Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis

Nat Commun. 2021 Oct 12;12(1):5954. doi: 10.1038/s41467-021-25859-y.

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.

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anorexia / chemically induced
  • Anorexia / mortality
  • Anorexia / pathology
  • Antineoplastic Agents, Immunological / administration & dosage*
  • Antineoplastic Agents, Immunological / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / mortality
  • Brain Neoplasms / secondary
  • Colitis / chemically induced
  • Colitis / mortality
  • Colitis / pathology
  • Exanthema / chemically induced
  • Exanthema / mortality
  • Exanthema / pathology
  • Fatigue / chemically induced
  • Fatigue / mortality
  • Fatigue / pathology
  • Female
  • Fever / chemically induced
  • Fever / mortality
  • Fever / pathology
  • Hepatitis / etiology
  • Hepatitis / mortality
  • Hepatitis / pathology
  • Humans
  • Ipilimumab / administration & dosage*
  • Ipilimumab / adverse effects
  • Male
  • Meningeal Carcinomatosis / drug therapy*
  • Meningeal Carcinomatosis / mortality
  • Meningeal Carcinomatosis / pathology
  • Meningeal Neoplasms / drug therapy*
  • Meningeal Neoplasms / mortality
  • Meningeal Neoplasms / pathology
  • Middle Aged
  • Nausea / chemically induced
  • Nausea / mortality
  • Nausea / pathology
  • Nivolumab / administration & dosage*
  • Nivolumab / adverse effects
  • Survival Analysis

Substances

  • Antineoplastic Agents, Immunological
  • Ipilimumab
  • Nivolumab

Associated data

  • ClinicalTrials.gov/NCT02939300