At 5 years’ minimum follow-up in CheckMate 227 Part 1, nivolumab plus ipilimumab continued to demonstrate long-term, durable clinical benefit for previously untreated patients with metastatic non-small cell lung cancer (NSCLC) versus chemotherapy, regardless of tumour PD-L1 expression. The 5-year overall survival (OS) rates of 24% and 19% with nivolumab plus ipilimumab in the PD-L1 ≥1% and <1% populations versus 14% and 7% with chemotherapy reflect a marked improvement when consider that the 5-year relative survival rate for patients with metastatic NSCLC was 7% in the US between 2012 and 2018. In long-term survivors treated with nivolumab plus ipilimumab, approximately two-thirds had been off study treatment for ≥3 years without having started subsequent systemic treatment at the 5-year time point, and quality-of-life (QoL) was similar to that of the general US population. The latest findings are published by Dr. Julie R. Brahmer of the Johns Hopkins Kimmel Cancer Center in Baltimore, MD, US and study colleagues on 12 October 2022 in the Journal of Clinical Oncology.

CheckMate 227 is a randomised, open-label, phase III study that evaluated first-line nivolumab plus ipilimumab or nivolumab-based regimens versus chemotherapy for the treatment of metastatic NSCLC. CheckMate 227 Part 1 met both of its independent primary endpoints, as nivolumab plus ipilimumab significantly prolonged progression-free survival in patients with high tumour mutational burden (≥10 mut/Mb) and OS in patients with tumour PD-L1 expression ≥1% versus chemotherapy. In a prespecified descriptive analysis, OS was also prolonged in patients with tumour PD-L1 <1%.

Nivolumab plus ipilimumab was consequently approved in the US and other regions as first-line treatment in adult patients with metastatic NSCLC with PD-L1 ≥1% and no EGFR or ALK aberrations, and in some countries regardless of PD-L1 expression. Nivolumab plus ipilimumab is recommended as a first-line treatment option by NCCN Clinical Practice Guidelines in Oncology and the ESMO Clinical Practice Guideline for metastatic NSCLC regardless of PD-L1 expression.

In the latest article, the study investigators reported CheckMate 227 Part 1 efficacy and safety data with a minimum follow-up of 5 years, the longest reported from a phase III study with a combination of immune checkpoint inhibitors (ICIs) for NSCLC and an important survival landmark for patients with metastatic NSCLC. They also reported post hoc analyses of outcomes in patients alive at 5 years, those who completed 2 years of ICI treatment, and those who discontinued nivolumab plus ipilimumab due to treatment-related adverse events (TRAEs).

At 61.3 months’ minimum follow-up, 5-year OS rates were 24% for nivolumab plus ipilimumab in PD-L1 ≥1% subgroup versus 14% for chemotherapy, and in PD-L1 <1% subgroup 19% versus 7%. Median duration of response was 24.5 versus 6.7 months in PD-L1 ≥1% and 19.4 versus 4.8 months in PD-L1 <1%. Among patients surviving 5 years, 66% in PD-L1 ≥1% subgroup and 64% in PD-L1 <1% were off nivolumab plus ipilimumab without initiating subsequent systemic treatment by the 5-year time point.

Survival benefit continued following nivolumab plus ipilimumab discontinuation due to TRAEs, with a 5-year OS rate of 39% in combined PD-L1 ≥1% and <1% populations. QoL in 5-year survivors treated with nivolumab plus ipilimumab was similar to the general population in US through 5 years’ follow-up. No new safety signals were observed.

The authors concluded that CheckMate 227 is the first phase III study to report 5-year clinical outcomes with a first-line combination of ICIs for patients with metastatic NSCLC. Nivolumab plus ipilimumab conferred long-term clinical benefit extending beyond treatment discontinuation, regardless of PD-L1 expression. This durable clinical benefit is consistent with the efficacy seen with nivolumab plus ipilimumab across multiple tumour types.

Overall, almost a quarter of patients with metastatic NSCLC, regardless of tumour PD-L1 expression, survived for ≥5 years following treatment with this dual ICI regimen. As long-term survivorship improves with treatment advances, aspects of patient experience such as QoL become increasingly relevant. Nivolumab plus ipilimumab preserved QoL for these long-term survivors. Future studies are needed to identify reliable biomarkers predicting benefit and to evaluate novel combinations for patients with primary or secondary resistance to ICI.

The study was funded by Bristol Myers Squibb.


Brahmer JR, Lee J-S, Ciuleanu T-E, et al. Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small Cell Lung Cancer in CheckMate 227. JCO; Published online 12 October 2022. DOI: 10.1200/JCO.22.01503