Concurrent Radiotherapy and Ipilimumab Immunotherapy for Patients with Melanoma

Discussion

This study was designed to assess the safety of concurrent non-brain radiotherapy and ipilimumab immunotherapy in patients with melanoma. Prior research suggested that radiotherapy during immunotherapy might be associated with high rates of AEs (7–9). Moreover, CTLA-4 blockade targets lymphocytes, which are known to be exquisitely sensitive to radiation, but it was not known whether radiotherapy might compromise the benefit of ipilimumab treatment. We found that the rates of local AEs or systemic ir-AEs were not increased with concurrent radiotherapy and ipilimumab treatment. Furthermore, combining these treatments did not compromise the local and survival benefits of radiotherapy and ipilimumab, respectively.

Of the 333 patients who received ipilimumab immunotherapy for metastatic or unresectable melanoma at our institution, 49% also received radiotherapy. This is consistent with results from a previous study based on an analysis of a United States medical claims database indicating that 45% of patients with metastatic melanoma receive radiotherapy (3). However, of all patients receiving ipilimumab for melanoma, very few (8.7%) received non-brain radiotherapy between their first and last doses of ipilimumab. This could be because of the short duration of immunotherapy relative to the longer duration of time that many patients live with metastatic melanoma. Alternatively, radiotherapy may not have been permitted as part of the treatment on research protocols. Likewise, clinicians may have been reluctant to prescribe radiotherapy during ipilimumab immunotherapy because of concerns about excessive toxicity or compromised efficacy.

We found that ir-AEs were more common in patients receiving a higher dose of ipilimumab (10 mg/kg), which is not the dose currently approved for use by the FDA. In a randomized dose-finding study of ipilimumab, it was found that higher doses of ipilimumab were associated with higher rates of grade 3–4 ir-AEs (7% at 3 mg/kg, 25% at 10 mg/kg, P = 0.005 by Fisher exact; ref. 17). Results from another study indicated that the rate of grade 3–4 ir-AEs was 38% to 42% with ipilimumab at 10 mg/kg (18). In the present study, the frequency of grade ≥3 ir-AEs was higher (20% at 3 mg/kg and 43% at 10 mg/kg) than previously reported, but this was not statistically different from historical controls. Further study will be necessary to validate this finding.

In previous studies, high rates of AEs were found when combining immunotherapy with radiotherapy for melanoma. Several retrospective studies have shown high rates of radiation-associated necrosis, myelitis, and dermatitis when radiotherapy was given during or within 4 weeks of interferon administration (7–9). However, results from a recent prospective phase I/II trial indicated that acute and long-term toxicity were not associated with higher than expected rates of AEs when combining interferon and adjuvant radiotherapy (19). Additional research is needed to determine whether combining radiotherapy and immunotherapy is associated with AEs.

Little data exist on the safety of combining ipilimumab and radiotherapy. A recent case series found higher than expected rates of brain necrosis after radiosurgery with 20 Gy in 1 fraction (EQD2 of 158 Gy; ref. 12). However, a prospective trial of patients with prostate cancer revealed no increase in toxicity with ipilimumab during 8 Gy in 1 fraction (EQD2 of 26 Gy; ref. 20). We found that the likelihood of AEs in radiotherapy is associated with higher radiation doses, which is consistent with these studies. Therefore, attention to radiation dose may be particularly important for patients receiving ipilimumab.

Therapies that block CTLA-4, such as ipilimumab, result in the activation and proliferation of lymphocytes. Ipilimumab treatment has been shown to lead to an increase in the ALC (17, 21). This effect may be important, as longer survival has been shown in patients with greater increases in ALC as well as higher levels of ALCs at various time points after the initiation of ipilimumab (21–24). As radiotherapy is known to be associated with lymphopenia, we explored the changes in ALC after radiotherapy. In the present study, a statistically significant reduction in 12-week average ALC was noted after radiotherapy. However, despite a reduction in the ALC after radiotherapy, there did not appear to be a negative effect on survival after treatment with ipilimumab. Future studies to characterize the immunologic response to radiotherapy and ipilimumab are necessary to better understand the significance of this finding.

The local symptomatic response to palliative radiotherapy in the present study was 77%, which is consistent with a 67% response rate found in a previous study of palliative radiotherapy for patients with metastatic melanoma (4). Postoperative locoregional radiotherapy was used infrequently among the present cohort, but no recurrences were noted in the irradiated targets, suggesting successful locoregional disease control.

Median OS of 9 months after radiotherapy during induction ipilimumab is comparable with the median survival of patients with unresectable or metastatic melanoma that failed a prior therapy and were treated with ipilimumab (3 mg/kg) alone (10.1 months, 95% confidence interval, 8.0–13.8 months; ref. 1). However, median OS among those receiving radiotherapy during maintenance ipilimumab (at 10 mg/kg) was 39 months. Previous studies have suggested longer OS in patients receiving ipilimumab at 10 mg/kg (median OS of 17.7–19.3 months), although studies comparing survival at these two doses are still ongoing (NCT01515189; ref. 18). The greater than expected median OS in patients receiving radiotherapy during maintenance ipilimumab is probably due to selection bias introduced by the protocol requirements. Maintenance therapy is not offered outside of a clinical trial and is not included in the FDA label for ipilimumab. However, the finding is provocative and suggests that if radiotherapy modifies the effect of ipilimumab, the timing and/or sequence of treatment may be important.

The present analysis has several limitations. First, the retrospective nature of the design may have led to under-reporting of AEs. Most patients treated with ipilimumab at our institution were enrolled on clinical trial protocols. Therefore, follow-up and documentation of AEs and response is robust, but not prospectively recorded for the present analysis. Second, the present cohort is heterogenous and the treatments rendered varied. This limitation is inherent in retrospective clinical research. As an exploratory and hypothesis-generating analysis, the present data may offer insight for the design of future studies combining radiotherapy and ipilimumab immunotherapy. Because ipilimumab is a relatively new therapy for melanoma, this series likely represents the largest experience with the combination of ipilimumab and radiotherapy at the present time.

The combination of ipilimumab and radiotherapy has generated considerable interest, and several prospective trials are currently underway to further characterize the safety and efficacy of this approach (Supplementary Table S2). Our retrospective study characterized the feasibility, toxicity, and preliminary efficacy of ipilimumab and radiotherapy given concurrently for patients with melanoma. We found that the AE rates for the combined regimen were not higher than expected, and that the local effect of radiotherapy or the survival benefit of ipilimumab immunotherapy was not compromised. These results suggest that future and ongoing studies combining radiotherapy and ipilimumab are warranted. Until results of ongoing studies are available, our experience suggests that combining radiotherapy with ipilimumab to treat patients with melanoma is safe if both are used cautiously.