Bristol-Myers Squibb has announced the first overall survival results from CheckMate -069, a Phase II trial evaluating the investigational combination of nivolumab and ipilimumab vs. ipilimumab alone in patients with previously untreated advanced melanoma. The combination regimen demonstrated a two-year overall survival rate of 69% compared to 53% for ipilimumab alone (HR=0.58 [95% CI: 0.31-1.08]) in patients with BRAF wild-type advanced melanoma.1 In these patients that received the combination therapy, 22% achieved a complete response, compared to 0% of patients treated with ipilimumab alone.1 These data were presented at The American Association for Cancer Research (AACR) Annual Meeting 2016 in New Orleans as late-breaking abstract #CT002. Melanoma is the most dangerous form of skin cancer.2 In 2013 around 14,500 people were diagnosed in the UK and approximately 2,100 people died from the disease.3
"Both nivolumab and ipilimumab have changed survival expectations in advanced melanoma over the last few years and these latest data show us that combining these two immunotherapies is an effective two- pronged attack against the cancer," said Dr. James Larkin, Consultant Medical Oncologist, The Royal Marsden. "The overall survival rates observed using the regimen of nivolumab plus ipilimumab are very promising and provide further hope for patients and their families affected by this disease."
The safety profile from the CheckMate -069 trial demonstrated that the regimen was consistent with previously-reported studies evaluating nivolumab and ipilimumab. Grade 3-4 treatment-related adverse events were reported more frequently with the combination regimen (54%) than with ipilimumab alone (20%).
Nivolumab is the first in a new class of medicines, called PD-1 immune checkpoint inhibitors.4 It has an innovative mode of action that works by harnessing the ability of the immune system to fight cancer.4 Ipilimumab has a similar mode of action but acts on a different receptor, called CTLA-4.5 Combining the two medicines means blocking both receptors at the same time, which then potentially allows the immune system to recognise and destroy tumour cells.4,5
Jean Viallet, M.D., Global Clinical Research Lead, Oncology, Bristol-Myers Squibb, commented, "We are encouraged to see that the nivolumab and ipilimumab combination showed improvement in overall survival versus ipilimumab alone based on two-year follow-up from CheckMate -069, the registrational study of the combination regimen. These data further validate our scientific rationale for studying the combination of these Immuno-Oncology agents."
The regimen of nivolumab and ipilimumab remains investigational and is not yet licensed in the UK; as single agents, both are approved for use on the NHS in England and Wales to treat patients with advanced melanoma.6,7 Earlier this month, the Committee for Medicinal Products for Human Use (CHMP) recommended that the regimen be licensed for use in Europe and a formal decision from the European Commission is expected in the first half of 2016.
Patients in the CheckMate -069 study had been diagnosed with melanoma, which is the most dangerous form of skin cancer, and can be fatal if it has advanced to a stage where it cannot be surgically removed because it has spread to other parts of the body (known as unresectable or metastatic melanoma).2 While it is not the most common form of skin cancer, globally, melanoma causes more deaths than any other forms of the disease.2
About the CheckMate -069 study
CheckMate -069 is a Phase II, double-blind randomised study which evaluated the nivolumab and ipilimumab regimen in patients with previously-untreated (unresectable or metastatic) melanoma. The study included patients with both BRAF wild-type and BRAF mutation-positive melanoma. The primary endpoint was confirmed objective response rate (ORR) in patients with BRAF wild-type tumours. Secondary endpoints included progression-free survival (PFS) in patients with BRAF wild-type tumours, ORR in patient with BRAF V600 mutation-positive tumours, and safety. Overall survival (OS) was an exploratory endpoint.
The trial enrolled 142 patients who were randomised to receive either the nivolumab and ipilimumab regimen (n=95) or ipilimumab monotherapy (n=47). Patients in the nivolumab and ipilimumab regimen group received 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab every 3 weeks for 4 doses, followed by 3 mg/kg of nivolumab every 2 weeks until progression or unacceptable toxic effects. In the ipilimumab monotherapy group, patients were treated with the same dosing schedule plus matching placebo.
In the trial, the combination demonstrated a clinically meaningful improvement in survival at two years with an OS rate of 69% compared to 53% for ipilimumab alone in patients with BRAF wild-type advanced melanoma (HR=0.58 [95% CI: 0.31-1.08]), with a minimum follow-up of 24 months. Similar results were observed in the overall study population, with an OS rate of 64% at two years for the combination regimen compared to 54% for ipilimumab alone (HR=0.74 [95% CI: 0.43-1.26]). A change in tumour burden was seen with the combination regimen, with a median change of 70% compared to 5% for ipilimumab alone. In addition, the nivolumab and ipilimumab combination regimen demonstrated improved ORR in both BRAF wild-type and BRAF V600 mutation-positive advanced melanoma compared to ipilimumab alone at 11 months.
In patients with BRAF wild-type advanced melanoma, ORR in the combination regimen arm was 61% with 22% of patients achieving a complete response and 39% achieving a partial response, compared to 11% ORR in the ipilimumab monotherapy arm with 0% of patients achieving a complete response and 11% of patient receiving a partial response. In all randomised patients, ORR in the combination regimen arm was 59% with 22% of patients achieving a complete response and 37% of patients achieving a partial response, compared to 11% in the ipilimumab monotherapy arm with 0% of patients achieving a complete response and 11% of patients achieving a partial response.
 Median duration of response was not reached in both arms, with ongoing responses seen in 80% of responders. Progression-free survival was significantly longer with the combination regimen (n=72) compared to ipilimumab alone (n=37). At two-years, PFS was 54% with the nivolumab and ipilimumab combination regimen vs. 11% for ipilimumab alone. In patients with BRAF wild-type advanced melanoma, median PFS has not been reached (8.6-NR) compared to 4.4 months (2.8-5.3) for ipilimumab alone (HR=0.35 [95% CI: 0.21-0.59; p<0.0001]). In all randomised patients, median PFS has also not been reached (7.36-NR) in patients treated with the combination regimen vs. 3.0 months (2.7-5.1) for patients treated with ipilimumab alone, with a two-year PFS rate of 51% vs. 12%, respectively. Similar efficacy was seen regardless of PD-L1 expression at 5% across endpoints with the nivolumab and ipilimumab combination regimen.
The most common treatment-related select adverse events of any grade with the combination regimen versus ipilimumab alone included rash (43% vs. 30%), pruritus (40% vs. 33%), diarrhea (45% vs. 35%), colitis (18% vs. 7%), hypothyroidism (17% vs. 13%), hypophysitis (13% vs. 7%), increased ALT (26% vs. 9%), increased AST (28% vs. 9%), pneumonitis (10% vs. 2%), and increased creatinine (2% vs. 0%).