On October 31, 2023, the FDA approved pembrolizumab (Keytruda; Merck), a PD1 inhibitor, combined with gemcitabine/cisplatin, for the treatment of locally advanced unresectable or metastatic biliary tract cancer.
This approval of pembrolizumab was supported by efficacy findings in the KEYNOTE-966 trial (NCT04003636), a multicenter, randomized, double-blind, placebo-controlled study in 1069 patients with locally advanced unresectable or metastatic biliary tract cancer who had not received systemic therapy for advanced disease. The patients were randomized to receive pembrolizumab on day 1 plus gemcitabine and cisplatin on days 1 and 8 every 3 weeks, or placebo on day 1 plus gemcitabine and cisplatin. Treatment continued until unacceptable adverse events or disease progression. Cisplatin was administered for up to 8 cycles, whereas treatment with gemcitabine was continued based on physician discretion. Pembrolizumab or placebo was continued until disease progression or unacceptable adverse events, or for a maximum of 2 years.
The primary efficacy measure was overall survival (OS). The median OS was 12.7 months in the pembrolizumab arm (95% confidence interval [CI], 11.5-13.6) and 10.9 months for those receiving placebo (95% CI, 9.9-11.6), for a significant difference (hazard ratio [HR], 0.83; 95% CI, 0.72-0.95; one-sided P=.0034).
“Cancers of the biliary tract can be highly aggressive tumors, underscoring the need for additional treatment options for the growing number of patients facing this challenging disease,” said Robin Kate Kelley, MD, Professor of Clinical Medicine in the Division of Hematology/Oncology, University of California, San Francisco, in a press release. “Today's approval of pembrolizumab in combination with chemotherapy offers patients with locally advanced unresectable or metastatic biliary tract cancer a new immunotherapy regimen that has demonstrated the potential to help these patients live longer.”
Adverse events led to the interruption of pembrolizumab treatment in 55% of patients. The most common (≥2%) adverse events or laboratory abnormalities leading to treatment interruption were decreased neutrophil count, decreased platelet count, anemia, decreased white blood cell count, pyrexia, fatigue, cholangitis, increased ALT, increased AST, and biliary obstruction.
For patients with advanced biliary tract cancer, the recommended dose of pembrolizumab is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression or unacceptable adverse events. Pembrolizumab should be administered before chemotherapy when given on the same day.
On November 7, 2023, the FDA restricted the existing indication of pembrolizumab with trastuzumab, fluoropyrimidine, and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. Specifically, the update restricts treatment with pembrolizumab to patients whose tumors express PD-L1 (combined positive score [CPS] ≥1) as determined by an FDA-approved test. The GEJ approval remains under accelerated approval regulations.
The FDA also approved the Agilent PD-L1 IHC 22C3 pharmDx as a companion diagnostic test to select patients with gastric or GEJ adenocarcinoma whose tumors express PD-L1 (CPS ≥1).
The updated indication for pembrolizumab in GEJ is based on a recent prespecified interim analysis of the fully enrolled KEYNOTE-811 trial (NCT03615326), which enrolled 698 patients. In a subgroup analysis in 104 patients with PD-L1 CPS <1, the HR for OS and PFS were 1.41 (95% CI, 0.9-2.2) and 1.03 (95% CI, 0.65-1.64), respectively.
The primary efficacy outcomes of KEYNOTE-811 were OS and progression-free survival (PFS). The original 2021 approval in GEJ was based on an interim analysis of objective response rate (ORR) and duration of response (DOR). At that time, ORR and DOR were assessed in the first 264 patients randomized. The ORR was 74% (95% CI, 66-82) in the pembrolizumab plus chemotherapy arm and 52% (95% CI, 43-61) in the placebo plus chemotherapy arm (P≤.0001). The median DOR was 10.6 months (range, 1.1+ to 16.5+) and 9.5 months (range, 1.4+ to 15.4+) in the 2 study arms, respectively.
The safety profile of pembrolizumab and trastuzumab plus chemotherapy in KEYNOTE-811 was generally consistent with the known adverse events of trastuzumab plus chemotherapy or pembrolizumab monotherapy.
For patients with GEJ whose tumors express PD-L1 (CPS ≥1), as determined by an FDA-approved test, the recommended dose of pembrolizumab is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression or unacceptable adverse events or for up to 24 months. Pembrolizumab should be administered before trastuzumab and chemotherapy when given on the same day.
On November 16, 2023, the FDA approved the use of pembrolizumab with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma. The FDA granted pembrolizumab an orphan drug designation for this indication.
This new approval of pembrolizumab was based on the efficacy results of the multicenter, randomized, double-blind, placebo-controlled KEYNOTE-859 (NCT03675737) trial, which included 1579 patients with HER2-negative advanced gastric or GEJ adenocarcinoma who had not received systemic therapy for metastatic disease. The study patients were randomized (1:1) to pembrolizumab 200 mg (n=790) or to placebo with the investigator’s choice of cisplatin 80 mg/m2 plus 5-FU 800 mg/m2 daily for 5 days or to oxaliplatin 130 mg/m2 on day 1 plus capecitabine 1000 mg/m2 (n=789) twice daily for 14 days every 3 weeks.
The primary efficacy outcome measure was OS. The secondary efficacy outcome measures were PFS, ORR, and DOR according to RECIST v1.1, which was modified to maximums of 10 target lesions in total and 5 target lesions per organ.
Significant improvement was seen in OS, PFS, and ORR in the patients who received pembrolizumab and chemotherapy versus those who received placebo. The median OS was 12.9 months (95% CI, 11.9-14) in the pembrolizumab arm versus 11.5 months (95% CI, 10.6-12.1) in the patients who received placebo (HR, 0.78; 95% CI, 0.7-0.87; P<.0001). The median PFS was 6.9 months (95% CI, 6.3-7.2) and 5.6 months (95% CI, 5.5-5.7), respectively (HR, 0.76; 95% CI, 0.67-0.85; P<.0001). The ORR was 51% in the pembrolizumab cohort (95% CI, 48-55) versus 42% in the placebo group (95% CI, 38-45; P<.0001), and the median DOR was 8 months (95% CI, 7-9.7) versus 5.7 months (95% CI, 5.5-6.9), respectively. In an additional exploratory subgroup analysis, significant improvements were seen in OS, PFS, and ORR in the pembrolizumab cohort versus the chemotherapy cohort based on PD-L1 CPS ≥1 and CPS ≥10 tumor expression.
In all, 45% of the patients who received pembrolizumab had serious adverse reactions, including pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). A total of 15% of the patients permanently discontinued treatment with pembrolizumab because of adverse events, with ≥1% resulting from infections and diarrhea. In all, 65% of patients had dosage interruptions of pembrolizumab that resulted from adverse events, the most common (≥2%) of which were neutropenia (21%), thrombocytopenia (13%), diarrhea (5.5%), fatigue (4.8%), infection (4.8%), anemia (4.5%), increased AST (4.3%), increased ALT (3.8%), increased blood bilirubin (3.3%), white blood cell count decreased (2.2%), nausea (2%), and palmar-plantar erythrodysesthesia syndrome and vomiting (2% each).
The recommended dosage of pembrolizumab is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression or unacceptable adverse events. Pembrolizumab should be administered before chemotherapy when received on the same day.