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

Amit Maity, Rosemarie Mick, Ramesh Rengan, Tara C Mitchell, Ravi K Amaravadi, Lynn M Schuchter, Daniel A Pryma, Dana M Patsch, Alisha P Maity, Andy J Minn, Robert H Vonderheide, John N Lukens, Amit Maity, Rosemarie Mick, Ramesh Rengan, Tara C Mitchell, Ravi K Amaravadi, Lynn M Schuchter, Daniel A Pryma, Dana M Patsch, Alisha P Maity, Andy J Minn, Robert H Vonderheide, John N Lukens

Abstract

We conducted a phase I dose-escalation trial of radiation with ipilimumab in patients with melanoma with ≥2 metastatic lesions. Here, we report the final full clinical analysis. Patients received RT (6 or 8 Gy x 2 or 3 doses) to a single lesion followed by 4 cycles of ipilimumab. The primary endpoint was maximum tolerated dose of RT, and secondary endpoint was response at non-radiated sites. Twenty-two patients with treatment-naïve (n = 11) or treatment-refractory (n = 11) Stage IV melanoma were enrolled. There were 31 treatment-related adverse events (AEs), of which 16 were deemed immune-related. Eleven patients had grade 3 AEs (no grade 4/5). There were no dose-limiting toxicities related to the radiation/ipilimumab combination. Five of 22 patients (22.7%, 95% CI 7.8-45.4%) had partial response as best response and three (13.6%) had stable disease. Median overall survival was 10.7 months (95% CI, 4.9 months to not-estimable) and median progression-free survival 3.6 months (95% CI, 2.9 months to 7.8 months). Seven patients were still alive at the time of last follow-up (median follow-up 89.2 months), most of whom received pembrolizumab after progression. Radiotherapy followed by ipilimumab was well tolerated and yielded a response rate that compares favorably to the objective response rate with ipilimumab alone. Furthermore, 32% of patients are long-term survivors, most of whom received pembrolizumab. Based on these results, the recommended dose that was used in subsequent Phase 2 trials was 8 Gy x 3 doses. Clinical Trial Registration: NCT01497808 (www.clinicaltrials.gov).

Keywords: CTLA-4; abscopal; hypofractionated radiation; ipilimumab; radiation.

© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.

Figures

Figure 1.
Figure 1.
Trial schema
Figure 2.
Figure 2.
Radiation + ipilimumab is associated with regression of unirradiated tumors in some patients. Waterfall plot of clinical response in unirradiated tumors after radiation treatment (RT) to a single index lesion with ipilimumab. Dashed lines are thresholds for progressive disease (PR; red) and partial response (PR; blue). * Patients with new lesions. ** Clinical progression without imaging
Figure 3.
Figure 3.
Survival curves

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