Comparative Analysis of Durable Responses on Immune Checkpoint Inhibitors Versus Other Systemic Therapies

A Pooled Analysis of Phase III Trials

Elvire Pons-Tostivint, MD; Aurélien Latouche, PhD; Pauline Vaflard, MD; Francesco Ricci, MD, PhD; Delphine Loirat, MD, PhD; Ségolène Hescot, MD, PhD; Marie-Paule Sablin, MD; Roman Rouzier, MD, PhD; Maud Kamal, PhD; Claire Morel, MSc; Charlotte Lecerf, MSc; Vincent Servois, MD; Xavier Paoletti, PhD; Christophe Le Tourneau, MD, PhD

Disclosures

JCO Precis Oncol. 2019;2019(3) 

In This Article

Patients and Methods

Search Strategy

We performed a PubMed database search from 2000 to March 2018 using the following keywords: pembrolizumab, nivolumab, atezolizumab, ipilimumab, tremelimumab, and durvalumab, which were the only ICIs evaluated in phase III trials at the time this study was conducted. The search was performed using the filter clinical trials. The language was restricted to English. We also reviewed reference lists of original articles and review articles to ensure that no eligible studies were missed. When a duplicate publication of the same trial was found, the study with the most complete and updated report was included.

Selection Criteria

Studies meeting all of the following criteria were selected: prospective randomized phase III trials of ICIs in patients with cancer treated in the recurrent and/or metastatic setting, trials with OS and/or progression-free survival (PFS) as a primary end point, and availability of the OS and PFS Kaplan-Meier survival curves in the publications. Phase I and phase II trials were excluded as were phase III trials in the adjuvant or neoadjuvant setting. Trials not involving an ICI as a single agent in one arm also were excluded. Finally, trials were excluded if the follow-up was insufficient to estimate the proportion of patients who experienced a durable response (see Statistical Analyses).

Data Extraction

Data extracted from eligible trials were tumor type, class of drugs in each treatment arm, number of patients in each treatment arm, number of previous lines of treatment in the recurrent and/or metastatic setting, median PFS, median OS, the proportion of patients with a PFS exceeding three times the median PFS in each arm, and the proportion of patients with an OS exceeding two times the median OS in each arm (Figure 1).

Figure 1.

Estimated proportion of patients with a survival probability that exceeded two times the median survival in each treatment arm.

Statistical Analyses

Because no definition of durable response existed, we arbitrarily defined as a durable response for a specific patient a PFS that exceeded three times the median PFS of all patients treated with the same drugs in the same trial. We also estimated the proportion of patients who experienced an OS that exceeded two times the median OS of all patients treated with the same drugs in the same trial. Using Digitizelt software (Digitzeit, Braunschweig, Germany), the proportions of patients who experienced a PFS/OS that exceeded three/two times the median PFS/OS in each arm were measured directly from the extracted Kaplan-Meier curves.[17,18] Proportions were compared using the Mann-Whitney U test and represented using GraphPad (GraphPad Software, La Jolla, CA). A multivariable linear regression was used to assess the effect of the predictors on the mean proportion of durable responses. P < .05 was considered statistically significant.

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