Filipe Martins1,2, Luis Schiappacasse3, Marc Levivier4, Constantin Tuleasca4,5,6, Michel A Cuendet7,8,9, Veronica Aedo-Lopez10, Bianca Gautron Moura10, Krisztian Homicsko10, Adrienne Bettini11, Gregoire Berthod10,12, Camille L Gérard7, Alexandre Wicky7, Jean Bourhis13, Olivier Michielin14. 1. Centre Hospitalier Universitaire Vaudois (CHUV), Hematology Service and Central Laboratory, Oncology Department, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland. filipe.martins@epfl.ch. 2. Swiss Federal Institute of Technology Lausanne (Ecole polytechnique Fédérale de Lausanne, EPFL), School of Life Sciences, Laboratory of Virology and Genetics (LVG), EPFL-SV-GHI-LVG, Station 11, CH-1015, Lausanne, Switzerland. filipe.martins@epfl.ch. 3. Centre Hospitalier Universitaire Vaudois (CHUV), Radio-Oncology Service, Oncology Department, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland. 4. Centre Hospitalier Universitaire Vaudois (CHUV), Neurosurgery Service and Gamma Knife Center, Clinical Neurosciences Department, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland. 5. Swiss Federal Institute of Technology Lausanne (Ecole polytechnique Fédérale de Lausanne, EPFL), Signal Processing Laboratory (LTS5), EPFL-STI-IEL-LTS5, Station 11, CH-1015, Lausanne, Switzerland. 6. University of Lausanne (UNIL), Faculty of Biology and Medicine (FBM), Rue du Bugnon 21, CH-1005, Lausanne, Switzerland. 7. Centre Hospitalier Universitaire Vaudois (CHUV), Precision Oncology Center, Oncology Department, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland. 8. Swiss Institute of Bioinformatics, Lausanne, Switzerland. 9. Weill Cornell Medicine, Department of Physiology and Biophysics, New York, USA. 10. Centre Hospitalier Universitaire Vaudois (CHUV), Oncology Service, Oncology Department, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland. 11. Fribourg Cantonal Hospital (HFR), Internal Medicine Department, Oncology Service, CH-1708, Fribourg, Switzerland. 12. Hospital Center for Valais Romand (CHVR), Martigny Hospital, Avenue de la Fusion 27, CH-1920, Martigny, Switzerland. 13. Centre Hospitalier Universitaire Vaudois (CHUV), Radio-Oncology Service, Oncology Department, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland. jean.bourhis@chuv.ch. 14. Centre Hospitalier Universitaire Vaudois (CHUV), Oncology Service, Precision Oncology Center, Oncology Department, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland. olivier.michielin@chuv.ch.
Abstract
BACKGROUND: Evidence pointing to a synergistic effect of stereotactic radiosurgery (SRS) with concurrent immunotherapy or targeted therapy in patients with melanoma brain metastases (BM) is increasing. We aimed to analyze the effect on overall survival (OS) of immune checkpoint inhibitors (ICI) or BRAF/MEK inhibitors initiated during the 9 weeks before or after SRS. We also evaluated the prognostic value of patients' and disease characteristics as predictors of OS in patients treated with SRS. METHODS: We identified patients with BM from cutaneous or unknown primary origin melanoma treated with SRS between 2011 and 2018. RESULTS: We included 84 patients. The median OS was 12 months (95% CI 9-20 months). The median follow-up was 30 months (95% CI 28-49). Twenty-eight patients with newly diagnosed BM initiated anti-PD-1 +/-CTLA-4 therapy (n = 18), ipilimumab monotherapy (n = 10) or BRAF+/- MEK inhibitors (n = 11), during the 9 weeks before or after SRS. Patients who received anti-PD-1 +/-CTLA-4 mAb showed an improved survival in comparison to ipilimumab monotherapy (OS 24 vs. 7.5 months; HR 0.32, 95% 0.12-0.83, p = 0.02) and BRAF +/-MEK inhibitors (OS 24 vs. 7 months, respectively; HR 0.11, 95% 0.04-0.34, p = 0.0001). This benefit remained significant when compared to the subgroup of patients treated with dual BRAF/MEK inhibition (BMi) (n = 5). In a multivariate Cox regression analysis an age > 65, synchronous BM, > 2 metastatic sites, > 4 BM, and an ECOG > 1 were correlated with poorer prognosis. A treatment with anti-PD-1+/-CTLA-4 mAbs within 9 weeks of SRS was associated with better outcomes. The presence of serum lactate dehydrogenase (LDH) levels ≥ 2xULN at BM diagnosis was associated with lower OS (HR 1.60, 95% CI 1.03-2.50; p = 0.04). CONCLUSIONS: The concurrent administration of anti-PD-1+/-CTLA-4 mAbs with SRS was associated with improved survival in melanoma patients with newly diagnosed BM. In addition to CNS tumor burden, the extension of systemic disease retains its prognostic value in patients treated with SRS. Elevated serum LDH levels are predictors of poor outcome in these patients.
BACKGROUND: Evidence pointing to a synergistic effect of stereotactic radiosurgery (SRS) with concurrent immunotherapy or targeted therapy in patients with melanoma brain metastases (BM) is increasing. We aimed to analyze the effect on overall survival (OS) of immune checkpoint inhibitors (ICI) or BRAF/MEK inhibitors initiated during the 9 weeks before or after SRS. We also evaluated the prognostic value of patients' and disease characteristics as predictors of OS in patients treated with SRS. METHODS: We identified patients with BM from cutaneous or unknown primary origin melanoma treated with SRS between 2011 and 2018. RESULTS: We included 84 patients. The median OS was 12 months (95% CI 9-20 months). The median follow-up was 30 months (95% CI 28-49). Twenty-eight patients with newly diagnosed BM initiated anti-PD-1 +/-CTLA-4 therapy (n = 18), ipilimumab monotherapy (n = 10) or BRAF+/- MEK inhibitors (n = 11), during the 9 weeks before or after SRS. Patients who received anti-PD-1 +/-CTLA-4 mAb showed an improved survival in comparison to ipilimumab monotherapy (OS 24 vs. 7.5 months; HR 0.32, 95% 0.12-0.83, p = 0.02) and BRAF +/-MEK inhibitors (OS 24 vs. 7 months, respectively; HR 0.11, 95% 0.04-0.34, p = 0.0001). This benefit remained significant when compared to the subgroup of patients treated with dual BRAF/MEK inhibition (BMi) (n = 5). In a multivariate Cox regression analysis an age > 65, synchronous BM, > 2 metastatic sites, > 4 BM, and an ECOG > 1 were correlated with poorer prognosis. A treatment with anti-PD-1+/-CTLA-4 mAbs within 9 weeks of SRS was associated with better outcomes. The presence of serum lactate dehydrogenase (LDH) levels ≥ 2xULN at BM diagnosis was associated with lower OS (HR 1.60, 95% CI 1.03-2.50; p = 0.04). CONCLUSIONS: The concurrent administration of anti-PD-1+/-CTLA-4 mAbs with SRS was associated with improved survival in melanomapatients with newly diagnosed BM. In addition to CNS tumor burden, the extension of systemic disease retains its prognostic value in patients treated with SRS. Elevated serum LDH levels are predictors of poor outcome in these patients.
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