Five-Year Data Shows CheckMate 9LA Regimen Maintains Survival in NSCLC

Ticiana Leal, MD

Associate Professor

Department of Hematology and Medical Oncology

Director

Thoracic Medical Oncology Program

Emory University School of Medicine

Winship Cancer Institute

Atlanta, GA

Targeted Oncology: Please discuss the long-term data for nivolumab [Opdivo] plus ipilimumab [Yervoy] in non–small cell lung cancer (NSCLC).

Ticiana Leal, MD: We now have 5-year updates from the CheckMate 9LA trial [NCT03215706], which included patients with stage IV NSCLC with no prior systemic therapy, [and] no actionable driver mutation for performance status.

Patients were stratified by PD-L1 [expression of] less than1% and 1% or greater. About 32% of the patients had a PD-L1 of 15% to 49% and then 24% of the patients had a PD-L1 of 50% or greater. There was 32% of the patients who were squamous histology and 68% that were non-squamous. More than one third of the enrolled participants in this study had PD-L1 expression of less than 1%.

These patients were randomly assigned 1:1 to [receive] nivolumab plus ipilimumab. The dose for ipilimumab is a low dose, 1 mg/kg every 6 weeks with only 2 cycles of chemotherapy vs chemotherapy for 4 cycles with optional maintenance in the pemetrexed group of patients with non-squamous histology.

It is important to note that adding the short course of chemotherapy was to help patients through a challenging phase for when they do not do well with immunotherapy alone in the first 3 months of treatment. You can synergize with immunotherapy to get a more rapid response, minimize toxicity of chemotherapy by reducing the number of cycles of chemotherapy, and then keep patients on maintenance immuno-oncology [IO].

The primary end point [for the trial] was overall survival [OS] and secondary end points were progression-free survival [PFS], overall response rate, efficacy by PD-L1 expression, and safety.

What was the efficacy with the combination in the CheckMate 9LA trial?

The results from CheckMate 9LA, which is [now] an approved regimen, led to improved OS for nivolumab/ipilimumab/chemotherapy vs chemotherapy [alone]. Now we have 5-year OS data that showed a median OS of 15.8 months vs 11.0 months for nivolumab/ipilimumab/chemotherapy vs chemotherapy, respectively, with an HR of 0.73. The 5-year OS rates are 18% vs 11% and this was in the all-comer population.

When examining the data related to PD-L1 expression, what stands out is the excitement surrounding the PD-L1 negative group. Traditionally, this population has experienced shorter survival rates, but they do show positive responses to combinations of chemotherapy with immunotherapy or dual immune-oncology treatments. Comparatively, they are receiving benefit from this combination strategy. We saw a median OS of 9.8 months with chemotherapy vs 17.7 months with combination therapy, and with a HR of 0.63. Then we saw a median OS that is translating now into this durable benefit at the 5-year update: 22% vs 8%, respectively, with the PD-L1 positive group also deriving benefit. It was 18% vs 11% for the PD-L1 negative group, 18% for the all comers [group], 22% for PD-L1 negative [group], and 18% for the PD-L1 positive [group].

Regarding histology with this regimen, a subgroup of patients showed benefit in the squamous and in the non-squamous population with a median OS of 9.1 [months with chemotherapy] vs 14.5 [with the combination], and an HR of 0.63 [in the squamous group]. The 5-year OS rates were 18% vs 7% [in the squamous group], and in the non-squamous group 19% vs 12%, [respectively].

For all patients who were randomly assigned by PD-L1 expression, the overall response rate was also higher in the PD-L1 greater than 1% group of patients. Importantly, the duration of response [DOR] was higher, with a median DOR of 4.3 [months with chemotherapy] vs 17.5 [with the combination]. This was also seen in the DOR in the PD-L1 negative group. When you look at the survival curve at the 5-year update, there was a DOR of 25% for nivolumab/ipilimumab vs 0% for chemotherapy, and then in the PD-L1 positive it is 15% vs 10%, respectively.

Regarding the main end points, we saw improvement in OS across all subgroups, even subgroups who have been known to have worse outcomes, including the PD-L1 negative and the squamous subgroup.

We also see meaningful improvement in the median DOR, and importantly, as a 5-year update. This combination led to long-term, durable survival benefit compared with chemotherapy, and in patients with historically poor outcomes. The other end points were improved PFS and improved treatment-free interval.

How did this patient population do in terms of safety with the nivolumab/ipilimumab regimen?

For toxicities, we know that when you use combination immunotherapy with dual checkpoint inhibition, you see greater incidence of adverse events [AEs], which can have an earlier onset. However, in terms of the time of the toxicity, it is reassuring to see over time and [with] more exposure to ipilimumab, we are not seeing higher rates of [grade] 3 or 4 toxicities.

The toxicities in terms of incidence are rash, which certainly has been the most common, but also pneumonitis, hepatitis, and certainly grade 3/4 toxicities can occur. Some of them can be life threatening and fatal, and this is something we monitor very closely.

One important aspect in the CheckMate 9LA [trial] is that for the patients who come off treatment because of toxicity from the CheckMate 9LA regimen, they did not see a negative impact on survival. In fact, it showed an impressive 5-year OS update for those patients despite having to come off therapy.

For brain metastasis, we have the 3-year follow up, and in the study, they did require treatment of brain metastasis at study entry. At the 3-year follow up, patients with baseline brain metastasis or without brain metastasis had improved outcomes with the addition of nivolumab/ipilimumab/chemotherapy vs chemotherapy alone. In the patients with brain metastasis, the 3-year update showed a survival rate of 16% vs 6%, and for patients without brain metastasis it was 13% vs 5%, respectively.

Select treatment-related AEs [TRAEs] with nivolumab/ipilimumab/chemotherapy were skin and endocrine [related], which is not surprising. The majority were grade 1 and 2, but certainly grade 3 and 4 AEs require frequent monitoring or potential intervention.

We saw greater incidents and earlier onset [with the combination], but when you look at the treatment discontinuation rates, they are similar across the trial [cohorts]. Many of the AEs are commonly related to the chemotherapy backbone, such as, anemia and neutropenia and there are only 2 cycles of chemotherapy.

The percentage of patients that discontinued was 41%, which is a small number of patients, [and] with a total population of 61 patients. These are the patients that discontinued [treatment] due to TRAEs at 48 months, and 35% [of patients] at 60 months, which is reassuring for the patients who had to discontinue all components due to TRAEs. Even after discontinuation, these patients had a median DOR at 14.5 months, and they had ongoing response for a year or greater after discontinuation, which is about half of the patients.

REFERENCE:

Reck M, Ciuleanu TE, Schenker M, et al. 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. J Clin Oncol. 2024;42(16_suppl):8560-8560. doi:10.1200/jco.2024.42.16_suppl.8560