Nivolumab/Ipilimumab Triplet Improves OS in Advanced NSCLC Compared With Chemotherapy Alone

Luis G. Paz-Ares, MD, PhD

A frontline regimen nivolumab (Opdivo), ipilimumab (Yervoy), and 2 cycles of chemotherapy yielded an improvement in overall survival (OS) vs chemotherapy alone in patients with advanced non–small cell lung cancer (NSCLC). The benefit was observed regardless of tumor mutational burden (TMB) status in the tissue or blood, according to findings from an analysis of the phase 3 CheckMate 9LA trial (NCT03215706) that were presented during the European Lung Cancer Virtual Congress 2021.¹

In the randomized population, the median OS was 15.6 months with the triplet vs 10.9 months with chemotherapy monotherapy (HR, 0.66; 95% CI, 0.55-0.80). The 1-year survival rates were 63% and 47%, respectively.

In the tissue TMB–evaluable population, the median OS was 15.6 months with the triplet vs 11.9 months with chemotherapy alone (HR, 0.75; 95% CI, 0.59-0.95). The 1-year survival rates were 61% and 50%, respectively.

In the blood TMB–evaluable population, the median OS was 15.3 months with the triplet vs 10.9 months with chemotherapy alone (HR, 0.68; 95% CI, 0.54-0.84). The 1-year survival rates were 62% and 48%, respectively.

“These findings from CheckMate 9LA show similar magnitude of OS benefit with nivolumab plus ipilimumab plus 2 cycles of chemotherapy vs chemotherapy regardless of TMB status in first-line advanced NSCLC, which is consistent with data previously reported for nivolumab plus ipilimumab,” said Luis G. Paz-Ares, MD, PhD, lead study author and chief of Medical Oncology Service at the Hospital Universitario 12 de Octubre in Madrid, Spain, in a virtual presentation of the data.

CheckMate 9LA enrolled patients with stage IV or recurrent NSCLC who did not have sensitizing EGFR mutations or ALK alterations, had not received prior systemic therapy, and had an ECOG performance status of 0 or 1. Patients were randomized 1:1 to 360 mg of nivolumab every 3 weeks plus 1 mg/kg of ipilimumab every 6 weeks plus two 3-week cycles of platinum-based chemotherapy (n = 361) or four 3-week cycles of platinum-based chemotherapy with optional pemetrexed (Alimta) maintenance.

OS served as the primary end point; secondary end points included progression-free survival (PFS), objective response rate (ORR), efficacy by PD-L1 expression, and efficacy by tissue TMB and blood TMB.

The combination of nivolumab and ipilimumab plus chemotherapy also led to a significant improvement in PFS and ORR vs chemotherapy alone as frontline treatment for patients with advanced NSCLC, according to primary findings from CheckMate 9LA.

On May 26, 2020, the FDA approved nivolumab plus ipilimumab and 2 cycles of platinum-doublet chemotherapy for the frontline treatment of patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations, based on data from CheckMate 9LA.²

Because the combination had shown clinical benefit vs chemotherapy irrespective of PD-L1 expression in the primary analysis, investigators evaluated the utility of TMB as a potential biomarker of response to the regimen. Tissue TMB was evaluated from baseline tumor samples using the FoundationOne CDx assay with the protocol-defined cutoff of 10 mutations per megabase. For blood TMB, plasma samples collected at baseline were used for isolation of circulating cell-free tumor DNA and then analyzed using the GuardantOMNI platform. Sixteen mutations per megabase and 20 mutations per megabase were the 2 protocol-defined cutoffs for blood TMB.

Among all randomized patients, 64% (n = 456) and 73% (n = 519) had tissue TMB– and blood TMB–evaluable samples, respectively.

Reasons for sample attrition in the tissue TMB and blood TMB groups, respectively, included lack of specimen (n = 19, n = 65), pre-analytical quality control failure (n = 3, n = 2), sample quality control failure (n = 142, n = 23), and next-generation sequencing quality control failure (n = 90, n = 84).

The baseline characteristics were generally well balanced among the randomized population, TMB-evaluable and -nonevaluable subgroups, and high- and low-tissue and blood TMB subgroups. Moreover, similar baseline characteristics were also seen among treatment arms across TMB subgroups.

A moderate correlation was seen between tissue TMB and blood TMB (Spearman rho, 0.54; 0.42-0.63). However, 1 discordant case was reported in which the blood TMB value was significantly higher than the paired tissue TMB value, at 172.6 mutations per megabase and 5.04 mutations per megabase, respectively.

Additional results indicated that higher tissue TMB and blood TMB appeared to be associated with greater ORR and PFS benefit.

Regarding response rates, the ORR in the tis-sue TMB group with at least 10 mutations per megabase was 46% in the triplet arm vs 28% in the chemotherapy-alone arm. In the less than 10 mutations per megabase group, the ORRs were 33% and 27%, respectively (FIGURE1).

In the blood TMB group with at least 16 muta-tions per megabase, the ORR was 49% in the triplet arm vs 27% in the chemotherapy-alone arm. In the less than 16 mutations per megabase group, the ORRs were 33% and 28%, respectively.

Notably, in the blood TMB group with at least 20 mutations per megabase, the ORR was 55% in the triplet arm vs 31% in the chemotherapy-alone arm. In the less than 20 mutations per megabase group, the ORRs were 33% and 27%, respectively.

Additionally, patients in the tissue TMB group with at least 10 mutations per megabase had a median PFS of 8.9 months with the triplet vs 4.7 months with chemotherapy alone (HR, 0.49; 95% CI, 0.34-0.70). The 1-year PFS rates were 45% and 13%, respectively.

Among patients with less than 10 mutations per megabase, the median PFS was 5.6 months with the triplet vs 5.0 months with chemotherapy alone (HR, 0.83; 95% CI, 0.63-1.10). The 1-year PFS rates were 25% and 19%, respectively.

In the blood TMB group, patients with at least 16 mutations per megabase derived a greater PFS benefit with the triplet (HR, 0.55; 95% CI, 0.39-0.78) vs those with less than 16 mutations per megabase (HR, 0.78; 95% CI, 0.60-1.00).

Similarly, patients with at least 20 mutations per megabase derived a greater PFS benefit with the triplet (HR, 0.48; 95% CI, 0.32-0.73) vs those with less than 20 mutations per megabase (HR, 0.78; 95% CI, 0.62-0.99).

However, similar OS outcomes were seen using tissue TMB and blood TMB at different cutoffs.

Among patients with a tissue TMB of at least 10 mutations per megabase, the median OS was 15.0 months in the triplet arm vs 10.8 months in the chemotherapy-alone arm (HR, 0.74; 95% CI, 0.51-1.08). The 1-year OS rates were 63% and 46%, respectively.

Among patients with less than 10 mutations per megabase, the median OS was 16.8 months in the triplet arm vs 12.4 months in the chemotherapy alone arm (HR, 0.75; 95% CI, 0.55-1.02). The 1-year OS rates were 58% and 52%, respectively.

Patients with a blood TMB of at least 16 mutations per megabase derived a modest OS benefit with the triplet (HR, 0.60; 95% CI, 0.42-0.86) vs those with less than 16 mutations per megabase (HR, 0.73; 95% CI, 0.55-0.96).

Similarly, patients with at least 20 mutations per megabase derived a subtle OS benefit with the triplet (HR, 0.54; 95% CI, 0.35-0.84) vs those with less than 20 mutations per megabase (HR, 0.74; 95% CI, 0.57-0.95).

When tissue TMB and blood TMB were evaluated as continuous variables, ranging from at least 5 mutations per megabase to at least 20 mutations per megabase and at least 5 mutations per megabase to at least 30 mutations per megabase, respectively, OS favored the triplet regimen across all categories.

Moreover, comparable OS benefit was seen across PD-L1 expression subgroups, irrespective of tissue or blood TMB level.

“Along with previously reported data from CheckMate 9LA, these results support the use of nivolumab plus ipilimumab plus 2 cycles of chemotherapy as first-line treatment for patients with advanced NSCLC regardless of PD-L1 expression, TMB status, or their combination,” concluded Paz-Ares.

_References:

_{1. Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles chemotherapy (chemo) versus 4 cycles che-motherapy in advanced non-small cell lung cancer (NSCLC): association of blood and tissue tumor mutational burden (TMB) with efficacy in Check-Mate 9LA. Presented at: European Lung Cancer Virtual Congress 2021; March 25, 2021, Accessed May 27 2021. https://bit.ly/3cvoblW}