Elsevier

The Lancet Oncology

Volume 22, Issue 2, February 2021, Pages 198-211
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(20)30641-0Get rights and content

Summary

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 febrile neutropenia (14 [4%] vs ten [3%]). 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.

Translations

For the Polish and Russian translations of the Article see Supplementary Materials section.

Introduction

First-line treatment with PD-1 or PD-L1 blockade, as monotherapy or combined with chemotherapy, has improved outcomes for patients with advanced non-small-cell lung cancer (NSCLC) with no targetable driver alterations.1, 2, 3, 4, 5, 6, 7 Although a subset of patients might have improved survival with available anti-PD-(L)1 therapies, such as pembrolizumab with or without chemotherapy, nivolumab plus ipilimumab, and atezolizumab, long-term outcomes for most patients remain poor.8

Research in context

Evidence before this study

We searched for articles in PubMed and abstracts from major oncology congresses for studies relevant to non-small-cell lung cancer (NSCLC) and cancer immunotherapy regimens with a focus primarily on phase 3 trials. Search terms were “non-small cell lung cancer”, “anti-PD-L1”, “anti-PD-1”, “anti-CTLA-4”, “chemotherapy”, “pembrolizumab”, “atezolizumab”, and “nivolumab” (full names and abbreviations), and relevant articles published from database inception to July 22, 2020, were identified. At the time of the design of CheckMate 9LA (2017), checkpoint inhibition had shown efficacy in patients with NSCLC expressing high levels of PD-L1; however, chemotherapy was the first-line standard of care for many patients with advanced or metastatic NSCLC and no actionable mutations, and was associated with poor survival outcomes. Since then, several clinical trials in patients with NSCLC have assessed first-line immunotherapy regimens versus chemotherapy; regimens included checkpoint inhibitors as monotherapies, in combination with chemotherapy, or alongside other immunotherapy. During the conduct of CheckMate 9LA, checkpoint inhibition in other studies was shown to improve the outcomes in patients with NSCLC regardless of PD-L1 expression, when administered in combination with chemotherapy. Additionally, data showing the clinical benefit of nivolumab plus ipilimumab in patients with NSCLC emerged in CheckMate 227. Improved disease control is needed during the initial phase of immunotherapy treatment to enhance clinical benefit. Because chemotherapy might provide rapid disease control, CheckMate 9LA was designed to investigate the efficacy and safety of nivolumab plus ipilimumab with a limited course (two cycles) of chemotherapy versus a full course (four cycles) of chemotherapy alone. A single-arm phase 2 study assessing nivolumab plus ipilimumab with a limited course (two cycles) of chemotherapy showed that this regimen was tolerable and had encouraging clinical activity.

Added value of this study

We provide results from the randomised CheckMate 9LA study, which to our knowledge is the first phase 3 study to show a significant overall survival benefit, regardless of PD-L1 expression or histology, with dual PD-1 and CTLA-4 inhibition combined with two cycles of chemotherapy versus a standard course (four cycles) of chemotherapy as first-line treatment in patients with advanced NSCLC. Results presented here build upon those previously reported in the single-arm, phase 2 study and confirm the clinical activity and tolerability of this regimen. Benefit improved with longer follow-up and was consistent across all efficacy endpoints. Notably, a survival benefit was observed across various patient subgroups, including populations with a high unmet medical need, such as those with CNS metastases. Furthermore, the safety profile of this combination therapy was consistent with the profiles of the components of the regimen in first-line treatment for patients with NSCLC, and no new safety signals were reported.

Implications of all the available evidence

Overall, efficacy and safety data from CheckMate 9LA support a favourable risk–benefit profile for nivolumab plus ipilimumab combined with two cycles of chemotherapy as first-line treatment for patients with advanced NSCLC. Nivolumab plus ipilimumab with two cycles of chemotherapy is now approved and indicated in the USA, Singapore, Australia, Canada, and other countries for first-line treatment of patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumour aberrations.

Nivolumab, a fully human anti-PD-1 antibody, and ipilimumab, a fully human anti-CTLA4 antibody, are immune checkpoint inhibitors with distinct but complementary mechanisms of action. Ipilimumab induces T-cell proliferation and de-novo anti-tumour T-cell responses, including in memory T cells, whereas nivolumab restores the function of existing anti-tumour T cells.9, 10, 11 In part 1 of the CheckMate 227 trial (NCT02477826), first-line nivolumab plus ipilimumab versus chemotherapy showed durable responses and overall survival benefit, which were maintained with longer follow-up, in patients with advanced NSCLC and PD-L1 expression on at least 1% of tumour cells. Similar benefit was also observed in patients with PD-L1 expression on less than 1% of tumour cells in the same study, based on a descriptive analysis.12, 13 A third of patients who were treated with nivolumab plus ipilimumab were still alive at 3 years in both the group of patients with PD-L1 expression of at least 1% and in those with PD-L1 expression less than 1%, compared with 22% and 15%, respectively, of those treated with chemotherapy.13

Nivolumab plus ipilimumab is indicated in the USA and other countries for the first-line treatment of adults with metastatic NSCLC with PD-L1 expression of at least 1% and no EGFR or ALK genomic tumour abberrations.14 However, as reported in other NSCLC trials that assessed first-line single-agent or dual immunotherapy,4, 7, 15, 16 there remains a need, in a subset of patients, for disease control during the first few weeks of immunotherapy to enhance clinical benefit. Previous studies have shown that chemotherapy elicits anti-tumour effects through the immune system, which might result in increased immunotherapy activity,17, 18 although whether this effect is additive or synergistic with immunotherapy, or potentially due to interpatient variability, is not known.19, 20, 21 We hypothesised that dual immunotherapy combined with two cycles of chemotherapy would provide early disease control while building on the durable survival benefit provided by nivolumab and ipilimumab, and minimise the side-effects that are associated with a full course of chemotherapy. A feasibility study showed that this regimen was tolerable.22 We therefore aimed to investigate nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles, with optional pemetrexed maintenance for patients with non-squamous histology) as first-line treatment for patients with advanced NSCLC.

Section snippets

Study design and participants

CheckMate 9LA was an international, randomised, open-label phase 3 trial that was done in 103 hospitals in 19 countries (appendix 3 pp 2–4, 33). Eligible patients were aged at least 18 years with histologically confirmed squamous or non-squamous stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer classification23), an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and no previous systemic anti-cancer therapy as the primary

Results

Between Aug 24, 2017, and Jan 30, 2019, 1150 patients were enrolled. 431 (37·5%) patients were excluded before randomisation, most commonly due to failure to meet study criteria (figure 1), the main reasons for which were patients having untreated CNS metastases (79 [22%] of 368 patients), known EGFR mutations or non-squamous histology with unknown EGFR status (59 [16%]), ECOG performance status greater than 1 (46 [12%]), and no tumour tissue sample available for PD-L1 testing before

Discussion

To our knowledge, CheckMate 9LA is the first phase 3 study to show a significant overall survival benefit by combining a limited course (two cycles) of chemotherapy with nivolumab plus ipilimumab versus a full course of chemotherapy (four cycles, with optional pemetrexed maintenance treatment permitted for patients with non-squamous histology) as first-line treatment in patients with advanced NSCLC, regardless of PD-L1 expression level or histology. Benefit improved with longer follow-up and

Data sharing

Bristol Myers Squibb's policy on data sharing is available online.

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