EU Panel Recommends Frontline Nivolumab/Chemo for PD-L1+ Unresectable Advanced, Recurrent or Metastatic ESCC

Ian M. Waxman, MD

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has granted a positive opinion to the use of nivolumab (Opdivo) in combination with chemotherapy in the first-line treatment of adult patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC) with a PD-L1 expression of 1% or higher.¹

The recommendation is based on findings from the phase 3 CheckMate-648 trial (NCT03143153), which showed that when the immunotherapy was paired with fluoropyrimidine- and platinum-based chemotherapy (n = 158), it significantly improved overall survival (OS) vs chemotherapy alone (n = 157) in the subset of patients with a PD-L1 expression of 1% or higher.² The median OS in the nivolumab arm was 15.4 months (95% CI, 11.9-19.5) vs 9.1 months (95% CI, 7.7-10.0) in the chemotherapy-alone arm (HR, 0.54; 99.5% CI, 0.37-0.80; P < .0001).

Nivolumab plus chemotherapy also showcased a statistically significant improvement in progression-free survival (PFS) vs chemotherapy arm per blinded independent central review (BICR) in this subset, at 6.9 months (95% CI, 5.7-8.3) and 4.4 months (95% CI, 2.9-5.8), respectively (HR, 0.65; 98.5% CI, 0.46-0.92; P = .0023). A clinically meaningful increase in objective response rate (ORR) was also observed with the addition of nivolumab to chemotherapy vs chemotherapy alone, at 53% (95% CI, 45%-61%) and 20% (95% CI, 14%-27%), respectively.

“This positive CHMP opinion brings us one step closer to providing another promising treatment option for an often aggressive disease,” Ian M. Waxman, MD, development lead of gastrointestinal cancers at Bristol Myers Squibb, stated in a press release. “The clinical data for [nivolumab] plus chemotherapy show the meaningful benefit this treatment combination may bring to patients with unresectable advanced or metastatic ESCC.”

The global, open-label, phase 3 CheckMate-648 trial enrolled patients with unresectable advanced, recurrent, or metastatic ESCC who have measurable disease and an ECOG performance status of 0 or 1. 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 chemotherapy every 4 weeks (n = 321), nivolumab at 3 mg/kg every 2 weeks plus ipilimumab (Yervoy) at 1 mg/kg every 6 weeks (n = 325), or chemotherapy alone every 4 weeks (n = 324). Those who received chemotherapy were given fluorouracil at 800 mg/m2 on days 1 through 5 and cisplatin at 80 mg/m2 on day 1 of a 4-week cycle.

Nivolumab was administered for up to 24 months or until progressive disease, intolerable toxicity, or withdrawn consent. Chemotherapy was delivered until disease progression, intolerable toxicity, or withdrawn consent.

Patients were stratified based on PD-L1 expression (≥ 1% vs < 1%), region (East Asia vs rest of Asia vs rest of world), ECOG 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. Key secondary end points included OS and PFS in the all-randomized population, and ORR in both the all-randomized and PD-L1–positive subset.

At a data cutoff of January 18, 2021, the minimum follow-up was 12.9 months. Baseline characteristics were noted to be balanced across the 3 treatment arms; it was also noted that they were consistent with that of those with a PD-L1 expression of 1% or higher.

In the nivolumab/chemotherapy arm, the median age was 64 years (range, 40-90), 79% were male, 70% were Asian, 54% had an ECOG performance status of 1, and 97% had ESCC. Additionally, 51% of patients had a PD-L1 expression of less than 1% and 49% had an expression of 1% or higher. Most patients had de novo metastatic disease (57%) at study entry, 22% had recurrent distant disease, 14% had unresectable advanced disease, and 7% had recurrent locoregional disease. Moreover, 51% of patients had 2 or more organs with metastases, and the remainder had 1 or fewer.

Among the 310 patients in the nivolumab/chemotherapy arm, the median duration of treatment was 5.7 months (range, 0.1-30.6). Ninety-two percent of patients discontinued treatment, with the most common reason being disease progression (59%), followed by treatment-related toxicity (11%), adverse effects (AEs) not related to treatment (9%), patient request (5%), or other reasons not specified (8%).

Additional data presented during the 2021 ASCO Annual Meeting showed that in the all-randomized population, nivolumab plus chemotherapy (n = 321) resulted in a median OS of 13.2 months (95% CI, 11.1-15.7) vs 10.7 months (95% CI, 9.4-11.9) with chemotherapy alone (n = 324; HR, 0.74; 95% CI, 0.58-0.96; P = .0021). Notably, OS was found to favor the nivolumab regimen across most prespecified subsets analyzed among all-randomized patients.

The BICR-assessed PFS with nivolumab plus chemotherapy vs chemotherapy alone was 5.8 months (95% CI, 5.6-7.0) vs 5.6 months (95% CI, 4.3-5.9), respectively, in the all-randomized population (HR, 0.81; 95% CI, 0.64-1.04; P = .03555). The 12-month PFS rates in the investigative and control arm in this population were 24% and 16%, respectively.

Moreover, the addition of nivolumab to chemotherapy resulted in an ORR per BICR of 47% (95% CI, 42%-53%) in the all-randomized population vs 27% (95% CI, 22%-32%) with chemotherapy alone.

The median duration of response (DOR) with nivolumab/chemotherapy (n = 84) in the subset of patients with a PD-L1 expression of 1% or higher was 8.4 months (95% CI, 6.9-12.4) vs 5.7 months (95% CI, 4.4-8.7) with chemotherapy alone (n = 31). In the all-randomized population, the median DOR in the investigative arm (n = 152) was 8.2 months (95% CI, 6.9-9.7) vs 7.1 months (95% CI, 5.7-8.2) in the control arm (n = 87).

Among 310 patients who received nivolumab plus chemotherapy, 96% experienced any-grade treatment-related AEs (TRAEs), and 47% had TRAEs that were grade 3 or 4. Serious TRAEs were experienced by 24% of patients, with 18% of experiencing grade 3 or 4 TRAEs. The most common any-grade TRAEs reported in the nivolumab/chemotherapy and chemotherapy arms included nausea, decreased appetite, and stomatitis.

Thirty-four percent of patients discontinued treatment with nivolumab plus chemotherapy because of any-grade TRAEs, and 9% did so because of grade 3 or 4 TRAEs. Five treatment-related deaths were reported.

In September 2021, the FDA accepted supplemental biologics license applications for nivolumab plus ipilimumab and nivolumab plus fluoropyrimidine- and platinum-containing chemotherapy in the first-line treatment of adult patients with unresectable advanced, recurrent, or metastatic ESCC based on findings from CheckMate-648.³

Under the Prescription Drug User Fee Act, the regulatory agency will decide on these applications by May 28, 2022.

References

1. Bristol Myers Squibb receives positive CHMP opinion for Opdivo (nivolumab) plus chemotherapy for first-line treatment of patients with unresectable advanced, recurrent of metastatic esophageal squamous cell carcinoma with tumor cell PD-L1. News release. Bristol Myers Squibb; February 25, 2022. Accessed February 25, 2022. https://bit.ly/3sn2KM8
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
3. 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 February 25, 2022. https://bit.ly/3oaXk5g