FDA Grants 2 Frontline Nivolumab-Based Regimens Approval for Unresectable Advanced or Metastatic ESCC

Nivolumab (Opdivo) in combination with fluoropyrimidine- and platinum-containing chemotherapy and nivolumab plus ipilimumab (Yervoy) received FDA approval as a first-line treatment for adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma, irrespective of PD-L1 status.¹

The regulatory decision is based on data from the phase 3 CheckMate-648 trial (NCT03143153), in which nivolumab plus chemotherapy or ipilimumab significantly improved overall survival (OS) vs chemotherapy alone in the all-randomized population and in the subset of patients with a PD-L1 expression of 1% or higher.²

In the all-randomized population, the median OS with nivolumab plus chemotherapy was 13.2 months (95% CI, 11.1-15.7) vs 10.7 months (95% CI, 9.4-11.9) with chemotherapy alone, translating to a 39% reduction in the risk of death (HR, 0.74; 95% CI, 0.61-0.90; P = .0021). The median PFS was 5.8 months (95% CI, 5.6-7.0) and 5.6 months (95% CI, 4.3-5.9), respectively (HR, 0.81; 95% CI, 0.67-0.99; P = not significant).

In the subset of patients with a PD-L1 expression of 1% or higher, the median OS with nivolumab/chemotherapy was 15.4 months (95% CI, 11.9-19.5) vs 9.1 months (95% CI, 7.7-10) with chemotherapy alone, translating to a 46% reduction in the risk of death (HR, 0.54; 95% CI, 0.41-0.71; P < .0001). The median PFS in the investigative and control arms was 6.9 months (95% CI, 5.7-8.3) and 4.4 months (95% CI, 2.9-5.8), respectively (HR, 0.63; 95% CI, 0.49-0.86; P = .0023).

The dual immunotherapy combination comprised of nivolumab and ipilimumab resulted in a median OS of 13.7 months (95% CI, 11.2-17.0) vs 9.1 months (95% CI, 7.7-10) with chemotherapy alone in the subset of patients with a PD-L1 expression of 1% or higher, translating to a 36% reduction in the risk of death (HR, 0.64; 95% CI, 0.49-0.84; P = .0010). In the all-randomized population, the median OS was 12.8 months (95% CI, 11.3-15.5) with the immunotherapy regimen vs 10.7 months (95% CI, 9.4-11.9) with chemotherapy alone, translating to a reduction in the risk of death by 22% (HR, 0.78; 95% CI, 0.65-0.95; P = .0110).

Moreover, in the subset with a PD-L1 expression of 1% or higher, the median PFS with nivolumab/ipilimumab was 4.0 months (95% CI, 2.4-4.9) vs 4.4 months (95% CI, 2.9-5.8) with chemotherapy alone (HR, 1.02; 95% CI, 0.78-1.34), failing to meet statistical significance. Because it was not significant, it was not hierarchically tested in the all-randomized population.

“Today brings welcome news for many advanced or metastatic esophageal squamous cell carcinoma patients and oncologists,” Jaffer A. Ajani, MD, lead investigator of CheckMate-648, and professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, stated in a press release. “Unresectable advanced or metastatic ESCC is a challenging disease, and there’s a need for additional treatment options that may extend survival in the first-line setting. In the CheckMate-648 trial, 2 nivolumab-based combinations showed a survival benefit compared to chemotherapy alone, offering new treatment options regardless of PD-L1 status.”

Patients with unresectable advanced, recurrent, or metastatic ESCC were enrolled to the global, randomized, open-label phase 3 CheckMate-648 trial. They were required to have an ECOG performance status of 0 or 1 and measurable disease. Notably, they could not have received prior systemic therapy for advanced disease.

Study participants (n = 970) were randomized 1:1:1 to receive nivolumab at 240 mg every 2 weeks plus fluorouracil and cisplatin every 4 weeks (n = 321), nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks (n = 325), or fluorouracil plus cisplatin every 4 weeks (n = 324).

Stratification factors included PD-L1 tumor cell expression (≥1% vs ≤1%), region (East Asia vs rest of Asia vs rest of the world), performance status (0 vs 1), and number of organs with metastases (≤1 vs ≥2).

The primary end points of the trial included OS and PFS in the subset of patients with a PD-L1 expression of 1% or higher, and key secondary end points include OS and PFS in the all-randomized population and objective response rate (ORR) in both populations.

At a data cutoff of January 18, 2021, the minimum follow-up was 12.9 months. Additional data presented during the 2021 ASCO Annual Meeting indicated that the combination of nivolumab and chemotherapy elicited an ORR of 53% (95% CI, 45%-61%) in the subset of patients with a PD-L1 expression of 1% or higher vs 20% (95% CI, 14%-27%) with chemotherapy alone. In the all-randomized population, these rates were 47% (95% CI, 42%-53%) and 27% (95% CI, 22%-32%), respectively.

The median duration of response (DOR) in the subset of patients with a PD-L1 expression of 1% or higher in the investigative and control arms was 8.4 months (95% CI, 6.9-12.4) and 5.7 months (95% CI, 4.4-8.7), respectively. In the all-randomized population, the median DOR was 8.2 months (95% CI, 6.9-9.7) and 7.1 months (95% CI, 5.7-8.2), respectively.

The dual immunotherapy combination produced an ORR of 35% (95% CI, 28%-43%) vs 20% (95% CI, 14%-27%) with chemotherapy alone in the subset of patients with a PD-L1 expression of 1% or higher. These rates were 28% (95% CI, 23%-33%) and 27% (95% CI, 22%-32%), respectively, in the all-randomized population.

The median DOR with nivolumab plus ipilimumab in the subset of patients with a PD-L1 expression of 1% or higher was 11.8 months (95% CI, 7.1-27.4) vs 5.7 months (95% CI, 4.4-8.7) with chemotherapy alone. In all-randomized patients, the median DOR was 11.1 months (95% CI, 8.3-14.0) in the investigative arm and 7.1 months (95% CI, 5.7-8.2) in the control arm.

Nivolumab monotherapy and in combination with ipilimumab is linked with severe and fatal immune-mediated adverse reactions such as pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, nephritis and renal dysfunction, dermatologic adverse reactions, other immune-mediated adverse reactions.

References

1. US Food and Drug Administration approves two Opdivo (nivolumab)-based regimens as first-line treatments for unresectable advanced or metastatic esophageal squamous cell carcinoma. News release. Bristol Myers Squibb. May 27, 2022. Accessed May 27, 2022. https://bit.ly/3PMxNeb
2. Chau I, Doki Y, Ajani JA, et al. Nivolumab (NIVO) plus ipilimumab (IPI) or NIVO plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): first results of the CheckMate 648 study. J Clin Oncol. 2021;39(suppl 15):LBA4001. doi:10.1200/JCO.2021.39.15_suppl.LBA4001