Lancet Oncol 2021 Jan 18
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.
Abstract
Background
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.
Methods
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.
Findings
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.
Interpretation
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.
Funding
Bristol Myers Squibb.
Related Questions
Would you consider using IO alone for lung cancer patients with PD-L1 <1% but who have high TMB?
The brief answer here is a resounding no. A more extended version might include a statement that this would be a case of not seeing the forest for the trees.And the tree here is the FDA approval of pembrolizumab in a tissue-agnostic fashion for patients with advanced TMB >10 mutations/Mbase- likely ...
What are best practices for oncologists during the national platinum shortage?
In breast cancer, we are prioritizing patients with curable disease in which platinum agents are a critical part of the regimen or have actually shown a clear advantage (the only example of this is shown below in bold).Use an alternative to a carboplatin-based regimen whenever possible. If no altern...
How would you approach second line treatment for prostate adenocarcinoma with diffuse neuroendocrine features?
Men with NEPC (histologic evidence of small cell carcinoma) face a poor prognosis and are typically refractory to all hormonal interventions, and in fact transformed NEPC much more typically evolves after potent AR inhibition than present de novo at diagnosis. Autopsy series and biopsy series sugges...
How do you approach treatment sequencing in KRAS G12C NSCLC?
Sequencing is an excellent question that will require a little more time to be answered. There are currently multiple ongoing trials in this space but at the current moment, the approval of sotorasib is in the second line space and I would not use KRAS inhibitors as first line off study. That being ...
How would use of adjuvant atezolizumab for PDL1+ NSCLC potentially impact your treatment choice at recurrence?
Certainly pattern of relapse is important, and those with local or locoregional recurrences could be treated with definitive intent SBRT, surgery, or concurrent chemotherapy and radiation for mediastinal recurrence. For those with recurrent not amenable to local therapy, this is a challenging questi...
How do you decide between checkpoint monotherapy versus chemo-immunotherapy approach for patients with PD-L1 High (>50%) NSCLC?
At this point, there are no prospective trials comparing checkpoint monotherapy and chemo-immunotherapy for patients with PD-L1 high NSCLC. The ongoing prospective INSIGNA trial will answer this question. If one does a cross trial comparison of pembrolizumab for patients with PD-L1 of >50% and chemo...
Are you selecting any specific patient cohort with metastatic NSCLC for treatment with the CheckMate 9LA protocol of ipilimumab + nivolumab + 2 cycles of chemotherapy?
I am not currently using this regimen although, it is certainly an acceptable regimen.