FDA Approval Sought for Frontline Nivolumab Plus Ipilimumab or Chemo in Advanced ESCC

The FDA has accepted the supplemental biologics license applications (sBLAs) for nivolumab (Opdivo) plus ipilimumab (Yervoy) and nivolumab plus fluoropyrimidine- and platinum-containing chemotherapy in the frontline treatment of adult patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma.¹

The applications are supported by data from the phase 3 CheckMate-648 trial (NCT03143153), which demonstrated that nivolumab with ipilimumab or chemotherapy resulted in a statistically significant and clinically meaningful improvement in overall survival (OS) vs chemotherapy alone in the subset of patients who have a PD-L1 expression of 1% or higher and in the all-randomized patient population.²

The dual immunotherapy combination (n = 158) resulted in a median OS of 13.7 months (95% CI, 11.2-17.0) vs 9.1 months (95% CI, 7.7-10.0) with chemotherapy alone (n = 157) in the subset of patients with a PD-L1 expression of 1% or higher (HR, 0.64; 98.6% CI, 0.46-0.90; P = .0010). Nivolumab plus ipilimumab led to a median progression-free survival (PFS) of 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; 98.5% CI, 0.73-1.43; P = .8958), missing the primary end point in this subset.

The addition of nivolumab to chemotherapy (n = 158) in the PD-L1 ≥1% subset led to a median OS of 15.4 months (95% CI, 11.9-19.5) vs 9.1 months (95% CI, 7.7-10.0) with chemotherapy alone (n = 157; HR, 0.54; 99.5% CI, 0.37-0.80; P < .0001). The median PFS with nivolumab/chemotherapy was 6.9 months (95% CI, 5.7-8.3) vs 4.4 months (95% CI, 2.9-5.8) with chemotherapy alone (HR, 0.65; 98.5% CI, 0.46-0.92; P = .0023).

The regulatory agency is anticipated to decide on the applications by May 28, 2022, under the Prescription Drug User Fee Act.

“Last year, over 19,000 people were diagnosed with esophageal cancer in the United States, and 15,000 people died as a result of this very aggressive disease,” Ian M. Waxman, MD, development lead, gastrointestinal cancers at Bristol Myers Squibb, stated in a press release. “Additional treatment options are needed to improve upon outcomes achieved with the current standard of care. We are confident that our immunotherapy-based combinations can provide further clinical benefit and address this critical need.”

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

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).

Patients were stratified based on 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 were 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.

Across the arms, the median age was 63.7 years, and most participants were male (82.3%) and Asian (70%). Moreover, 53.6% of patients had an ECOG performance status of 1 and 98.0% had ESCC. More than half of patients across the arms had de novo metastatic disease at the time of study entry, and 51% of patients had 2 or more organs with metastases. Eighty percent of all patients were current or former smokers.

Regarding PD-L1 expression, 49% of those in the nivolumab/chemotherapy arm had a PD-L1 expression of 1% or higher, as did 54% of those in the dual immunotherapy arm and 53% of those in the chemotherapy-alone arm. Fifty-one percent of those the in the nivolumab/chemotherapy arm had an expression that was less than 1%, along with 54% and 53% of patients in the other arms, respectively.

At a data cutoff of January 18, 2021, the minimum follow-up was 12.9 months. The median duration of treatment on the nivolumab/chemotherapy arm was 5.7 months (range, 0.1-30.6), 2.8 months (range, 0.0-24.0) on the nivolumab/ipilimumab arm, and 3.4 months (range, 0.0-19.5) on the chemotherapy-alone arm.

More patients on the chemotherapy alone arm discontinued treatment vs those on the nivolumab/chemotherapy and nivolumab/ipilimumab arms, at 99% vs 92% and 93%, respectively.

The most common reason for discontinuation was progressive disease (63% vs 59% vs 54%, respectively), followed by treatment-related toxicity (13% vs 11% vs 18%), adverse effect (AE) not related to treatment (4% vs 9% vs 6%), patient request (7% vs 5% vs 4%), and other (12% vs 8% vs 11%). Moreover, 55% of the all-randomized population went on to receive subsequent treatment, which was predominantly chemotherapy across the 3 arms.

Additional data from the CheckMate-638 trial were presented during the 2021 ASCO Annual Meeting and showed that in the all-randomized population, nivolumab/chemotherapy (n = 321) resulted in a 26% reduction in the risk of death and a 2.5-month improvement in median OS over chemotherapy alone (n = 324). The median OS in the investigative arm was 13.2 months (95% CI, 11.1-15.7) vs 10.7 months (95% CI, 9.4-11.9) in the chemotherapy arm (HR, 0.74; 99.1% CI, 0.58-0.96; P = .0021).

The median PFS in this population with nivolumab plus chemotherapy vs chemotherapy alone was 5.8 months (95% CI, 5.6-7.0) and 5.6 months (95% CI, 4.3-5.9), respectively (HR, 0.81; 98.5% CI, 0.64-1.04; P = .0355).

Nivolumab plus 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 combination of nivolumab plus ipilimumab (n = 325) resulted in a median OS of 12.8 months (95% CI, 11.3-15.5) vs 10.7 months (95% CI, 9.4-11.9) with chemotherapy alone (n = 324) in the all-randomized population (HR, 0.78; 98.2% CI, 0.62-0.98; P = .0110). The median PFS was 2.9 months (95% CI, 2.7-4.2) vs 5.6 months (95% CI, 4.3-5.9), respectively (HR, 1.26; 95% CI, 1.04-1.52; P value, not tested).

The dual immunotherapy combination induced 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.

Regarding safety, the most common any-grade treatment-related AEs (TRAEs) were nausea, decreased appetite, and stomatitis in those who received nivolumab plus chemotherapy or chemotherapy alone, and rash, pruritus, and hypothyroidism in those who were given the dual immunotherapy regimen. The incidence of TRAEs in those with a PD-L1 expression of 1% or higher proved to be consistent with all treatment patients across the arms.

The majority of select TRAEs reported were grade 1 or 2 in severity. Grade 3 or 4 effects were reported in 6% or less of patients across all organ categories.

References

1. US Food and Drug Administration accepts Bristol Myers Squibb’s applications for Opdivo (nivolumab) + Yervoy (ipilimumab) and Opdivo + chemotherapy for unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma. News release. September 27, 2021. Accessed September 27, 2021. https://bit.ly/3oaXk5g
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