EMA Validates Applications for Nivolumab/Ipilimumab, Nivolumab/Chemo in Frontline ESCC

The European Medicines Agency has validated its Type II Variation Marketing Authorization Applications for nivolumab (Opdivo) plus ipilimumab (Yervoy) and nivolumab plus fluoropyrimidine- and platinum-containing chemotherapy as frontline options for adult patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC).¹

The applications are supported by data from the phase 3 CheckMate-648 trial (NCT03143153), in which both nivolumab-based regimens resulted in a statistically significant improvement in overall survival (OS) vs chemotherapy in patients with unresectable advanced or metastatic ESCC with a tumor cell PD-L1 expression of 1% or higher, and in all randomized patients.²

The median OS in the subset of patients with a PD-L1 expression of 1% or higher with nivolumab plus chemotherapy was 15.4 months (95% CI, 11.9-19.5) vs 9.1 months (95% CI, 7.7-10.0) with chemotherapy (hazard ratio [HR], 0.54; 95% CI, 0.37-0.80; P < .0001). In the all-randomized patient population, the median OS with nivolumab/chemotherapy was 13.2 months (95% CI, 11.1-15.7) vs 10.7 months (95% CI, 9.4-11.9) with chemotherapy (HR, 0.74; 95% CI, 0.58-0.96; P = .0021).

Nivolumab plus ipilimumab resulted in a median OS of 13.7 months (95% CI, 11.2-17.0) in patients with a PD-L1 expression of 1% or higher, compared with 9.1 months (95% CI, 7.7-10.0) with chemotherapy (HR, 0.64; 98.6% CI, 0.46-0.90; P = .0010). In the all-randomized population, the median OS with nivolumab/ipilimumab was 12.8 months (95% CI, 11.3-15.5) vs 10.7 months (95% CI, 9.4-11.9) with chemotherapy (HR, 0.78; 98.2% CI, 0.62-0.98; P = .0110).

“Outcomes for patients with advanced ESCC treated with chemotherapy alone remain poor, and there is a clear need for additional options beyond this long-standing standard of care,” Ian M. Waxman, MD, development lead of gastrointestinal cancers at Bristol Myers Squibb, stated in a press release. “The validation of our applications moves us a step closer to potentially bringing these 2 [nivolumab]-based regimens to patients in the European Union who may benefit.”

The global, open-label phase 3 CheckMate-648 trial enrolled patients with unresectable, advanced, recurrent, or metastatic ESCC with an ECOG performance status of 0 or 1 and measurable disease. Patients could not have previously received systemic treatment for advanced disease.

Patients were stratified based on PD-L1 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).

A total of 970 participants were randomized 1:1:1 to receive either 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).

The primary end points of the trial were OS and progression-free survival (PFS) in the population of patients who had a PD-L1 expression of 1% or higher. Secondary end points included OS and PFS in the all-randomized population, and objective response rate (ORR) in both populations.

Baseline characteristics were observed to be balanced across the 3 treatment arms and were consistent with that of patients who had a PD-L1 expression of 1% or higher. Across the arms, the median age was 63.6 years, 82.3% were male, 70% were Asian, 53.6% had an ECOG performance status of 1, and 51% had 2 or more organs with metastases. Regarding PD-L1 expression, 48.6% of patients had an expression of 1% or higher, and 51.3% had an expression of less than 1%.

Findings presented during the 2021 ASCO Annual Meeting had a data cutoff of January 18, 2021, and a minimum follow-up of 12.9 months. The median treatment duration in the nivolumab/chemotherapy group (n = 310), the nivolumab/ipilimumab group (n = 322), and the chemotherapy group (n = 304) was 5.7 months, 2.8 months, and 3.4 months, respectively. In these 3 groups, 92%, 93%, and 99% of patients, respectively, discontinued treatment.

The most common reason for treatment discontinuation was disease progression, followed by treatment-associated toxicities, an adverse effect (AE) not related to treatment, a patient request, or others. Fifty-five percent of patients received subsequent treatments, with most receiving chemotherapy.

Additional data from the trial showed that the median PFS per blinded independent central review (BICR) in patients with a PD-L1 expression of 1% or higher who received nivolumab/chemotherapy was 6.9 months (95% CI, 5.7-8.3) vs 4.0 months (95% CI, 2.4-4.9) with nivolumab/ipilimumab, and 4.4 months (95% CI, 2.9-5.8) with chemotherapy.

The HR between nivolumab/chemotherapy and chemotherapy alone in this patient subset was 0.65 (98.5% CI, 0.46-0.92; P = .0023), meeting the primary end point. The HR between nivolumab/ipilimumab and chemotherapy alone was 1.02 (98.5% CI, 0.73-1.43; P = .8958), missing the primary end point.

In the all-randomized patient population, the median PFS with nivolumab/chemotherapy was 5.8 months (95% CI, 5.6-7.0) vs 2.9 months (95% CI, 2.7-4.2) with nivolumab/ipilimumab, and 5.6 months (95% CI, 4.2-5.9) with chemotherapy. The HR between nivolumab/chemotherapy and chemotherapy in this subset was 0.81 (98.5% CI, 0.64-1.04; P = .0355), which did not meet the prespecified significance boundary of PFS per BICR. The PFS per BICR was not hierarchically tested in all randomized patients between nivolumab/ipilimumab and chemotherapy.

Nivolumab/chemotherapy elicited an ORR of 53% (95% CI, 45%-61%) in patients with a PD-L1 expression of 1% or higher, vs 35% (95% CI, 28%-43%) with nivolumab plus ipilimumab and 20% (95% CI, 14%-27%) with chemotherapy. The median duration of response (DOR) in the nivolumab/chemotherapy arm, the dual immunotherapy arm, and the control arm was 8.4 months (95% CI, 6.9-12.4), 11.8 months (95% CI, 7.1-27.4), and 5.7 months (95% CI, 4.4-8.7), respectively.

In the all-randomized patient population, nivolumab/chemotherapy resulted in an ORR of 47% (95% CI, 42%-53%) vs 28% (95% CI, 23%-33%) with nivolumab/ipilimumab and 27% (95% CI, 22%-32%) with chemotherapy. The median DOR in these arms was 8.2 months (95% CI, 6.9-9.7), 11.1 months (95% CI, 8.3-14.0), and 7.1 months (95% CI, 5.7-8.2), respectively.

The most frequent any-grade treatment-related AEs (TRAEs) that were reported in 10% or more of patients comprised nausea, decreased appetite, and stomatitis in those who received nivolumab plus chemotherapy, and rash, pruritus, and hypothyroidism in those given nivolumab plus ipilimumab. Notably, the incidence of TRAEs in those with a PD-L1 expression of 1% or higher proved to be consistent with all treated patients across all trial arms.

Most of the TRAEs that were experienced were grade 1 or 2 in severity. Grade 3 or 4 toxicities were reported in less than 6% of patients across all organ categories.

References

1. EMA validates Bristol Myers Squibb’s applications for Opdivo (nivolumab) + Yervoy (ipilimumab) and Opdivo + chemotherapy as first-line treatments for unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma. News release. Bristol Myers Squibb. August 17, 2021. Accessed August 17, 2021. https://bit.ly/3AUDDlD
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