Toshihiko Doi, MD, PhD
Pembrolizumab (Keytruda) induced an overall response rate (ORR) of 30% (95% CI, 13%-53%) in patients with heavily pretreated, PD-L1–positive advanced esophageal carcinoma, according to findings from the phase Ib KEYNOTE-028 trial published in the Journal of Clinical Oncology.
All 7 responses were partial responses. Two additional patients experienced confirmed stable disease.
“There is a high unmet need for effective and well-tolerated treatments for patients with advanced esophageal carcinoma,” first author Toshihiko Doi, MD, PhD, Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Japan, and co-investigators wrote. “Pembrolizumab demonstrated promising preliminary antitumor activity and a manageable safety profile in this heavily pretreated population of patients with PD-L1–positive advanced squamous cell carcinoma or adenocarcinoma of the esophagus.”
KEYNOTE-028 is an international, multicenter, multicohort trial of pembrolizumab in patients with 20 different types of PD-L1–positive advanced solid tumors with high unmet need. Patients in the esophageal carcinoma cohort were enrolled at nine investigational sites in France, Japan, South Korea, Taiwan, the UK, and the US.
Eligible patients in this cohort had PD-L1–positive, histologically or cytologically confirmed, locally advanced, or metastatic squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction adenocarcinoma for which prior standard therapy was ineffective, or for which standard therapy did not exist or was not considered appropriate.
Investigators evaluated PD-L1 status in 83 patients and ultimately enrolled 23 patients from March 2014 to June 2014. Patients received 10 of mg/kg pembrolizumab every 2 weeks for up to 2 years or until confirmed progression, intolerable toxicity, or patient or investigator decision to discontinue. Computed tomography or magnetic resonance imaging was performed every 8 weeks for the first 6 months and every 12 weeks thereafter.
Median age was 65 years, 83% of patients were men, and 78% had squamous cell carcinoma histology. Nearly two-thirds of patients (61%) had received previous radiation therapy. All patients had received platinum-based therapy for early-stage or advanced/metastatic disease. All but 1 patient had received previous therapy for advanced/metastatic disease and 87% had received at least 2 previous therapies for advanced/metastatic disease.
As of the data cutoff date of February 20, 2017, the median follow-up duration was 7 months (range, 1-33) and 21 patients (91%) had discontinued treatment, mostly for progressive disease (57%) or adverse events (AEs; 9%).
Twelve patients (52%) experienced a decrease from baseline in target lesion burden, which was generally maintained across subsequent tumor assessments. The median decrease from baseline in target lesion burden was -44.7% (range, -77.7% to -22.7%).
Among the 7 patients with a confirmed partial response, 3 had received prior radiation therapy. By histologic subtype, ORR was 28% (5 of 18 patients) for patients with squamous cell carcinoma and 40% (2 of 5 patients) for those with adenocarcinoma.
Median progression-free survival (PFS) was 1.8 months (95% CI, 1.7-2.9). PFS was 30% at 6 months and 22% at 12 months. Median overall survival (OS) was 7.0 months (95% CI, 4.3-17.7). OS at 6 months was 60% and 40% at 12 months.
All 23 patients were included in the safety analysis and 9 experienced treatment-related AEs. Rash/generalized rash was the most commonly reported AE (3 patients) along with decreased appetite and decreased lymphocyte count (2 patients each).
Four patients (17%) experienced grade 3 treatment-related AEs. These included 2 patients who had decreased lymphocyte count, and 1 incidence each of decreased appetite, liver disorder, and generalized rash. All of the grade 3 treatment-related AEs resolved with either discontinuation (liver disorder), no action taken (decreased appetite and one event of decreased lymphocyte count), or dose interruption (for one event of decreased lymphocyte count and for generalized rash).
Three patients experienced serious treatment-related AEs: grade 2 pemphigoid, grade 3 decreased appetite, and grade 3 liver disorder in 1 patient each. All resolved with either discontinuation (liver disorder) or no action taken (pemphigoid and decreased appetite). There were no deaths due to treatment-related AEs.
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 [published online November 8, 2017]. J Clin Oncol doi: 10.1200/JCO.2017.74.9846.