During a Case-Based Roundtable® event, Ticiana Leal, MD, discusses combination therapy with nivolumab plus ipilimumab and chemotherapy for patients with non–small cell lung cancer in the first article of a 2-part series.
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.