First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in advanced non-small cell lung cancer: a subanalysis of Asian patients in CheckMate 9LA.
CheckMate 9LA, a phase 3, randomized, open-label study in first-line advanced non-small cell lung cancer (NSCLC), showed significantly improved overall survival (OS) with nivolumab plus ipilimumab combined with 2 cycles of chemotherapy versus chemotherapy alone (4 cycles). We present results for the Asian subpopulation enrolled in Japan and China.
Patients aged ≥ 18 years with treatment-naive, histologically confirmed stage IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0-1 and no sensitizing EGFR/ALK mutations were randomized 1:1 to nivolumab [360 mg every 3 weeks (Q3W)] plus ipilimumab (1 mg/kg Q6W) combined with chemotherapy (Q3W for 2 cycles), or chemotherapy alone (Q3W for 4 cycles). Primary endpoint was OS; secondary endpoints included progression-free survival (PFS) and objective response rate (ORR).
Twenty-eight patients received nivolumab plus ipilimumab combined with chemotherapy and 30 received chemotherapy. At a minimum follow-up of 12.7 months, median OS was not reached with nivolumab plus ipilimumab combined with chemotherapy versus 13.3 months with chemotherapy [hazard ratio (HR) 0.33; 95% confidence interval (CI) 0.14-0.80]. Median PFS was 8.4 versus 5.4 months (HR 0.47; 95% CI 0.24-0.92) and ORR was 57% versus 23%, respectively. Grade 3-4 treatment-related adverse events were observed in 57% versus 60% of patients, respectively.
Consistent with results in the all randomized population, nivolumab plus ipilimumab combined with chemotherapy improved efficacy in the Asian subpopulation versus chemotherapy alone and had a manageable safety profile, supporting its use as first-line treatment for advanced NSCLC in Asian patients.
John T
，Sakai H
，Ikeda S
，Cheng Y
，Kasahara K
，Sato Y
，Nakahara Y
，Takeda M
，Kaneda H
，Zhang H
，Maemondo M
，Minato K
，Hisada T
，Misumi Y
，Satouchi M
，Hotta K
，Li A
，Oukessou A
，Lu S
... -
《-》
First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update.
To further characterize survival benefit with first-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone, we report updated data from the phase III CheckMate 9LA trial with a 2-year minimum follow-up.
Adult patients were treatment naïve, with stage IV/recurrent non-small-cell lung cancer, no known sensitizing EGFR/ALK alterations, and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with two cycles of chemotherapy, or four cycles of chemotherapy. Updated efficacy and safety outcomes are reported, along with progression-free survival (PFS) after next line of treatment (PFS2), treatment-related adverse events (TRAEs) by treatment cycle, and efficacy outcomes in patients who discontinued all treatment components in the experimental arm due to TRAEs.
With a median follow-up of 30.7 months, nivolumab plus ipilimumab with chemotherapy continued to prolong overall survival (OS) versus chemotherapy. Median OS was 15.8 versus 11.0 months [hazard ratio 0.72 (95% confidence interval 0.61-0.86)]; 2-year OS rate was 38% versus 26%. Two-year PFS rate was 20% versus 8%. ORR was 38% versus 25%, respectively; 34% versus 12% of all responses were ongoing at 2 years. Median PFS2 was 13.9 versus 8.7 months. Improved efficacy outcomes in the experimental versus control arm were observed across most subgroups, including by programmed death-ligand 1 and histology. No new safety signals were observed; onset of grade 3/4 TRAEs was mostly observed during the first two treatment cycles in the experimental arm. In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy treatment due to TRAEs (n = 61) median OS was 27.5 months; 56% of responders had an ongoing response ≥1 year after discontinuation.
With a 2-year minimum follow-up, nivolumab plus ipilimumab with two cycles of chemotherapy provided durable efficacy benefits over chemotherapy with a manageable safety profile and remains an efficacious first-line treatment of advanced non-small-cell lung cancer.
Reck M
，Ciuleanu TE
，Cobo M
，Schenker M
，Zurawski B
，Menezes J
，Richardet E
，Bennouna J
，Felip E
，Juan-Vidal O
，Alexandru A
，Sakai H
，Lingua A
，Reyes F
，Souquet PJ
，De Marchi P
，Martin C
，Pérol M
，Scherpereel A
，Lu S
，Paz-Ares L
，Carbone DP
，Memaj A
，Marimuthu S
，Zhang X
，Tran P
，John T
... -
《ESMO Open》
First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial.
First-line nivolumab plus ipilimumab has shown improved overall survival in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to investigate whether the addition of a limited course (two cycles) of chemotherapy to this combination would further enhance the clinical benefit.
This randomised, open-label, phase 3 trial was done at 103 hospitals in 19 countries. Eligible patients were aged 18 years or older with treatment-naive, histologically confirmed stage IV or recurrent NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) by an interactive web response system via permuted blocks (block size of four) to nivolumab (360 mg intravenously every 3 weeks) plus ipilimumab (1 mg/kg intravenously every 6 weeks) combined with histology-based, platinum doublet chemotherapy (intravenously every 3 weeks for two cycles; experimental group), or chemotherapy alone (every 3 weeks for four cycles; control group). Randomisation was stratified by tumour histology, sex, and PD-L1 expression. The primary endpoint was overall survival in all randomly assigned patients. Safety was analysed in all treated patients. Results reported here are from a pre-planned interim analysis (when the study met its primary endpoint) and an exploratory longer-term follow-up analysis. This study is active but no longer recruiting patients, and is registered with ClinicalTrials.gov, number NCT03215706.
Between Aug 24, 2017, and Jan 30, 2019, 1150 patients were enrolled and 719 (62·5%) randomly assigned to nivolumab plus ipilimumab with two cycles of chemotherapy (n=361 [50%]) or four cycles of chemotherapy alone (n=358 [50%]). At the pre-planned interim analysis (median follow-up 9·7 months [IQR 6·4-12·8]), overall survival in all randomly assigned patients was significantly longer in the experimental group than in the control group (median 14·1 months [95% CI 13·2-16·2] vs 10·7 months [9·5-12·4]; hazard ratio [HR] 0·69 [96·71% CI 0·55-0·87]; p=0·00065). With 3·5 months longer median follow-up (median 13·2 months [IQR 6·4-17·0]), median overall survival was 15·6 months (95% CI 13·9-20·0) in the experimental group versus 10·9 months (9·5-12·6) in the control group (HR 0·66 [95% CI 0·55-0·80]). The most common grade 3-4 treatment-related adverse events were neutropenia (in 24 [7%] patients in the experimental group vs 32 [9%] in the control group), anaemia (21 [6%] vs 50 [14%]), diarrhoea (14 [4%] vs two [1%]), increased lipase (22 [6%] vs three [1%]), and asthenia (tjree [1%] vs eight [2%]). Serious treatment-related adverse events of any grade occurred in 106 (30%) patients in the experimental group and 62 (18%) in the control group. Seven (2%) deaths in the experimental group (acute kidney failure, diarrhoea, hepatotoxicity, hepatitis, pneumonitis, sepsis with acute renal insufficiency, and thrombocytopenia; one patient each) and six (2%) deaths in the control group (anaemia, febrile neutropenia, pancytopenia, pulmonary sepsis, respiratory failure, and sepsis; one patient each) were treatment related.
Nivolumab plus ipilimumab with two cycles of chemotherapy provided a significant improvement in overall survival versus chemotherapy alone and had a favourable risk-benefit profile. These data support this regimen as a new first-line treatment option for patients with advanced NSCLC.
Bristol Myers Squibb.
Paz-Ares L
，Ciuleanu TE
，Cobo M
，Schenker M
，Zurawski B
，Menezes J
，Richardet E
，Bennouna J
，Felip E
，Juan-Vidal O
，Alexandru A
，Sakai H
，Lingua A
，Salman P
，Souquet PJ
，De Marchi P
，Martin C
，Pérol M
，Scherpereel A
，Lu S
，John T
，Carbone DP
，Meadows-Shropshire S
，Agrawal S
，Oukessou A
，Yan J
，Reck M
... -
《-》
First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients.
Nivolumab plus ipilimumab demonstrated clinically meaningful improvement in efficacy versus chemotherapy with a manageable safety profile in patients with advanced non-small cell lung cancer (NSCLC) and tumor programmed death-ligand 1 (PD-L1) expression ≥1% or <1% in Part 1 of CheckMate 227. Here we report efficacy and safety results for the Asian subpopulation.
Patients with stage IV/recurrent NSCLC were randomized 1 : 1 : 1 to nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy (PD-L1 ≥1%) or nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L1 <1%). Overall survival (OS), progression-free survival, objective response rate, duration of response, and safety were evaluated among patients in Japan, South Korea, and Taiwan.
In the Asian subpopulation with PD-L1 ≥1%, 81 patients received nivolumab plus ipilimumab and 81 received chemotherapy. Median OS was not reached with nivolumab plus ipilimumab versus 24.8 months with chemotherapy; 3-year OS rate was 53% versus 37% [hazard ratio (HR), 0.72; 95% confidence interval (CI) 0.47-1.11]. The 3-year progression-free survival rate was 26% versus 7% (HR, 0.65; 95% CI 0.45-0.96), objective response rate was 56% versus 37%, and median duration of response was 29.0 months (95% CI 15.0 months-not reached) versus 6.9 months (95% CI 3.9-11.1 months). Similar results were observed regardless of tumor PD-L1 expression and in Japanese patients. Grade 3-4 treatment-related adverse events occurred in 40% of patients receiving nivolumab plus ipilimumab and 36% receiving chemotherapy, in the overall Asian subpopulation (tumor PD-L1 expression ≥1% and <1%); no new safety signals were identified.
At 3-year follow-up, nivolumab plus ipilimumab provided durable long-term efficacy benefits versus chemotherapy regardless of tumor PD-L1 expression in the Asian subpopulation, including Japanese patients. Consistent with findings for all randomized patients, these data support the use of nivolumab plus ipilimumab as first-line treatment of Asian patients with advanced NSCLC.
O'Byrne KJ
，Lee KH
，Kim SW
，Park K
，Nishio M
，Sakai H
，Ohe Y
，Fukuhara T
，Kang JH
，Daga H
，Yu CJ
，Hotta K
，Tanaka H
，Takeda M
，Yokoyama T
，Nathan FE
，Lee JS
... -
《ESMO Open》
ResearchGate
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