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Review
October 14, 2021

Interstitial Lung Disease Induced by Anti-ERBB2 Antibody-Drug Conjugates: A Review

Author Affiliations
  • 1Division of Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy
  • 2Department of Oncology and Hematology, University of Milan, Milan, Italy
  • 3Breast Medicine Service, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York
  • 4Dana-Farber Cancer Institute, Boston, Massachusetts
  • 5International Breast Cancer Center, Quironsalud Group and Vall d'Hebron Institute of Oncology, Barcelona, Spain
  • 6Vall d´Hebron Institute of Oncology, Barcelona, Spain
  • 7Sarah Cannon Research Institute/Tennessee Oncology, Nashville
  • 8Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
  • 9Breast Cancer Unit, Kyoto University Hospital, Kyoto University Graduate School of Medicine, Kyoto, Japan
  • 10Department of Medical Oncology, Gustave Roussy, Villejuif, France
JAMA Oncol. Published online October 14, 2021. doi:10.1001/jamaoncol.2021.3595
Abstract

Importance  In the past decade, ERBB2 (formerly HER2)–directed antibody-drug conjugates (ADCs) have substantially changed treatment of both advanced and early-stage ERBB2-positive breast cancer. Novel conjugates are now showing activity in trials of other ERBB2-associated tumors, leading to the recent US Food and Drug Administration approval of trastuzumab deruxtecan for ERBB2-positive gastric cancer, as well as beneficial results in colorectal, lung, and bladder cancer. It is thus possible that anti-ERBB2 ADCs may become a treatment option for multiple types of tumors because many have at least some expression of ERBB2. Despite an improved overall therapeutic index, clinical observations have recently raised a concern regarding potential lung toxicity of anti-ERBB2 ADCs. Deaths related to interstitial lung disease (ILD) have been reported with variable incidence in trials testing anti-ERBB2 conjugates, warranting appropriate training of clinicians for the identification and management of this toxic effect.

Observations  Although no specific guidelines are available for the diagnosis and management of ADC-related ILD, some recommendations can be derived based on general principles adopted for drug-induced and immunotherapy-related ILD. Overall, in symptomatic ILD, the ADC should be discontinued. Reintroduction of the conjugate can be considered only in asymptomatic cases after complete resolution. Corticosteroids represent the cornerstone of ILD treatment, and dosing should be adapted according to the severity of the event. Additional treatments can be considered based on the clinical scenario.

Conclusions and Relevance  This review summarizes the current knowledge on the pathogenesis and epidemiologic characteristics of anti-ERBB2 ADC-related lung toxicity, proposing strategies for its diagnosis and treatment. Earlier diagnosis and more adequate treatment of ADC-induced ILD may improve the therapeutic index of this important class of anticancer agents, allowing for a safe expansion of anti-ERBB2 ADCs across tumor types.

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    1 Comment for this article
    EXPAND ALL
    Onset of Interstitial lung disease in Japanese breast cancer patients treated with T-DXd
    takuma hayashi, MBBS, DMSci, GMRC, PhD | National Hospital Organization Kyoto Medical Center
    The report by Tarantino et al. provides important information for healthcare professionals treating HER2-positive breast cancer patients with anti-HER2 antibody drugs in Japan.

    Trastuzumab Deruxtecan (T-DXd) is an antitumor drug developed in Japan. In clinical trials Phase II, the high response of T-DXd to HER2-positive breast cancer was demonstrated. As a result, Japan Ministry of Health, Labor and Welfare approved T-DXd at the stage when the results of the clinical trial phase III were not obtained.

    In a clinical trial conducted in Japan, the therapeutic effect of T-DXd on patients with HER2-positive breast cancer was 4.4% for complete
    response (CR) and 56.1% for partial response (PR). The median time to response of T-DXd is 1.5 months, and the effect is observed relatively quickly. And the median progression-free survival (PFS) was 16.4 months.

    In clinical trials Phase II, side effects such as nausea, fatigue, vomiting, neutropenia, anemia, leukopenia, and thrombocytopenia were observed in patients treated with T-DXd. If side effects are observed, the dose of T-DXd should be reduced or discontinued.

    T-DXd is an antitumor drug with a very high response, but it can cause lethal Interstitial lung disease; (ILD). ILD occurs in 13.6% of cancer patients treated with T-DXd. Most of the ILD found in cancer patients treated with T-DXd is grade 1-2. However, the frequency of deaths from grade 5 ILD is 2.2%. During treatment with T-DXd, healthcare professionals should pay close attention to the development of ILD.

    In clinical trials conducted in Japan, the time of onset of ILD is not necessarily the initial stage of administration, and the time of onset of ILD has not been specified. Interstitial pneumonia occurs at all times during the administration of T-DXd, so healthcare professionals should always observe the patient carefully. Compared with other races, many Japanese patients with breast cancer developed ILD. In particular, it has been shown that breast cancer patients with a larger number of treatment regimens before T-DXd treatment are more likely to develop ILD.

    There are several types of interstitial pneumonia, but diffuse alveolar injury is refractory pneumonia with fatal symptoms. Therefore, patients who develop diffuse alveolar injury must be treated by a respiratory specialist. Organized pneumonia and hypersensitivity pneumonitis are easily cured by steroids. Therefore, treatment with T-DXd for patients with HER2-positive breast cancer should be performed by a comprehensive team of medical care including mammary gland specialists, respiratory specialists, radiologists, pharmacists, and nurses.

    Disclosure
    The authors declare no potential conflicts of interest. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

    Dr. Hayashi T. and Dr. Konishi I.
    National Hospital Organization Kyoto Medical Center
    CONFLICT OF INTEREST: None Reported
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