Stereotactic Body Radiation Therapy for Metastatic Colorectal Cancer: Comprehensive Review from a Large Academic Institution

560 Background: AMP-224, a PD-L2 Fc fusion protein, binds to PD-1, an inhibitory receptor that is present on the cell surface of exhausted, activated, effector, and memory T cells. AMP-224 has a unique mechanism of action in that it binds specifically to PD-1HI T cells (chronically stimulated / exhausted T cells) but not PD-1LO cells which represent the normal activated T cell population. Preclinical studies have documented an increase in antitumor immunity following radiation therapy (RT), but also tumor PD-L1 expression as an escape mechanism. The aim of the study is to evaluate whether inhibition of PD-1/PDL-1 axis could improve anti-tumor immunity effects of RT. Methods: Patients with histologically confirmed metastatic colorectal cancer to liver were treated with SBRT to a site of liver metastasis at 8Gy in a single fraction (DL1) or 8Gy in 3 daily fractions (DL2). All patients received AMP-224 10mg/kg IV beginning Day 1 after SBRT preceded by cyclophosphamide 200mg/m2 (D0). Primary objective was to determine the safety and feasibility of AMP-224 in combination with stereotactic body radiation therapy (SBRT) to metastatic hepatic metastasis in patients with advanced colorectal cancer. Mandatory pre- and post-treatment biopsies were attempted on all patients. Results: N = 17 patients with refractory metastatic CRC were enrolled. N = 2 pts were unevaluable. 6pts were treated at DL1 (8Gy x 1fraction SBRT, AMP-224 10mg/kg q2-weekly) and 9pts were treated at DL2 (8Gy x 3fractions SBRT, AMP-224 10mg/kg q2-weekly) No DLT was encountered. The most common toxicity was fatigue (G1/2) in all patients in DL2. N = 3 patients experienced G2 infusion reaction which responded to standard interventions. 5/15 pts did not complete treatment due to rapid PD. No objective responses have been seen, although N = 6 pts remain on study. Pre- and post-tumor biopsies were performed on 7 of first 11 pts. Conclusions: AMP-224 in combination with SBRT to site of colorectal hepatic metastases is safe and feasible. Preliminarily no objective responses have been seen. Full clinical and correlative data including post-therapeutic radiated and non-radiated tumor biopsies will be presented. Clinical trial information: NCT02298946.

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A pilot study of AMP-224—a PD-1 inhibitor—in combination with stereotactic body radiation therapy (SBRT) in patients with metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.tps788 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. TPS788-TPS788 ◽

Cited By ~ 2

Author(s):

Austin G. Duffy ◽

Oxana V. Makarova-Rusher ◽

Suzanne Fioravanti ◽

Melissa Walker ◽

Aradhana Venkatesan ◽

...

Keyword(s):

Colorectal Cancer ◽

T Cells ◽

Radiation Therapy ◽

Pilot Study ◽

Metastatic Colorectal Cancer ◽

Tumor Immunity ◽

Stereotactic Body Radiation Therapy ◽

Cytotoxic T Cells ◽

Stereotactic Body Radiation ◽

Activated T Cell

TPS788 Background: AMP-224, a B7-DC Fc fusion protein, binds to PD-1, an inhibitory receptor that is present on the cell surface of exhausted, activated, effector, and memory T cells. AMP-224 has a unique mechanism of action in that it binds specifically to PD-1HI T cells (chronically stimulated / exhausted T cells) but not to PD-1LOcells which represent the normal activated T cell population. Several preclinical studies have documented an increase in peripheral antitumor immunity following radiation, a phenomenon known as the “abscopal effect”. Tumor PD-L1 expression has also been shown to be induced by radiation, which can suppress the anti-tumor immune response. Inhibition of PD-1/PDL-1 axis has been shown to improve anti-tumor immunity by blocking the tumor-mediated suppression of cytotoxic T cells. The aim of the study is to evaluate whether the anti-tumor immunity of anti-PD1 therapy (with AMP-224) can be enhanced by radiation therapy. Methods: Patients with histologically confirmed metastatic colorectal cancer to liver are being enrolled to this pilot study. The objectives are to determine the safety, tolerability and feasibility of AMP-224 in combination with stereotactic body radiation therapy (SBRT) to metastatic hepatic metastasis in patients with advanced colorectal cancer. Select eligibility are as follows: at least 1 measurable metastatic hepatic lesion by RECIST 1.1 criteria and amenable to SBRT. Patient must have progressed on or been intolerant of at least one prior oxaliplatin- and/or irinotecan-containing regimen and have metastatic lesions that are not amenable to curative resection; ECOG ≤ 1; Life expectancy of greater than 3 months. Acceptable organ and bone marrow function. No active or prior documented autoimmune or inflammatory disorders. Clinical trial information: awaited.

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