Knowledge Gaps and Research Priorities in Immune Checkpoint Inhibitor–related Pneumonitis. An Official American Thoracic Society Research Statement

Rationale: Immune checkpoint inhibitors (ICIs) have revolutionized cancer care but are associated with unique adverse events, including potentially life-threatening pneumonitis. The diagnosis of ICI-pneumonitis is increasing; however, the biological mechanisms, clinical and radiologic features, and the diagnosis and management have not been well defined. Objectives: To summarize evidence, identify knowledge and research gaps, and prioritize topics and propose methods for future research on ICI-pneumonitis. Methods: A multidisciplinary group of international clinical researchers reviewed available data on ICI-pneumonitis to develop and refine research questions pertaining to ICI-pneumonitis. Results: This statement identifies gaps in knowledge and develops potential research questions to further expand knowledge regarding risk, biologic mechanisms, clinical and radiologic presentation, and management of ICI-pneumonitis. Conclusions: Gaps in knowledge of the basic biological mechanisms of ICI-pneumonitis, coupled with a precipitous increase in the use of ICIs alone or combined with other therapies, highlight the importance in triaging research priorities for ICI-pneumonitis.

[1]  J. Nieva,et al.  Tuberculosis following PD-1 blockade for cancer immunotherapy , 2019, Science Translational Medicine.

[2]  J. Sugisaka,et al.  Profiling Preexisting Antibodies in Patients Treated With Anti–PD-1 Therapy for Advanced Non–Small Cell Lung Cancer , 2019, JAMA oncology.

[3]  C. Lin,et al.  Immune Checkpoint Immunotherapy for Non-Small Cell Lung Cancer: Benefits and Pulmonary Toxicities. , 2018, Chest.

[4]  C. Lin,et al.  Pneumonitis in Non–Small Cell Lung Cancer Patients Receiving Immune Checkpoint Immunotherapy: Incidence and Risk Factors , 2018, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[5]  R. Sullivan,et al.  Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis , 2018, JAMA oncology.

[6]  D. Planchard,et al.  Hyperprogressive Disease in Patients With Advanced Non–Small Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or With Single-Agent Chemotherapy , 2018, JAMA oncology.

[7]  S. Negoro,et al.  Efficacy of anti-PD-1/PD-L1 antibodies after discontinuation due to adverse events in non-small cell lung cancer patients (HANSHIN 0316) , 2018, BMC Cancer.

[8]  T. Creasy,et al.  Impaired Tumor‐Infiltrating T Cells in Patients with Chronic Obstructive Pulmonary Disease Impact Lung Cancer Response to PD‐1 Blockade , 2018, American journal of respiratory and critical care medicine.

[9]  A. Tafreshi,et al.  Pembrolizumab plus Chemotherapy for Squamous Non–Small‐Cell Lung Cancer , 2018, The New England journal of medicine.

[10]  Gregory Riely,et al.  Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung Cancer. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  V. Velculescu,et al.  Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC) , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[12]  Tetsuya Tanimoto,et al.  EGFR–TKI-Associated Interstitial Pneumonitis in Nivolumab-Treated Patients With Non–Small Cell Lung Cancer , 2018, JAMA oncology.

[13]  J. Minna,et al.  Diagnosis and management of pulmonary toxicity associated with cancer immunotherapy. , 2018, The Lancet. Respiratory medicine.

[14]  L. Zitvogel,et al.  Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[15]  Young Hak Kim,et al.  Efficacy and safety of nivolumab in non‐small cell lung cancer with preexisting interstitial lung disease , 2018, Thoracic cancer.

[16]  J. Riess,et al.  Safety of Programmed Death-1 Pathway Inhibitors Among Patients With Non-Small-Cell Lung Cancer and Preexisting Autoimmune Disorders. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  W. Shi,et al.  Safety of combining thoracic radiation therapy with concurrent versus sequential immune checkpoint inhibition , 2018, Advances in radiation oncology.

[18]  John A Thompson,et al.  New NCCN Guidelines: Recognition and Management of Immunotherapy-Related Toxicity. , 2018, Journal of the National Comprehensive Cancer Network : JNCCN.

[19]  J. Szustakowski,et al.  Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden , 2018, The New England journal of medicine.

[20]  S. Novello,et al.  Pembrolizumab plus Chemotherapy in Metastatic Non–Small‐Cell Lung Cancer , 2018, The New England journal of medicine.

[21]  M. Suarez‐Almazor,et al.  Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  F. Khuri,et al.  Comparison of the toxicity profile of PD‐1 versus PD‐L1 inhibitors in non–small cell lung cancer: A systematic analysis of the literature , 2018, Cancer.

[23]  Matthew D. Hellmann,et al.  Immune‐Related Adverse Events Associated with Immune Checkpoint Blockade , 2018, The New England journal of medicine.

[24]  Laurence Zitvogel,et al.  Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors , 2018, Science.

[25]  A. Diab,et al.  The impact of immune checkpoint inhibitor-related adverse events and their immunosuppressive treatment on patients' outcomes , 2018, Journal of Immunotherapy and Precision Oncology.

[26]  B. Besse,et al.  Infectious complications associated with the use of immune checkpoint inhibitors in oncology: reactivation of tuberculosis after anti PD-1 treatment. , 2017, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[27]  J. Horton,et al.  A Phase II Study of Pembrolizumab in EGFR‐Mutant, PD‐L1+, Tyrosine Kinase Inhibitor Naïve Patients With Advanced NSCLC , 2017, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[28]  D. Costa,et al.  Radiologic and autopsy findings in a case of fatal immune checkpoint inhibitor-associated pneumonitis. , 2018, Cancer treatment and research communications.

[29]  M. Suarez‐Almazor,et al.  Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group , 2017, Journal of Immunotherapy for Cancer.

[30]  R. Sullivan,et al.  Immune Checkpoint Inhibitor Cancer Therapy: Spectrum of Imaging Findings. , 2017, Radiographics : a review publication of the Radiological Society of North America, Inc.

[31]  B. E. El Osta,et al.  Not all immune-checkpoint inhibitors are created equal: Meta-analysis and systematic review of immune-related adverse events in cancer trials. , 2017, Critical reviews in oncology/hematology.

[32]  Tarek Mekhail,et al.  Durvalumab after Chemoradiotherapy in Stage III Non–Small‐Cell Lung Cancer , 2017, The New England journal of medicine.

[33]  K. Shannon,et al.  1220PDPhase 2 study of neoadjuvant dabrafenib + trametinib (D+T) for resectable stage IIIB/C BRAF V600 mutant melanoma , 2017 .

[34]  V. Rusch,et al.  Initial Experience With Lung Cancer Resection After Treatment With T-Cell Checkpoint Inhibitors. , 2017, The Annals of thoracic surgery.

[35]  M. Wiese,et al.  Predicting response and toxicity to immune checkpoint inhibitors using routinely available blood and clinical markers , 2017, British Journal of Cancer.

[36]  K. Kerr,et al.  Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[37]  S. Formenti,et al.  Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. , 2017, The Lancet. Oncology.

[38]  K. Kerr,et al.  Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[39]  F. Hodi,et al.  Monitoring immune-checkpoint blockade: response evaluation and biomarker development , 2017, Nature Reviews Clinical Oncology.

[40]  M. Socinski,et al.  First‐Line Nivolumab in Stage IV or Recurrent Non–Small‐Cell Lung Cancer , 2017, The New England journal of medicine.

[41]  P. Mazzone,et al.  Incidence of Pneumonitis With Use of Programmed Death 1 and Programmed Death‐Ligand 1 Inhibitors in Non‐Small Cell Lung Cancer: A Systematic Review and Meta‐Analysis of Trials , 2017, Chest.

[42]  C. Rudin,et al.  Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  R. Sullivan,et al.  Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[44]  R. Stupp,et al.  Ipilimumab and early signs of pulmonary toxicity in patients with metastastic melanoma: a prospective observational study , 2017, Cancer Immunology, Immunotherapy.

[45]  A. Giobbie-Hurder,et al.  Incidence of Programmed Cell Death 1 Inhibitor-Related Pneumonitis in Patients With Advanced Cancer: A Systematic Review and Meta-analysis. , 2016, JAMA oncology.

[46]  T. Mio,et al.  Anti-PD1 Antibody Treatment and the Development of Acute Pulmonary Tuberculosis. , 2016, Journal of Thoracic Oncology.

[47]  G. Redelman-Sidi,et al.  The Spectrum of Serious Infections Among Patients Receiving Immune Checkpoint Blockade for the Treatment of Melanoma. , 2016, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[48]  A. Adjei,et al.  Anti-PD-1 Antibody Treatment and the Development of Acute Pulmonary Tuberculosis. , 2016, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[49]  Y. Shentu,et al.  Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. , 2016, The New England journal of medicine.

[50]  M. Postow,et al.  Treatment of the Immune-Related Adverse Effects of Immune Checkpoint Inhibitors: A Review. , 2016, JAMA oncology.

[51]  J. Mortensen,et al.  Pulmonary Function in Patients With Germ Cell Cancer Treated With Bleomycin, Etoposide, and Cisplatin. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[52]  F. Hodi,et al.  PD-1 Inhibitor–Related Pneumonitis in Advanced Cancer Patients: Radiographic Patterns and Clinical Course , 2016, Clinical Cancer Research.

[53]  Y. Shentu,et al.  Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial , 2016, The Lancet.

[54]  M. Ahn,et al.  Osimertinib combined with durvalumab in EGFR‐mutant non‐small cell lung cancer: Results from the TATTON phase Ib trial: 136O , 2016, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[55]  J. Larkin,et al.  Management of toxicities of immune checkpoint inhibitors. , 2016, Cancer treatment reviews.

[56]  P. Jänne,et al.  Anti–PD-1 Inhibitor–Related Pneumonitis in Non–Small Cell Lung Cancer , 2016, Cancer Immunology Research.

[57]  R. Sullivan,et al.  Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders. , 2016, JAMA oncology.

[58]  J. Soria,et al.  Immune-related adverse events with immune checkpoint blockade: a comprehensive review. , 2016, European journal of cancer.

[59]  M. Ahn,et al.  459PRisk of pneumonitis in patients with advanced NSCLC treated with pembrolizumab in KEYNOTE-001 , 2015 .

[60]  F. Ginhoux,et al.  Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota , 2015, Science.

[61]  A. Amin,et al.  Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities. , 2015, Translational lung cancer research.

[62]  F. Hodi,et al.  Anti-PD-1-Related Pneumonitis during Cancer Immunotherapy. , 2015, The New England journal of medicine.

[63]  P. Lorigan,et al.  Optimal management of immune-related toxicities associated with checkpoint inhibitors in lung cancer. , 2015, Lung cancer.

[64]  Martin L. Miller,et al.  Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer , 2015, Science.

[65]  S. Krengel,et al.  Case Reports of Fatal or Metastasizing Melanoma in Children and Adolescents: A Systematic Analysis of the Literature , 2015, Pediatric dermatology.

[66]  Charlie Strange,et al.  An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. , 2012, American journal of respiratory and critical care medicine.

[67]  C. Drake,et al.  Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. , 2012, The New England journal of medicine.

[68]  David C. Smith,et al.  Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. , 2012, The New England journal of medicine.

[69]  M. Perry,et al.  Pulmonary toxicity of chemotherapy. , 2006, Seminars in oncology.

[70]  L. Marks,et al.  Challenges in defining radiation pneumonitis in patients with lung cancer. , 2005, International journal of radiation oncology, biology, physics.

[71]  T. Honjo,et al.  Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. , 1999, Immunity.

[72]  H. Griesser,et al.  Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4 , 1995, Science.

[73]  N L Müller,et al.  Clinical value of high-resolution CT in chronic diffuse lung disease. , 1991, AJR. American journal of roentgenology.