2328 - A Pilot Study of Pembrolizumab Combined with Stereotactic Ablative Radiotherapy for Patients with Metastatic Sarcoma
Presenter(s)
J. P. Harris1, K. S. Hanubal1, S. N. Seyedin2, R. Stitzlein3, A. Goldin3, W. P. Chen4, C. McLaren4, and W. Chow5; 1Department of Radiation Oncology, University of California - Irvine, Orange, CA, 2University of California, San Francisco, Department of Radiation Oncology, San Francisco, CA, 3Department of Orthopedic Surgery, University of California - Irvine, Orange, CA, 4Biostatistics Shared Resource, University of California - Irvine, Orange, CA, 5Department of Hematology/Oncology, University of California - Irvine, Orange, CA
Purpose/Objective(s): In SARC028, pembrolizumab demonstrated an 18% overall response rate (ORR) for various soft-tissue sarcomas. Certain subtypes, including undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated/pleomorphic liposarcoma were more likely to respond. Stereotactic body radiation therapy (SBRT) can potentially enhance the antitumor CD8 T cell response and prime a more diverse class of T cell receptors through the release of tumor-specific antigens.
Materials/Methods: We conducted a phase 0, feasibility clinical trial at a single academic center. In Arm A, patients were treated with pembrolizumab 400 mg (42-day cycle), and SBRT was delivered in 1-5 fractions starting on C1D15-28. In Arm B, patients were eligible if they had recently begun pembrolizumab (200 mg on 21-day cycle or 400 mg on 42-day cycle) and were treated with SBRT. iRECIST was used to evaluate unirradiated tumors.
Results: From October, 2022 to May, 2025 the study enrolled 7 patients on Arm A and 2 patients on Arm B, which formed the feasibility cohort. One participant died from progression prior to the start of pembrolizumab, one patient had progression prior to starting SBRT, and one patient died prior to imaging assessment. 6 patients completed =1 cycle of pembrolizumab, SBRT, and imaging reassessment; meeting the pre-specified feasibility threshold and ending enrollment. The median time from start of pembrolizumab to SBRT was 19 days (range 6 to 26 days).
The overall rate of Grade 3-5 events was 62.5% (n=5/8). Treatment-related severe adverse events included two instances of Grade 3 hematologic events (anemia, lymphopenia) and one case of Grade 3 esophagitis in a patient treated with 24 Gy in 4 fractions to a 10.0 cm lung tumor abutting the esophagus. The best responses at unirradiated sites were 3 patients with partial responses (iPR, 2 UPS and 1 dedifferentiated liposarcoma tumors), 1 with stable disease (iSD, a dedifferentiated liposarcoma tumor), and 3 with progressive disease (iCPD or iUPD, 3 UPS tumors); for an ORR of 42.9%. The median PFS for the overall cohort was 18 weeks (range 4 to 95 weeks) and 10 weeks (range 4 to 28 weeks) for non-responders. The longest duration of response was 95 weeks in a patient who received 31 cycles of pembrolizumab (200 mg on 21-day cycle) with a plan for continued pembrolizumab. There were no tertiary lymphoid structures identified on retrospective pathologic review of 6 available specimens. One specimen had incipient lymphoid aggregates, and it was the only tumor positive for PD-L1 (5%); this patient had dedifferentiated liposarcoma and achieved PR. No tumors had a tumor mutational burden =10 (mut/Mb).Conclusion: The combination of SBRT with pembrolizumab was feasible. Although the ORR signal was encouraging, PFS results were on par with prior clinical trial results. With two patients who progressed prior to SBRT and PFS of 10 weeks for non-responders, this small study highlights the challenges of combination therapy in this aggressive disease.