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The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended the approval of pembrolizumab plus platinum- and fluoropyrimidine-based chemotherapy for the frontline treatment of patients with locally advanced unresectable or metastatic esophageal carcinoma or HER2-negative gastroesophageal junction adenocarcinoma with PD-L1 positivity.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of pembrolizumab (Keytruda) plus platinum- and fluoropyrimidine-based chemotherapy for the frontline treatment of patients with locally advanced unresectable or metastatic esophageal carcinoma or HER2-negative gastroesophageal junction (GEJ) adenocarcinoma with PD-L1 positivity.1
The positive opinion is supported by data from the phase 3 KEYNOTE-590 trial (NCT03189719), which showed that the combination significantly improved overall survival (OS), progression-free survival (PFS), and objective response rates (ORR) vs chemotherapy alone in this patient population.2
Specifically, the median OS with the combination was 12.4 months (95% CI, 10.5-14.0) with the chemoimmunotherapy regimen compared with 9.8 months (95% CI, 8.8-10.8) with chemotherapy alone (hazard ratio [HR], 0.73; 95% CI, 0.62-0.86; P <.0001). The 12-month OS rates were 51% and 39% with pembrolizumab plus chemotherapy and chemotherapy alone, respectively; these rates at 24 months were 28% and 16%, respectively.
The median PFS per investigator assessment and a RECIST v1.1 criteria was 6.3 months (95% CI, 6.2-6.9) with the pembrolizumab regimen vs 5.8 months (95% CI, 5.0-6.0) with chemotherapy alone (HR, 0.65; 95% CI, 0.55-0.76; P <.0001). The 12-month PFS rates were 35% and 12% in the investigative and control arms, respectively; the 18-month rates were 16% and 6%, respectively.
“Patients with metastatic esophageal cancer currently face 5-year survival rates of just 5%,” Scot W. Ebbinghaus, MD, vice president and clinical research at Merck Research Laboratories, stated in a press release. “There is a critical need for new treatment options in the first-line setting that can potentially extend their lives. Today’s positive opinion for [pembrolizumab] is an important step forward for patients in Europe with certain types of gastrointestinal cancers.”
The phase 3 KEYNOTE-590 trial enrolled patients with locally advanced, unresectable, or metastatic esophageal cancer, esophageal squamous cell carcinoma (ESCC), or advanced or metastatic EGJ Siewert type 1 adenocarcinoma. To be eligible for enrollment, patients needed to be treatment naïve, have an ECOG performance status of either 0 or 1, and have measurable disease per RECIST v1.1 criteria.
Study participants were randomized 1:1. Patients in the investigative arm received intravenous (IV) pembrolizumab at 200 mg every 3 weeks for up to 35 cycles plus chemotherapy comprised of IV 5-fluororacil (5-FU) at 800 mg/m2 for days 1 to 5 every 3 weeks for up to 35 cycles plus IV cisplatin at 80 mg/m2 every 3 weeks for up to 6 cycles (n = 373). Patients in the control arm were just given the chemotherapy (n = 376).
The co-primary end points of the trial were OS and PFS per RECIST v1.1 criteria and investigator assessment. The secondary end point of the trial was ORR per RECIST v1.1 and investigator assessment. Investigators also evaluated tumor response at week 9 and then every 9 weeks thereafter.
The median age across the arms was 63 years, the majority were male (83.4%), 52.4% were from the Asia region, and 59.8% had an ECOG performance status of 1. Moreover, the majority (91.2%) had metastatic disease, 73.2% had squamous cell carcinoma, and 8.8% had unresectable or locally advanced disease. Approximately 27% of patients had adenocarcinoma; 14.7% had esophageal cancer, while 12% had esophagogastric junction cancer. Fifty-one percent of patients had a PD-L1 combined positive score (CPS) of 10 or higher.
Additional data presented during the 2020 ESMO Virtual Congress showed that the median OS in just patients with ESCC and a PD-L1 CPS of 10 or higher was 13.9 months (95% CI, 11.1-17.7) with the chemoimmunotherapy vs 8.8 months (95% CI, 7.8-10.5) with chemotherapy alone (HR, 0.57; 95% CI, 0.43-0.75; P < .0001). The HR for OS in patients with ESCC in general was 0.72 (95% CI, 0.60-0.88; P = .0006) and it was 0.62 (95% CI, 0.49-0.78; P <.0001) in those with just a PD-L1 CPS of 10 or higher; both favored the investigative arm.
The median PFS in just patients with ESCC was 6.3 months (95% CI, 6.2-6.9) with the chemoimmunotherapy regimen vs 5.8 months (95% CI, 5.0-6.1) with chemotherapy alone (HR, 0.65; 95% CI, 0.54-0.78; P <.0001). The hazard for PFS in the subset of patients with a PD-L1 CPS of 10 or higher was 0.51 (95% CI, 0.41-0.65; P <.0001) favoring the pembrolizumab regimen.
The addition of pembrolizumab to the chemotherapy backbone resulted in an ORR of 45.0% (95% CI, 39.9%-50.2%) vs 29.3% (95% CI, 24.7%-34.1%) with chemotherapy alone (P <.0001). The median duration of response was 8.3 months in the investigative arm vs 6.0 months in the control arm.
Treatment-related adverse effects were reported in 98.4% and 97.3% of those who received the pembrolizumab regimen vs chemotherapy alone, respectively; 71.9% and 67.6% of patients, respectively, had grade 3 or higher effects. Toxicities that resulted in discontinuation were observed in 19.5% and 11.6% of those on the investigative and control arms, respectively; these effects resulted in death in 2.4% and 1.4% of patients, respectively. Immune-mediated toxicities were reported in 25.7% of those in the investigative arm vs 11.6% of those in the control arm; these effects were grade 3 in 7.0% and 2.2% of patients, respectively.
Additional findings presented at the 2021 Gastrointestinal Cancers Symposium showed that the health-related quality of life (HRQoL) during the 18-week period proved to be comparable between the 2 arms.3 The addition of the immunotherapy to chemotherapy maintained HRQoL measures relative to baseline and did not worsen HRQoL vs chemotherapy alone.