Ipilimumab and early signs of pulmonary toxicity in patients with metastastic melanoma: a prospective observational study
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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.
KeywordsIpilimumab Metastatic melanoma Drug toxicity Pneumonitis
List of abbreviations
Acute respiratory distress syndrome
Chronic obstructive pulmonary disease
Cytotoxic T-lymphocyte-associated antigen 4
Diffusion capacity of the lung for carbon monoxide
18-Fluorodeoxyglucose positron emission tomography combined with computed tomography
Forced vital capacity
Non-small cell lung cancer
Pulmonary function tests
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.
Compliance with ethical standards
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.
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).
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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