This protocol has been superseded due to the availability of superior alternatives. The preferred regimen is ID 4013 Mesothelioma ipilimumab and nivolumab (flat dosing).
The evidence supporting this protocol is provided by a phase III multicentre international open-label randomised trial (CheckMate 743) involving 605 patients comparing nivolumab plus ipilimumab with pemetrexed plus cisplatin or carboplatin in patients with previously untreated unresectable malignant pleural mesothelioma.r
Between November 2016 and April 2018, 605 patients were randomised in a 1:1 ratio. 303 patients were randomised to nivolumab (3 mg/kg, every 2 weeks) plus ipilimumab (1 mg/kg, every 6 weeks) for up to two years. 302 patients were randomised to pemetrexed 500 mg/m2 plus either cisplatin 75 mg/m2 or carboplatin AUC 5, every 3 weeks for up to 6 cycles.r
The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), time to response, duration of response, disease control rate; and OS, PFS and ORR by PD-L1 expression. Exploratory end points included safety and tolerability.r
Efficacy
After a median follow up of 29.7 months, median OS was 18.1 months (95% CI 16.8 to 21.4) in the nivolumab plus ipilimumab arm versus 14.1 months (95% CI 12.4 to 16.2) in the chemotherapy arm (HR= 0.74, 96.6% CI 0.60 to 0.91; p=0.002).r The median OS in nivolumab plus ipilimumab group was reasonably consistent across subgroups, including by histology (non-epithelioid: 18.1 months, 95% CI 12.2 to 22.8 vs. epithelioid: 18.7 months, 95% CI 16.9 to 22.0) and tumour PD-L1 expression (tumours with PD-L1 expression of ≥ 1%: 18.0 months, 95% CI 16.8 to 21.5 vs. tumours with PD-L1 expression of < 1%: 17.3 months, 95% CI 10.1 to 24.3). However, nivolumab plus ipilimumab showed better efficacy compared to chemotherapy in non-epithelioid subtype (HR=0.46, 95% CI 0.31 to 0.68 vs. HR=0.86, 95% CI 0.69 to1.08 for epithelioid subtype) and tumours with PD-L1 expression of ≥ 1% (HR=0.69, 95% CI 0.55 to 0.87 vs. HR=0.94, 95% CI 0.62 to 1.40 in patients with expression < 1%), primarily due to inferior effect of chemotherapy in these subgroups.r
Kaplan-Meier curves for overall survival in all patients (A), patients with epithelioid (B) and non-epithelioid (C) tumour histologyr
© Lancet 2021
Summary of secondary endpoints analysisr
Secondary endpoint |
Nivolumab + ipilimumab |
Chemotherapy |
Median PFS (months, 95% CI) |
6.8 (5.6 to 7.4) |
7.2 (6.9 to 8.0) |
HR=1.00 (95% CI
0.82 to 1.21) |
ORR (%, 95% CI) |
40 (34.1 to 45.4) |
43 (37.1 to 48.5) |
Median time to response (months, IQR) |
2.7 (1.45 to 3.27) |
2.5 (1.41 to 3.02) |
Median duration of response (months, 95% CI) |
11 (8.1 to 16.5) |
6.7 (5.3 to 7.1) |
Disease control rate (%, 95% CI) |
77 (71.4 to 81.2) |
85 (80.6 to 88.9) |
Toxicity
Treatment-related adverse events were reported in 79% of patients receiving nivolumab plus ipilimumab and 82% of those receiving chemotherapy. Grade 3-4 toxicities were similar in both groups (30% in nivolumab plus ipilimumab, and 32% in chemotherapy group). The most common serious adverse event experienced with nivolumab plus ipilimumab regimen was colitis.r
Treatment discontinuation due to adverse events occurred in 23% of patients in the nivolumab plus ipilimumab group vs 16% in the chemotherapy group. There were 3 treatment-related deaths (1% of total deaths) in the nivolumab plus ipilimumab arm (pneumonitis, encephalitis, and heart failure) and 1 treatment-related death (<1% of total deaths) in the comparator arm (myelosuppression).r
Treatment-related adverse eventsr
© Lancet 2021