A stratified phase I dose escalation trial of hypofractionated radiotherapy followed by ipilimumab in metastatic melanoma: long-term follow-up and final outcomes

References

• Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–8. doi:10.1056/NEJMoa1003466.
   PubMed Web of Science ®Google Scholar
• Bajor DL, Mick R, Riese MJ, Huang AC, Sullivan B, Richman LP, Torigian DA, George SM, Stelekati E, Chen F, et al. Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma. Oncoimmunology. 2018;7:e1468956. doi:10.1080/2162402X.2018.1468956.
   PubMed Web of Science ®Google Scholar
• Demaria S, Kawashima N, Yang AM, Devitt ML, Babb JS, Allison JP,  Formenti SC. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res. 2005;11:728–734.
   PubMed Web of Science ®Google Scholar
• Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, Demaria S. 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.
   PubMed Web of Science ®Google Scholar
• Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520:373–377. doi:10.1038/nature14292.
   PubMed Web of Science ®Google Scholar
• Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, 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.
   PubMed Web of Science ®Google Scholar
• Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, Mu Z, Rasalan T, Adamow M, Ritter E, 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.
   PubMed Web of Science ®Google Scholar
• Luo LY, O’Hara MH, Mitchell TC, Vonderheide RH, Wherry EJ, Minn AJ, Maity A. Combining radiation with immunotherapy: the University of Pennsylvania experience. Semin Radiat Oncol. 2020;30:173–180. doi:10.1016/j.semradonc.2019.12.007.
   PubMed Web of Science ®Google Scholar
• Rodriguez-Ruiz ME, Vanpouille-Box C, Melero I, Formenti SC, Demaria S. Immunological mechanisms responsible for radiation-induced abscopal effect. Trends Immunol. 2018;39:644–655. doi:10.1016/j.it.2018.06.001.
   PubMed Web of Science ®Google Scholar
• Hiniker SM, Reddy SA, Maecker HT, Subrahmanyam PB, Rosenberg-Hasson Y, Swetter SM, Saha S, Shura L, Knox SJ. A prospective clinical trial combining radiation therapy with systemic immunotherapy in metastatic melanoma. Int J Radiat Oncol Biol Phys. 2016;96(3):578–588. doi:10.1016/j.ijrobp.2016.07.005.
   PubMed Web of Science ®Google Scholar
• Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006–2017. doi:10.1056/NEJMoa1414428.
   PubMed Web of Science ®Google Scholar
• Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019;20:1239–1251. doi:10.1016/S1470-2045(19)30388-2.
   PubMed Web of Science ®Google Scholar
• Barker CA, Postow MA, Khan SA, Beal K, Parhar PK, Yamada Y, Lee NY, Wolchok JD. Concurrent radiotherapy and ipilimumab immunotherapy for patients with melanoma. Cancer Immunol Res. 2013;1:92–98. doi:10.1158/2326-6066.CIR-13-0082.
   PubMed Web of Science ®Google Scholar
• Theurich S, Rothschild SI, Hoffmann M, Fabri M, Sommer A, Garcia-Marquez M, Thelen M, Schill C, Merki R, Schmid T, et al. Local tumor treatment in combination with systemic ipilimumab immunotherapy prolongs overall survival in patients with advanced malignant melanoma. Cancer Immunol Res. 2016;4:744–754.
   PubMed Web of Science ®Google Scholar
• Koller KM, Mackley HB, Liu J, Wagner H, Talamo G, Schell TD, Pameijer C, Neves RI, Anderson B, Kokolus KM, et al. Improved survival and complete response rates in patients with advanced melanoma treated with concurrent ipilimumab and radiotherapy versus ipilimumab alone. Cancer Biol Ther. 2017;18:36–42. doi:10.1080/15384047.2016.1264543.
   PubMed Web of Science ®Google Scholar
• Qin R, Olson A, Singh B, Thomas S, Wolf S, Bhavsar NA, Hanks BA, Salama JK, Salama AKS. Safety and efficacy of radiation therapy in advanced melanoma patients treated with ipilimumab. Int J Radiat Oncol Biol Phys. 2016;96:72–77. doi:10.1016/j.ijrobp.2016.04.017.
   PubMed Web of Science ®Google Scholar
• Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, Waterfield W, Schadendorf D, Smylie M, Guthrie T, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155–164. doi:10.1016/S1470-2045(09)70334-1.
   PubMed Web of Science ®Google Scholar
• Chandra RA, Wilhite TJ, Balboni TA, Alexander BM, Spektor A, Ott PA, Ng AK, Hodi FS, Schoenfeld JD. A systematic evaluation of abscopal responses following radiotherapy in patients with metastatic melanoma treated with ipilimumab. Oncoimmunology. 2015;4:e1046028. doi:10.1080/2162402X.2015.1046028.
   PubMed Web of Science ®Google Scholar
• Sundahl N, De Wolf K, Kruse V, Meireson A, Reynders D, Goetghebeur E, Van Gele M, Speeckaert R, Hennart B, Brochez L, et al. Phase 1 dose escalation trial of ipilimumab and stereotactic body radiation therapy in metastatic melanoma. Int J Radiat Oncol Biol Phys. 2018;100:906–915. doi:10.1016/j.ijrobp.2017.11.029.
   PubMed Web of Science ®Google Scholar
• Young KH, Baird JR, Savage T, Cottam B, Friedman D, Bambina S, Messenheimer DJ, Fox B, Newell P, Bahjat KS, et al. Optimizing timing of immunotherapy improves control of tumors by hypofractionated radiation therapy. PLoS One. 2016;11:e0157164. doi:10.1371/journal.pone.0157164.
   PubMed Web of Science ®Google Scholar
• Gandhi SJ, Minn AJ, Vonderheide RH, Wherry EJ, Hahn SM, Maity A. Awakening the immune system with radiation: optimal dose and fractionation. Cancer Lett. 2015;368:185–190. doi:10.1016/j.canlet.2015.03.024.
   PubMed Web of Science ®Google Scholar
• Rogiers A, Boekhout A, Schwarze JK, Awada G, Blank CU, Neyns B. Long-term survival, quality of life, and psychosocial outcomes in advanced melanoma patients treated with immune checkpoint inhibitors. J Oncol. 2019;2019:5269062. doi:10.1155/2019/5269062.
   PubMed Web of Science ®Google Scholar
• Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, Patt D, Chen -T-T, Berman DM, Wolchok JD, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015;33:1889–1894. doi:10.1200/JCO.2014.56.2736.
   PubMed Web of Science ®Google Scholar
• Larkin J, Chiarion-Sileni V, Gonzalez R, Grob -J-J, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381:1535–1546. doi:10.1056/NEJMoa1910836.
   PubMed Web of Science ®Google Scholar
• Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16:908–918. doi:10.1016/S1470-2045(15)00083-2.
   PubMed Web of Science ®Google Scholar
• Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH, Lao CD, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16:375–384. doi:10.1016/S1470-2045(15)70076-8.
   PubMed Web of Science ®Google Scholar
• Marciscano AE, Ghasemzadeh A, Nirschl TR, Theodros D, Kochel CM, Francica BJ, Muroyama Y, Anders RA, Sharabi AB, Velarde E, et al. Elective nodal irradiation attenuates the combinatorial efficacy of stereotactic radiation therapy and immunotherapy. Clin Cancer Res. 2018;24:5058–5071. doi:10.1158/1078-0432.CCR-17-3427.
   PubMed Web of Science ®Google Scholar
• Formenti SC, Rudqvist NP, Golden E, Cooper B, Wennerberg E, Lhuillier C, Vanpouille-Box C, Friedman K, Ferrari de Andrade L, Wucherpfennig KW, et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat Med. 2018;24:1845–1851. doi:10.1038/s41591-018-0232-2.
   PubMed Web of Science ®Google Scholar
• Tang C, Welsh JW, de Groot P, Massarelli E, Chang JY, Hess KR, Basu S, Curran MA, Cabanillas ME, Subbiah V, et al. Ipilimumab with stereotactic ablative radiation therapy: phase I results and immunologic correlates from peripheral T cells. Clin Cancer Res. 2017;23:1388–1396. doi:10.1158/1078-0432.CCR-16-1432.
   PubMed Web of Science ®Google Scholar
• Maity A, Mick R, Huang AC, George SM, Farwell MD, Lukens JN, Berman AT, Mitchell TC, Bauml J, Schuchter LM, et al. A phase I trial of pembrolizumab with hypofractionated radiotherapy in patients with metastatic solid tumours. Br J Cancer. 2018;119:1200–1207. doi:10.1038/s41416-018-0281-9.
   PubMed Web of Science ®Google Scholar