Nivolumab/Ipilimumab Plus Chemotherapy as Frontline Therapy Shows Continued Efficacy in mNSCLC

David P. Carbone, MD, PhD

In the phase 3 CheckMate 9LA trial (NCT03215706), patients with advanced non–small cell lung cancer (NSCLC), particularly those with PD-L1–negative and squamous disease, derived durable benefit from first-line treatment with nivolumab (Opdivo) plus ipilimumab (Yervoy), results presented at the 2023 ASCO Annual Meeting show.¹

In all patients who were randomly assigned, median overall survival (OS) was 15.8 months with the triplet (n = 361) vs 11.0 months with chemotherapy alone (n = 358; HR, 0.74; 95% CI, 0.63-0.87); four-year OS rates were 21% and 16%, respectively.

In the PD-L1 less than 1% population, median OS was 17.7 months with the triplet (n = 135) vs 9.8 months with chemotherapy alone (n = 129), with 4-year OS rates of 23% vs 13%, respectively (HR, 0.66; 95% CI, 0.50-0.86). In the PD-L1–positive population (PD-L1 ≥1%), median OS was 15.8 months with the triplet (n = 204) vs 10.9 months with chemotherapy alone (n = 204; HR, 0.74; 95% CI, 0.60-0.92); four-year OS rates were 21% vs 16%, respectively.

Broken down by histology, median OS was 14.5 months with the triplet (n = 115) vs 9.1 months with chemotherapy alone (n = 112) in the squamous population (HR, 0.64; 95% CI, 0.48-0.84). In the nonsquamous population, median OS was 17.8 months with the triplet (n = 246) vs 12.0 months with chemotherapy alone (n = 246; HR, 0.80; 95% CI, 0.66-0.97).

“With a 4-year minimum follow-up, patients treated with nivolumab plus ipilimumab and chemotherapy continued to derive long-term, durable OS benefit vs chemotherapy alone, regardless or tumor PD-L1 expression or histology,” lead study author David P. Carbone, MD, PhD, professor, Barbara J. Bonner Chair in Lung Cancer Research, and director, James Thoracic Center, The Ohio State University Comprehensive Cancer Center–James in Columbus, and co-authors, wrote in a poster of the data.

The triplet regimen is approved for the treatment of patients with metastatic NSCLC without EGFR or ALK alterations in the United States, European Union, and several other countries based on previously reported data from the pivotal trial.

Image Credit: © David A Litman -www.stock.adobe.com

The study enrolled patients with stage IV or recurrent NSCLC who had not received prior systemic therapy and had no sensitizing EGFR mutations or known ALK alterations. A total of 719 patients were randomly assigned 1:1 to 360 mg of nivolumab every 3 weeks plus 1 mg/kg of ipilimumab every 6 weeks plus 2 cycles of chemotherapy given once every 3 weeks, or 4 cycles of chemotherapy alone once every 3 weeks with optional pemetrexed maintenance for patients with nonsquamous histology. Treatment was continued until disease progression, unacceptable toxicity, or for 2 years for immunotherapy.

OS served as the primary end point. Secondary end points included progression-free survival (PFS), objective response rate (ORR), and efficacy by tumor PD-L1 expression. OS by tumor histologic subtype served as an exploratory end point. 

In the all-randomized population, the ORR was 38.0% (95% CI, 33%-43%) with the triplet vs 25.1% (95% CI, 21%-30%) with chemotherapy alone. Median duration of response (DOR) was 12.4 months with the triplet vs 5.6 months with chemotherapy alone. The likelihood of remaining in response at 4 years was 25% (95% CI, 17%-33%) with the triplet vs 12% (95% CI, 6%-20%) with chemotherapy alone.

In the PD-L1 less than 1% population, the ORR was 31.1% (95% CI, 23%-40%) with the triplet vs 20.2% (95% CI, 14%-28%) with chemotherapy alone. Median DOR with the triplet and chemotherapy alone was 17.5 months and 4.3 months, respectively. The likelihood of remaining in response at 4 years was 29% (95% CI, 15%-45%) vs 0%, respectively.

In the PD-L1–positive population, the ORR was 42.6% (95% CI, 36%-50%) with the triplet vs 27.5% (95% CI, 22%-34%) with chemotherapy alone, with median DORs of 11.8 and 5.6 months, respectively. The likelihood of remaining in response at 4 years was 24% (95% CI, 15%-34%) with the triplet vs 15% (95% CI, 7%-26%) with chemotherapy alone.

By histology, the ORR was 49% (95% CI, 39%-58%) with the triplet vs 31% (95% CI, 23%-41%) with chemotherapy alone in the squamous population. The estimated 4-year DOR rate was 17% (95% CI, 8%-29%) with the triplet vs 6% (95% CI, 1%-17%) with chemotherapy alone. In the nonsquamous population, the ORRs were 33% (95% CI, 27%-39%) with the triplet vs 22% (95% CI, 17%-28%) with chemotherapy alone. The estimated 4-year DOR rate was 30% (95% CI, 19%-41%) with the triplet vs 16% (95% CI, 7%-28%) with chemotherapy alone.

Among patients who discontinued the study regimen because of treatment-related adverse effects (TRAEs) the 4-year OS rate was 41% (median OS, 27.5 months; ORR, 51%) vs 21% in the all-randomized population. These patients in the triplet arm had a median treatment-free interval of 10.6 months, and 27% of patients were off treatment 4 years after discontinuing study therapy.

Moreover, PFS was improved with the triplet across the all randomized (HR, 0.70; 95% CI, 0.59-0.83), PD-L1 less than 1% (HR, 0.70; 95% CI, 0.53-0.92), PD-L1–positive (HR, 0.70; 95% CI, 0.56-0.87), squamous (HR, 0.64; 95% CI, 0.48-0.86), and nonsquamous (HR, 0.75; 95% CI, 0.61-0.91) populations.

Additional results demonstrated prolonged median OS with the triplet in patients with solid and acinar nonsquamous NSCLC. In patients with solid tumors, median OS was 17.9 months with the triplet (n = 80) vs 9.5 months with chemotherapy alone (n = 87), with 4-year OS rates of 26% and 19%, respectively (HR, 0.70; 95% CI, 0.49-0.99). In the acinar tumor population, median OS was 18.7 months with the triplet (n = 63) vs 12.7 months with chemotherapy alone (n = 53), both with 4-year OS rates of 20% (HR, 0.77; 95% CI, 0.51-1.15).

Notably, the median treatment-free interval in all patients treated with the triplet was 2.2 months. A 4-year treatment-free interval was experienced by 11% of patients who completed the triplet regimen.

With the triplet, TRAEs, serious TRAEs, TRAEs leading to discontinuation, and treatment-related deaths occurred in 91%, 26%, 25%, and 2% of patients with solid tumor histology compared with 89%, 38%, 24%, and 3%, respectively, for those with acinar tumor histology.

“Safety in all treated patients was consistent with previous reports, and no new safety signals were identified with nivolumab plus ipilimumab and chemotherapy based on tumor histologic subtype,” the authors wrote.

“These data further support the use of nivolumab plus ipilimumab and chemotherapy as an efficacious first-line treatment option for patients with metastatic NSCLC, particularly for those with tumor PD-L1 [expression] less than 1% or squamous histology, populations with high unmet needs,” Carbone and co-authors concluded.

_REFERENCE:

_{First-line (1L) nivolumab (N) + ipilimumab (I) + chemotherapy (C) vs C alone in patients (pts) with metastatic NSCLC (mNSCLC) from CheckMate 9LA: 4‑y clinical update and outcomes by tumor histologic subtype (THS).J Clin Oncol. 2023;41(suppl 17):LBA9023. doi:10.1200/JCO.2023.41.17_suppl.LBA9023}