Second-line treatment with pembrolizumab (Keytruda) improved overall survival (OS) versus chemotherapy in patients with advanced or metastatic esophageal or esophagogastric junction carcinoma whose tumors expressed PD-L1, according to topline phase III findings announced by Merck (MSD), the developer of the PD-1 inhibitor.
In the open-label, randomized, phase III KEYNOTE-181 trial (NCT02564263), pembrolizumab was associated with a statistically significant improvement in OS compared with either paclitaxel, docetaxel, or irinotecan in patients with a PD-L1 combined positive score (CPS) ≥10, regardless of histology. Full data will be presented at an upcoming medical meeting and will be submitted to global regulatory agencies, Merck announced in a news release.
“In this pivotal trial, Keytruda resulted in a statistically significant and clinically meaningful improvement over standard chemotherapy in overall survival for patients with advanced esophageal or esophagogastric junction carcinoma whose tumors express PD-L1 with a CPS of 10 or greater,” Roy Baynes, MD, senior vice president and head of global clinical development, chief medical officer, of Merck Research Laboratories, said in the news release. “This marks the sixth tumor type where Keytruda has demonstrated a survival benefit, and represents the first time an anti–PD-1 therapy has achieved overall survival for this patient population.”
In the study, pembrolizumab was investigated in patients with advanced or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of the esophagogastric junction that has progressed following frontline standard therapy. The primary endpoint was OS in all patients, as well as those with PD-L1 CPS ≥10 and in those with squamous cell disease.
More than 600 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.
Although it was directionally favorable, the OS in patients with squamous cell histology and in the entire intent-to-treat population were not found to be statistically significant. Key secondary endpoints—progression-free survival and objective response rate (ORR)—were not formally tested as per the statistical analysis plan.
According to Merck, the safety profile of pembrolizumab was consistent with what has been observed in prior studies.
“We are encouraged by these results of Keytruda as monotherapy in previously treated patients, and look forward to continuing our research efforts in this significant area of unmet need with our ongoing phase III trial, KEYNOTE-590, evaluating Keytruda in combination with chemotherapy as a first-line treatment for patients with esophageal carcinoma,” concluded Baynes.
Phase Ib findings from the KEYNOTE-028 trial demonstrated encouraging activity in patients with advanced PD-L1–positive esophageal carcinoma. At a median follow-up of 7.1 months, the ORR with pembrolizumab was 30%, with a median duration of response of 15 months (range, 6-26).2
Additionally, a 6-gene interferon-γ gene expression signature analysis suggested that delayed progression and increased response occur among those treated with pembrolizumab with higher interferon-γ composite scores.
Patients enrolled on the study previously received adjuvant or neoadjuvant therapy (26%) and various lines of therapy for advanced disease. Most patients had received 2 or ≥3 prior therapies (39% and 48%, respectively). The most common prior therapies were platinum-based chemotherapy (100%) and fluoropyrimidine (91%), and 1 patient had received prior treatment with trastuzumab (Herceptin).
The double-blind, placebo-controlled, randomized phase III KEYNOTE-590 trial (NCT03189719) is examining cisplatin and 5-fluorouracil with pembrolizumab or placebo as first-line treatment for approximately 700 patients with advanced or metastatic esophageal carcinoma. The trial has an estimated completion date of August 2021.
Pembrolizumab was granted an accelerated FDA approval in September 2017 for the treatment of patients with PD-L1–positive recurrent or advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received 2 or more lines of chemotherapy, including fluoropyrimidine- and platinum-containing chemotherapy, and, if appropriate, HER2/neu-targeted therapy.
The decision was based on data from the phase II KEYNOTE-059 study, in which the ORR in PD-L1–positive patients with microsatellite stable tumor status or undetermined microsatellite instability or mismatch repair status was 13.3% (95% CI, 8.2-20.0), including a complete response rate of 1.4% and a partial response rate of 11.9%.3
Pembrolizumab is also approved for melanoma, lung cancer, head and neck cancer, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, microsatellite instability-high cancer, cervical cancer, and hepatocellular carcinoma.
- Merck. Merck’s KEYTRUDA® (pembrolizumab) significantly improved overall survival (OS) compared to chemotherapy in patients with advanced esophageal or esophagogastric junction carcinoma whose tumors express PD-L1 (CPS ≥10). Published November 14, 2018. https://bit.ly/2Q35yMs. Accessed November 14, 2018.
- Doi T, Piha-Paul SA, Jalal SI, et al. Safety and antitumor activity of the anti–programmed death-1 antibody pembrolizumab in patients with advanced esophageal carcinoma. J Clin Oncol. 2018;36(1):61-67. doi: 10.1200/JCO.2017.74.9846.
- Merck. FDA approves Merck’s KEYTRUDA® (pembrolizumab) for previously treated patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction cancer whose tumors express PD-L1 (CPS greater than or equal to 1). Published September 22, 2017. http://bit.ly/2wberGs. Accessed September 22, 2017.