The checkpoint inhibitor pembrolizumab (Keytruda) was well tolerated and demonstrated results in patients with PD-L1–positive, advanced esophageal tumors in the Merck-sponsored phase IB KEYNOTE-028 trial.
As shown in the study, published online in the Journal of Clinical Oncology, there were partial responses in seven of 23 heavily pretreated patients, for an overall response rate (ORR) of 30%.
The median duration of response was 15 months, and 12 patients (53%) showed a decrease in target lesion burden. Nine patients had treatment-related adverse effects — most commonly reduced appetite, decreased lymphocyte count, and rash.
“There is a high unmet need for effective and well-tolerated treatments for patients with advanced esophageal carcinoma,” the researchers wrote. “Pembrolizumab demonstrated manageable toxicity and durable antitumor activity in patients with heavily pretreated, PD-L1–positive advanced esophageal carcinoma.”
KEYNOTE-028 is an international trial of pembrolizumab in patients with 20 different types of PD-L1–positive advanced solid tumors. Patients in the esophageal carcinoma cohort were enrolled at nine sites in France, Japan, the Republic of Korea, Taiwan, the United Kingdom, and the United States.
Patients could participate if they were age 18 or older, had measurable disease at baseline, had an Eastern Cooperative Oncology Group performance status of 0 or 1, demonstrated adequate organ function, and had PD-L1–positive, squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction for which standard therapy did not exist or was ineffective.
Participants received 10 mg/kg of pembrolizumab intravenously once every 2 weeks for up to 2 years or until progression was confirmed, toxicity became intolerable, or the patient or investigator decided to stop. Patients had computed tomography (CT) or magnetic resonance imaging (MRI) scans every 8 weeks for the first 6 months and every 12 weeks thereafter. The researchers also profiled the gene expression of each patient’s tumor tissue.
Primary endpoints of the study were safety and overall response rate (ORR). Secondary endpoints were progression-free survival, overall survival, and duration of response.
Of the 23 patients enrolled in the study, 83% were men and 78% had squamous cell carcinoma histology; median age was 65. All but one patient had received previous therapy for advanced/metastatic disease; 87% had received at least two previous therapies for advanced/metastatic disease, and most (61%) had received previous radiation therapy.
The ORR was 30% (95% CI 13-53); all seven responses were confirmed partial responses. Of these seven patients, three (43%) had received prior radiation therapy. There was no discernible pattern in the previous chemotherapy regimen among these patients. For patients with squamous cell carcinoma, ORR was 28% (five of 18 patients); for those with adenocarcinoma, ORR was 40% (two of five patients).
Twelve patients (52%) experienced a decrease from baseline in target lesion burden; tumors shrank a median of -44.7% (range, -77.7 to -2.7).
Median progression-free survival was 1.8 months (95% CI 1.7-2.9); 6- and 12-month progression-free survival rates were 30% and 22%, respectively. Median overall survival was 7 months (95% CI 4.3-17.7); the overall survival rate was 60% at 6 months and 40% at 12 months.
All-grade treatment-related adverse events occurred in nine patients. Rash in three patients (13%), and reduced appetite and decreased lymphocyte count in two patients (9%) each, were most common.
Four patients had grade 3 treatment-related adverse events — two patients had decreased lymphocyte count, and one patient each had decreased appetite, liver disorder, and generalized rash. None had grade 4 adverse events.
Three patients had treatment-related serious adverse events: grade 2 pemphigoid, grade 3 decreased appetite, and grade 3 liver disorder in one patient each. No patients died because of a treatment-related adverse event.
The overall safety profile in the study was similar to that previously reported for pembrolizumab in patients with other advanced malignancies, the authors noted. Similar to the results from other studies of immune checkpoint inhibition in cancer, only a subset of patients with PDL1–positive esophageal cancer showed a clinical benefit from PD-1 blockade, suggesting that additional biomarkers could help predict clinical response.
Gene analysis showed delayed progression and increased response among pembrolizumab-treated patients with higher interferon-γ composite scores, consistent with findings in head and neck and gastric cancer, the researchers reported. However, they cautioned, there are limitations to this analysis, including the small sample size, variability in tissue biopsy storing, and potential sampling bias.
“These preliminary results regarding the potential predictive value of gene expression signature for pembrolizumab activity in esophageal carcinoma will therefore require additional exploration in a larger patient population.”
In addition, the team added, because all patients enrolled in KEYNOTE-028 had tumors with some degree of PD-L1 expression, the study cannot provide information about pembrolizumab in patients with advanced esophageal carcinoma and PD-L1–negative tumors.
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