Nivolumab/Ipilimumab Nears EU Approval for Frontline 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 recommended the approval of nivolumab (Opdivo) and ipilimumab (Yervoy) for use in the frontline 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 the doublet (n = 158) resulted in a median overall survival (OS) of 13.7 months (95% CI, 11.2-17.0) vs 9.1 months (95% CI, 7.7-10.0) with chemotherapy (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).² The 12-month OS rates in the investigative and control arms were 57% and 37%, respectively.

However, the primary end point of progression-free survival (PFS) per blinded independent central review (BICR) was not met with nivolumab plus ipilimumab vs chemotherapy, at 4.0 months (95% CI, 2.4-4.9) and 4.4 months (95% CI, 2.9-5.8), respectively (HR, 1.02; 98.5% CI, 0.73-1.43; P = .8958). The 12-month PFS rates in the investigative and control arms were 26% and 10%, respectively.

The dual immunotherapy combination produced an objective response rate (ORR) of 35% (95% CI, 28%-43%) per BICR in the PD-L1–positive subset vs 20% (95% CI, 14%-27%) with chemotherapy.

“Currently, the median OS for advanced ESCC patients is around 10 months with standard chemotherapy,” Ian M. Waxman, MD, development lead and gastrointestinal cancers at Bristol Myers Squibb, stated in a press release. “The CHMP’s positive recommendation for [nivolumab] plus [ipilimumab] as a first-line treatment option for patients with unresectable advanced, recurrent or metastatic ESCC with tumor cell PD-L1 expression of 1% or higher marks an important step forward for patients in the European Union awaiting new therapeutic options for their disease.”

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

A total of 970 participants underwent 1:1:1 randomization 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). The chemotherapy regimen was comprised of 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 delivered for up to 24 months or until progressive disease, 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 included OS and PFS in patients with a PD-L1 expression of 1% or higher. Key secondary end points comprised OS and PFS in the all-randomized population, and ORR in both the all-randomized and the subset of patients with PD-L1–positive disease.

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 dual immunotherapy arm, the median age was 63 years (range, 28-81), 83% were male, 70% were Asian, 54% had an ECOG performance status of 1, and 99% had ESCC. Fifty-one percent of these patients had a PD-L1 expression of less than 1% on tumor cells, and 49% had an expression of 1% or higher.

Sixty percent of patients had de novo metastatic disease, 22% had recurrent distant disease, 10% had unresectable advanced disease, and 8% had recurrent locoregional disease. Moreover, 51% had 2 or more organs with metastases and 49% had 0 or 1 organs with metastases. Eighty-two percent of patients in this group were current or former smokers.

The median duration of treatment in the 322 patients within the nivolumab/ipilimumab arm was 2.8 months (range, 0.0-24.0). Ninety-three percent of these patients discontinued treatment, with 54% doing so because of disease progression, 18% doing so because of treatment-related toxicities, 6% because of an adverse effect (AE) not related to treatment, 4% due to patient request, and 11% for another reason not specified.

Additional data presented during the 2021 ASCO Annual Meeting showed that in the all-randomized population, the median OS with nivolumab/ipilimumab (n = 325) was 12.8 months (95% CI, 11.3-15.5) vs 10.7 months (95% CI, 9.4-11.9) with chemotherapy (n = 324; HR, 0.78; 98.2% CI, 0.62-0.98; P = .0110). The 12-month OS rates in the investigative and control arms were 54% and 44%, respectively.

The PFS per BICR was not hierarchically tested in this population, but the median PFS with the dual immunotherapy regimen was 2.9 months (95% CI, 2.7-4.2) in this population vs 5.6 months (95% CI, 4.3-5.9) with chemotherapy (HR, 1.26; 95% CI, 1.05-1.52).

Nivolumab plus ipilimumab elicited an ORR of 28% (95% CI, 23%-33%) in the all-randomized population vs 27% (95% CI, 22%-32%) with chemotherapy. The median DOR in the subset of patients with PD-L1–positive disease who received the immunotherapy regimen was 11.8 months (95% CI, 7.1-27.4) vs 5.7 months (95% CI, 4.4-8.7) with chemotherapy. In the all-randomized population, the median DOR was 11.1 months (95% CI, 8.3-14.0) in the investigative arm vs 7.1 months (95% CI, 5.7-8.2) in the control arm.

Any-grade treatment-related AEs (TRAEs) were experienced by 80% of those who received the immunotherapy combination, with 32% of patients experienced grade 3 or 4 toxicities. Serious TRAEs were experienced by 32% of patients; 23% reported grade 3 or 4 serious effects. Eighteen percent of patients experienced TRAEs that resulted in discontinuation; 13% experienced TRAEs that were grade 3 or 4 and resulted in discontinuation. Five treatment-related deaths occurred.

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 recommending approval for Opdivo (nivolumab) plus Yervoy (ipilimumab) for first-line treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma. News release. Bristol Myers Squibb; February 25, 2022. Accessed February 25, 2022. https://bit.ly/3IpKBTw
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