ESTRO 36 Abstract Book

S5 ESTRO 36 _______________________________________________________________________________________________

SP-0016 Radiotherapy and immunotherapy combination: paradigm changing or just hype? S.J. Dovedi 1 1 The University of Manchester, Targeted Therapy Group, Manchester, United Kingdom Radiotherapy (RT) is a highly effective anti-cancer treatment forming part of the standard of care for the majority of patients. In addition to the direct cytoreductive effect of RT there is increasing evidence that this treatment may also be immunogenic; however, the contribution and mechanisms of RT induced immune responses are unknown. Moreover, as a monotherapy, RT is rarely able to generate to abscopal responses outside of the treatment field, suggesting that any immune response generated may be suboptimal. Longitudinal profiling of the tumour microenvironment following RT in syngeneic mouse models, which have a fully competent immune system, reveals the impact of local RT on both the innate and adaptive components of the immune system. Using next-generation sequencing of the T-cell receptor repertoire (TCR) we show that treatment with daily low-dose fractionated RT leads to a T-cell response that is dominated by polyclonal expansion of pre-existing T-cell clones. Moreover, we show that both local and distal tumour control following RT can be improved by combination with immunotherapies that target both immunosuppressive checkpoints (such as the PD-1/PD-L1 axis) and immune-stimulatory pathways to ultimately enhance anti-tumor activity by CD8+ T-cells. Importantly, preclinical data suggests that RT dose, fractionation and scheduling with immunotherapy may impact tumour control. In this presentation we will review the data from preclinical models and emerging clinical studies to explore the immunological effects of RT and how these insights may be used to guide clinical translation. OC-0017 Combined High Dose Radiation and Ipilimumab in Metastatic Melanoma, a Phase I Dose Escalation Trial. K. De Wolf 1 , V. Kruse 2 , L. Brochez 3 , N. Sundahl 1 , M. Van Gele 3 , R. Speeckaert 3 , P. Ost 1 1 University Hospital Ghent, radiotherapy and oncology, Gent, Belgium 2 University Hospital Ghent, medical oncology, Gent, Belgium 3 University Hospital Ghent, dermatology, Gent, Belgium Ipilimumab, a CTLA-4 blocking monoclonal antibody, induces durable, potentially curative, tumour regressions in some patients with metastatic melanoma, but unfortunately the majority of patients do not have long- term benefit from ipilimumab monotherapy. Preclinical data and early clinical data suggest synergistic antitumor activity between ipilimumab and high-dose radiotherapy (e.g. doses higher than 8 Gy per fraction). Therefore, the combination of ipilimumab with high-dose radiotherapy holds substantial promise for improving clinical benefit. We conducted a phase I trial to determine the safety and tumour responses of this combination. Material and Methods Patients with metastatic melanoma, with at least three distinct measurable sites of disease, received four infusions of ipilimumab every three weeks at 3 mg/kg in combination with dose-escalated stereotactic body radiotherapy to one lesion after the second infusion of ipilimumab (level 1: 24 Gy in 8 Gy per fraction, level 2: 30 Gy in 10 Gy per fraction and level 3: 36 Gy in 12 Gy per fraction). For the patient randomization, a time-to-event continual reassessment method was used. The primary endpoint was to determine the maximum tolerated radiotherapy doses. Secondary endpoints were local control and tumour response as per RECIST 1.1. Clinical benefit was defined as complete response, partial response or stable disease.

Results From March 18, 2015, to April 7, 2016, 13 patients with metastatic melanoma were enrolled. Median age was 68 years (range 23 - 80), with 58% male and 42% female patients. One patient experienced disease progression before receiving radiotherapy and was not eligible for evaluation. No dose-limiting toxicities were noted at dose levels 1, 2 or 3. Grade 3 or 4 ipilimumab-related adverse events (AEs) occurred in 25% of patients. Treatment- related AEs are shown in Table 1.

Table 1: Treatment-related adverse events

Local control of the irradiated lesions was achieved in 11 of 12 patients. There was a complete local response in 1 irradiated lesion (8%), a partial response in 6 irradiated lesions (46%), stable disease in 4 irradiated lesions (31%), and progressive disease in 1 irradiated lesion (8%). Evaluation of the non-irradiated lesions demonstrated that 3 patients (24%) experienced clinical benefit (one patient (8%) developed a confirmed partial response and 2 patients (16%) had confirmed stable disease). Figure 1: Best local response of irradiated lesions and overall response of non-irradiated target lesions

Conclusion Ipilimumab 3 mg/kg with concurrent high-dose radiotherapy can be delivered safely in patients with metastatic melanoma with excellent local control and indications of systemic antitumor responses in a subset of patients.