A phase I trial of pembrolizumab with hypofractionated radiotherapy in patients with metastatic solid tumours
Amit Maity, Rosemarie Mick, Alexander C Huang, Sangeeth M George, Michael D Farwell, John N Lukens, Abigail T Berman, Tara C Mitchell, Josh Bauml, Lynn M Schuchter, Mark O'Hara, Lilie L Lin, Angela Demichele, John P Christodouleas, Naomi B Haas, Dana M Patsch, Stephen M Hahn, Andy J Minn, E John Wherry, Robert H Vonderheide, Amit Maity, Rosemarie Mick, Alexander C Huang, Sangeeth M George, Michael D Farwell, John N Lukens, Abigail T Berman, Tara C Mitchell, Josh Bauml, Lynn M Schuchter, Mark O'Hara, Lilie L Lin, Angela Demichele, John P Christodouleas, Naomi B Haas, Dana M Patsch, Stephen M Hahn, Andy J Minn, E John Wherry, Robert H Vonderheide
Abstract
Background: We conducted a phase I trial evaluating pembrolizumab+hypofractionated radiotherapy (HFRT) for patients with metastatic cancers.
Methods: There were two strata (12 patients each): (i) NSCLC/melanoma progressing on prior anti-PD-1 therapy, (ii) other cancer types; anti-PD-1-naive. Patients received 6 cycles of pembrolizumab, starting 1 week before HFRT. Patients had ≥2 lesions; only one was irradiated (8 Gy × 3 for first half; 17 Gy × 1 for second half in each stratum) and the other(s) followed for response.
Results: Of the 24 patients, 20 (83%) had treatment-related adverse events (AEs) (all grade 1 or 2). There were eight grade 3 AEs, none treatment related. There were no dose-limiting toxicities or grade 4/5 AEs. Stratum 1: two patients (of 12) with progression on prior PD-1 blockade experienced prolonged responses (9.2 and 28.1 months). Stratum 2: one patient experienced a complete response and two had prolonged stable disease (7.4 and 7.0 months). Immune profiling demonstrated that anti-PD-1 therapy and radiation induced a consistent increase in the proliferation marker Ki67 in PD-1-expressing CD8 T cells.
Conclusions: HFRT was well tolerated with pembrolizumab, and in some patients with metastatic NSCLC or melanoma, it reinvigorated a systemic response despite previous progression on anti-PD-1 therapy.
Clinical trial registration: NCT02303990 ( www.clinicaltrials.gov ).
Conflict of interest statement
Merck, which manufactures pembrolizumab, provided the drug for free and provided personnel support via an investigator-sponsored research agreement to A.M. The authors declare no competing interests.
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References
- Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359:1350–1355. doi: 10.1126/science.aar4060.
- Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr. Opin. Immunol. 2012;24:207–212. doi: 10.1016/j.coi.2011.12.009.
- Gandhi SJ, et al. Awakening the immune system with radiation: Optimal dose and fractionation. Cancer Lett. 2015;368:185–190. doi: 10.1016/j.canlet.2015.03.024.
- Vanpouille-Box C, Formenti SC, Demaria S. Toward precision radiotherapy for use with immune checkpoint blockers. Clin. Cancer Res. 2018;24:259–265. doi: 10.1158/1078-0432.CCR-16-0037.
- Weichselbaum RR, Liang H, Deng L, Fu YX. Radiotherapy and immunotherapy: a beneficial liaison? Nat. Rev. Clin. Oncol. 2017;14:365–379. doi: 10.1038/nrclinonc.2016.211.
- Reits EA, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J. Exp. Med. 2006;203:1259–1271. doi: 10.1084/jem.20052494.
- Burnette BC, et al. The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Cancer Res. 2011;71:2488–2496. doi: 10.1158/0008-5472.CAN-10-2820.
- Gupta A, et al. Radiotherapy promotes tumor-specific effector CD8+T cells via dendritic cell activation. J. Immunol. 2012;189:558–566. doi: 10.4049/jimmunol.1200563.
- Lugade AA, et al. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J. Immunol. 2005;174:7516–7523. doi: 10.4049/jimmunol.174.12.7516.
- Harding SM, et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature. 2017;548:466–470. doi: 10.1038/nature23470.
- Chakravarty PK, et al. Flt3-ligand administration after radiation therapy prolongs survival in a murine model of metastatic lung cancer. Cancer Res. 1999;59:6028–6032.
- Golden EB, Demaria S, Schiff PB, Chachoua A, Formenti SC. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol. Res. 2013;1:365–372. doi: 10.1158/2326-6066.CIR-13-0115.
- Postow MA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 2012;366:925–931. doi: 10.1056/NEJMoa1112824.
- Twyman-Saint Victor C, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520:373–377. doi: 10.1038/nature14292.
- Deng L, Liang H, Fu S, Weichselbaum RR, Fu YX. From DNA damage to nucleic acid sensing: a strategy to enhance radiation therapy. Clin. Cancer Res. 2016;22:20–25. doi: 10.1158/1078-0432.CCR-14-3110.
- Dovedi SJ, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 2014;74:5458–5468. doi: 10.1158/0008-5472.CAN-14-1258.
- Herter-Sprie GS, et al. Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer. JCI Insight. 2016;1:e87415. doi: 10.1172/jci.insight.87415.
- Park SS, et al. PD-1 restrains radiotherapy-induced abscopal effect. Cancer Immunol. Res. 2015;3:610–619. doi: 10.1158/2326-6066.CIR-14-0138.
- Sharabi AB, et al. Stereotactic radiation therapy augments antigen-specific PD-1-mediated antitumor immune responses via cross-presentation of tumor antigen. Cancer Immunol. Res. 2015;3:345–355. doi: 10.1158/2326-6066.CIR-14-0196.
- Eisenhauer EA, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur. J. Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026.
- Huang AC, et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature. 2017;545:60–65. doi: 10.1038/nature22079.
- Daud AI, et al. Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma. J. Clin. Invest. 2016;126:3447–3452. doi: 10.1172/JCI87324.
- Hamid O, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 2013;369:134–144. doi: 10.1056/NEJMoa1305133.
- Reck M, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 2016;375:1823–1833. doi: 10.1056/NEJMoa1606774.
- Weber JS, Yang JC, Atkins MB, Disis ML. Toxicities of immunotherapy for the practitioner. J. Clin. Oncol. 2015;33:2092–2099. doi: 10.1200/JCO.2014.60.0379.
- Luke JJ, et al. Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J. Clin. Oncol. 2018;36:1611–1618. doi: 10.1200/JCO.2017.76.2229.
- Ribeiro Gomes J, et al. Analysis of the abscopal effect with anti-PD1 therapy in patients with metastatic solid tumors. J. Immunother. 2016;39:367–372. doi: 10.1097/CJI.0000000000000141.
- Hodi FS, et al. Evaluation of immune-related response criteria and RECISTv1.1 in patients with advanced melanoma treated with pembrolizumab. J. Clin. Oncol. 2016;34:1510–1517. doi: 10.1200/JCO.2015.64.0391.
- Dewan MZ, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin. Cancer Res. 2009;15:5379–5388. doi: 10.1158/1078-0432.CCR-09-0265.
- Vanpouille-Box C, et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 2017;8:15618–15632. doi: 10.1038/ncomms15618.
- Antonia SJ, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N. Engl. J. Med. 2017;377:1919–1929. doi: 10.1056/NEJMoa1709937.
- Nanda R, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J. Clin. Oncol. 2016;34:2460–2467. doi: 10.1200/JCO.2015.64.8931.
- Topalian SL, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 2012;366:2443–2454. doi: 10.1056/NEJMoa1200690.
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