Toshihiko Doi, MD, PhD
The PD-1 inhibitor pembrolizumab (Keytruda) elicited encouraging activity with mild adverse events (AEs) as a treatment for patients with advanced PD-L1–positive esophageal carcinoma, according to findings from the phase Ib KEYNOTE-028 study presented at the 2015 Gastrointestinal Cancers Symposium.
After a median follow-up duration of 7.1 months, the objective response rate (ORR) with pembrolizumab was 30%, which consisted entirely of partial responses. Nine percent of patients had stable disease and more than half of patients treated with pembrolizumab demonstrated some degree of tumor shrinkage.
“KEYNOTE-028 shows promising antitumor activity in a heavily pretreated population. It showed a manageable toxicity profile,” lead investigator Toshihiko Doi, MD, PhD, National Cancer Center Hospital East, Chiba, Japan, said during a presentation of the results. “Further evaluation of pembrolizumab in esophageal cancer is ongoing.”
In the KEYNOTE-028 study, 23 patients with PD-L1–positive esophagus or gastroesophageal junction carcinoma received intravenous pembrolizumab at 10 mg/kg every 2 weeks. The median age of patients, who were primary Asians (52%), was 65 years and most were male (83%). Patients primarily had squamous cell histology (74%) and an ECOG PS of 1 (65%).
Prior to entering the trial, patients had 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%). One patient had received prior treatment with trastuzumab.
PD-L1–positivity was defined as ≥1% expression on tumor or inflammatory cells by immunohistochemistry using the 22C3 antibody. Of those screened, 44.6% were deemed PD-L1–positive. The primary endpoint of the study was ORR, with key secondary outcome measures focused on progression-free survival (PFS), overall survival (OS), duration of response, and safety.
At a data cutoff of November 4, 2015, a statistically significant difference was not observed based upon histology. The response rate for those with squamous cell carcinoma (n = 17) was 29%. In the group with adenocarcinoma (n = 5), the ORR was 40%. Across the study, 56% of patients developed progressive disease. Data for OS and PFS were not yet mature.
A decrease in target lesion burden, defined as any amount of tumor shrinkage from baseline, was experienced by 52.2% of patients treated with pembrolizumab. In most cases, tumor shrinkage persisted on subsequent scans, with up to 70 weeks of follow-up for some patients. The median duration of response was not yet reached (range, 5.5-11.8+ months) and the time to response was 3.7 months (range, 1.8-8.3 months).
“Some patients showed durable responses but in contrast some of the patients had rapid progression within the first cycle, so it is very important to define a biomarker for immune checkpoint treatment,” said Doi.
To help uncover a potential biomarker of response, investigators selected a 6-gene signature that was associated with interferon gamma-related adaptive immune response within the tumor microenvironment. To help inform the findings, a signature score was created based on the normalization of expression values for the 6 genes (IDO1, CXCL10, CXCL9, HLA-DRA, STAT1, IFN-gamma).
Analysis of the signature was conducted following gene expression profiling on formalin-fixed paraffin-embedded tissues samples that were collected at baseline. Overall, those with higher signature scores experienced a more robust response to pembrolizumab and substantial delays in progression. In the non-inflamed, low score group, the ORR was 11% compared with an 43% for those with a higher signature score.
In addition to esophageal cancer, the 6-gene signature demonstrated similar results in samples from patients with head and neck cancer and gastric cancer; however, the test still needs validation and further study. “We have to further examine the responders and the non-responders,” explained Doi.
Treatment-related AEs of any grade occurred in 39% of patients, with 17% experiencing a grade 3 event. There were not any pembrolizumab-related deaths or treatment discontinuations. The most commonly observed grade 1/2 AEs were decreased appetite (9%), hypothyroidism (9%), rash (9%), and adrenal insufficiency (4%). The most frequently seen grade 3 AEs were lymphocytopenia (9%), pruritic rash (4%), liver disorder (4%), and decreased appetite (4%).
“Immune-related adverse events—hypothyroidism, adrenal insufficiency, and rash—these adverse events were recovered from after treatment with proper management, such as corticosteroids and interruption of dosing,” said Doi.