We did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov , number NCT00636168. Findings Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2·74 years (IQR 2·28–3·22), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26·1 months (95% CI 19·3–39·3) in the ipilimumab group versus 17·1 months (95% CI 13·4–21·6) in the placebo group (hazard ratio 0·75; 95% CI 0·64–0·90; p=0·0013); 3-year recurrence-free survival was 46·5% (95% CI 41·5–51·3) in the ipilimumab group versus 34·8% (30·1–39·5) in the placebo group. The most common grade 3–4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 16% vs four <1% in the placebo group), hepatic (50 11% vs one <1%), and endocrine (40 8% vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 39% during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barré syndrome. Interpretation Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk–benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value. Funding Bristol-Myers Squibb.
Abstract Current developments in systemic therapies for melanoma are spectacular. Over the last 40 years no one drug or combination of drugs demonstrated any impact on survival in metastatic ...melanoma. In contrast, in 2011 a number of new drugs will be approved. In 2011 immunomodulation with ipilimumab, a monoclonal antibody targeting the ligand CTLA-4, has been approved for patients with advanced melanoma in first- and second-line treatment by the Food and Drug Administration (FDA) and in second-line treatment by the European Medicines Agency (EMA). Also in 2011, a significant survival benefit of the combination of ipilimumab with dacarbazine compared with dacarbazine alone for first-line treatment was reported. Other monoclonal antibodies targeting T-cell ligands, such as programmed death-1 (PD-1), also show promise. Various inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) yield high response rates in patients harbouring the BRAF-V600E mutation. A significant impact on both progression-free and overall survival was demonstrated for vemurafenib compared with dacarbazine in a phase-III trial. Approval is expected in 2011. Both drugs had only modest effects of 2–3 months on median survival, so combination therapies must be explored. BRAF inhibitors in combination with mitogen-activated protein kinase (MEK) inhibitors show great potential. Moreover, combinations of immunomodulators and pathway inhibitors are expected to be very active, and phase-III trials are planned. Pegylated interferon-α2b was approved in 2011 on the basis of the results of the European Organisation for Research and Treatment of Cancer (EORTC) 18991 phase-III trial demonstrating a sustained impact on relapse-free survival in patients with lymph-node-positive melanoma. The efficacy of adjuvant therapy with ipilimumab is assessed in the now fully accrued EORTC18071 trial. Adjuvant trials with BRAF and MEK inhibitors are in the planning phase. Never was there a more exciting period in the world of melanoma treatment.
To detect a pretreatment gene expression signature (GS) predictive of response to MAGE-A3 immunotherapeutic in patients with metastatic melanoma and to investigate its applicability in a different ...cancer setting (adjuvant therapy of resected early-stage non-small-cell lung cancer NSCLC).
Patients were participants in two phase II studies of the recombinant MAGE-A3 antigen combined with an immunostimulant (AS15 or AS02B). mRNA from melanoma biopsies was analyzed by microarray analysis and quantitative polymerase chain reaction. These results were used to identify and cross-validate the GS, which was then applied to the NSCLC data.
In the patients with melanoma, 84 genes were identified whose expression was potentially associated with clinical benefit. This effect was strongest when the immunostimulant AS15 was included in the immunotherapy (hazard ratio HR for overall survival, 0.37; 95% CI, 0.13 to 1.05; P = .06) and was less strong with the other immunostimulant AS02B (HR, 0.84; 95% CI, 0.36 to 1.97; P = .70). The same GS was then used to predict the outcome for patients with resected NSCLC treated with MAGE-A3 plus AS02B; actively treated GS-positive patients showed a favorable disease-free interval compared with placebo-treated GS-positive patients (HR, 0.42; 95% CI, 0.17 to 1.03; P = .06), whereas among GS-negative patients, no such difference was found (HR, 1.17; 95% CI, 0.59 to 2.31; P = .65). The genes identified were mainly immune related, involving interferon gamma pathways and specific chemokines, suggesting that their pretreatment expression influences the tumor's immune microenvironment and the patient's clinical response.
An 84-gene GS associated with clinical response for MAGE-A3 immunotherapeutic was identified in metastatic melanoma and confirmed in resected NSCLC.
Coronavirus disease 2019 (COVID-19) has affected more than 96 million people worldwide, leading the World Health Organization (WHO) to declare a pandemic in March 2020. Although an optimal medical ...treatment of COVID-19 remains uncertain, an unprecedented global effort to develop an effective vaccine hopes to restore pre-pandemic conditions. Since cancer patients as a group have been shown to be at a higher risk of severe COVID-19, the development of safe and effective vaccines is crucial. However, cancer patients may be underrepresented in ongoing phase 3 randomised clinical trials investigating COVID-19 vaccines. Therefore, we encourage stakeholders to provide real-time data about the characteristics of recruited participants, including clearly identifiable subgroups, like cancer patients, with sample sizes large enough to determine safety and efficacy. Moreover, we envisage a prompt implementation of suitable registries for pharmacovigilance reporting, in order to monitor the effects of COVID-19 vaccines and immunisation rates in patients with cancer. That said, data extrapolation from other vaccine trials (e.g. anti-influenza virus) showed a favourable safety and efficacy profile for cancer patients. On the basis of the evidence discussed, we believe that the benefits of the vaccination outweigh the risks. Consequently, healthcare authorities should prioritise vaccinations for cancer patients, with the time-point of administration agreed on a case-by-case basis. In this regard, the American Society of Clinical Oncology and the European Society of Medical Oncology are advocating for cancer patients a high priority status, in the hope of attenuating the consequences of the pandemic in this particularly vulnerable population.
•COVID-19 has affected more than 96 million people. WHO declared a pandemic in March 2020.•Cancer patients as a group have been shown to be at a higher risk of severe COVID-19.•Evidence from ongoing vaccine RCTs is currently lacking for cancer patients.•Data extrapolation from other vaccines showed a favourable safety and efficacy profile.•Cancer patients need vaccination prioritisation and tailored administration time-point.
PDF
