Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors
Open accessAbstract
Purpose: Stereotactic body radiotherapy (SBRT) may stimulate innate and adaptive immunity to augment immunotherapy response. Multisite SBRT is an emerging paradigm for treating metastatic disease. Anti-PD-1–treatment outcomes may be improved with lower disease burden. In this context, we conducted a phase I study to evaluate the safety of pembrolizumab with multisite SBRT in patients with metastatic solid tumors. Patients and Methods: Patients progressing on standard treatment received SBRT to two to four metastases. Not all metastases were targeted, and metastases > 65 mL were partially irradiated. SBRT dosing varied by site and ranged from 30 to 50 Gy in three to five fractions with predefined dose de-escalation if excess dose-limiting toxicities were observed. Pembrolizumab was initiated within 7 days after completion of SBRT. Pre- and post-SBRT biopsy specimens were analyzed in a subset of patients to quantify interferon-γ–induced gene expression. Results: A total of 79 patients were enrolled; three patients did not receive any treatment and three patients only received SBRT. Patients included in the analysis were treated with SBRT and at least one cycle of pembrolizumab. Most (94.5%) of patients received SBRT to two metastases. Median follow-up for toxicity was 5.5 months (interquartile range, 3.3 to 8.1 months). Six patients experienced dose-limiting toxicities with no radiation dose reductions. In the 68 patients with imaging follow-up, the overall objective response rate was 13.2%. Median overall survival was 9.6 months (95% CI, 6.5 months to undetermined) and median progression-free survival was 3.1 months (95% CI, 2.9 to 3.4 months). Expression of interferon-γ–associated genes from post–SBRT tumor biopsy specimens significantly correlated with nonirradiated tumor response. Conclusion: Multisite SBRT followed by pembrolizumab was well tolerated with acceptable toxicity. Additional studies exploring the clinical benefit and predictive biomarkers of combined multisite SBRT and PD-1–directed immunotherapy are warranted.
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Accumulating evidence indicates that chemotherapy, radiotherapy, angiogenesis inhibitor, STING agonist, FMT, epigenetic modulators, or other immunomodulators could synergize α-PD-1/PD-L1, by enhancing cancer antigen release, APC function, or effector activity.
“Accumulating evidence indicates that chemotherapy, radiotherapy, angiogenesis inhibitor, stimulator of interferon genes (STING) agonist, fecal microbiota transplantation (FMT), epigenetic modulators, or other immunomodulators could synergize α-PD-1/PD-L1, by enhancing cancer antigen release, APC function, or effector activity [22–31].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [24]
α-PD-1/PD-L1 combined with SBRT was well-tolerable in a phase 1 study NCT02608385.
“The results of the phase 1 study NCT02608385 demonstrated that α-PD-1/PD-L1 combined with SBRT was well-tolerable (Table 3) [24].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [24]
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- Authors
- Luke, J. J., Lemons, J. M., Karrison, T. G., Pitroda, S. P., Melotek, J. M., Zha, Y., Al-Hallaq, H. A., Arina, A., Khodarev, N. N., Janisch, L., Chang, P., Patel, J. D., Fleming, G. F., Moroney, J., Sharma, M. R., White, J. R., Ratain, M. J., Gajewski, T. F., Weichselbaum, R. R., & Chmura, S. J.
- Affiliations
- University of Chicago (US)
- Jason J. Luke, Jeffrey M. Lemons, Theodore G. Karrison, Sean P. Pitroda, James M. Melotek, Yuanyuan Zha, Hania A. Al-Hallaq, Ainhoa Arina, Nikolai N. Khodarev, Linda Janisch, Paul Chang, Jyoti D. Patel, Gini F. Fleming, John Moroney, Manish R. Sharma, Mark J. Ratain, Thomas F. Gajewski, Ralph R. Weichselbaum, and Steven J. Chmura, The University of Chicago, Chicago, IL; Julia R. White, The Ohio State University, Columbus, OH.
- Corresponding author
- Chmura, Steven J.
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2018-06-01
- Volume
- 36
- Issue
- 16
- Pages
- 1611-1618
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC5978468
- OpenAlex
- W2787553571
- Cited by
- 588
- References
- 30
- Citations by year
- 2026: 29 · 2025: 54 · 2024: 59 · 2023: 79 · 2022: 73 · 2021: 92 · 2020: 92 · 2019: 74 · 2018: 36
- FWCI
- 27.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (K12CA139160, P30CA014599)
- National Center for Research Resources (UL1RR024999)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Physical Sciences › Physics and Astronomy › Radiation › Advanced Radiotherapy Techniques
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Brain Metastases and Treatment
- Keywords
- pembrolizumab, stereotactic body radiotherapy, metastatic solid tumors, anti-PD-1 therapy, radiosensitization, dose-limiting toxicity, objective response rate, overall survival
- MeSH terms
- Antineoplastic Agents, Immunological, Adult, Aged, Aged, 80 and over, Biopsy, Combined Modality Therapy, Dose-Response Relationship, Radiation, Female, Humans, Male, Middle Aged, Neoplasm Metastasis, Neoplasms, Radiotherapy Dosage, Radiosurgery, Treatment Outcome, Antibodies, Monoclonal, Humanized, Response Evaluation Criteria in Solid Tumors
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