The efficacy of combining two immunotherapy agents will be assessed in a randomized, double-blind phase III study.
Jedd D. Wolchok, MD, PhD
The efficacy of combining two immunotherapy agents to treat advanced melanoma will be assessed in a randomized, double-blind phase III study that will measure the combination’s ability to prolong survival in patients with newly diagnosed metastatic disease.
The two agents, nivolumab and ipilimumab, are immune checkpoint inhibitors, monoclonal antibodies that target distinct pathways that tumor cells use to prevent the immune system from mobilizing against them. Although the drugs operate independently to stimulate the body’s defenses, results from an earlier trial suggest that their antitumor action is complementary, making them more effective when deployed together than as single agents. The current trial, CheckMate 067, is designed to test that hypothesis directly.
Nivolumab, an investigational compound, binds with the programmed death-1 (PD-1) receptor on activated T-cells, preventing them from interacting with tumor proteins that weaken the ability of T-cells to fight disease. Ipilimumab, approved by the FDA in 2011 to treat melanoma patients with advanced disease, adheres to another T-cell receptor, cytotoxic T-lymphocyte antigen-4 (CTLA-4), blocking it from binding with tumor proteins. PD-1 contributes to T-cell exhaustion in peripheral tissues, and CTLA-4 inhibits at earlier points in T-cell activation.1
“The goal is to induce a more robust immune response. The best case response is durable regression in a large number of patients,” said Jedd D. Wolchok, MD, PhD, associate director of the Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center in New York City, and the principal investigator for the trial.
In the phase III trial now under way, more than 900 patients with newly diagnosed metastatic disease and no prior systemic therapy will be divided among three arms. One group will take nivolumab plus ipilimumab, a second cohort will be given nivolumab alone, and a third group will receive ipilimumab alone. To maintain the blinded nature of the trial, all patients will come in 2 out of every 3 weeks to receive injections, Wolchok said.
The dosing combination of nivolumab at 1 mg per kilogram of body weight and ipilimumab at 3 mg per kilogram, established as safe and effective in a phase I trial,1has been carried over to the current study. Patients in the phase III trial will also receive nivolumab maintenance therapy after the combination therapy, receiving nivolumab alone every 2 weeks after 12 weeks for up to 2 years. “We combine the two agents upfront for activity and then proceed to maintenance,” Wolchok said.
The primary endpoint of the CheckMate 067 trial is overall survival (OS). Secondary outcome measures include progression-free survival (PFS) and objective response rate (ORR).
Results from the earlier dose-escalation trial were encouraging, Wolchok said. Although not formally compared in that study, concurrent treatment with nivolumab and ipilimumab was associated with ORRs that exceeded the previously reported results with either nivolumab or ipilimumab alone.1
CLINICALTRIALS.GOV IDENTIFIER: NCT01774721
Primary outcome measure:
OS, with data collected continuously while subjects are on study medication and every 3 months via in-person or phone contact after discontinuation of study medication
Secondary outcome measures:
PFS, with data collected on day 1 and week 12 and then every 6 weeks up to week 49, and then every 12 weeks; ORR, with data collected on day 1 and week 12 and every 6 weeks up to week 49, and then every 12 weeks until disease progression is documented; differences in OS, PFS, and ORR between the two experimental arms (time frame: OS: approximately up to 44.1 months); PFS and ORR: baseline (day 1), week 12, every 6 weeks thereafter up to week 49, and then every 12 weeks until disease progression is documented--approximately around 5 years; OS based on PD-L1 expression; mean changes from baseline in EORTC-QLQ-C30
Study start date:
Estimated study completion date:
Adults 18 years and older
SELECTED INCLUSION CRITERIA:
Histologically confirmed stage III (unresectable) or stage IV melanoma
Measurable disease determined by computed tomography (CT) or magnetic resonance imaging (MRI)
Tumor tissue from an unresectable or metastatic site of disease for biomarker analyses
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
No prior treatment with an anti-programmed death receptor-1 (PD-1), anti-programmed death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) antibody
No active brain metastases or leptomeningeal metastases
No ocular melanoma
No active, known, or suspected autoimmune disease
No conditions requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of treatment
Nivolumab 3 mg/kg solution intravenously every 2 weeks plus placebo matching with ipilimumab 0 mg/kg solution intravenously on weeks 1 and 4 and placebo matching with nivolumab on week 4 for cycles 1 and 2, until documented disease progression, discontinuation due to toxicity, withdrawal of consent, or the end of the study
Nivolumab 1 mg/kg solution intravenously combined with ipilimumab 3 mg/kg solution intravenously every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg solution intravenously every 2 weeks plus placebo matching with nivolumab on weeks 3 and 5 for cycles 1 and 2, until documented disease progression, discontinuation due to toxicity, withdrawal of consent, or the study ends
Ipilimumab 3 mg/kg solution intravenously every 3 weeks for a total of 4 doses plus placebo matching with nivolumab 0 mg/kg solution intravenously on weeks 3 and 5 for cycles 1 and 2, until documented disease progression, discontinuation due to toxicity, withdrawal of consent, or the study ends
Principal adverse events observed in the phase I study of nivolumab plus ipilimumab were fatigue, rash, itching, and diarrhea, and asymptomatic elevation of liver and pancreatic enzymes.
EORTC-QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30.
In the phase I study, patients in one multicohort arm took the drugs concurrently, receiving intravenous doses of nivolumab and ipilimumab every 3 weeks for four doses, followed by nivolumab alone every 3 weeks for four doses (concurrent regimen). The combined treatment was subsequently administered every 12 weeks for up to eight doses. A second arm followed a sequenced regimen in which patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses.
Patients in the concurrent arm who received the maximum dosages deemed acceptable (nivolumab 1 mg/kg and ipilimumab 3 mg/kg) had the greatest response and had tumor reductions that were swift, substantial, and durable.
“More than half of those patients exhibited tumor burden regression of greater than 80% by their first set of radiological scans at 12 weeks. This represents a speed and depth of response we hadn’t seen yet with immunotherapy drugs,” said Wolchok.
Responses were ongoing in about 90% of patients who responded to the combination therapy, with the duration ranging from 6.1 to 72.1 weeks at the time of data analysis in February 2013, according to published results. Median OS had not been reached after approximately 13 months of follow-up in the concurrent arm. The estimated 1-year survival rate across all concurrent cohorts with various dosing levels was 82% (95% CI, 69.0- 94.4).2
Grade 3 or 4 adverse events (AEs) related to therapy occurred in 53% of patients in the concurrent- regimen group. AEs were similar to previous experience with monotherapy and were generally reversible. Treatment-related AEs in this arm included rash (55%), pruritus (47%), fatigue (38%), and diarrhea (34%). The most common grade 3/4 treatment-related AEs were elevations in lipase (13%), aspartate aminotransferase (13%), and alanine aminotransferase (11%). In the sequencedregimen arm, treatment-related AEs occurred in 73% of patients; the most common were pruritus (18%) and lipase elevation (12%). The most common grade 3/4 AE in this group was lipase elevation (6%).1
In addition to the phase III CheckMate 067, the phase II CheckMate 064 trial is also recruiting participants. The trial will randomize patients with advanced or metastatic melanoma to a regimen of nivolumab sequentially with ipilimumab, and the primary endpoint is the incidence of treatmentrelated grade 3-5 AEs during the induction period (ClinicalTrials.gov Identifer NCT01783938).
Wolchok noted that prospects for patients with melanoma have improved measurably since he began practicing in 2000. He pointed to FDA approvals in 2011 for ipilimumab and vemurafenib, and to a number of new drugs in late-stage development. “We now have conventional tools and new agents in development, and we are accruing a body of knowledge about which pathways drive this cancer,” he said. “The challenge is that it’s a heterogeneous disease. Some people progress after a long time, while the process is much more rapid in others. In some cases, we’re not sure which mutations are driving the cancer; we’re learning in real time which take over when the disease becomes refractory.”
Wolchok sees immunotherapy as a promising direction for cancer treatment. “With immunotherapy we’re treating the patient, not the cancer. It’s a different mindset,” he said. “Responses with immunotherapy tend to be durable, keeping disease under control for longer periods of time.”
Ipilimumab and nivolumab are immune system modulators; both were developed by Bristol-Myers Squibb. “The immune system must defend the body, but not become overactivated so that it attacks itself. It has balances and checkpoints that we can press. PD-1 and CTLA-4 are checkpoints in that on/off system,” said Fouad Namouni, MD, global development lead for nivolumab. “With nivolumab and ipilimumab, we are trying to prevent the T-cell receptor ligands from access to that on/off button so that the immune system, turned off by cancer, can work again.”
Research in the area began with investigations of the CTLA-4 pathway and the mechanisms that cancer uses to stimulate the pathway, causing the T-lymphocytes to become exhausted and ineffective against the tumor, he said. Ipilimumab, which was designed to block that action, demonstrated survival benefits in two phase III studies in patients with advanced disease.
“This showed us for the first time that an immune system modulating agent could work,” Namouni said. The results prompted further research of the PD-1 pathway, another major brake on the T-cell, and the ligand PD-L1, which is expressed by tumors to transform the T-cell from active to exhausted.
Investigators say there is still much to learn from the phase III study. Wolchok noted that it was not clear from the earlier study, for example, why some patients responded and others didn’t, and research on potential biomarkers is ongoing.
Fouad Namouni, MD
“We looked at tumors with a high level of the ligand PD-L1 expressed on the tumor cells to see if that played a major role,” said Namouni. “We wondered whether tumors with high levels would be most likely to respond. The answer appears to be not necessarily.”
Of note, biomarkers relevant to each of the monotherapies (PD-L1 expression by tumor for nivolumab and absolute lymphocyte count for ipilimumab) may not be relevant for combination therapy.
Bristol-Myers Squibb is also exploring the use of immunotherapy in other tumor types. Based on data from a series of phase I trials, the company has accelerated its development program for nivolumab and now has seven potential registration trials in non-small cell lung cancer (NSCLC), advanced renal cell carcinoma, and advanced melanoma, including one in combination with ipilimumab. Phase I trials also are evaluating nivolumab in advanced hepatocellular carcinoma and hematologic malignancies. The company has begun exploratory work to better define what other tumor types may respond to nivolumab. Earlier this year, the FDA granted nivolumab Fast Track status for melanoma, lung cancer, and kidney cancer. Ipilimumab is being evaluated in phase III trials in NSCLC, smallcell lung cancer, and castration-resistant prostate cancer, and as adjuvant therapy in melanoma.