SummaryBackgroundPembrolizumab 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. MethodsKEYNOTE-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. FindingsBetween 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. InterpretationPembrolizumab 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. FundingMerck Sharp & Dohme.
SummaryBackgroundImmunotherapy combination treatments can improve patient outcomes. Epacadostat, an IDO1 selective inhibitor, and pembrolizumab, a PD-1 inhibitor, showed promising antitumour activity ...in the phase 1–2 ECHO-202/KEYNOTE-037 study in advanced melanoma. In this trial, we aimed to compare progression-free survival and overall survival in patients with unresectable stage III or IV melanoma receiving epacadostat plus pembrolizumab versus placebo plus pembrolizumab. MethodsIn this international, randomised, placebo-controlled, double-blind, parallel-group, phase 3 trial, eligible participants were aged 18 years or older, with unresectable stage III or IV melanoma previously untreated with PD-1 or PD-L1 checkpoint inhibitors, an ECOG performance status of 0 or 1, and had a known BRAFV600 mutant status or consented to BRAFV600 mutation testing during screening. Patients were stratified by PD-L1 expression and BRAFV600 mutation status and randomly assigned (1:1) through a central interactive voice and integrated web response system to receive epacadostat 100 mg orally twice daily plus pembrolizumab 200 mg intravenously every 3 weeks or placebo plus pembrolizumab for up to 2 years. We used block randomisation with a block size of four in each stratum. Primary endpoints were progression-free survival and overall survival in the intention-to-treat population. The safety analysis population included randomly assigned patients who received at least one dose of study treatment. The study was stopped after the second interim analysis; follow-up for safety is ongoing. This study is registered with ClinicalTrials.gov, number NCT02752074. FindingsBetween June 21, 2016, and Aug 7, 2017, 928 patients were screened and 706 patients were randomly assigned to receive epacadostat plus pembrolizumab (n=354) or placebo plus pembrolizumab (n=352). Median follow-up was 12·4 months (IQR 10·3–14·5). No significant differences were found between the treatment groups for progression-free survival (median 4·7 months, 95% CI 2·9–6·8, for epacadostat plus pembrolizumab vs 4·9 months, 2·9–6·8, for placebo plus pembrolizumab; hazard ratio HR 1·00, 95% CI 0·83–1·21; one-sided p=0·52) or overall survival (median not reached in either group; epacadostat plus pembrolizumab vs placebo plus pembrolizumab: HR 1·13, 0·86–1·49; one-sided p=0·81). The most common grade 3 or worse treatment-related adverse event was lipase increase, which occurred in 14 (4%) of 353 patients receiving epacadostat plus pembrolizumab and 11 (3%) of 352 patients receiving placebo plus pembrolizumab. Treatment-related serious adverse events were reported in 37 (10%) of 353 patients receiving epacadostat plus pembrolizumab and 32 (9%) of 352 patients receiving placebo plus pembrolizumab. There were no treatment-related deaths in either treatment group. InterpretationEpacadostat 100 mg twice daily plus pembrolizumab did not improve progression-free survival or overall survival compared with placebo plus pembrolizumab in patients with unresectable or metastatic melanoma. The usefulness of IDO1 inhibition as a strategy to enhance anti-PD-1 therapy activity in cancer remains uncertain. FundingIncyte Corporation, in collaboration with Merck Sharp & Dohme.
Summary Background Dabrafenib plus trametinib treatment provides significant benefits over BRAF-inhibitor monotherapy in patients with BRAFV600E -mutant or BRAFV600K -mutant advanced melanoma; ...however, in many patients the disease progresses, leading to death. With many treatment options available, understanding clinical factors that predict long-term response and survival for treatments is important for optimisation of patient management. We aimed to identify clinical factors associated with long-term response and survival using pooled data from randomised trials of dabrafenib plus trametinib in patients with metastatic BRAF -mutant melanoma. Methods We did a retrospective individual data analysis based on all published randomised trials that included treatment-naive patients with BRAFV600E -mutant or BRAFV600K -mutant metastatic melanoma who received the approved dose of dabrafenib 150 mg twice daily plus trametinib 2 mg once daily. Data were pooled from patients in the BRF113220 (part C; March 26, 2010, to Jan 15, 2015), COMBI-d (May 4, 2012, to Jan 12, 2015), and COMBI-v (June 4, 2012, to March 13, 2015) randomised trials. Patients with untreated brain metastases were not permitted to enrol in these trials. Baseline factors, identified a priori based on known melanoma clinical or prognostic characteristics, were analysed for association with progression-free survival and overall survival using univariate and multivariate analyses and assessed for hierarchical effect on outcomes using regression tree analyses. We also analysed factors identified after baseline, on treatment, and at progression, for associations with survival after progression. The trials included in this analysis are registered with ClinicalTrials.gov : BRF113220, number NCT01072175 ; COMBI-d, number NCT01584648 ; COMBI-v, number NCT01597908. Findings 617 patients were included in this analysis with a median follow-up of 20·0 months (range 0−48·0, IQR 10·1−24·8); 396 patients had progression events (ie, disease progression or death) and 290 patients had died. Median progression-free survival (11·1 months 95% CI 9·7−12·9), median overall survival (25·6 months 23·1−34·3), 1-year progression-free survival (48% 44–52) and overall survival (74% 71–78), and 2-year progression-free survival (30% 26–34) and overall survival (53% 49–57) were consistent with those in the individual trials. Patients with normal lactate dehydrogenase (LDH) concentration and fewer than three organ sites containing metastases (n=237) had the longest 1-year progression-free survival (68% 95% CI 62–74) and overall survival (90% 87–94) and 2-year progression-free survival (46% 40–54) and overall survival (75% 70–81), whereas patients with LDH concentration at least two times the upper limit of normal (n=70) had the shortest 1-year progression-free survival (8% 3–19) and overall survival (40% 29–55) and 2-year progression-free survival (2% 0–13) and overall survival (7% 3–19). Of patients with disease progression (n=379), survival after progression was longest in those with progression in baseline or new non-CNS lesions (n=205; median 10·0 months 95% CI 7·9−12·0) and shortest in those with new CNS lesions or concurrent progression in baseline and new lesions (n=171; median 4·0 months 3·5−4·9). Interpretation Several patient and clinical characteristics at and after baseline are associated with outcomes with dabrafenib plus trametinib, and durable benefit is possible with targeted treatment in defined patient subsets. Funding Novartis.
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 Background The Hedgehog pathway inhibitor vismodegib has shown clinical benefit in patients with advanced basal cell carcinoma and is approved for treatment of patients with advanced basal ...cell carcinoma for whom surgery is inappropriate. STEVIE was designed to assess the safety of vismodegib in a situation similar to routine practice, with a long follow-up. Methods In this multicentre, open-label trial, adult patients with histologically confirmed locally advanced basal cell carcinoma or metastatic basal cell carcinoma were recruited from regional referral centres or specialist clinics. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and adequate organ function. Patients with locally advanced basal cell carcinoma had to have been deemed ineligible for surgery. All patients received 150 mg oral vismodegib capsules once a day on a continuous basis in 28-day cycles. The primary objective was safety (incidence of adverse events until disease progression or unacceptable toxic effects), with assessments on day 1 of each treatment cycle (28 days) by principal investigator and coinvestigators at the site. Efficacy variables were assessed as secondary endpoints. The safety evaluable population included all patients who received at least one dose of study drug. Patients with histologically confirmed basal cell carcinoma who received at least one dose of study drug were included in the efficacy analysis. An interim analysis was pre-planned after 500 patients achieved 1 year of follow-up. This trial is registered with ClinicalTrials.gov , number NCT01367665 . The study is still ongoing. Findings Between June 30, 2011, and Nov 6, 2014, we enrolled 1227 patients. At clinical cutoff (Nov 6, 2013), 499 patients (468 with locally advanced basal cell carcinoma and 31 with metastatic basal cell carcinoma) had received study drug and had the potential to be followed up for 12 months or longer. Treatment was discontinued in 400 (80%) patients; 180 (36%) had adverse events, 70 (14%) had progressive disease, and 51 (10%) requested to stop treatment. Median duration of vismodegib exposure was 36·4 weeks (IQR 17·7–62·0). Adverse events happened in 491 (98%) patients; the most common were muscle spasms (317 64%), alopecia (307 62%), dysgeusia (269 54%), weight loss (162 33%), asthenia (141 28%), decreased appetite (126 25%), ageusia (112 22%), diarrhoea (83 17%), nausea (80 16%), and fatigue (80 16%). Most adverse events were grade 1 or 2. We recorded serious adverse events in 108 (22%) of 499 patients. Of the 31 patients who died, 21 were the result of adverse events. As assessed by investigators, 302 (66·7%, 62·1–71·0) of 453 patients with locally advanced basal cell carcinoma had an overall response (153 complete responses and 149 partial responses); 11 (37·9%; 20·7–57·7) of 29 patients with metastatic basal cell carcinoma had an overall response (two complete responses, nine partial responses). Interpretation This study assessed the use of vismodegib in a setting representative of routine clinical practice for patients with advanced basal cell carcinoma. Our results show that treatment with vismodegib adds a novel therapeutic modality from which patients with advanced basal cell carcinoma can benefit substantially. Funding F Hoffmann-La Roche.
Summary Background Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF ...Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article. Methods We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov , number NCT01584648. Findings Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2–not reached) in the dabrafenib and trametinib group versus 18·7 months (15·2–23·7) in the dabrafenib only group (hazard ratio HR 0·71, 95% CI 0·55–0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0–13·9) in the dabrafenib and trametinib group and 8·8 months (5·9–9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53–0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group. Interpretation The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing. Funding GlaxoSmithKline.
Summary Background Vismodegib, a first-in-class Hedgehog-pathway inhibitor, is approved for use in adults with advanced basal-cell carcinoma. Patients with multiple basal-cell carcinomas, including ...those with basal-cell nevus (Gorlin) syndrome, need extended treatment. We assessed the safety and activity of two long-term intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas. Methods In this randomised, regimen-controlled, double-blind, phase 2 trial, we enrolled adult patients with multiple basal-cell carcinomas, including those with basal-cell nevus syndrome, who had one or more histopathologically confirmed and at least six clinically evident basal-cell carcinomas. From a centralised randomisation schedule accessed via an interactive voice or web-based response system, patients were randomly assigned (1:1) to treatment group A (150 mg oral vismodegib per day for 12 weeks, then three rounds of 8 weeks of placebo daily followed by 12 weeks of 150 mg vismodegib daily) or treatment group B (150 mg oral vismodegib per day for 24 weeks, then three rounds of 8 weeks of placebo daily followed by 8 weeks of 150 mg vismodegib daily). Treatment assignment was stratified by diagnosis of basal-cell nevus syndrome, geographical region, and immunosuppression status. The primary endpoint was percentage reduction from baseline in the number of clinically evident basal-cell carcinomas at week 73. The primary analysis was by intention to treat. The safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , number NCT01815840 , and the study is ongoing. Findings Between April 30, 2013, and April 9, 2014, 229 patients were randomly assigned treatment, 116 in treatment group A and 113 in treatment group B. The mean number of basal-cell carcinoma lesions at week 73 was reduced from baseline by 62·7% (95% CI 53·0–72·3) in treatment group A and 54·0% (43·6–64·4) in treatment group B. 216 (95%) of 227 patients included in the safety analysis had at least one treatment-emergent adverse event deemed to be related to study treatment (107 94% of 114 in treatment group A and 109 97% of 113 in treatment group B). The most common grade 3 or worse treatment-related adverse events were muscle spasms (four 4% patients in treatment group A vs 12 11% in treatment group B), increased blood creatine phosphokinase (one 1% vs four 4%), and hypophosphataemia (zero vs three 3%). Serious treatment-emergent events were noted in 22 (19%) patients in treatment group A and 19 (17%) patients in treatment group B. Four (2%) patients died from adverse events; one (pulmonary embolism in treatment group A) was possibly related to treatment. Interpretation Both intermittent dosing schedules of vismodegib seemed to show good activity in long-term regimens in patients with multiple basal-cell carcinomas. Further study is warranted. Funding F Hoffmann-La Roche.
Summary Background Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a manageable safety profile in studies of phase 1 and 2 in patients with BRAFV600 -mutated metastatic melanoma. ...We studied the efficacy of dabrafenib in patients with BRAFV600E -mutated metastatic melanoma. Methods We enrolled patients in this open-label phase 3 trial between Dec 23, 2010, and Sept 1, 2011. This report is based on a data cutoff date of Dec 19, 2011. Patients aged 18 years or older with previously untreated, stage IV or unresectable stage III BRAFV600E mutation-positive melanoma were randomly assigned (3:1) to receive dabrafenib (150 mg twice daily, orally) or dacarbazine (1000 mg/m2 intravenously every 3 weeks). Patients were stratified according to American Joint Committee on Cancer stage (unresectable III+IVM1a+IVM1b vs IVM1c). The primary endpoint was investigator-assessed progression-free survival and was analysed by intention to treat; safety was assessed per protocol. This study is registered with ClinicalTrials.gov , number NCT01227889. Findings Of the 733 patients screened, 250 were randomly assigned to receive either dabrafenib (187 patients) or dacarbazine (63 patients). Median progression-free survival was 5·1 months for dabrafenib and 2·7 months for dacarbazine, with a hazard ratio (HR) of 0·30 (95% CI 0·18–0·51; p<0·0001). At data cutoff, 107 (57%) patients in the dabrafenib group and 14 (22%) in the dacarbazine group remained on randomised treatment. Treatment-related adverse events (grade 2 or higher) occurred in 100 (53%) of the 187 patients who received dabrafenib and in 26 (44%) of the 59 patients who received dacarbazine. The most common adverse events with dabrafenib were skin-related toxic effects, fever, fatigue, arthralgia, and headache. The most common adverse events with dacarbazine were nausea, vomiting, neutropenia, fatigue, and asthenia. Grade 3–4 adverse events were uncommon in both groups. Interpretation Dabrafenib significantly improved progression-free survival compared with dacarbazine. Funding GlaxoSmithKline.
Summary Background A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3–4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg ...in patients with advanced melanoma. We report a phase 3 trial comparing the benefit–risk profile of ipilimumab 10 mg/kg versus 3 mg/kg. Methods This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov , number NCT01515189. Findings Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6–42·3) for the ipilimumab 10 mg/kg group and 11·2 months (4·9–29·4) for the ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6–17·8) for ipilimumab 10 mg/kg compared with 11·5 months (9·9–13·3) for ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70–0·99; p=0·04). The most common grade 3–4 treatment-related adverse events were diarrhoea (37 10% of 364 patients in the 10 mg/kg group vs 21 6% of 362 patients in the 3 mg/kg group), colitis (19 5% vs nine 2%), increased alanine aminotransferase (12 3% vs two 1%), and hypophysitis (ten 3% vs seven 2%). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (<1%) patients died from treatment-related adverse events. Interpretation In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment. Funding Bristol-Myers Squibb.
Summary Background Ipilimumab is a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 and has shown promising activity in advanced melanoma. We aimed to ascertain the antitumour ...efficacy of ipilimumab in patients with advanced melanoma. Methods We undertook a randomised, double-blind, phase 2 trial in 66 centres from 12 countries. 217 patients with previously treated stage III (unresectable) or stage IV melanoma were randomly assigned a fixed dose of ipilimumab of either 10 mg/kg (n=73), 3 mg/kg (n=72), or 0·3 mg/kg (n=72) every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. Randomisation was done with a permuted block procedure, stratified on the basis of type of previous treatment. The primary endpoint was best overall response rate (the proportion of patients with a complete or partial response, according to modified WHO criteria). Efficacy analyses were done by intention to treat, whereas safety analyses included patients who received at least one dose of ipilimumab. This study is registered with ClinicalTrials.gov , number NCT00289640. Findings The best overall response rate was 11·1% (95% CI 4·9–20·7) for 10 mg/kg, 4·2% (0·9–11·7) for 3 mg/kg, and 0% (0·0–4·9) for 0·3 mg/kg (p=0·0015; trend test). Immune-related adverse events of any grade arose in 50 of 71, 46 of 71, and 19 of 72 patients at doses of 10 mg/kg, 3 mg/kg, and 0·3 mg/kg, respectively; the most common grade 3–4 adverse events were gastrointestinal immune-related events (11 in the 10 mg/kg group, two in the 3 mg/kg group, none in the 0·3 mg/kg group) and diarrhoea (ten in the 10 mg/kg group, one in the 3 mg/kg group, none in the 0·3 mg/kg group). Interpretation Ipilimumab elicited a dose-dependent effect on efficacy and safety measures in pretreated patients with advanced melanoma, lending support to further studies at a dose of 10 mg/kg. Funding Bristol-Myers Squibb.
