Clinical Benefit Yielded With Pembrolizumab and Chemotherapy in Esophageal/GEJ Adenocarcinoma

The KEYNOTE-590 study (NCT03189719) found patients in all subgroups at the 12-month follow-up with esophageal cancer and gastroesophageal junction (GEJ) adenocarcinoma treated with first-line pembrolizumab (Keytruda) plus chemotherapy yielded a clinical benefit, according to a presentation from the 2022 Gastrointestinal Symposium.¹

The data were from an additional 12 months of follow-up. In an overall survival (OS) analysis of all evaluable patients, those who received the experimental regimen achieved a median OS of 12.4 months vs 9.8 months among those who received chemotherapy (HR, 0.73; 95% CI, 0.63-0.86). The 1-year OS rates were 51% and 39% with pembrolizumab/chemotherapy and chemotherapy alone, respectively; 2-year OS rates were 26% and 16%, respectively.

The median progression-free survival (PFS) across all patients was 6.3 months with pembrolizumab/chemotherapy and 5.8 months with chemotherapy alone (HR, 0.64; 95% CI, 0.55-0.75). The 1-year PFS rates were 25% with pembrolizumab/chemotherapy and 12% with chemotherapy; the 2-year PFS rates were 12% and 3%, respectively.

Furthermore, quality of life (QOL) as reported to be similar between the 2 groups and no new safety signals were detected with the experimental treatment.

“These longer-term data further support first-line pembrolizumab plus chemotherapy as a new standard of care in patients with locally advanced and metastatic esophageal cancer, including GEJ adenocarcinoma,” Jean-Phillipe Metges, MD, MSc, CHRU de Brest - Hôpital Morvan, in France, said during a presentation of the findings.

In March 2021, the FDA approved pembrolizumab for use in combination with platinum and fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or gastroesophageal carcinoma who are ineligible for surgical resection or definitive chemoradiation. The approval is based on earlier findings from the KEYNOTE-590 trial.²

Overall, 749 treatment-naïve patients with locally advanced and metastatic esophageal cancer—including GEJ adenocarcinoma—were randomly assigned to receive either pembrolizumab plus chemotherapy or placebo plus chemotherapy, with 370 patients on each arm. Chemotherapy consisted of 5-fluouroacil at 800 mg/m2 intravenously (IV) for days 1 to 5 every 3 weekends for 35 or fewer cycles plus cisplatin at 80 mg/m2 IV every 3 weeks for 6 or fewer cycles.

In the experimental group, there is still 1 patient who is continuing treatment; 33 patients have completed therapy, and 336 patients have discontinued therapy. In the control group, 5 have completed therapy and 365 have discontinued treatment.

The data cutoff date was July 9, 2020, and the median follow-up was 34.8 months.

In the experimental group, the median age was 64.0 years (range, 28-94); 82.0% of participants were male, and 49.9% had PD-L1 combined positive score (CPS) greater than or equal to 10. In the control group, the median age was 62.0 years (range, 27-89); 84.8% of participants were male, and 52.4% had PD-L1 CPS greater than or equal to 10.

Prespecified primary end points included OS in all patients, in patients with ESCC who have PD-L1 CPS 10 or higher, patients with ESCC, and in patients with PD-L1 CPS 10 or higher, as well as PFS (per RECIST v1.1 investigator assessment) in all patients, patients with ESCC, and those with PD-L1 CPS 10 or higher.

Secondary end points included overall response rate (ORR) per RECIST v1.1 investigator assessment, changes from baseline to week 18 in health-related QOL (HRQOL), and tumor response data. Researchers collected responses via patient-reported outcomes (PRO) at baseline, during treatment, and 30 days after treatment discontinuation.

In the ESCC PD-L1 CPS 10 or higher subgroup, the median OS was 13.9 months with pembrolizumab/chemotherapy and 8.8 months with chemotherapy alone (HR, 0.59; 95% CI, 0.45-0.76). In the ESCC subgroup, the median OS was 12.6 months and 9.8 months, respectively (HR, 0.73; 95% CI, 0.61-0.88). Lastly, in the PD-L1 CPS 10 or higher subgroup, the median OS was 13.6 months and 9.4 months, respectively (HR, 0.64; 95% CI, 0.51-0.80).

Furthermore, in the ESCC subgroup, the median PFS was 6.3 months with pembrolizumab/chemotherapy vs 5.8 months with chemotherapy alone (HR, 0.65; 95% CI, 0.54-0.78). In the PD-L1 CPS 10 or higher subgroup, the median PFS was 7.5 months vs 5.5 months, respectively (HR, 0.51; 95% CI, 0.41-0.65).

Patients experienced antitumor responses across both groups. ORR between the combination and control cohorts were 45.0% (n = 168) and 29.3% (n = 100) respectively. The complete response (CR) was 6.7% (n = 25) vs 2.4% (n = 9); the partial response (PR) rate was 38.3% vs 26.9%. The stable disease rates were 33.8% vs 46.3%; disease control rates were 78.8% vs 75.5%, and progressive disease rates were 11.5% vs 15.7%, respectively. Of note, 9.6% of patients receiving pembrolizumab plus chemotherapy did not exhibit evaluable antitumor response; this rate was 8.7% of patients in the chemotherapy group.

The median duration of response (DOR) was 8.3 months (range, 1.2+ to 41.7+) in the combination group and 6.0 months (range, 1.5+ to 34.9+) in the chemotherapy group. However, 20.4% of patients in the combination group achieved a response duration greater than equal to 24 months, and 6.2% of patients in the chemotherapy group did so, as well.

In addition, an assessment of changes from baseline in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-OES 18 Pain and Dysphagia indicated that QOL was similar across both treatment groups. The least square means (LSM) difference between the 2 cohorts in QLQ-OES-18 Pain was –2.94 (95% CI, -5.86 to -0.02), LSM difference for QLQ-OES-18 Dysphagia was -5.54 (95% CI, -10.92 to -0.16), and the difference in global health status/QOL was -0.10 (95% CI, -3.40 to 3.20).

Overall, 98.4% of patients in the combination cohort experienced some degree of treatment-related adverse events (TRAEs) vs 97.3% in the chemotherapy-alone group. In 21.1% of patients receiving pembrolizumab plus chemotherapy, a grade 3 or more AE led to treatment discontinuation; this occurred in 12.4% of patients who received chemotherapy. Furthermore, AE-related deaths occurred in 2.4% of patients receiving the combination and 1.4% of patients receiving the monotherapy.

Immune-mediated AEs and infusion reactions occurred in 26.8% of patients in the experimental cohort and in 13.8% of patients in the control group. Among this subset of AEs, the percentage of grade 3 or higher events were 7.0% and 2.2%, respectively. 

The most common AEs in both arms included nausea, anemia, decreased appetite, and fatigue. Additional AEs included decreased neutrophil count, vomiting, diarrhea, neutropenia, stomatitis, decreased white blood cells, and mucosal inflammation.

Reference

1. Metges JP, Kato K, Sun JM, et a. First-line pembrolizumab plus chemotherapy versus chemotherapy in advanced esophageal cancer: longer-term efficacy, safety, and quality-of-life results from the phase 3 KEYNOTE-590 study. J Clin Oncol. 2022;40(suppl; abstr 241). doi:10.1200/JCO.2022.40.4_suppl.241

2. FDA approves pembrolizumab for esophageal or GEJ carcinoma. News release. FDA. March 22, 2021. Accessed March 22, 2021. http://bit.ly/31908Di