Melanoma and Radioimmunotherapy
Immune checkpoint blockade immunotherapy is rapidly changing the standard of care for advanced melanoma and lung cancer. The PD-1/PD-L1 and CTLA-4 immune checkpoint pathways protect against autoimmune disease, ensuring that immune cells do not attack “self” cells or tissues, but tumors can sometimes co-opt these signaling pathways to evade immune attack. Immune checkpoint blockade disrupts this evasion technique to facilitate T-cell-mediated antitumor immunity. These immunotherapeutic agents were pioneered in the treatment of melanoma.3,4,6,7
Continue Reading
Authors of a recent systematic review of 16 clinical trials reporting abscopal effects among a total of 451 patients who underwent both ipilimumab CLTA-4-targeting immune checkpoint blockade and radiotherapy for metastatic melanoma reported increased abscopal response rates and improved overall survival without increased toxicities.4 They called for prospective randomized, controlled clinical trials to confirm the link.4 The median reported abscopal effect was 26.5% and toxicity rates for grade 3 or higher adverse events ranged from 10% to 20% (median 18%) in both study treatment and control groups.4 The most frequent toxicities associated with ipilimumab monotherapy and radioimmunotherapy alike were immune-mediated colitis, skin and mucosal toxicity, and diarrhea.4
A retrospective database records review at the Washington University School of Medicine similarly found improved overall survival among patients with metastatic melanoma brain tumors who had undergone immunotherapy plus stereotactic brain radiosurgery (median 11.1 months vs 6.2 months for patients undergoing radiosurgery without immunotherapy).6
The same research team separately reported that among patients treated for extracranial metastatic melanoma, those receiving radiotherapy in addition to immunotherapy experienced significantly shorter overall survival (median OS 15.4 vs 19.4; P =.02).7 However, this was very likely an artifact caused by the inclusion of patients with bone metastases in the radiotherapy group; in a subsequent multivariate analysis, only patients undergoing bone radiotherapy experienced worse outcomes.7
The timing and sequencing of radiotherapy and immunotherapy also mattered, the study suggested. Patients who received radiotherapy at least 30 days prior to immunotherapy for soft-tissue melanoma metastases experienced longer overall survival times than those treated within 30 days of immunotherapy initiation or postimmunotherapy radiotherapy (26.1 vs 16.0 vs 15.4 months; P <.01).7
“The site and timing of radiotherapy may have important interaction with immunotherapy and need to be carefully considered in future clinical trials,” the authors cautioned.7
Bryant Furlow is a medical reporter based in Albuquerque, New Mexico.
References
1. Rodriguez-Ruiz ME, Vanpouille-Box C, Melero I, Formenti SC, Demaria S. Immunological mechanisms responsible for radiation-induced abscopal effect. Trends Immunol. 2018;39(8):644-655.
2. Sindoni A, Minutoli F, Ascenti G, Pergolizzi S. Combination of immune checkpoint inhibitors and radiotherapy: review of the literature. Crit Rev Oncol Hematol. 2017;113:63-70.
3. Ahmed KA, Kim S, Harrison LB. Novel opportunities to use radiation therapy with immune checkpoint inhibitors for melanoma management. Surg Oncol Clin N Am. 2017;26(3):515-529.
4. Chicas-Sett R, Morales-Orue I, Rodriguez-Abreu D, Lara-Jimenez P. Combining radiotherapy and ipilimumab induces clinically relevant radiation-induced abscopal effects in metastatic melanoma patients: a systematic review. Clin Transl Radiat Oncol. 2018;9:5-11.
5. Franceschini D, Franzese C, Navarria P, et al. Radiotherapy and immunotherapy: can this combination change the prognosis of patients with melanoma brain metastases? Cancer Treat Rev. 2016;50:1-8.
6. Gabani P, Fischer-Valuck BW, Johanns TM, et al. Stereotactic radiosurgery and immunotherapy in melanoma brain metastasis: patterns of care and treatment outcomes [published online June 27, 2018]. Radiother Oncol. doi: 10.1016/j.radonc.2018.06.017
7. Gabani P, Robinson CG, Ansstas G, Johanns TM, Huang J. Use of extracranial radiation therapy in metastatic melanoma patients receiving immunotherapy. Radiother Oncol. 2018;127(2):310-317.
8. Demaria S, Kawashima N, Yang AM, et al. Immune-mediated inhibition of metastasis after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res. 2005;11(2):728-734.
9. Honeychurch J, Illidge TM. The influence of radiation in the context of developing combination immunotherapies in cancer. Ther Adv Vaccines Immunother. 2017;5(6):115-122. doi: 10.1177/2051013617750561
10. Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124(2):687-695.
11. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366(10):925-931.
12. Grimaldi AM, Simeone E, Giannarelli D, et al. Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy. Oncoimmunology. 2014;3:e28780.
13. Shaverdian N, Lisberg AE, Bornazyan K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol. 2017;18(7):895-903.
