On July 30, 2019, pembrolizumab was approved for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express programmed cell death ligand 1 (PD-L1; Combined Positive Score [CPS] ≥ 10), as determined by a U.S. Food and Drug Administration (FDA)-approved test, with disease progression after one or more prior lines of systemic therapy.1,2 The FDA also approved a new use for the PD-L1 IHC 22C3 pharmDx kit as a companion diagnostic device for selecting patients for this indication.
Supporting Efficacy Data
Approval was based on findings from the open-label phase III KEYNOTE-181 trial (ClinicalTrials.gov identifier NCT02564263) and the phase II KEYNOTE-180 trial (NCT02559687).
KEYNOTE-181: In KEYNOTE-181,2,3 628 patients with recurrent locally advanced or metastatic esophageal cancer whose disease progressed on or after one prior line of systemic treatment for advanced or metastatic disease were randomly assigned to receive either pembrolizumab at 200 mg every 3 weeks (n = 314) or investigator’s choice (n = 314). The investigator’s choice regimens included paclitaxel at 80 to 100 mg/m2 on days 1, 8, and 15 of every 4‑week cycle; docetaxel at 75 mg/m2 every 3 weeks; or irinotecan at 180 mg/m2 every 2 weeks (control group). Patients with a history of noninfectious pneumonitis that required steroids or current pneumonitis, active autoimmune disease, or a medical condition that required immunosuppression were ineligible. Patients treated with pembrolizumab without disease progression could be treated for up to 24 months. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit.
The primary efficacy outcome measures in the trial were overall survival in patients with squamous cell carcinoma of the esophagus, patients with tumors expressing PD-L1 CPS ≥ 10, and all randomly assigned patients. Overall survival hazard ratios (HRs) for pembrolizumab vs control treatment were 0.77 (95% confidence interval [CI] = 0.63–0.96) in patients with squamous cell carcinoma of the esophagus, 0.70 (95% CI = 0.52– 0.94) in patients with tumors expressing PD-L1 CPS ≥ 10, and 0.89 (95% CI = 0.75–1.05) among all randomly assigned patients.
A total of 167 patients (27% of study population) had squamous cell carcinoma of the esophagus that expressed PD-L1 with a CPS ≥ 10; of them, 85 were in the pembrolizumab group and 82 were in the control group (paclitaxel, n = 50; docetaxel, n = 19; irinotecan, n = 13). Among these patients, the median overall survival was 10.3 months vs 6.7 months (HR = 0.64, 95% CI = 0.46–0.90). With regard to other endpoints, the median progression-free survival was 3.2 vs 2.3 months (HR = 0.66, 95% CI = 0.48–0.92), and the objective response rate was 22% vs 7%.
KEYNOTE-180: In KEYNOTE-180,2,4 121 patients with locally advanced or metastatic esophageal cancer whose disease progressed on or after at least two prior systemic treatments for advanced disease received pembrolizumab at the same dosage as in KEYNOTE-181. Among the 35 patients with squamous cell carcinoma of the esophagus expressing PD-L1 CPS ≥ 10, the objective response rate was 20%. Among the seven responders, response durations ranged from 4.2 to 25.1+ months, with five (71%) having responses of at least 6 months and three (57%) having responses of at least 12 months.
How It Works
Binding of PD-L1 and PD-L2 to the programmed cell death protein 1 (PD-1) receptor found on T cells inhibits T-cell proliferation and cytokine production. Pembrolizumab is an anti–PD-1 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby releasing PD-1 pathway–mediated inhibition of the immune response, including antitumor immune response. Upregulation of PD-1 ligands is observed in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor immune surveillance. In syngeneic mouse models, inhibition of PD-1 activity resulted in decreased tumor growth.
How It Is Used
The recommended dose of pembrolizumab in esophageal cancer is 200 mg via intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
No dose reductions of pembrolizumab are recommended. Treatment should be withheld or discontinued to manage adverse reactions. Pembrolizumab infusion should be interrupted or slowed for grade 1 or 2 infusion-related reactions and permanently discontinued for grade 3 or 4 reactions. Specific management guidelines for immune-mediated adverse events are provided in the warnings/precautions section of product labeling.
Product labeling provides recommended dosing modifications, including withholding, resuming, and discontinuing treatment for the following adverse reactions: immune-mediated pneumonitis; immune-mediated colitis; immune-mediated hepatitis in patients with and without hepatocellular carcinoma; immune-mediated endocrinopathies; immune-mediated nephritis; immune-mediated skin adverse reactions; hematologic toxicity in patients with classical Hodgkin lymphoma or primary mediastinal large B-cell lymphoma; other immune-mediated adverse reactions; recurrent immune-mediated adverse reactions; inability to taper corticosteroid treatment; persistent grade 2 or 3 adverse reactions (excluding endocrinopathy); and infusion-related reactions.
The most common adverse events (reported in ≥ 20% of patients) observed in patients receiving pembrolizumab as a single agent in clinical trials have been fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.
Prescribing information does not provide specific safety data for patients with esophageal cancer receiving pembrolizumab in the KEYNOTE-181 or KEYNOTE-180 studies. It states: “Among the 314 patients with esophageal cancer enrolled in KEYNOTE-181…treated with [pembrolizumab], the median duration of exposure to [pembrolizumab] was 2.1 months (range, 1 day to 24.4 months)…. Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in 2,799 patients with melanoma or [non–small cell lung cancer] treated with [pembrolizumab] as a single agent.”
Pembrolizumab carries warnings/precautions for immune-mediated pneumonitis, colitis, hepatitis (and hepatotoxicity in combination with axitinib), endocrinopathies (including hypophysitis, thyroid disorders, and type 1 diabetes), nephritis, skin adverse reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, and other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation before and after pembrolizumab treatment; and embryofetal toxicity. Treatment of patients with multiple myeloma with a PD-1– or PD-L1–blocking antibody in combination with a thalidomide analog plus dexamethasone is not recommended outside of controlled clinical trials. Patients should be monitored for hepatic, renal, and thyroid function and for hyperglycemia. Patients should be advised not to breastfeed while receiving pembrolizumab. ■
1. U.S. Food and Drug Administration: FDA approves pembrolizumab for advanced esophageal squamous cell cancer. Available at www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-advanced-
esophageal-squamous-cell-cancer. Accessed August 12, 2019.
2. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck & Co, July 2019. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514s055s056lbl.pdf. Accessed August 12, 2019.
3. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase 3 KEYNOTE-181 study. 2019 ASCO Annual Meeting. Abstract 4010. Presented June 3, 2019.
4. 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 5:546-550, 2019.