Ipilimumab plus radiotherapy may benefit patients with metastatic melanoma

Christopher Barker, MD

This clinical trial assessed the safety and efficacy of ipilimumab (Yervoy, Bristol-Myers Squibb) and radiotherapy in 22 patients with metastatic melanoma. Earlier this year, a phase 1 clinical trial using a similar combination reported no grade 4 to grade 5 events, and an overall response rate of 18%. The current study reported grade 3 to grade 4 adverse events in 15% of patients. RECIST-defined complete response was noted in 3 of 22 (14%) patients, with an overall response rate of 28%. Correlative immunologic evaluations revealed that higher interleukin-2 (IL-2) expression and central memory CD8-positive T cells were associated with response to therapy. 

We and others have observed the interaction of radiotherapy and immunotherapy for melanoma. Nevertheless, it remains unclear whether the addition of radiotherapy to immunotherapy improves clinical outcome over immunotherapy alone. The complete response rate of 14% in this study is higher than would be expected with ipilimumab alone (0% to 2% in prospective studies), and suggests that radiotherapy may improve response. Similarly, a phase 1 trial of IL-2 and radiotherapy was associated with an overall response rate of 71.4%, which is significantly higher than what is typically observed with IL-2 alone. However, the small number of patients in these studies warrants cautious interpretation.  Ultimately, randomized trials will be necessary to test the hypothesis that radiotherapy improves response to ipilimumab or other immunotherapeutics.

Importantly, the optimal radiotherapeutic approach to combine with immunotherapy has yet to be determined. Compared with the previously reported phase 1 trial of ipilimumab and radiotherapy, the radiation doses in this study were slightly higher and radiation was delivered 5 days after starting ipilimumab, rather than before; these differences may be associated with the difference in observed overall response rate (28% vs. 18%). As the radiation dose, fractionation and targets in this trial were left to physician discretion, interpretation of the safety and efficacy data is somewhat challenging, and further studies using pre-specified radiotherapy parameters seem necessary. Studies detailing the immunomodulatory effects of radiation may help determine the appropriate integration of radiotherapy and immunotherapy.

Finally, combination checkpoint blockade of CTLA-4 and PD-1 with ipilimumab and nivolumab (Opdivo, Bristol-Myers Squibb) appears more effective than ipilimumab alone for melanoma. Therefore, investigating radiotherapy and combination checkpoint blockade seems clinically warranted, particularly in light of preclinical data supporting this strategy.

References:

Barker CA and Postow MA. Int J Radiat Oncol Biol Phys. 2014;doi:10.1016/j.ijrobp.2013.08.035.

Callahan MK and Wolchok JD. Semin Oncol. 2015;doi:10.1053/j.seminoncol.2015.05.008.

Larkin J, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1504030.

Postow MA, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1414428.

Seung SK, et al. Sci Transl Med. 2012;doi:10.1126/scitranslmed.3003649.

Twyman-Saint Victor C, et al. Nature. 2015;doi:10.1038/nature14292.

Shlomo Koyfman, MD

This study is notable for prospectively validating the safety of combining palliative radiotherapy with immunotherapy in metastatic melanoma and resulting in encouraging response data. In addition, novel pro-inflammatory cytokine biomarkers were identified that are promising candidates for predictors of response. This combination is exciting as several preclinical models suggest a potential synergistic effect to combining radiation with immunotherapy and enhancing the innate immune antitumor response through a variety of potential mechanisms. This has spawned a number of clinical trials currently ongoing and in development that investigate this combination in a number of different tumor types.

The conclusions of this study, however, are premature as the lack of a comparison immunotherapy-alone arm precludes the ability to assess how much the radiation in this study contributed to response rates or overall outcomes, especially as the radiation delivered was quite variable in site and dosing. Future randomized studies of immunotherapy with and without radiation are needed to properly test this hypothesis.  Caution must also be paid to the response rate endpoint in this study, especially as the majority of the 55% of responders achieved stable disease only, the benefit of which needs to be understood against the natural history of each patient’s individual tumor. Ultimately, survival endpoints will likely be needed to define a new standard of care. This study laudably investigated biomarkers of response, which should be pursued in all studies testing these combinations of therapeutic modalities, as proper patient selection for these therapies will be crucial to their success.

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