FDA Approves Nivolumab/Chemo and Nivolumab/Ipilimumab for Unresectable Advanced ESCC

Approval Alert | <b>Nivolumab-Based Regimens for Esophageal Squamous Cell Carcinoma</b>

The FDA has granted approval to nivolumab plus ipilimumab and nivolumab plus chemotherapy for patients with unresectable advanced or metastatic esophageal squamous cell carcinoma.

Nivolumab (Opdivo) plus chemotherapy and nivolumab plus ipilimumab (Yervoy) was approved by the FDA as a treatment for patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) regardless of PD-L1 expression, according to a press release from Bristol Myers Squibb.1

The approval was based on results from the phase 3 CheckMate 648 trial (NCT03143153), which assessed the use of nivolumab in combination with chemotherapy or ipilimumab vs chemotherapy alone to treat adults with previously untreated, unresectable advanced or metastatic esophageal squamous cell carcinoma.2

Nivolumab had better overall survival vs the chemotherapy arm in all randomized patients (Hazard ratio, 0.74; 95% CI, 0.41-0.71; P <.0001) and in those whose tumors have a PD-L1 expression (HR, 0.54; 95% CI, 0.41-0.71; P <.0001).The median overall survival for those with a PD-L1 expression of 1% or more in those treated with nivolumab plus chemotherapy, was 15.4 months (95% CI, 11.9-19.5) compared with 9.1 months (95% CI, 7.7-10.0) in the chemotherapy arm (HR, 0.54; 99.5% CI, 0.37-0.80; P <.001). The median OS for all randomized patients was 13.2 months (95% CI, 11.1-15.7) compared with 10.7 months (95% CI, 9.4-11.9) in the chemotherapy arm (HR, 0.74; 99.1% CI, 0.58-0.96; P = .002).

The median OS in patients with PD-L1 expression greater than 1% in those treated with nivolumab plus ipilimumab was 13.7 months (95% CI, 11.2-17.0) compared with 9.1 months (95% CI, 7.7-10.0) for those receiving chemotherapy (HR, 0.64; 98.6% CI, 0.46-0.90; P = .001). Among those who were randomized, the median OS was 12.7 months (95% CI, 11.3-15.5) in the combination arm compared with 10.7 months (95% CI, 9.4-11.9) for those receiving chemotherapy (HR, 0.78; 98.2% CI, 0.62-0.98; P = .01).

A total of 970 patients enrolled on the trial, of whom 321 received 240 mg of nivolumab every 2 weeks plus fluorouracil and cisplatin every 4 weeks vs 324 patients treated with the chemotherapy backbone alone. Additionally, 325 patients received 3 mg/kg of nivolumab every 2 weeks and 1 mg/kg of ipilimumab every 6 weeks.

Nivolumab Plus Chemotherapy

“If [patients have high] tumor burden associated with high symptom burden, then you want to start with chemotherapy plus nivolumab because they need relief fast. Chemotherapy is good in providing fast relief,” Jaffer A. Ajani, MD, professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, said during an interview with CancerNetwork®.

The median PFS for patients with PD-L1 tumor expression of 1% or more in the combination arm was 6.9 months (95% CI, 5.7-8.3) compared with 4.4 months (95% CI, 2.9-5.8) in the chemotherapy arm (HR, 0.65; 98.5% CI, 0.46-0.92; P = .002). In the overall population, the median PFS was 5.8 months (95% CI, 5.6-7.0) in the combination arm compared with 5.6 months (95% CI, 4.3-5.9) in the chemotherapy arm; however, these results did not meet the pre-specified boundary for significance of P = .015 (HR, 0.81; 98.5% CI, 0.64-1.04; P = .04).

An ORR for patients with PD-L1 expression of 1% or more was 53% (95% CI, 45%-61%) in the combination arm vs 20% (95% CI, 14%-27%) in the chemotherapy arm, with complete response (CR) rates of 16% vs 5%, and partial response (PR) rates of 37% vs 15%, respectively. The median duration of response (DOR) in the combination arm was 8.4 months (95% CI, 6.9-12.4) compared with 5.7 months (95% CI, 4.4-8.7) in the chemotherapy arm.

The ORR in the overall population was 47% (95% CI, 42%-53%) for those in the combination arm and 27% (95% CI, 22%-32%) in the chemotherapy arm. The CR rates were 13% vs 6% and the PR rates were 34% vs 21% in either respective groups. The median DOR was 8.2 months (95% CI, 6.9-9.7) in the combination arm and 7.1 months (95% CI, 5.7-8.2) in the chemotherapy arm.

In the nivolumab/chemotherapy arm, 47% of patients experienced grade 3/4 treatment-related adverse effects (TRAEs) compared with 36% in the chemotherapy arm. Additionally, 24% vs 16% of patients in each respective group had serious TRAEs; 34% vs 19% had TRAEs leading to discontinuation; and 2% vs 2% had treatment-related AEs leading to death, respectively.

To be eligible for the study, patients were required to have unresectable advanced, recurrent, or metastatic ESCC; an ECOG performance status of 0 or 1; received no prior systemic therapy; and measurable disease. The primary end points were overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR). Secondary end points included OS and PFS in all randomized patients and objective overall response rate (ORR) by BICR.

Baseline characteristics in the nivolumab plus chemotherapy and chemotherapy groups included a median age of 64 years, with men comprising 79% and 85% of patients, respectively. Most patients were of Asian descent at 71% and 70% in the 2 respective groups. ECOG performance status of 1 was most common in 53% and 52% of patients in the active vs comparator groups, respectively, and 97% vs 98% had ESCC. At study entry, corresponding rates of de novo disease were 57% vs 58%. Two or more organs with metastases were observed in 51% of patients in both respective groups, and 79% were current or former smokers in each group.

Nivolumab Plus Ipilimumab

Patient characteristics in both groups indicated that 70% were from Asian countries and 49% had PD-L1 expression of 1% or greater. The median age was 63 years in the combination arm vs 64 in the chemotherapy arm, with 83% vs 85% being men, respectively. An ECOG performance score of 1 was reported in 54% of patients in the combination arm vs 52% in the chemotherapy-alone arm. At trial entry, 60% vs 58% had metastatic disease, 8% vs 8% had recurrent or locoregional disease, 22% vs 19% had recurrent or distant disease, and 10% vs 16% had unresectable advanced disease in the combination and chemotherapy alone arms, respectively.

The median duration of treatment was 2.8 months with nivolumab plus ipilimumab vs 3.4 months with chemotherapy alone. Treatment was discontinued in 54% of patients in the combination arm compared with 63% who received chemotherapy alone. Discontinuation occurred because of disease progression.

The median PFS in the combination arm was 4.0 months (95% CI, 2.4-4.9) vs 4.4 months (95% CI, 2.9-5.8) in the chemotherapy arm (HR, 1.02; 98.5% CI, 0.73-1.43; P = .8958) for those with PD-L1 expression of 1% or more. In all randomized patients in the combination arm, the median PFS was 2.9 months (95% CI, 2.7-4.2) vs 5.6 months (95% CI, 4.3-5.9) in the chemotherapy arm (HR, 1.26; 95% CI, 1.04-1.52). Outcomes for neither comparison met the prespecified boundary for significance.

Grade 3/4 treatment-related AEs (TRAEs) were observed in 32% of patients in the combination arm vs 36% in the chemotherapy arm. Serious TRAEs were observed in 32% vs 16% of patients, respectively, and 18% vs 19% had TRAEs leading to discontinuation. In each arm, TRAEs led to death in 2% of patients.

The eligibility criteria included those with unresectable advanced, recurrent, or metastatic ESCC or adenosquamous cell carcinoma of esophagus; an ECOG score of 0 or 1; no prior treatment for advanced disease; and measurable disease. The minimum follow-up was 12.9 months.

The primary end points were overall survival (OS) and progression-free survival (PFS) with tumor cell PD-L1 expression of 1% or greater. Secondary end points included OS and PFS in all randomized patients and overall response rate.

The supplemental biologics license application for nivolumab plus chemotherapy for the treatment of unresectable advanced ESCC was accepted by the FDA in October 2021.

References

  1. U.S. 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 31, 2022. https://bit.ly/3GGDd6j
  2. Doki Y, Ajani JA, Kato K, et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med. 2022;386(5):449-462. doi:10.1056/NEJMoa2111380