Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis

Abstract

Leptomeningeal disease (LMD) is a common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We present a single arm Phase II study of 18 patients with LMD receiving combined ipilimumab and nivolumab until progression or unacceptable toxicity (NCT02939300). The primary end point is overall survival at 3 months (OS3). Secondary end points include toxicity, cumulative time-to-progression at 3 months, and progression-free survival. A Simon two-stage design is used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Median follow up based on patients still alive is 8.0 months (range: 0.5 to 15.9 months). The study has met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients are alive at three months. One third of patients have experienced one (or more) grade-3 or higher adverse events. Two patients have discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events include fatigue (N = 7), nausea (N = 6), fever (N = 6), anorexia (N = 6) and rash (N = 6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients. Larger, multicenter clinical trials are needed to validate these results.

Conflict of interest statement

P.K.B. has received compensation for consulting from Lilly, Angiochem, ElevateBio, Voyager Therapeutics, Tesaro, Genentech-Roche, SK Life Sciences, Pfizer, Dantari and Speaker’s Honoraria from Genentech-Roche and Merck Sharp & Co. P.K.B. has received research funding (to MGH) from Merck & Co, BMS, Eli Lilly, Mirati and Pfizer. J.V.C. has received consulting fees from Sanofi-Genzyme and BMS. D.P.C. has consulted for Lilly and Boston Pharmaceuticals, and has received travel/speaking fees from Merck. N.U.L. has received institutional research funding from Seattle Genetics, Genentech, Merck, and Pfizer. She has served on an advisory board or consulted for PUMA Biotechnology, Seattle Genetics, and Daichii Sankyo. R.J.S. has received research funding from Amgen and Merck, and served as a paid consultant and/or on an advisory board for Array BioPharma, Amgen, Asan Biosciences, BMS, Compugen, Genentech, Merck, Novartis, and Replimmune. E.Q.L. has received royalties from Wolters Kluwers (Up to Date, Inc) and has consulted for Lilly. M.D.W. is a consultant at Boston Pharmaceuticals. I.D.J. has received honoraria from Foundation Medicine, consulting fees from Boehringer Ingelheim and AstraZeneca, travel fees from Array and Pfizer, and research support from Array, Genentech, Guardant, and Pfizer. J.D. is a consultant for Unum Therapeutics and Blue Earth Diagnostics and has received royalties from Kluwer Wolters. A.B. reports grants from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics, Biothernostics Inc. and personal fees from Biothernostics Inc., Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics, Taiho, Sanofi, Diiachi Pharma/Astra Zeneca, Puma, Phillips, Eli Lilly and Foundation Medicine, outside the submitted work. B.O. has received clinical trial support from Eisai and Incyte. D.F. holds shares in Eli Lilly. All other authors declare no competing interests.

© 2021. The Author(s).

Figures

Fig. 1. Overall survival in 18 patients with LMD from solid tumors.

Median overall survival was 2.9 months (90% CI: 1.6–5.0 months).