During a Targeted Oncology case-based roundtable event, Rafael Santana-Davila, MD, discussed 3-year data on overall survival and subgroup analysis for the CheckMate 9LA trial of ipilimumab, nivolumab, and 2 cycles of chemotherapy.
Targeted OncologyTM: Please describe the study design of the CheckMate 9LA trial (NCT03215706) of nivolumab (Opdivo), ipilimumab (Yervoy), and chemotherapy for patients with non–small cell lung cancer (NSCLC).
SANTANA-DAVILA: The CheckMate 9LA trial was for patients that had treatment-naive metastatic NSCLC. They [could not have] sensitizing EGFR mutations or ALK alterations—[which is] typical for clinical trials. They had to have an ECOG performance status of 0 or 1, and they were stratified by PD-L1 into negative versus positive expression, as well as by sex and histology, with squamous versus non-squamous. Patients were randomly assigned on a 1:1 basis to the experimental arm [or the control arm]. [The experimental arm] is 2 cycles of nivolumab every 3 weeks with a 360-mg flat dose and ipilimumab at a dose of 1 mg/kg every 6 weeks.
Patients also received chemotherapy every 3 weeks. Chemotherapy was chosen by the investigator and was mainly pemetrexed [Alimta] plus cisplatin or carboplatin for those who had non-squamous histology versus paclitaxel and carboplatin for those with squamous histology. Remember that this study was planned when the standard of care was chemotherapy. This was prior to the approval of a combination of chemoimmunotherapy, so that was why this control arm was chosen in the middle—once they finished accrual, the standard of care was now chemotherapy and immunotherapy, so we don't have a real comparison of 2 different regimens.
What do the most recent results from this study show?
This study was initially published a couple years ago, and the 3-year update was presented at the 2022 American Society of Clinical Oncology Annual Meeting in Chicago.1 The overall survival [OS] in all cases strongly favored the experimental arm, with the 3-year OS of a little bit more than a quarter of patients; 27% of patients were alive at 3 years in the experimental arm versus 20% in the chemotherapy arm. There was a median OS of 15.8 months in the experimental arm versus 11 months, which is what you would expect for chemotherapy alone in the control arm.
The median progression-free survival [PFS] was 6.4 months in the experimental arm versus 5.3 months with chemotherapy, which was of statistical significance. We also had an increase in overall response rate, at 38% in the investigational arm versus 25% in the chemotherapy arm, which is what you would expect for chemotherapy alone. The duration of response was 12.4 months in the investigational arm versus 5.6 in the chemotherapy arm. Ongoing response at 3 years was a little bit less than a quarter of patients [23%] in the experimental arm versus only 14% in the chemotherapy alone arm.
PD-L1 staining did not appear to have much of a difference. Those who had a PD-L1 [expression of at least] 1% had the important finding of 28% of patients alive at 36 months, in contrast to the PD-L1–negative [subgroup, where] there was a quarter of patients that were alive at 36 months. Those [Kaplan-Meier] curves look very similar.
For patients who had a high PD-L1 expression [of at least 50%], where you expect that these patients have a better response to immunotherapy, you can see a little bit better OS for this patient population, with a median of 19 months.
What did this study show about the safety and tolerability of this combination?
Concentrating on immunotherapy-related adverse events [irAEs], the great majority of them were grade 1 or 2.2 When people think about ipilimumab/nivolumab, they are reminded of the AE profile when this regimen was first started, where patients would receive docetaxel plus ipilimumab at 3 mg/kg every 3 weeks, and that is a regimen that has a lot of AEs. This is in a regimen that uses ipilimumab every 6 weeks, and is not a benign regimen by any means, but the tolerance is much better than with a higher dose of [ipilimumab].
Grade 3 and 4 AEs occurred in 4% of patients with skin toxicity, 3% of patients with endocrine toxicity, 6% of patients with gastrointestinal toxicity—I would expect the majority of those are immune-related colitis—liver function abnormalities in 4% of patients, kidney disease in 2% of patients, and what appears to be pneumonitis in 2% of patients.
[The overall treatment-related AEs are] the typical AEs associated with chemotherapy because the control arm basically continued on chemotherapy. You just see more of the AEs associated with chemotherapy [in the control arm]: a greater degree of anemias and neutropenias, the alopecia is the same [as the experimental arm], because that happens early on, but there was a greater degree of thrombocytopenia. Interestingly, febrile neutropenia didn't [differ between arms], and as you would expect, there was a greater degree of peripheral neuropathy because they got more chemotherapy down the road.
In patients who developed irAEs and had to stop treatment because of irAEs with any type of immunotherapy, these patients appeared to benefit even more from treatment. That was shown with 54% of patients alive at 2 years, which is something that was even unheard of 10 years ago, with half the patients being alive and well at 2 years.3
1. Paz-Ares LG, Ciuleanu T, Cobo-Dols M, et al. First-line (1L) nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients (pts) with metastatic non–small cell lung cancer (NSCLC): 3-year update from CheckMate 9LA. J Clin Oncol. 2022;40(17_suppl):LBA9026. doi:10.1200/JCO.2022.40.17_suppl.LBA9026
2. Paz-Ares L, Ciuleanu TE, Cobo M, et al. 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. Lancet Oncol. 2021;22(2):198-211. doi:10.1016/S1470-2045(20)30641-0
3. Reck M, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update. ESMO Open. 2021;6(5):100273. doi:10.1016/j.esmoop.2021.100273