FDA Approves Pembrolizumab for PD-L1+ Esophageal Cancer

The FDA has approved pembrolizumab (Keytruda) for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (combined positive score [CPS] ≥10) as determined by an FDA-approved test, with disease progression after ≥1 prior line of systemic therapy.

The approval is based on findings from the phase III KEYNOTE-181 and phase II KEYNOTE-180 trials, in which pembrolizumab led to an improvement in median overall survival (OS) compared with chemotherapy and elicited encouraging overall response rates (ORR) in patients with PD-L1—positive esophageal cancer, respectively.

"Historically, patients with advanced esophageal cancer have had limited treatment options, particularly after their disease has progressed," Jonathan Cheng, MD, vice president, oncology clinical research, Merck Research Laboratories, the developer of the PD-1 inhibitor., stated in a press release. "With this approval, Keytruda is now the first anti-PD-1 therapy approved for the treatment of previously-treated patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS ≥10), providing an important new monotherapy option for physicians and patients in the United States."

In the multicenter, randomized, open-label, active-controlled KEYNOTE-181 (NCT02564263) trial, investigators enrolled 628 patients with recurrent locally advanced or metastatic esophageal cancer who progressed on or after 1 prior line of systemic therapy for advanced disease. Patients with HER2/neu- positive esophageal cancer were required to have received treatment with approved HER2/neu-targeted therapy.

Patients were randomized 1:1 to receive either pembrolizumab at 200 mg every 3 weeks or investigator’s choice of intravenous chemotherapy: docetaxel at 75 mg/m2 on day 1 of each 21-day cycle; paclitaxel at 80 to 100 mg/m2 on days 1, 8, and 15 of each 28-day cycle; or irinotecan at 80 mg/m2 on day 1 of each 14-day cycle. Randomization was stratified by tumor histology (esophageal squamous cell carcinoma [ESCC] vs esophageal adenocarcinoma [EAC]/Siewert type I EAC of the gastroesophageal junction [GEJ]), and geographic region (Asia vs ex-Asia). Treatment with either pembrolizumab or chemotherapy continued until unacceptable toxicity or disease progression. However, those receiving the PD-1 inhibitor were permitted to continue beyond the first RECIST v1.1-defined disease progression if clinically stable until the first radiographic evidence of progression was confirmed ≥5 weeks later with repeat imaging. Patients could receive pembrolizumab without disease progression for up to 24 months.

To be eligible for enrollment, all patients were required to have tumor specimens for PD-L1 testing at a central laboratory. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx assay. Patients with a history of non-infectious pneumonitis that required steroids or current pneumonitis, active autoimmune disease, or a condition that required immunosuppression were ineligible.

Patients' tumors were assessed every 9 weeks. The primary endpoint was OS in patients with ESCC, patients with tumors expressing PD-L1 CPS ≥10, and all randomized patients. Secondary endpoints were progression-free survival (PFS), ORR, and duration of response (DOR), according to RECIST v1.1 as assessed by blinded independent central review (BICR).

Results showed that pembrolizumab led to a 23% reduction in the risk of death compared with chemotherapy in patients with ESCC (HR, 0.77; 95% CI, 0.63-0.96), and a 30% reduction in those with PD-L1—positive tumors CPS ≥10 (HR, 0.70; 95% CI, 0.52-0.94), and an 11% reduction in the risk of death in all randomized patients (HR, 0.89; 95% CI, 0.75-1.05). Additional follow-up showed that there was an improvement in OS in patients with ESCC who also had PD-L1–positive tumors (CPS ≥10) with pembrolizumab versus chemotherapy.

In the PD-L1 (CPS ≥10) cohort, there were 68 events (80%) observed for patients receiving pembrolizumab (n = 85) and 72 events (88%) for those receiving chemotherapy (n = 82). The median OS was 10.3 months (95% CI, 7.0-13.5) compared with 6.7 months (95% CI, 4.8-8.6) for pembrolizumab and chemotherapy, respectively (HR, 0.64; 95% CI, 0.46-0.90). Additionally, the median PFS was 3.2 months (range, 2.1-4.4) for those who received pembrolizumab compared with 2.3 months (range, 2.1-3.4) in the chemotherapy arm (HR, 0.66; 95% CI, 0.48-0.92). The ORR with pembrolizumab was 22% (95% CI, 14.0-33.0), which included a 5% complete response (CR) rate and an 18% partial response (PR) rate. With chemotherapy, the ORR was 7% (95% CI, 3.0-15.0), with a 1% CR rate and a 6% PR rate. The median DOR was 9.3 months (range, 2.1+ to 18.8+) in the pembrolizumab arm versus 7.7 months (range, 4.3-16.8+) with those who were treated with chemotherapy.

Also in the pembrolizumab arm, the median duration of exposure was 2.1 months (range, 1 day to 24.4 months). Regarding safety, adverse events associated with pembrolizumab were similar to prior data with the PD-1 inhibitor in patients with melanoma and non—small cell lung cancer.

In the multicenter, nonrandomized, open-label KEYNOTE-180 trial (NCT02559687), 121 patients with locally advanced or metastatic esophageal cancer who progressed on or after ≥2 prior systemic therapies for advanced disease. The eligibility criteria and dosage regimen were similar to what was used in the KEYNOTE-181 study. The primary endpoint was ORR and DOR, according to RECIST v1.1 criteria as assessed by BICR.

Findings showed that in 35 patients with PD-L1—positive (CPS ≥10) ESCC, the ORR was 20% (95% CI, 8.0-37.0). Among the 7 responding patients, the DOR ranged from 4.2 to 25.1+ months; 5 patients (71%) had a response ≥6 months and 3 patients (57%) had a response of ≥12 months.

FDA Approves New Monotherapy Indication for Merck’s KEYTRUDA® (pembrolizumab). FDA. Published July 31, 2019. https://bit.ly/2YzDArN. Accessed July 31, 2019.