SUMMARY: The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States and accounts for about 13% of all new cancers and 21% of all cancer deaths. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.
Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the immune system T cells. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.
Nivolumab (OPDIVO®) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. Ipilimumab (YERVOY®) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4. In the CheckMate-227, Part 1, Phase III trial, a combination of Nivolumab plus Ipilimumab significantly improved Overall Survival (OS), Progression Free Survival (PFS), Objective Response Rates (ORR) and Duration of Response, compared to chemotherapy, independent of PD-L1 expression level. The authors in this study hypothesized that a limited course of chemotherapy combined with Nivolumab plus Ipilimumab could provide rapid disease control, while building on the durable Overall Survival benefit seen with dual PD-1 and CTLA-4 inhibition, as well as minimizing the toxicities associated with a full course of chemotherapy.
CheckMate-9LA is a pivotal, randomized, open-label, global, multi-center, Phase III trial, designed to evaluate the long-term efficacy and safety of a combination of immunotherapy and chemotherapy compared to chemotherapy alone in patients with metastatic NSCLC. In this study, 719 adults treatment naïve patients with histological confirmed Stage IV/recurrent NSCLC, with ECOG Performance Status 0-1, and no known sensitizing EGFR/ALK alterations, were randomly assigned 1:1 to receive either Nivolumab 360 mg every 3 weeks IV plus Ipilimumab 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy (N=361), or 4 cycles of platinum-doublet chemotherapy alone (N=358). Chemotherapy was based on histology. Patients with non-squamous NSCLC in the chemo-only randomized group could receive optional Pemetrexed maintenance treatment. Patients were treated with immunotherapy until disease progression, unacceptable toxicity, or for 2 years. Patients were stratified by PD-L1 status (less than 1% versus 1% or more), sex, and histology (squamous versus non-squamous). Demographics in treatment groups were well balanced. Crossover between treatment groups was not permitted. However, at physician discretion, patients could receive subsequent immunotherapy upon discontinuation of study treatment in either group. The Primary end point was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR), Duration of Response (DOR) and efficacy by PD-L1 subgroups. Exploratory Endpoints included Treatment-Free Interval (TFI), efficacy in patients who discontinued due to Treatment-Related Adverse Events (TRAEs), and outcomes among 5-year survivors. This trial met its Primary and Secondary endpoints, showing statistically significant improvements in OS, PFS, and Objective Response Rate (ORR), when compared to chemotherapy alone. This clinical benefit was noted across tumor PD-L1 expression levels and histology. The researchers herein reported updated efficacy and safety data with a 5-year follow up, and outcomes in 5-year survivors.
At a median follow up of 64.5 months, the combination of Nivolumab, Ipilimumab, and chemotherapy demonstrated a continued survival benefit over chemotherapy alone. The 5-year OS rate was 18% for the experimental group compared to 11% for the control group, with a Hazard Ratio (HR) of 0.73. In patients with tumor PD-L1 expression less than 1%, a subgroup with historically poorer outcomes, the 5-year OS rate was 22% in the experimental group versus 8% in the control group (HR=0.63). The 5-year PFS rate in this subgroup was also significantly better with Nivolumab plus Iipilimumab and chemotherapy (9% versus 3%).
The median DOR in the experimental arm was 12.4 months compared to 5.6 months in the control arm. The 5-year DOR rates were 19% for the experimental group and 8% for the control group. Regarding Treatment-Free Interval (TFI), among patients who survived to 5 years, 72% of those in the experimental group were treatment-free compared to 35% in the control group. The TFI rates underscore the durability of the response achieved with the combination therapy.
In Squamous NSCLC patients, the median OS was 14.5 months with the experimental regimen compared to 9.1 months with chemotherapy alone (HR, 0.63). For non-squamous NSCLC patients, the median OS was 17.8 months versus 12.0 months (HR, 0.77). In patients with PD-L1 expression less than 1%, the experimental regimen had a median OS of 17.7 months compared to 9.8 months for the control group. For those with PD-L1 expression 1% or greater, the median OS was 15.8 months versus 10.9 months. Among patients who discontinued the experimental regimen due to TRAEs (N=61), 37% were alive at 5 years. The median OS in this subgroup was 27.5 months, with a 5-year OS rate of 37%.
No new safety signals emerged with extended follow up. Grade 3 and 4 immune-mediated AEs were relatively low across different Ipilimumab dosing groups. The most common severe AEs were hepatitis, rash, pneumonitis, and adrenal insufficiency, with incidence varying by the number of Ipilimumab doses.
Exploratory Analyses suggested that among the 5-year survivors, the median PFS was not reached in the experimental group compared to 16.8 months in the control group (HR, 0.52). The ORR at 5 years was 73% in the experimental group versus 60% in the control group.
In conclusion, the 5-year follow-up results from the CheckMate -9LA trial reinforce the long-term efficacy of Nivolumab plus Ipilimumab combined with chemotherapy as a first-line treatment for metastatic NSCLC. The combination therapy not only improved OS and PFS compared to chemotherapy alone, but also showed a significant benefit in patients with low PD-L1 expression and Squamous histology. The extended follow-up underscores the durability of the response and supports the combination as a robust treatment option for patients with metastatic NSCLC, with manageable safety profiles over the long term.
Five-year outcomes with first-line (1L) nivolumab + ipilimumab + chemotherapy (N + I + C) vs C in patients (pts) with metastatic NSCLC (mNSCLC) in CheckMate 9LA. Reck M, Ciuleanu TE, Schenker M, et al. J Clin Oncol. 2024;42(suppl 16):8560-8560. doi:10.1200/JCO.2024.42.16_suppl.8560.
