David R. Minor

Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma

BACKGROUND In a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response, including complete responses, among patients with advanced melanoma. METHODS In this double-blind study involving 142 patients with metastatic melanoma who had not previously received treatment, we randomly assigned patients in a 2:1 ratio to receive ipilimumab (3 mg per kilogram of body weight) combined with either nivolumab (1 mg per kilogram) or placebo once every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) or placebo every 2 weeks until the occurrence of disease progression or unacceptable toxic effects. The primary end point was the rate of investigator-assessed, confirmed objective response among patients with BRAF V600 wild-type tumors. RESULTS Among patients with BRAF wild-type tumors, the rate of confirmed objective response was 61% (44 of 72 patients) in the group that received both ipilimumab and nivolumab (combination group) versus 11% (4 of 37 patients) in the group that received ipilimumab and placebo (ipilimumab-monotherapy group) (P<0.001), with complete responses reported in 16 patients (22%) in the combination group and no patients in the ipilimumab-monotherapy group. The median duration of response was not reached in either group. The median progression-free survival was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy (hazard ratio associated with combination therapy as compared with ipilimumab monotherapy for disease progression or death, 0.40; 95% confidence interval, 0.23 to 0.68; P<0.001). Similar results for response rate and progression-free survival were observed in 33 patients with BRAF mutation-positive tumors. Drug-related adverse events of grade 3 or 4 were reported in 54% of the patients who received the combination therapy as compared with 24% of the patients who received ipilimumab monotherapy. Select adverse events with potential immunologic causes were consistent with those in a phase 1 study, and most of these events resolved with immune-modulating medication. CONCLUSIONS The objective-response rate and the progression-free survival among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipilimumab monotherapy. Combination therapy had an acceptable safety profile. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01927419.).

Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial

BACKGROUND Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigators choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma. METHODS In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries. Eligible patients were 18 years or older, had unresectable or metastatic melanoma, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAF(V 600) mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m(2) every 3 weeks or paclitaxel 175 mg/m(2) combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used permuted blocks (block size of six) within each stratum. Primary endpoints were the proportion of patients who had an objective response and overall survival. Treatment was given open-label, but those doing tumour assessments were masked to treatment assignment. We assessed objective responses per-protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. The trial is closed and this is the first interim analysis, reporting the objective response primary endpoint. This study is registered with ClinicalTrials.gov, number NCT01721746. FINDINGS Between Dec 21, 2012, and Jan 10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab and 133 to ICC. Confirmed objective responses were reported in 38 (31·7%, 95% CI 23·5-40·8) of the first 120 patients in the nivolumab group versus five (10·6%, 3·5-23·1) of 47 patients in the ICC group. Grade 3-4 adverse events related to nivolumab included increased lipase (three [1%] of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two [1%] each); for ICC, these included neutropenia (14 [14%] of 102), thrombocytopenia (six [6%]), and anaemia (five [5%]). We noted grade 3-4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths occurred. INTERPRETATION Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need. FUNDING Bristol-Myers Squibb.

A Randomized, Double-Blind, Placebo-Controlled, Phase II Study Comparing the Tolerability and Efficacy of Ipilimumab Administered with or without Prophylactic Budesonide in Patients with Unresectable Stage III or IV Melanoma

Purpose: Diarrhea (with or without colitis) is an immune-related adverse event (irAE) associated with ipilimumab. A randomized, double-blind, placebo-controlled, multicenter, multinational phase II trial was conducted to determine whether prophylactic budesonide (Entocort EC), a nonabsorbed oral steroid, reduced the rate of grade ≥2 diarrhea in ipilimumab-treated patients with advanced melanoma. Experimental Design: Previously treated and treatment-naïve patients (N = 115) with unresectable stage III or IV melanoma received open-label ipilimumab (10 mg/kg every 3 weeks for four doses) with daily blinded budesonide (group A) or placebo (group B) through week 16. The first scheduled tumor evaluation was at week 12; eligible patients received maintenance treatment starting at week 24. Diarrhea was assessed using Common Terminology Criteria for Adverse Events (CTCAE) 3.0. Patients kept a diary describing their bowel habits. Results: Budesonide did not affect the rate of grade ≥2 diarrhea, which occurred in 32.7% and 35.0% of patients in groups A and B, respectively. There were no bowel perforations or treatment-related deaths. Best overall response rates were 12.1% in group A and 15.8% in group B, with a median overall survival of 17.7 and 19.3 months, respectively. Within each group, the disease control rate was higher in patients with grade 3 to 4 irAEs than in patients with grade 0 to 2 irAEs, although many patients with grade 1 to 2 irAEs experienced clinical benefit. Novel patterns of response to ipilimumab were observed. Conclusions: Ipilimumab shows activity in advanced melanoma, with encouraging survival and manageable adverse events. Budesonide should not be used prophylactically for grade ≥2 diarrhea associated with ipilimumab therapy. (Clin Cancer Res 2009;15(17):5591–8)

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial

BACKGROUND Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma. METHODS In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAFV600 wild-type melanoma achieving an investigator-assessed objective response. Overall survival was an exploratory endpoint and is reported in this Article. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all treated patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01927419, and is ongoing but no longer enrolling patients. FINDINGS Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24·5 months (IQR 9·1-25·7), 2-year overall survival was 63·8% (95% CI 53·3-72·6) for those assigned to nivolumab plus ipilimumab and 53·6% (95% CI 38·1-66·8) for those assigned to ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0·74, 95% CI 0·43-1·26; p=0·26). Treatment-related grade 3-4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received ipilimumab alone. The most common treatment-related grade 3-4 adverse events were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten [11%]) in the combination group and diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]) in the ipilimumab alone group. Serious grade 3-4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus ipilimumab (including colitis in ten [11%] of 94 patients, and diarrhoea in five [5%]) compared with four (9%) of 46 patients who received ipilimumab alone (including diarrhoea in two [4%] of 46 patients, colitis in one [2%], and hypophysitis in one [2%]). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis. INTERPRETATION Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients. FUNDING Bristol-Myers Squibb.

Phase II Trial (BREAK-2) of the BRAF Inhibitor Dabrafenib (GSK2118436) in Patients With Metastatic Melanoma

PURPOSE Dabrafenib (GSK2118436) is a potent inhibitor of mutated BRAF kinase. Our multicenter, single-arm, phase II study assessed the safety and clinical activity of dabrafenib in BRAF(V600E/K) mutation-positive metastatic melanoma (mut(+) MM). PATIENTS AND METHODS Histologically confirmed patients with stage IV BRAF(V600E/K) mut(+) MM received oral dabrafenib 150 mg twice daily until disease progression, death, or unacceptable adverse events (AEs). The primary end point was investigator-assessed overall response rate in BRAF(V600E) mut(+) MM patients. Secondary end points included progression-free survival (PFS) and overall survival (OS). Exploratory objectives included the comparison of BRAF mutation status between tumor-specific circulating cell-free DNA (cfDNA) and tumor tissue, and the evaluation of cfDNA as a predictor of clinical outcome. RESULTS Seventy-six patients with BRAF(V600E) and 16 patients with BRAF(V600K) mut(+) MM were enrolled onto the study. In the BRAF(V600E) group, 45 patients (59%) had a confirmed response (95% CI, 48.2 to 70.3), including five patients (7%) with complete responses. Two patients (13%) with BRAF(V600K) mut(+) MM had a confirmed partial response (95% CI, 0 to 28.7). In the BRAF(V600E) and BRAF(V600K) groups, median PFS was 6.3 months and 4.5 months, and median OS was 13.1 months and 12.9 months, respectively. The most common AEs were arthralgia (33%), hyperkeratosis (27%), and pyrexia (24%). Overall, 25 patients (27%) experienced a serious AE and nine patients (10%) had squamous cell carcinoma. Baseline cfDNA levels predicted response rate and PFS in BRAF(V600E) mut(+) MM patients. CONCLUSION Dabrafenib was well tolerated and clinically active in patients with BRAF(V600E/K) mut(+) MM. cfDNA may be a useful prognostic and response marker in future studies.

Talimogene Laherparepvec in Combination With Ipilimumab in Previously Untreated, Unresectable Stage IIIB-IV Melanoma

PURPOSE Combining immunotherapeutic agents with different mechanisms of action may enhance efficacy. We describe the safety and efficacy of talimogene laherparepvec (T-VEC; an oncolytic virus) in combination with ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 checkpoint inhibitor) in patients with advanced melanoma. METHODS In this open-label, multicenter, phase Ib trial of T-VEC in combination with ipilimumab, T-VEC was administered intratumorally in week 1 (10(6) plaque-forming units/mL), then in week 4 and every 2 weeks thereafter (10(8) plaque-forming units/mL). Ipilimumab (3 mg/kg) was administered intravenously every 3 weeks for four infusions, beginning in week 6. The primary end point was incidence of dose-limiting toxicities. Secondary end points were objective response rate by immune-related response criteria and safety. RESULTS Median duration of treatment with T-VEC was 13.3 weeks (range, 2.0 to 95.4 weeks). Median follow-up time for survival analysis was 20.0 months (1.0 to 25.4 months). Nineteen patients were included in the safety analysis. No dose-limiting toxicities occurred, and no new safety signals were detected. Grade 3/4 treatment-related adverse events (AEs) were seen in 26.3% of patients; 15.8% had AEs attributed to T-VEC, and 21.1% had AEs attributed to ipilimumab. The objective response rate was 50%, and 44% of patients had a durable response lasting ≥ 6 months. Eighteen-month progression-free survival was 50%; 18-month overall survival was 67%. CONCLUSION T-VEC with ipilimumab had a tolerable safety profile, and the combination appeared to have greater efficacy than either T-VEC or ipilimumab monotherapy.

Sunitinib Therapy for Melanoma Patients with KIT Mutations

Purpose: Recent studies have shown activating KIT mutations in melanoma originating from mucosa, acral, or cumulative sun-damaged skin sites. We aimed to assess the predictive role of KIT mutation, amplification, or overexpression for response to treatment with the kinase inhibitor sunitinib. Experimental Design: Tumor tissues from 90 patients with stage III or IV acral, mucosal, or cumulative sun-damaged skin melanoma underwent sequencing of KIT, BRAF, NRAS, and GNAQ genes, FISH analysis for KIT amplification, and immunohistochemistry of KIT protein (CD117). Patients with mutations, amplifications, or overexpression of KIT were treated with sunitinib and responses measured by Response Evaluation Criteria in Solid Tumors (RECIST). Results: Eleven percent of the melanomas tested had mutations in KIT, 23% in BRAF, 14% in NRAS, and none in GNAQ. Of 12 patients treated with sunitinib, 10 were evaluable. Of the 4 evaluable patients with KIT mutations, 1 had a complete remission for 15 months and 2 had partial responses (1- and 7-month duration). In contrast, only 1 of the 6 patients with only KIT amplification or overexpression alone had a partial response. In 1 responder with rectal melanoma who later progressed, the recurring tumor had a previously undetected mutation in NRAS, which was found in addition to the persisting mutation in KIT. Interestingly, among patients with manifest stage IV disease, KIT mutations were associated with a significantly shortened survival time (P < 0.0001). Conclusions: Sunitinib may have activity in patients with melanoma and KIT mutations; more study is needed. KIT mutations may represent an adverse prognostic factor in metastatic melanoma. Clin Cancer Res; 18(5); 1457–63. ©2012 AACR.

Safety and clinical activity of ipilimumab in melanoma patients with brain metastases: retrospective analysis of data from a phase 2 trial.

Melanoma has a high propensity to metastasize to the brain, and this is often responsible for treatment failure in patients with advanced disease. Melanoma patients with brain metastases are usually excluded from clinical trials because of their expected survival of approximately 5 months. A growing body of evidence suggests that ipilimumab, a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has activity against melanoma brain metastases. We conducted a retrospective analysis of data from a phase II study of ipilimumab in advanced melanoma patients. Twelve of 115 patients randomized in the parent trial had stable brain metastases at baseline, as identified by an Independent Review Committee, and were evaluated for efficacy. Two of the 12 patients achieved a partial response and three had stable disease. Both patients with a partial response and one with stable disease were alive at the last follow-up, with survival time of more than 4 years. The median overall survival of the 12 patients was 14 months (range: 2.7–56.4+). An additional four patients with stable brain metastases at baseline were identified by a secondary Independent Review Committee reviewer, and were evaluated for safety. Central nervous system-related adverse events of grade 3–4, specifically cerebral edema and convulsion/seizure, occurred in two of 16 patients. Although the present study is limited by the fact that it is a retrospective analysis of a small number of patients, the results provide further evidence for the safety and efficacy of ipilimumab in melanoma patients with stable brain metastases.

Releasing the Brake on the Immune System: Ipilimumab in Melanoma and Other Tumors

Advanced melanoma has proven difficult to treat for many years, and no previous agent has shown improved survival in a phase 3 trial. The deepening understanding of tumor immunobiology and the complexity of the interactions between host T cells and cancer have led to novel treatment approaches. Among these, ipilimumab is a first-in-class T-cell potentiator that works by blocking cytotoxic T-lymphocyte antigen-4, a critical negative regulator of the antitumor T-cell response. From phase 1 studies, ipilimumab has shown encouraging activity in melanoma and other cancers, with unusual response patterns and mechanism-related, predictable toxicities that are medically manageable and mostly reversible but can sometimes be life threatening unless recognized and treated early. Early indications of a survival benefit in phase 2 studies have been confirmed recently in the first randomized phase 3 trial; the primary endpoint of the trial, overall survival (OS), was met with ipilimumab significantly prolonging median OS both as a single agent (10.1 months; p = 0.003) and combined with gp100 vaccine (10.0 months; p < 0.001) compared with vaccine control (6.4 months). Even more noteworthy was the improvement in long-term survival at 24 months from 13.7% (gp100 alone) to 21.6% and 23.5% for the combination and single ipilimumab, respectively. The addition of gp100 vaccine did not appear to impact OS since data for ipilimumab alone were similar to those for the combination with vaccine. Re-induction with ipilimumab in selected patients who progressed gave further clinical benefits. Ipilimumab has also shown promising activity in melanoma patients with brain metastases, and patients with non-small cell lung cancer, renal cell cancer, and castrate-resistant prostate cancer. Ipilimumab not only has a novel mechanism of action but demonstrates unique immune-related toxicities that require particular care in their recognition and treatment.

Infliximab in the Treatment of Anti-CTLA4 Antibody (Ipilimumab) Induced Immune-Related Colitis

The anti-CTLA4 antibody, ipilimumab, has shown clinical activity against melanoma. Diarrhea due to immune-related colitis is the most frequent serious toxicity and, if untreated, may lead to intestinal perforation. Diarrhea treatment guidelines were developed based on clinical experience in over 2000 patients treated with ipilimumab, and these safety guidelines recommend systemic steroids as the first choice for the treatment of severe diarrhea. In this article, we present an alternative approach to the control of immune-related colitis by using the antitumor necrosis factor antibody, infliximab. Patients with metastatic melanoma received ipilimumab 10 mg/kg every 3 weeks for 4 doses, then every 3 months. Those who developed grade 2 diarrhea were treated with infliximab 5 mg/kg weeks 0 and 2 with mesalamine and loperamide. Steroids were given only for refractory cases requiring hospitalization. Of the first 3 cases of ipilimumab-induced diarrhea, 2 proved refractory and required hospitalization, but 1 recovered quickly without systemic steroids. We then added hydrocortisone enemas daily to the above regimen, and the next 3 patients recovered from grade 2 ipilimumab-induced colitis without difficulty. Treatment with infliximab, mesalamine, and hydrocortisone enemas may produce a rapid improvement in ipilimumab-induced colitis and avoid the administration of systemic steroids.