AT THE GASTROINTESTINAL CANCERS SYMPOSIUM
SAN FRANCISCO (FRONTLINE MEDICAL NEWS) – Two immune checkpoint inhibitors that help restore the antitumor response are active and well tolerated in patients with advanced, generally heavily pretreated gastric and esophageal cancers, according to a pair of early-phase trials reported at the Gastrointestinal Cancers Symposium.
Results from CheckMate-032 showed that nivolumab, an antibody that targets the cell surface receptor programmed death-1 (PD-1), yielded a response rate of 14% in patients with advanced gastric and related cancers. And updated results from KEYNOTE-028 showed that pembrolizumab, another antibody targeting PD-1, led to a response rate of 30% in patients with advanced esophageal and related cancers that expressed the ligand programmed death ligand 1 (PD-L1).
“Checkpoint inhibitors are clearly promising new agents … All compounds are still in development, but we already have at least phase 1 data that they are effective,” commented invited discussant Dr. Markus H. Möhler of the University Medical Center Mainz (Germany). “Combination treatment strategies are clearly under investigation, and it is our task as a scientific community to look into interesting modern combinations, like combinations with antiangiogenic agents or maybe even with stem cell inhibition.”
He commended the KEYNOTE-028 investigators, in particular, for their development of a tumor gene signature that appeared to predict benefit from pembrolizumab.
“Molecular and immunological characterization of the patients is key, and we have seen now in the pembrolizumab study with the six-gene signature the first step in the right direction,” Dr. Möhler said, recommending that it be correlated with data from The Cancer Genome Atlas project, which has identified four distinct molecular subtypes of esophagogastric cancer.
“It is now clear that some of these subtypes express higher PD-L1 compared to the others, particularly inflamed subtypes,” he elaborated. “Therefore, it is clear that all the studies in the future really should try to look into the correlation with these four gene subgroups characterized.”
CheckMate-032 trial
Patients with a variety of solid tumors were eligible for CheckMate-032 , a phase I/II trial. First author Dr. Dung T. Le reported results for 59 patients with locoregionally advanced or metastatic gastric cancer, esophageal, or gastroesophageal junction cancer who had received at least one prior therapy.
The patients were treated with nivolumab (Opdivo) every 2 weeks. (Nivolumab is currently FDA approved for the treatment of melanoma, non–small cell lung cancer, and renal cancer.)
With a median follow-up of 4.6 months, the response rate was 14%, reported Dr. Le of Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, at the symposium, which was sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
However, “PD-L1 expression appears to be numerically associated with a higher objective response rate,” she noted. Specifically, the response rate was 27% among patients whose tumor cells showed 1% or greater PD-L1 staining, and an even higher 33% among those whose tumor cells showed 5% or greater PD-L1 staining.
Median overall survival was 5 months. The 6-month overall survival rate was 49%, and the 12-month rate was 36%.
“The adverse event profile was similar to that seen in patients with other tumor types,” Dr. Le commented.
In all, 17% of patients experienced grade 3 or 4 treatment-related adverse events, and 5% experienced grade 3 or 4 treatment-related serious adverse events. These events included elevation of liver enzymes, pneumonitis, fatigue, diarrhea, and vomiting. There were no treatment-related deaths.
KEYNOTE-028 trial
Patients with various types of advanced solid tumors were eligible for KEYNOTE-028 , a phase Ib trial, if at least 1% of their tumor or inflammatory cells expressed PD-L1. First author Dr. Toshihiko Doi reported results for 23 patients with esophageal or gastroesophageal junction cancer who had experienced failure of standard therapy or were unable to tolerate it.
The patients were treated with pembrolizumab (Keytruda) every 2 weeks. (Pembrolizumab is currently FDA approved for the treatment of melanoma and non–small cell lung cancer.)
With a median follow-up of 7.1 months, the overall response rate was 30%, reported Dr. Doi of the National Cancer Center Hospital East in Chiba, Japan. By tumor histology, it was 29% for squamous cell carcinomas and 40% for adenocarcinomas.
He and his colleagues performed gene expression profiling of tumor tissue, identifying a six-gene interferon gamma signature that appeared predictive.
Specifically, patients with high signature scores, indicating more inflamed tumors, tended to have a better response rate than those with low scores (43% vs. 11%) as well as longer progression-free survival.
In all, 17% of patients experienced grade 3 treatment-related adverse events (reduced appetite, lymphopenia, liver disorder, and pruritic rash). There were no treatment-related deaths or discontinuations. With respect to adverse events of special interest because of their immune etiology, 9% of patients experienced hypothyroidism, 4% adrenal insufficiency, and 4% pruritic rash.
“Further evaluation of pembrolizumab in esophageal cancer is ongoing,” Dr. Doi concluded, pointing to the KEYNOTE-180 trial, which is testing the agent as third-line therapy, and the KEYNOTE-181 trial, which is pitting it against treatment of physician’s choice as second-line therapy.
