Combining pembrolizumab and palliative radiotherapy in gastroesophageal cancer to enhance anti-tumor T-cell response and augment the abscopal effect.

Abstract

TPS220 Background: Pembrolizumab has demonstrated encouraging preliminary evidence of activity in small cohorts of gastroesophageal cancer patients (pts) when selected for tumor PD-L1 overexpression. Strategies should be further developed to enhance the potency of PD-1 inhibitors, even in pts whose tumors are not considered to have detectable PD-L1 expression. The abscopal effect is a rarely observed though well annotated clinical phenomenon in cancer radiotherapy (RT), in which non-irradiated metastatic lesions are noted to regress after radiation to the primary tumor site. In preclinical models, this phenomenon has been attributed to immune-mediated effects, while RT has been observed to increase tumor PD-L1 expression. This lends credence to ongoing efforts to combine RT and immune checkpoint inhibition. We present the study design for a phase II trial combining pembrolizumab and palliative RT in metastatic gastroesophageal squamous cell and adenocarcinoma pts. Methods: A target accrual of 14 pts will be assigned to palliative RT of 30 Gy over 10 fractions for symptoms from their primary tumor or a single target metastatic site in combination with fixed dose pembrolizumab 200 mg every 3 weeks. Symptomatic brain metastases will be excluded. Pembrolizumab will be continued until disease progression, intolerable toxicity, or 35 administrations (~2 years). Pts will be required to undergo sequential biopsies of a non-target metastatic site (inclusive of malignant ascites) with timepoints occurring pre-treatment and ~21 days after completion of RT. Biomarkers of immune response and overall response rate (RECIST1.1, irRECIST) will be a composite primary endpoint; progression-free and overall survival, and toxicities will be secondary endpoints. Quantitative spatial image analyses of biopsy samples will be performed to examine changes in tumor cell-stromal interactions inclusive of CD4, CD8, Treg, and MDSC populations as well as tumor PD-L1/PD-1 expression levels. The results will assist in determining mechanisms of response and resistance to combination RT and PD-1 targeting strategies. Clinical trial information: NCT02830594.