Priority Review Granted to Pembrolizumab Combo in Metastatic Esophageal and GEJ Cancer

The FDA has granted a Priority Review designation for a new supplemental Biologics License Application (sBLA) submitted for pembrolizumab (Keytruda), seeking approval in combination with platinum and fluoropyrimidine-based chemotherapy as frontline treatment of patients with locally advanced unresectable or metastatic carcinoma of the esophagus and gastroesophageal junction (GEJ), Merk announced in a press release.¹

The sBLA is supported by findings from the pivotal phase 3 KEYNOTE-590 clinical trial (NCT03189719), which demonstrated significant improvements with the combination in the primary end points of overall survival (OS) and progression-free survival (PFS) compared with chemotherapy, regardless of PD-L1 expression and tumor histology. The Prescription Drug User Fee Act target action date is April 13, 2021.

“Patients with newly diagnosed esophageal and GEJ cancer face an aggressive disease with a poor prognosis, despite the currently available treatment options," said Vicki Goodman, MD, vice president, clinical research, Merck Research Laboratories, in a statement. "We look forward to working with the FDA to bring a new option to patients in the first-line setting."

Findings from the KEYNOTE-590 study were recently presented during the 2020 European Society for Medical Oncology (ESMO) Virtual Congress. The study randomized 749 patients to receive treatment with cisplatin at 80 mg/m² IV on day 1 of every 3-week cycle for up to 6 cycles and 5-fluorouracil (5-FU) at a dose of 800 mg/m² IV per day on day 1 to 5 of every 3-week cycle, or per local standard for 5-FU administration, for up to 35 cycles, with either pembrolizumab 200 mg intravenously (IV) on day 1 of every 3-week cycle for up to 35 cycles or placebo.²

The median OS was 12.4 months with pembrolizumab (95% CI, 10.5-14.0) compared with 9.8 months (95% CI, 8.8-10.8) in the control arm (HR, 0.73; 95% CI, 0.62-0.86; P <.0001). Among patients who received the chemoimmunotherapy regimen versus those who received chemotherapy with placebo, the 12-month OS rates were 51% versus 39%, respectively, and the 24-month OS rates were 28% versus 16%.

According to investigator assessment, the median PFS was 6.3 months with the combination (95% CI, 6.1-6.9), while the median was 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 and 18-month PFS rates with the pembrolizumab regimen were, respectively, 25% and 16% compared with 12% and 6% in the control arm.

Treatment-related adverse events (TRAEs) were observed in 98.4% of the experimental arm and 97.3% of the control arm, and grade 3 or higher TRAEs were observed in 71.9% and 67.6%, respectively. TRAEs that led to treatment discontinuation occurred in 19.5% of the combination arm versus 11.6% with chemotherapy, and 2.4% versus 1.4%, respectively, experienced TRAEs that resulted in death.

In terms of immune-mediated toxicities and infusion reactions, these occurred in 25.7% of patients receiving the chemoimmunotherapy and 11.6% receiving chemotherapy alone, and these events were grade 3 or higher in 7.0% and 2.2%, respectively.

Pembrolizumab is currently approved in the second-line setting as monotherapy for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1, in the United States, China, and Japan. This approval was based on findings from the phase 2 KEYNOTE-180 trial (NCT02559687), which elicited an objective response rate of 14% with a median duration of response that had not been reached in the third-line setting for patients with esophageal squamous cell carcinoma (ESCC) and a PD-L1 combined positive score (CPS) of 10 or higher.³

Additional supportive data for this treatment were also observed in the phase 3 KEYNOTE-181 clinical trial (NCT02564263), which demonstrated a 23% reduction in the risk of death when pembrolizumab was added to chemotherapy in patients with ESCC (HR, 0.77; 95% CI, 0.63-0.96). The reduction observed in patients with PD-L1–positive tumors with a CPS ≥10 was higher at 30% (HR, 0.70; 95% CI, 0.52-0.94), while there was an 11% reduction in the risk of death in all randomized patients on the study (HR, 0.89; 95% CI, 0.75-1.05).⁴

Through Merck’s broad clinical program, the company is continuing to study this therapy as treatment of multiple gastrointestinal cancer types, including gastric, hepatobiliary, esophageal, pancreatic, colorectal, and anal cancers.¹

_References

_{1. FDA grants priority review to Merck’s supplemental biologics license application for KEYTRUDA® (pembrolizumab) plus chemotherapy as first-line treatment for locally advanced unresectable or metastatic esophageal and gastroesophageal junction cancer. News Release. Merck. December 17, 2020. Accessed December 17, 2020. https://bwnews.pr/3moQPHL}

_{2. Enzinger P. Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: the phase 3 KEYNOTE-590 study. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA8_PR.}

_{3. Shah MA, Kojima T, Hochhauser D, et al. Efficacy and safety of pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: the phase 2 KEYNOTE-180 study. JAMA Oncol. 2019;5(4):546-550. doi:10.1001/jamaoncol.2018.5441}

_{4. Shah MA, Adenis A, Enzinger PC, et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: phase 3 KEYNOTE-181. J Clin Oncol. 2019;27(suppl 15):4010. doi:10.1200/JCO.2019.37.15_suppl.4010}