221 - Nivolumab and Ipilimumab with or without Stereotactic Body Radiation in Advanced or Recurrent Merkel Cell Carcinoma: Long Term Results and Biomarker Analysis from a Phase II Multi-Institutional Study
Presenter(s)
S. Kim1, E. Keit2, J. Y. Nakashima2, R. Thapa3, D. T. Chen4, M. Wang5, E. Buechelmaier1, S. Jun1, A. E. Berglund1, K. Yamoah6, J. J. Caudell6, D. M. Blakaj7, C. Verschraegen8, A. S. Brohl3, and E. J. Wuthrick9; 1Mayo Clinic, Jacksonville, FL, 2H. Lee Moffitt Cancer Center and Research Institute, Department of Radiation Oncology, Tampa, FL, 3Moffitt Cancer Center, Tampa, FL, 4H. Lee Moffitt Cancer Center and Research Institute, Department of Biostatistics and Bioinformatics, Tampa, FL, 5Taipei Veterans Hospital, Taipei, Taiwan, 6Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 7Department of Radiation Oncology, James Cancer Hospital/Wexner Medical Center, The Ohio State University, Columbus, OH, 8The Ohio State University Wexner Medical Center, Columbus, OH, 9H. Lee Moffitt Cancer Center, Tampa, FL
Purpose/Objective(s):
Merkel cell carcinoma is one of the most aggressive and deadly primary cutaneous malignancies, characterized by a strong tendency for distant spread, anti-PD1/PDL1 monotherapy is the standard of care in advanced Merkel cell carcinoma. In this study, we evaluated the efficacy of combination therapy with nivolumab and ipilimumab, administered either alone or alongside stereotactic body radiotherapy (SBRT), in patients with advanced Merkel cell carcinoma, used as first-line treatment or after prior anti–PD-1/PD-L1 monotherapy. The primary endpoint was objective response rate (ORR) per immune-related criteria. Key secondary endpoints included progression-free survival, overall survival, local control of irradiated lesions, safety, and exploratory biomarker.Materials/Methods:
This randomized, open-label phase 2 trial enrolled adults with advanced (unresectable, recurrent, or stage IV) Merkel cell carcinoma at two U.S. centers and assigned them 1:1 to nivolumab plus ipilimumab, with or without stereotactic body radiotherapy (SBRT) to 24Gy in 3 fractions. Eligible patients had at least two measurable lesions and available tumor tissue. Tumor response was evaluated every 12 weeks.Results:
A total of 50 patients were enrolled. Median follow-up is 54.5 months for ICI-naïve cohort and 10.8 months for Prior ICI cohort. Among 22 evaluable ICI-naïve patients, 11 patients achieved CR (50%, 31 – 69% 95% CI) and 11 patients PR (50%, 31 -69% 95% CI). Among 26 patients who received prior ICI, 4 patients achieved CR (15%, 5- 36% 95% CI), 4 patients PR (15%, 5 – 36% 95% CI), 1 patient SD (4%, 0 – 22% 95% CI) and 17 patients PD (65%, 44 – 82% 95% CI). Median DOR was 56.3 (43.7 - N.E. 95% CI) months for ICI-naive cohort and 10.8 (4.9 - N.E. 95% CI) months for Prior ICI cohort. Grade 3 or higher treatment-related toxicity was observed in 44% of patients. Among ICI-naïve patients in Arm A (no SBRT), median OS and PFS were 64.6 (46.4 - N.E. 95% CI) months and 54.9 (36.6, N.E 95% CI) months respectively while Arm B (with SBRT), median OS was not reached and PFS was 64.9 (N.E. - N.E. 95% CI) months. The numerically improved OS and PFS seen in Arm B (with SBRT) was not statistically significant (p = 0.18). Local control of irradiated lesions was 100% at 5 years. Exploratory analysis revealed increased IL2, IL4 and IL7 as well as CD8 and NK cells in the peripheral blood of responders at week 2 following initial immunotherapy infusion. Enhanced clonality of intratumoral TCR repertoire was also observed among responders.Conclusion:
In this long-term analysis of Nivolumab and Ipilimumab with or without SBRT in advanced or recurrent Merkel cell carcinoma, 100% ORR was achieved in ICI-naïve cohort with an impressive DOR and OS outcome. OS and PFS were higher in Arm B (with SBRT) but was not statistically significant. None of the irradiated lesions progressed in Arm B. . The trial is registered at ClinicalTrials.gov (NCT03071406).