Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma

Abstract

New, effective therapies are needed for pancreatic ductal adenocarcinoma. Ipilimumab can mediate an immunologic tumor regression in other histologies. This phase II trial evaluated the efficacy of Ipilimumab for advanced pancreatic cancer. Subjects were adults with locally advanced or metastatic pancreas adenocarcinoma with measurable disease, good performance status, and minimal comorbidities. Ipilimumab was administered intravenously (3.0 mg/kg every 3 wk; 4 doses/course) for a maximum of 2 courses. Response rate by response evaluation criteria in solid tumors criteria and toxicity were measured. Twenty-seven subjects were enrolled (metastatic disease: 20 and locally advanced: 7) with median age of 55 years (27 to 68 y) and good performance status (26 with Eastern Cooperative Oncology Group performance status =0 to 1). Three subjects experienced ≥ grade 3 immune-mediated adverse events (colitis:1, encephalitis:1, hypohysitis:1). There were no responders by response evaluation criteria in solid tumors criteria but a subject experienced a delayed response after initial progressive disease. In this subject, new metastases after 2 doses of Ipilimumab established progressive disease. But continued administration of the agent per protocol resulted in significant delayed regression of the primary lesion and 20 hepatic metastases. This was reflected in tumor markers normalization, and clinically significant improvement of performance status. Single agent Ipilimumab at 3.0 mg/kg/dose is ineffective for the treatment of advanced pancreas cancer. However, a significant delayed response in one subject of this trial suggests that immunotherapeutic approaches to pancreas cancer deserve further exploration.

FIGURE 1.

Maximal response in sum of maximal diameters of index lesions for subjects in this study. The single patient with a decrease exceeding 30% was not a responder by RECIST criteria due to new lesions at evaluation. These lesions subsequently regressed. Two patients with locally advanced disease showed a minor response.

FIGURE 2.

Overall survival of patients on trial. One patient is lost to follow-up after progression of disease at 12 weeks. Many patients entered with metastatic disease receiving Ipilimumab as second line therapy. Short survival is characteristic for these patients.

FIGURE 3.

A patient with pancreas adenocarcinoma was treated with Ipilimumab (3 mg/kg) every 3 weeks with immune-mediated tumor regression evident after the mid-course 1 evaluation. A–C, The primary tumor (white arrows with the letter “P”) and liver metastases (white arrows) regress after mid-course 1 evaluation in representative tumors. Four new metastases developed between start of treatment and the midcourse evaluation. A new metastasis is shown by the right hepatic vein at midcourse evaluation in (B). D, Tumor markers during the 2 courses of treatment show a decline in all measures after mid course-1 evaluation. E, Change in tumor size relative to size at the presentation of the lesion. Four new hepatic metastases are depicted at mid course-1 evaluation with baseline tumor size measured at 100% at this time point