23 | Combined immunotherapy with nivolumab and ipilimumab with and without sequential or concomitant stereotactic radiotherapy in patients with melanoma brain metastasis: an international retrospective study

Maria Chiara Sergi*¹, Teresa Amaral*², Piotr Rutkowski*³, Marie-Lena Rasch², Naima Benannoune⁴, Patricio Serra⁵, Maria Grazia Vitale⁶, Diana Giannarelli⁷, Ana Maria Arance⁸, Eva Munoz Couselo⁹, Bart Neyns¹⁰, Iris Dirven¹¹, Marco Tucci¹², Michele Guida¹³, Francesco Spagnolo¹⁴, Ernesto Rossi¹⁵, Paola Queirolo¹⁶, Pietro Quaglino¹⁷, Roberta Depenni¹⁸, Joanna Placzke³, Anna Maria Di Giacomo¹⁹, Michele Del Vecchio²⁰, Alice Indini²⁰, Ines Pires da Silva²¹, Alexander M. Menzies²², Angela Hong²³, Paul Lorigan⁵, Caroline Robert²⁴, Georgina V. Long²², Paolo A. Ascierto⁶, Mario Mandalà²⁵ | ¹Unit of Medical Oncology, "Mons. A.R. Dimiccoli" Hospital, Asl BT, Barletta, Italy; ²Skin Cancer Clinical Trials Center, Department of Dermatology, Eberhard Karls University, Tuebingen, Germany. ³Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland. ⁴Gustave Roussy Cancer Campus, Villejuif, France. ⁵The University of Manchester, Manchester, UK. ⁶Department of Melanoma, Cancer Immunotherapy and Development Therapeutics, I.N.T. IRCCS Fondazione "G. Pascale" Napoli, Naples, Italy; ⁷Epidemiology and Biostatistics, Fondazione Policlinico Universitario, A. Gemelli IRCCS, Rome, Italy; ⁸Hospital Clínic Barcelona and IDIBAPS, Barcelona, Spain; ⁹Department of medical oncology. Vall d"Hebron Hospital, Barcelona, Spain & Vall d’Hebron Institute of oncology, VHIO. Barcelona, Spain; ¹⁰Department of Medical Oncology, UZ Brussel, Brussels, Belgium. ¹¹Department of medical oncology, Vrije Universiteit Brussel, VUB, Universitair Ziekenhuis Brussel, Brussels, Belgium; ¹²Medical Oncology Unit, University of Bari Aldo Moro, Policlinico Hospital of Bari, 70124 Bari, Italy. ¹³Rare Tumors and Melanoma Unit, IRCCS Istituto dei Tumori "Giovanni Paolo II," Bari, Italy. ¹⁴IRCCS Ospedale Policlinico San Martino, Skin Cancer Unit, Genova, Italy; ¹⁵Medical Oncology, Fondazione Policlinico Universitario, A. Gemelli IRCCS, Rome, Italy; ¹⁶IEO European Institute of Oncology, IRCCS, Milan, Italy. ¹⁷Department of Dermatology, University of Turin, Turin, Italy. ¹⁸University of Modena and Reggio Emilia, Department of Oncology, Hematology, Modena, Emilia-Romagna, Italy; ¹⁹Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy. ²⁰Unit of Melanoma Medical Oncology, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; ²¹Melanoma Institute Australia, University of Sydney, and Blacktown Hospital, Sydney, New South Wales, Australia; ²²Melanoma Institute Australia, University of Sydney, and Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia; ²³Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, Australia; Department of Radiation Oncology, Chris O'Brien Lifehouse, Camperdown, NSW, Australia; ²⁴Gustave Roussy and Paris-Saclay University, Villejuif, France; ²⁵Unit of Medical Oncology, University of Perugia, Perugia, Italy. ^§ on behalf of the Italian Melanoma Intergroup - IMI.

Background: Ipilimumab plus nivolumab (COMBO) is the standard treatment in patients with asymptomatic melanoma brain metastases (MBM) (1)(2)(3). We report a retrospective study aiming to assess the outcome of patients with MBM treated with COMBO with or without sequential/concomitant stereotactic radiotherapy (SRT).

Methods: MBM patients treated with COMBO with or without SRT have been retrieved: demographics, steroid treatment, Central Nervous System [CNS]-related symptoms, BRAF status, radiotherapy (yes/no and timing) or surgery, number of MBM, maximum diameter of metastasis, overall response rate (ORR), progression-free (PFS) and overall survival (OS) have been analyzed.

Results: 453 patients were included: 190 received COMBO alone, 107 received COMBO and concomitant SRT, 156 COMBO and sequential SRT, respectively. At multivariable analysis the line of treatment [> 1st vs 1st: HR 2.60 (1.93-3.50)], sequential SRT vs no radiotherapy [HR 0.45 (0.32-0.64)], concomitant SRT vs no radiotherapy [HR 0.48 (0.33-0.69)], steroids [HR 1.56 (1.17-2.08)], age [HR 1.01 (1.00-1.02)] and number of MBM [≥3 vs 1 HR 1.55 (1.11-2.17)), 2 vs 1 HR 1.53 (1.02-2.31)] at baseline were associated with OS. There was no significant difference between patients who received concomitant vs sequential SRT. At a median follow-up of 29 months, the median-OS in the overall population was 17.8 months while in those who received SRT was 27.3 (15.3-39.4) for patients receiving sequential radiotherapy and 22.2 (12.7-31.7) for those receiving radiotherapy concomitantly to COMBO. The incidence of radionecrosis was 10.3%. Toxicities were consistent with previous studies.

Conclusions: Our results suggest a better OS in patients who receive SRT plus COMBO, regardless of timing of SRT. Prospective studies are needed to validate our findings.

References:
[1] Tawbi HA, Forsyth PA, Hodi FS, et al. Safety and efficacy of the combination of nivolumab plus ipilimumab in patients with melanoma and asymptomatic or symptomatic brain metastases (CheckMate 204). Neuro Oncol 2021. 
[2] Long GV, Atkinson V, Lo S, et al. Five-year overall survival from anti-PD1 brain collaboration (ABC study): randomised phase 2 study of nivolumab or nivolumab+ipilimumab in patients 23 with melanoma brain metastases. Presented at the 2021 American Society of Clinical Oncology (ASCO) Virtual Congress; June 8–12, 2021; Abstract 9508.
[3] Di Giacomo AM, Chiarian-Sileni V, Del Vecchio M, et al. Primary analysis and 4-year follow-up of the phase III NIBIT-M2 trial in melanoma patients with brain metastases. Clin Cancer Res 2021.