Nivolumab/Ipilimumab Plus Short-Course Chemo Improves OS Regardless of TMB Status in Advanced NSCLC

Luis G. Paz-Ares, MD, PhD

The frontline combination of nivolumab (Opdivo) and ipilimumab (Yervoy) plus 2 cycles of chemotherapy demonstrated an improvement in overall survival (OS) vs chemotherapy alone in patients with advanced non–small cell lung cancer (NSCLC) 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 that were presented during the 2021 European Lung Cancer Virtual Congress.¹

In the randomized population, the median OS was 15.6 months with the triplet vs 10.9 months with chemotherapy alone (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 physician at the Hospital Universitario 12 de Octubre, 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 led to a significant improvement in OS, PFS, and ORR vs chemotherapy alone as frontline treatment for patients with advanced NSCLC, according to primary findings from the CheckMate 9LA trial.

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 mut/Mb. 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 mut/Mb and 20 mut/Mb 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), preanalytical 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 between the randomized population, TMB-evaluable and non-evaluable subgroups, and high- and low-tissue and blood TMB subgroups. Moreover, similar baseline characteristics were also seen between 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 where the blood TMB value was significantly higher than the paired tissue TMB value, at 172.6 mut/Mb and 5.04 mut/Mb, 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 tissue TMB group with at least 10 mut/Mb was 46% in the triplet arm vs 28% in the chemotherapy-alone arm. In the less than 10 mut/Mb group, the ORRs were 33% and 27%, respectively.

In the blood TMB group with at least 16 mut/Mb, the ORR was 49% in the triplet arm vs 27% in the chemotherapy-alone arm. In the less than 16 mut/Mb group, the ORRs were 33% and 28%, respectively.

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

Additionally, patients in the tissue TMB group with at least 10 mut/Mb 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 mut/Mb, 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 mut/Mb derived a greater PFS benefit with the triplet (HR, 0.55; 95% CI, 0.39-0.78) vs those with less than 16 mut/Mb (HR, 0.78; 95% CI, 0.60-1.00).

Similarly, patients with at least 20 mut/Mb derived a greater PFS benefit with the triplet (HR, 0.48; 95% CI, 0.32-0.73) vs those with less than 20 mut/Mb (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 mut/Mb, 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 less than 10 mut/Mb, 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 mut/Mb derived a modest OS benefit with the triplet (HR, 0.60; 95% CI, 0.42-0.86) vs those with less than 16 mut/Mb (HR, 0.73; 95% CI, 0.55-0.96).

Similarly, patients with at least 20 mut/Mb derived a subtle OS benefit with the triplet (HR, 0.54; 95% CI, 0.35-0.84) vs those with less than 20 mut/Mb (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 mut/Mb to at least 20 mut/Mb and at least 5 mut/Mb to at least 30 mut/Mb, 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 + ipilimumab + 2 cycles chemotherapy versus 4 cycles chemotherapy in advanced non-small cell lung cancer: association of blood and tissue tumor mutational burden with efficacy in CheckMate 9LA. Presented at: 2021 European Lung Cancer Virtual Congress; March 25-27, 2021; virtual. Abstract 98O.
2. FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic NSCLC. News release. FDA. May 26, 2020. Accessed March 25, 2021. https://bit.ly/39b4XAs.