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Ipilimumab and early signs of pulmonary toxicity in patients with metastastic melanoma: a prospective observational study

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Abstract

Ipilimumab, an immune checkpoint inhibitor, is approved for treatment metastastic melanoma and is a promising agent against other malignancies. There is some preliminary evidence from case reports that ipilimumab treatment may be associated with pulmonary side effects. However, data from prospective studies on ipilimumab-related pulmonary toxicity are still scarce. Serial spirometries and measurements of CO-diffusion capacity (DLCO) in patients with metastatic melanoma before and during treatment with ipilimumab were performed. A reduction from baseline of forced vital capacity (FVC) of ≥ 10%, or ≥ 15% of DLCO was defined as clinically meaningful and indicative for pulmonary toxicity. Of 71 patients included in this study, a clinically meaningful lung function decline was registered in 6/65 (9%), 5/44 (11%), and 9/38 (24%) patients after 3, 6, and 9 weeks of treatment initiation, respectively. Even after adjusting for age, concomitant melanoma treatment, progressive pulmonary metastases, and baseline pulmonary function values, mean ± SD DLCO decreased significantly during follow-up (−4.3% ± 13.6% from baseline, p = 0.033). Only 7% of patients reported respiratory symptoms. Clinically manifest ipilimumab-related pneumonitis was diagnosed only in one patient (1.4%). DLCO decline maybe an early indicator of subclinical pulmonary drug toxicity. Therefore, routine pulmonary function testing including DLCO measurement during treatment might help for risk stratification to screen for ipilimumab-related pneumonitis.

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Abbreviations

ARDS:

Acute respiratory distress syndrome

BAL:

Broncho-alveolar lavage

COPD:

Chronic obstructive pulmonary disease

CTLA-4:

Cytotoxic T-lymphocyte-associated antigen 4

DLCO:

Diffusion capacity of the lung for carbon monoxide

FDG-PET/CT:

18-Fluorodeoxyglucose positron emission tomography combined with computed tomography

FVC:

Forced vital capacity

HR-CT:

High-resolution CT

NSCLC:

Non-small cell lung cancer

OR:

Odds ratio

OP:

Organizing pneumonia

PFT:

Pulmonary function tests

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Author contributions

Conception: Daniel Franzen, Karin Schad, Reinhard Dummer, Malcolm Kohler. Data collection: Daniel Franzen, Karin Schad, Benedikt Kowalski, Christian F. Clarenbach. Data analysis and interpretation: Daniel Franzen, Benedikt Kowalski, Roger Stupp, Reinhard Dummer, Malcolm Kohler. Drafting of the article: Daniel Franzen, Karin Schad, Benedikt Kowalski. Critical revision: Roger Stupp, Reinhard Dummer, Malcolm Kohler. Final approval: All authors.

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Authors and Affiliations

  1. Department of Pulmonology, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland

    Daniel Franzen, Benedikt Kowalski, Christian F. Clarenbach & Malcolm Kohler

  2. Department of Dermatology, University Hospital Zurich, 8091, Zurich, Switzerland

    Karin Schad & Reinhard Dummer

  3. Department of Medical Oncology, University Hospital Zurich, 8091, Zurich, Switzerland

    Roger Stupp

Authors
  1. Daniel Franzen
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  2. Karin Schad
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  3. Benedikt Kowalski
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  6. Reinhard Dummer
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  7. Malcolm Kohler
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Corresponding author

Correspondence to Daniel Franzen.

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Conflict of interest

Reinhard Dummer received research funding from Novartis, Merck Sharp & Dome (MSD), Bristol-Myers Squibb (BMS), Roche, GlaxoSmithKline (GSK) and has a consultant or advisory board relationship with Novartis, Merck Sharp & Dome, Bristol-Myers Squibb, Roche, GlaxoSmithKline, and Amgen, all outside the submitted work. All other authors report no conflicts of interest that could influence the results of the study.

Ethical approval

The study is in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the local Ethics committee (KEK-ZH 2013-0191) and is registered at ClinicalTrials.gov (NCT02755233).

Informed consent

Written informed consent to participate in the study and to publish the data was given by all subjects included in the study. Particularly, the publication of the CT scan was consented by the individual patient.

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Franzen, D., Schad, K., Kowalski, B. et al. Ipilimumab and early signs of pulmonary toxicity in patients with metastastic melanoma: a prospective observational study. Cancer Immunol Immunother 67, 127–134 (2018). https://doi.org/10.1007/s00262-017-2071-2

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  • DOI: https://doi.org/10.1007/s00262-017-2071-2

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