Elsevier

European Journal of Cancer

Volume 91, March 2018, Pages 21-29
European Journal of Cancer

Original Research
Safety and efficacy of anti-programmed death 1 antibodies in patients with cancer and pre-existing autoimmune or inflammatory disease

https://doi.org/10.1016/j.ejca.2017.12.008Get rights and content

Highlights

  • In patients treated with anti-PD-1 antibodies, the presence of a pre-existing auto-immune or inflammatory disease is associated with a higher risk of immune-related adverse events.

  • Immunotherapies provide similar levels of effectiveness (overall survival) in patients with and without pre-existing auto-immune or inflammatory disease.

  • Half of these immune-related adverse events are flares or manifestations of the pre-existing autoimmune or inflammatory disease.

  • Anti-PD-1 antibodies can be maintained in 75% of the patients despite the immune-related adverse events.

Abstract

Objective

Patients with autoimmune or inflammatory disease (AID) are susceptible to immune-related adverse events (irAEs) when treated with immune check-point inhibitors (ICIs). We decided to analyse the safety and effectiveness of anti-PD-1 antibodies in AID patients and look for an association between the presence of pre-existing AID and the clinical outcome.

Methods

In a prospective study of the REISAMIC registry of grade ≥2 irAEs occurring in ICI-treated patients, we studied the associations between pre-existing AID on one hand and irAE-free survival, overall survival and best objective response rate on the other.

Results

We identified 45 patients with 53 AIDs in REISAMIC. The cancer diagnoses included melanoma (n = 36), non–small-cell lung cancer (n = 6) and others (n = 3). The most frequent pre-existing AIDs were vitiligo (n = 17), psoriasis (n = 12), thyroiditis (n = 7), Sjögren syndrome (n = 4) and rheumatoid arthritis (n = 2). Twenty patients (44.4%) presented with at least one irAE: eleven of these were associated with a pre-existing AID (‘AID flare’). Treatment with anti-PD-1 antibodies was maintained in 15 of the 20 patients with an irAE. The IrAE-free survival time was significantly shorter in AID patients (median: 5.4 months) than in AID-free patients (median: 13 months, p = 2.1 × 10−4). The AID and AID-free groups did not differ significantly with regard to the overall survival time and objective response rate (p = 0.38 and 0.098, respectively).

Conclusion

In patients treated with anti-PD-1 antibody, pre-existing AID was associated with a significantly increased risk of irAEs. Our results indicate that cancer treatments with anti-PD-1 antibodies are just as effective in AID patients as they are in AID-free patients.

Introduction

The immune check-point inhibitors (ICIs, i.e. antibodies against cytotoxic T-lymphocyte–associated protein 4 [CTLA-4] or programmed death 1 [PD-1]) are effective in the treatment of several types of cancer [1], [2], [3], [4], [5]. The clinical success of this immunotherapeutic strategy has confirmed the immune system's role weight in controlling cancer and that the ability of neoplastic cells to hide from the immune system is one of the hallmarks of cancer [6], [7].

With anti-CTLA-4 and anti-PD-1 antibodies, oncologists have been confronted with the occurrence of immune-related adverse events (irAEs) [9], [8], [10], [11]. Interestingly, the occurrence of irAE has been linked to greater anti-tumour effectiveness of anti-PD-1 treatment in patients with advanced melanoma and non–small-cell lung cancer (NSCLC) [16], [17], [18]. Patients with pre-existing autoimmune and/or inflammatory disease (AID) were initially excluded from clinical trials of ICI because of the possible increase of irAE [12]. Despite this initial reluctance, patients with mild-to-moderate pre-existing AID are now often treated with ICI. Recent studies have shown that both anti-CTLA-4 and anti-PD-1 antibodies can be effective AID patients [13], [14], [15]. However, all the data published to date were collected in retrospective studies of small numbers of patients.

Using data from a prospective multicenter registry, we therefore decided to describe and analyse the safety and effectiveness of anti-PD-1 antibodies in patients with a pre-existing AID.

Section snippets

Patients

We described ICI-treated patients with pre-existing AID and compared them with AID-free patient groups in terms of the occurrence of toxicity, overall survival (OS) and the best overall response rate (ORR). The patients had been included in the prospective REISAMIC registry (‘Registry of Severe Adverse Events of Immunomodulating Monoclonal Antibodies in Oncology’) between June 1st, 2014, and December 31st, 2016. REISAMIC includes all patients treated with anti-PD-1 antibodies following

Results

A total of 45 patients enrolled in REISAMIC were assessed (median [IQR] age: 63.3 (56.6–70.7); males: 46.7%; Fig. 1). We then compared the 45 patients enrolled in REISAMIC with 352 AID-free patients included in REISAMIC over the same period.

Discussion

Our results highlighted at least three important points. First, pre-existing AID of mild-to-moderate severity was associated with an elevated risk of an irAE which can occur earlier than in non-AID patients. However, more than half of the patients with AID did not experience a flare of their disease. Second, anti-PD-1 had to be stopped only in 25% of the cases of irAEs and steroids were required in only 6 patients. These results are in accordance with retrospective studies [13], [14]. This

Conclusion

When treated with anti-PD-1 antibodies, patients with pre-existing AID were found to have an elevated risk of irAE and flares. However, with appropriate management, anti-PD-1 antibodies seem to be just as safe and effective in AID patients as in AID-free patients. Our observations highlight the importance of collaboration between oncologists, organ specialists, internists and clinical immunologists for improving patient care.

Conflict of interest statement

JMM is a member of BMS Board consultancy. ER is sub-investigator for BMS, Roche, Novartis, Merk and Amgen. SC received paid expert testimony for AstraZeneca, BMS, Janssen, MSD and Roche. CM acknowledges his participation to advisory boards and is speaker or investigator for Amgen, Astellas, AstraZeneca, Bayer, Celgene, Genentech, Ipsen, Jansen, Lilly, Novartis, Pfizer, Roche, Sanofi and Orion. NG received paid expert testimony for BMS, MSD, AstraZeneca, Merck and Roche. SD received paid expert

Funding support

None.

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    Current address: Institut du Thorax Curie Montsouris, Institut Curie, F-75014 Paris, France.

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