Summary Background Patients with melanoma that progresses on ipilimumab and, if BRAFV600 mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and ...safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma. Methods We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAFV600 mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0–1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAFV600 mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT01704287 . The study is closed to enrolment but continues to follow up and treat patients. Findings Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45–0·73; p<0·0001) and those assigned to pembrolizumab 10 mg/kg (0·50, 0·39–0·64; p<0·0001) compared with those assigned to chemotherapy. 6-month progression-free survival was 34% (95% CI 27–41) in the pembrolizumab 2 mg/kg group, 38% (31–45) in the 10 mg/kg group, and 16% (10–22) in the chemotherapy group. Treatment-related grade 3–4 adverse events occurred in 20 (11%) patients in the pembrolizumab 2 mg/kg group, 25 (14%) in the pembrolizumab 10 mg/kg group, and 45 (26%) in the chemotherapy group. The most common treatment-related grade 3–4 adverse event in the pembrolizumab groups was fatigue (two 1% of 178 patients in the 2 mg/kg group and one <1% of 179 patients in the 10 mg/kg group, compared with eight 5% of 171 in the chemotherapy group). Other treatment-related grade 3–4 adverse events include generalised oedema and myalgia (each in two 1% patients) in those given pembrolizumab 2 mg/kg; hypopituitarism, colitis, diarrhoea, decreased appetite, hyponatremia, and pneumonitis (each in two 1%) in those given pembrolizumab 10 mg/kg; and anaemia (nine 5%), fatigue (eight 5%), neutropenia (six 4%), and leucopenia (six 4%) in those assigned to chemotherapy. Interpretation These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma. Funding Merck Sharp & Dohme.
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.
Summary The burden of cancer is growing, and the disease is becoming a major economic expenditure for all developed countries. In 2008, the worldwide cost of cancer due to premature death and ...disability (not including direct medical costs) was estimated to be US$895 billion. This is not simply due to an increase in absolute numbers, but also the rate of increase of expenditure on cancer. What are the drivers and solutions to the so-called cancer-cost curve in developed countries? How are we going to afford to deliver high quality and equitable care? Here, expert opinion from health-care professionals, policy makers, and cancer survivors has been gathered to address the barriers and solutions to delivering affordable cancer care. Although many of the drivers and themes are specific to a particular field—eg, the huge development costs for cancer medicines—there is strong concordance running through each contribution. Several drivers of cost, such as over-use, rapid expansion, and shortening life cycles of cancer technologies (such as medicines and imaging modalities), and the lack of suitable clinical research and integrated health economic studies, have converged with more defensive medical practice, a less informed regulatory system, a lack of evidence-based sociopolitical debate, and a declining degree of fairness for all patients with cancer. Urgent solutions range from re-engineering of the macroeconomic basis of cancer costs (eg, value-based approaches to bend the cost curve and allow cost-saving technologies), greater education of policy makers, and an informed and transparent regulatory system. A radical shift in cancer policy is also required. Political toleration of unfairness in access to affordable cancer treatment is unacceptable. The cancer profession and industry should take responsibility and not accept a substandard evidence base and an ethos of very small benefit at whatever cost; rather, we need delivery of fair prices and real value from new technologies.
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.
Summary Surgery is essential for global cancer care in all resource settings. Of the 15·2 million new cases of cancer in 2015, over 80% of cases will need surgery, some several times. By 2030, we ...estimate that annually 45 million surgical procedures will be needed worldwide. Yet, less than 25% of patients with cancer worldwide actually get safe, affordable, or timely surgery. This Commission on global cancer surgery, building on Global Surgery 2030, has examined the state of global cancer surgery through an analysis of the burden of surgical disease and breadth of cancer surgery, economics and financing, factors for strengthening surgical systems for cancer with multiple-country studies, the research agenda, and the political factors that frame policy making in this area. We found wide equity and economic gaps in global cancer surgery. Many patients throughout the world do not have access to cancer surgery, and the failure to train more cancer surgeons and strengthen systems could result in as much as US$6·2 trillion in lost cumulative gross domestic product by 2030. Many of the key adjunct treatment modalities for cancer surgery—eg, pathology and imaging—are also inadequate. Our analysis identified substantial issues, but also highlights solutions and innovations. Issues of access, a paucity of investment in public surgical systems, low investment in research, and training and education gaps are remarkably widespread. Solutions include better regulated public systems, international partnerships, super-centralisation of surgical services, novel surgical clinical trials, and new approaches to improve quality and scale up cancer surgical systems through education and training. Our key messages are directed at many global stakeholders, but the central message is that to deliver safe, affordable, and timely cancer surgery to all, surgery must be at the heart of global and national cancer control planning.
Summary Background The EORTC 18071 phase 3 trial compared adjuvant ipilimumab with placebo in patients with stage III melanoma. The primary endpoint, recurrence-free survival, was significantly ...longer in the ipilimumab group than in the placebo group. Investigator-reported toxic effects of ipilimumab consisted mainly of skin, gastrointestinal, endocrine, and hepatic immune-related adverse events. Adjuvant treatment with ipilimumab in this setting was approved in October, 2014, by the US Food and Drug Administration based on the results of the primary outcome of this trial. Here, we report the results of the secondary endpoint, health-related quality of life (HRQoL), of this trial. Methods EORTC 18071 was a multinational, double-blind, randomised, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) in 19 countries worldwide. Participants were randomly assigned (1:1) centrally by an interactive voice response system, to receive either ipilimumab 10 mg/kg 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. HRQoL was assessed with the EORTC QLQ-C30 quality-of-life instrument at baseline, weeks 4, 7, 10, and 24, and every 12 weeks thereafter up to 2 years, irrespective of disease progression. Results were summarised by timepoint and in a longitudinal manner in the intention-to-treat population. Two summary scores were calculated for each HRQoL scale: the average score reported during induction (ipilimumab or placebo at a dose of 10 mg/kg, administered as one single dose at the start of days 1, 22, 43, and 64—ie, four doses in 3 weeks), and the average score reported after induction. A predefined threshold of a 10 point difference between arms was considered clinically relevant. The primary HRQoL endpoint was the global health scale, with the predefined hypothesis of no clinically relevant differences after induction between groups. 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 treatment: 475 in the ipilimumab group and 476 in the placebo group. Compliance with completing the HRQoL questionnaire was 893 (94%) of 951 patients at baseline, 693 (75%) of 924 at week 24, and 354 (51%) of 697 at week 108. Patient mean global health scores during (77·32 SD 17·36 vs 72·96 17·82; p=0·00011) and after induction (76·48 17·52 vs 72·32 18·60; p=0·00067) were statistically significantly different between groups but were not clinically relevant. Mean global health scores differed most between the groups at week 7 (77 SD 19 in the placebo group vs 72 22 in the ipilimumab group) and week 10 (77 20 vs 70 23). Mean HRQoL scores differed by more than 10 points at week 10 between treatment groups for diarrhoea (7·67 SD 17·05 for placebo vs 18·17 28·35 for ipilimumab) and insomnia (15·17 22·53 vs 25·60 29·19). Interpretation Despite increased toxicity, which led to treatment discontinuation for most patients during the induction phase of ipilimumab administration, overall HRQoL, as measured by the EORTC QLQ-C30, was similar between groups, as no clinically relevant differences (10 points or more) in global health status scores were observed during or after induction. Clinically relevant deterioration for some symptoms was observed at week 10, but after induction, no clinically relevant differences remained. Together with the primary analysis, results from this trial show that treatment with ipilimumab results in longer recurrence-free survival compared with that for treatment with placebo, with little impairment in HRQoL despite grade 3–4 investigator-reported adverse events. Funding Bristol-Myers Squibb.
Summary Background Any benefit of adjuvant interferon alfa-2b for melanoma could depend on dose and duration of treatment. Our aim was to determine whether pegylated interferon alfa-2b can facilitate ...prolonged exposure while maintaining tolerability. Methods 1256 patients with resected stage III melanoma were randomly assigned to observation (n=629) or pegylated interferon alfa-2b (n=627) 6 μg/kg per week for 8 weeks (induction) then 3 μg/kg per week (maintenance) for an intended duration of 5 years. Randomisation was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumour thickness, sex, and centre. Randomisation was done with a minimisation technique. The primary endpoint was recurrence-free survival. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00006249. Findings All randomised patients were included in the primary efficacy analysis. 608 patients in the interferon group and 613 patients in the observation group were included in safety analyses. The median length of treatment with pegylated interferon alfa-2b was 12 (IQR 3·8–33·4) months. At 3·8 (3·2–4·2) years median follow-up, 328 recurrence events had occurred in the interferon group compared with 368 in the observation group (hazard ratio 0·82, 95% CI 0·71–0·96; p=0·01); the 4-year rate of recurrence-free survival was 45·6% (SE 2·2) in the interferon group and 38·9% (2·2) in the observation group. There was no difference in overall survival between the groups. Grade 3 adverse events occurred in 246 (40%) patients in the interferon group and 60 (10%) in the observation group; grade 4 adverse events occurred in 32 (5%) patients in the interferon group and 14 (2%) in the observation group. In the interferon group, the most common grade 3 or 4 adverse events were fatigue (97 patients, 16%), hepatotoxicity (66, 11%), and depression (39, 6%). Treatment with pegylated interferon alfa-2b was discontinued because of toxicity in 191 (31%) patients. Interpretation Adjuvant pegylated interferon alfa-2b for stage III melanoma has a significant, sustained effect on recurrence-free survival. Funding Schering Plough Research International.
Summary Background Recent phase 3 trials have shown an overall survival benefit in metastatic melanoma. We aimed to assess whether progression-free survival (PFS) could be regarded as a reliable ...surrogate for overall survival through a meta-analysis of randomised trials. Methods We systematically reviewed randomised trials comparing treatment regimens in metastatic melanoma that included dacarbazine as the control arm, and which reported both PFS and overall survival with a standard hazard ratio (HR). We correlated HRs for overall survival and PFS, weighted by sample size or by precision of the HR estimate, assuming fixed and random effects. We did sensitivity analyses according to presence of crossover, trial size, and dacarbazine dose. Findings After screening 1649 reports and meeting abstracts published before Sept 8, 2013, we identified 12 eligible randomised trials that enrolled 4416 patients with metastatic melanoma. Irrespective of weighting strategy, we noted a strong correlation between the treatment effects for PFS and overall survival, which seemed independent of treatment type. Pearson correlation coefficients were 0·71 (95% CI 0·29–0·90) with a random-effects assumption, 0·85 (0·59–0·95) with a fixed-effects assumption, and 0·89 (0·68–0·97) with sample-size weighting. For nine trials without crossover, the correlation coefficient was 0·96 (0·81–0·99), which decreased to 0·93 (0·74–0·98) when two additional trials with less than 50% crossover were included. Inclusion of mature follow-up data after at least 50% crossover (in vemurafenib and dabrafenib phase 3 trials) weakened the PFS to overall survival correlation (0·55, 0·03–0·84). Inclusion of trials with no or little crossover with the random-effects assumption yielded a conservative statement of the PFS to overall survival correlation of 0·85 (0·51–0·96). Interpretation PFS can be regarded as a robust surrogate for overall survival in dacarbazine-controlled randomised trials of metastatic melanoma; we postulate that this association will hold as treatment standards evolve and are adopted as the control arm in future trials. Funding None.
Summary Background In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAFV600 mutation-positive melanoma. ...We present an extended follow-up analysis of the total population and in the BRAFV600E and BRAFV600K mutation subgroups. Methods Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAFV600 mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m2 of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov , NCT01006980. Findings 675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7–16·0) on vemurafenib and 9·5 months (3·1–14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months 95% CI 12·0–15·2 vs 9·7 months 7·9–12·8; hazard ratio HR 0·70 95% CI 0·57–0·87; p=0·0008), as was median progression-free survival (6·9 months 95% CI 6·1–7·0 vs 1·6 months 1·6–2·1; HR 0·38 95% CI 0·32–0·46; p<0·0001). For the 598 (91%) patients with BRAFV600E disease, median overall survival in the vemurafenib group was 13·3 months (95% CI 11·9–14·9) compared with 10·0 months (8·0–14·0) in the dacarbazine group (HR 0·75 95% CI 0·60–0·93; p=0·0085); median progression-free survival was 6·9 months (95% CI 6·2–7·0) and 1·6 months (1·6–2·1), respectively (HR 0·39 95% CI 0·33–0·47; p<0·0001). For the 57 (9%) patients with BRAFV600K disease, median overall survival in the vemurafenib group was 14·5 months (95% CI 11·2–not estimable) compared with 7·6 months (6·1–16·6) in the dacarbazine group (HR 0·43 95% CI 0·21–0·90; p=0·024); median progression-free survival was 5·9 months (95% CI 4·4–9·0) and 1·7 months (1·4–2·9), respectively (HR 0·30 95% CI 0·16–0·56; p<0·0001). The most frequent grade 3–4 events were cutaneous squamous-cell carcinoma (65 19% of 337 patients) and keratoacanthomas (34 10%), rash (30 9%), and abnormal liver function tests (38 11%) in the vemurafenib group and neutropenia (26 9% of 287 patients) in the dacarbazine group. Eight (2%) patients in the vemurafenib group and seven (2%) in the dacarbazine group had grade 5 events. Interpretation Inhibition of BRAF with vemurafenib improves survival in patients with the most common BRAFV600E mutation and in patients with the less common BRAFV600K mutation. Funding F Hoffmann-La Roche-Genentech.
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