Efficacy and immune-related adverse event associations in avelumab-treated patients

Abstract

Background: Adverse events (AEs) of special interest that arise during treatment with immune checkpoint inhibitors, including immune-related AEs (irAEs), have been reported to be associated with improved clinical outcomes. We analyzed patients treated with avelumab from the JAVELIN Solid Tumor and Merkel 200 trials, examining the association between AEs and efficacy while adjusting for confounding factors such as treatment duration and event order.

Methods: We analyzed efficacy and safety data from 1783 patients treated with the programmed death ligand 1 inhibitor avelumab who were enrolled in expansion cohorts of the JAVELIN Solid Tumor and Merkel 200 trials. To analyze the association between irAEs and efficacy with regard to survival, we used a time-dependent Cox model with time-varying indicators for irAEs, as well as multistate models that accounted for competing risks and time inhomogeneity.

Results: 295 patients (16.5%) experienced irAEs and 454 patients (25.5%) experienced infusion-related reactions. There was a reduced risk of death in patients who experienced irAEs compared with those who did not (HR 0.71, 95% CI 0.59 to 0.85) using the time-dependent Cox model. The multistate model did not suggest that the occurrence of irAEs could predict response; however, it predicted a higher chance of irAEs occurring after a response. No association was observed between response and infusion-related reactions.

Conclusions: Patients who experience irAEs showed improved survival. Although irAEs are not predictors for response to immune checkpoint inhibitors, increased vigilance for irAEs is needed after treatment with avelumab.

Trial registration numbers: NCT01772004 and NCT02155647.

Keywords: biostatistics; immunotherapy; programmed cell death 1 receptor.

Conflict of interest statement

Competing interests: KK has received research grants from EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany) and Merck & Co; has served on advisory boards for EMD Serono and Merck & Co; and has received an honorarium from Merck & Co. JM, MB and JW are employees of EMD Serono Research & Development Institute (an affiliate of Merck KGaA, Darmstadt, Germany). VK was an employee of EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany) at the time this analysis was conducted. IS is an employee of Merck KGaA, Darmstadt, Germany. SPD reports serving as a consultant or advisor for Amgen, EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany), GlaxoSmithKline, Immunocore, Immune Design, Incyte, Merck & Co, and Nektar; has received research grants from Amgen, Bristol Myers Squibb, Deciphera, EMD Serono, Incyte, Merck & Co, and Nektar; and has received reimbursement for travel and accommodation expenses from Adaptimmune, EMD Serono, Immunocore and Nektar. AR and JLG are employees of the National Cancer Institute, which has a cooperative research and development agreement with EMD Serono (an affiliate of Merck KGaA, Darmstadt, Germany).

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Multistate model definition and hypotheses to be addressed. Diagram shows the transition states that the multistate model aims to capture, which all begin with treatment, lead to either a response or irAE, and then may further lead to both response and irAE. Blue and pink arrows along with accompanying text describe two research questions regarding treatment sequencing to be investigated by the multistate model. irAE, immune-related adverse events.

Figure 2

Onset of first AESI. Shown are the number of infusions administered before the onset of the first irAE (aquamarine) or IRR (magenta) across the study population. AE, adverse event; AESI, adverse event of special interest; irAE, immune-related adverse event; IRR, infusion-related reaction.

Figure 3

Estimated probabilities that a patient transitions between given treatment events. Each row of panels depicts the probability beginning at three different time points (42, 90 and 182 days) after initiation of treatment that a patient transitions from a given model state to another. Shaded areas indicate 90% CIs. The first row compares the time varying transition probability for response given previous occurrence of irAE or not. The second row compares the time varying transition probability for irAE given previous occurrence of response or not. The third and fourth rows depict time varying transition probability for discontinuation with or without response comparing previous occurrence of irAE or not. irAE, immune-related adverse event.

Figure 4

DOR according to occurrence of IRRs. Kaplan-Meier plot shows the estimated DOR based on whether or not a patient experienced an IRR throughout the course of treatment, along with number of patients at risk and breakdown of censored patients at each time point below. Shaded areas indicate 95% CIs. DOR, duration of response; IRR, infusion-related reaction.