Edouard Auclin1, Perrine Vuagnat2, Cristina Smolenschi2, Julien Taieb1, Jorge Adeva3, Laetitia Nebot-Bral4,5, Marta Garcia de Herreros6, Rosario Vidal Tocino7, Federico Longo-Muñoz8, Yola El Dakdouki2, Patricia Martín-Romano2, Lydia Gaba6,9, Tamara Saurí6,9, Helena Oliveres6,9, Eduardo Castañón10, Rocio Garcia-Carbonero3, Benjamin Besse11, Christophe Massard2, Laura Mezquita6,9,11, Antoine Hollebecque2. 1. Gastrointestinal and Medical Oncology Department, Hôpital Européen Georges Pompidou, Université de Paris, 75015 Paris, France. 2. Early Drug Development Department, Institut Gustave Roussy, 94805 Villejuif, France. 3. Medical Oncology Department, Hospital Universitario 12 de Octubre, Imas 12, UCM, 28041 Madrid, Spain. 4. UMR9019 Genome Integrity and Cancers, Gustave Roussy Cancer Campus, 94805 Villejuif, France. 5. Paris Saclay, Paris Sud University Orsay, 91400 Orsay, France. 6. Medical Oncology Department, Hospital Clinic of Barcelona, 08036 Barcelona, Spain. 7. Medical Oncology Department, Hospital Universitario de Salamanca, IBSAL, 37007 Salamanca, Spain. 8. Medical Oncology Department, Hospital Universitario Ramon y Cajal, IRYCIS, CIBERONC, 28034 Madrid, Spain. 9. Translational Genomics and Targeted Therapies in Solid Tumors, IDIBAPS, 08036 Barcelona, Spain. 10. Department of Oncology, CUN-Madrid, 28027 Madrid, Spain. 11. Medical Oncology, Institut Gustave Roussy, 94805 Villejuif, France.
Abstract
Background: MSI-H/dMMR is considered the first predictive marker of efficacy for immune checkpoint inhibitors (ICIs). However, around 39% of cases are refractory and additional biomarkers are needed. We explored the prognostic value of pretreatment LIPI in MSI-H/dMMR patients treated with ICIs, including identification of fast-progressors. Methods: A multicenter retrospective study of patients with metastatic MSI-H/dMMR tumors treated with ICIs between April 2014 and May 2019 was performed. LIPI was calculated based on dNLR > 3 and LDH > upper limit of normal. LIPI groups were good (zero factors), intermediate (one factor) and poor (two factors). The primary endpoint was overall survival (OS), including the fast-progressor rate (OS < 3 months). Results: A total of 151 patients were analyzed, mainly female (59%), with median age 64 years, performance status (PS) 0 (42%), and sporadic dMMR status (68%). ICIs were administered as first or second-line for 59%. The most frequent tumor types were gastrointestinal (66%) and gynecologic (22%). LIPI groups were good (47%), intermediate (43%), and poor (10%). The median follow-up was 32 months. One-year OS rates were 81.0%, 67.1%, and 21.4% for good, intermediate, and poor-risk groups (p < 0.0001). After adjustment for tumor site, metastatic sites and PS, LIPI remained independently associated with OS (HR, poor-LIPI: 3.50, 95%CI: 1.46-8.40, p = 0.02. Overall, the fast-progressor rate was 16.0%, and 35.7% with poor-LIPI vs. 7.5% in the good-LIPI group (p = 0.02). Conclusions: LIPI identifies dMMR patients who do not benefit from ICI treatment, particularly fast-progressors. LIPI should be included as a stratification factor for future trials.
Background: MSI-H/dMMR is considered the first predictive marker of efficacy for immune checkpoint inhibitors (ICIs). However, around 39% of cases are refractory and additional biomarkers are needed. We explored the prognostic value of pretreatment LIPI in MSI-H/dMMRpatients treated with ICIs, including identification of fast-progressors. Methods: A multicenter retrospective study of patients with metastatic MSI-H/dMMR tumors treated with ICIs between April 2014 and May 2019 was performed. LIPI was calculated based on dNLR > 3 and LDH > upper limit of normal. LIPI groups were good (zero factors), intermediate (one factor) and poor (two factors). The primary endpoint was overall survival (OS), including the fast-progressor rate (OS < 3 months). Results: A total of 151 patients were analyzed, mainly female (59%), with median age 64 years, performance status (PS) 0 (42%), and sporadic dMMR status (68%). ICIs were administered as first or second-line for 59%. The most frequent tumor types were gastrointestinal (66%) and gynecologic (22%). LIPI groups were good (47%), intermediate (43%), and poor (10%). The median follow-up was 32 months. One-year OS rates were 81.0%, 67.1%, and 21.4% for good, intermediate, and poor-risk groups (p < 0.0001). After adjustment for tumor site, metastatic sites and PS, LIPI remained independently associated with OS (HR, poor-LIPI: 3.50, 95%CI: 1.46-8.40, p = 0.02. Overall, the fast-progressor rate was 16.0%, and 35.7% with poor-LIPI vs. 7.5% in the good-LIPI group (p = 0.02). Conclusions: LIPI identifies dMMRpatients who do not benefit from ICI treatment, particularly fast-progressors. LIPI should be included as a stratification factor for future trials.