The combination of ipilimumab (Yervoy) and nivolumab (Opdivo) showed a 42% improvement in overall survival compared with ipilimumab monotherapy for patients with advanced melanoma in a 2-year assessment of the phase II CheckMate-069 trial.
Michael A. Postow, MD
The combination of ipilimumab (Yervoy) and nivolumab (Opdivo) showed a 42% improvement in overall survival (OS) compared with ipilimumab monotherapy for patients with advanced melanoma in a 2-year assessment of the phase II CheckMate-069 trial, announced Michael Postow, MD, at the 2016 AACR Annual Meeting.1
The results extend the enthusiasm for combination immunotherapy owing to complementary and non-redundant mechanisms of action between anti-CTLA-4 ipilimumab and anti-PD-1 therapy nivolumab, said Postow, Melanoma-Sarcoma Oncology Service, Memorial Sloan Kettering Cancer Center.
The 2-year OS rate with the combination was 69% compared with 53% for ipilimumab alone, for patients with BRAF wild-type melanoma. The median OS among patients was not been reached with the combination regimen and was 24.8 months with ipilimumab monotherapy (HR, 0.58, 95% CI, 0.31-1.08).
In the overall study population, the 2-year OS rate was 64% with the combination compared with 54% for ipilimumab alone (HR, 0.74; 95% CI, 0.43-1.26). The median OS at 2 years in patients randomized to either the combination or monotherapy has not been reached.
Findings from the CheckMate-069 study add to results from the phase III CheckMate-067 study, which showed improvements in progression-free survival (PFS) and objective response rates (ORR). The FDA granted an accelerated approval to the combination for BRAF wild-type tumors in October 2015 and for those with BRAF mutations in January 2016.
In the phase II study, treatment-naïve patients (n =142) with unresectable stage III or metastatic stage IV melanoma were randomized in a 2:1 ratio to either 3 mg/kg of ipilimumab in combination with 1 mg/kg of nivolumab (n = 95) or placebo (n = 47) once every 3 weeks for 4 doses. This was followed by nivolumab at the same dose or placebo every 2 weeks until disease progression or unacceptable toxicity.
Randomization was stratified by BRAF status, with the primary endpoint being ORR among patients with BRAF wild type tumors. OS was an exploratory endpoint and was intended to be descriptive. The current analysis reflects an OS analysis from a database lock occurring in February 2016, representing a minimum follow-up of 2 years.
Eighty-one percent of patients in the combination arm and 89% in the ipilimumab monotherapy arm had American Joint Committee on Cancer stage IV disease, and about half the patients in each arm had M1c melanoma. Lactate dehydrogenase (LDH) levels were above the upper limit of normal in about 25% in each arm. PD-L1 expression was ≥5% in about one fourth in each arm, and 21% to 24% were BRAF V600 mutation-positive.
As reported previously, with 11 months of follow-up, the ORR in the BRAF wild-type group (the primary endpoint) was 61% in the combination arm compared with 11% in the ipilimumab monotherapy arm.2 The results were similar among all randomized patients, which included patients with BRAF-mutant melanoma.
With 2-year follow-up, among all patients randomized to combination treatment, the median tumor burden by RECIST v1.1 decreased by 70%, whereas the median tumor burden among all patients randomized to ipilimumab increased by a median of 5%. The median duration of response was not reached in either arm. Eighty percent of responses to the combination (45 of 56) and ipilimumab monotherapy (4 of 5) were ongoing at the 2-year follow-up.
“The majority of these responses happened early, at the time of the first scan,” said Postow. “The median time to response was 2.8 months in the combination arm and 2.7 months for ipilimumab alone.” Twenty-nine of 45 patients (64%) who discontinued combination treatment remain in response.
Median PFS at 2 years in the BRAF wild-type population was not reached in the combination arm and was 4.4 months in patients randomized to ipilimumab alone, for a hazard ratio of 0.35 in favor of the combination (P <.0001). “This reflects a statistically significant difference in the reduction of progression or death in favor of the combination over ipilimumab monotherapy,” he said.
The 2-year PFS rate with combination treatment in BRAF wild-type tumors was 54% compared with 11% with ipilimumab alone. Similar PFS rates were observed in the all-randomized population. The combination of ipilimumab and nivolumab resulted in a median PFS that still has not been reached at the 2-year follow-up. With ipilimumab monotherapy, the median PFS was 3 months. “This reflects a 64% reduction in the hazard of progression or death in this all-randomized patient population, which is very impressive and statistically significant [P <.0001],” Postow said.
Overall, 35% of patients in the combination arm and 70% in the monotherapy arm received any subsequent therapy. Altogether 64% of patients randomized to ipilimumab crossed over to receive any systemic therapy at the time of progression. Eighteen percent of patients in the combination group received subsequent anti-PD-1 therapy at progression, compared with 62% in the ipilimumab monotherapy arm. The median time to initiation of the subsequent therapy was not reached in the combination arm and was 6.1 months in the ipilimumab alone arm.
When assessing efficacy of combination immunotherapy by PD-L1 status, there was no difference in the ORR at the 1-month data cut, and no difference in PFS or OS at 2 years between patients who were defined as PD-L1-positive versus those defined as PD-L1-negative.
Treatment-related adverse events were consistent with the initial reports, with higher rates of gastrointestinal and hepatic adverse events of any grade with the combination compared with monotherapy.
Grade 3/4 treatment-related AEs occurred in 54% of patients treated with the combination regimen versus 20% with ipilimumab alone. AEs led to discontinuation in 37% of patients treated with the combination regimen compared with 9% for ipilimumab alone.
Further information on survival outcomes with nivolumab plus ipilimumab are expected from the larger randomized phase III CheckMate-067 trial, said Postow. Initial findings from this study were reported at the 2015 ASCO Annual Meeting.