Pneumonitis is defined as a focal or diffuse inflammation of the lung parenchyma, and is a known, potentially fatal toxicity of anti–programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint inhibitors. Herein we discuss two patients who developed pneumonitis secondary to anti–PD-1/PD-L1 immune checkpoint inhibitor therapy and illustrate a stepwise approach to the diagnostic evaluation and management of anti–PD-1/PD-L1–related pneumonitis. In the majority of patients who develop this toxicity, pneumonitis appears to clinically resolve with corticosteroid therapy alone; however, a subset of patients require additional immunosuppressive medications. Patients who clinically improve with steroid treatment must be monitored closely in the outpatient setting. If pneumonitis management results in complete clinical and radiologic resolution, patients may be able to restart their immune checkpoint inhibitor therapy. It is currently unclear which population of patients is more susceptible to developing higher-grade or steroid-refractory pneumonitis.
Immune checkpoint molecules serve as a system of checks and balances to limit immunologic activity against self-antigens. In a patient with cancer, tumor cells can hijack the expression of immune checkpoint molecules to evade immunologic destruction. Immune checkpoint inhibitors are a class of anticancer agents that have been used as a therapeutic strategy in a variety of solid tumors and hematologic malignancies to counteract the effects of immune checkpoint molecules. By inhibiting the ability of tumor-induced checkpoint molecule expression to deactivate immune cells, immune checkpoint inhibitors reinvigorate an antitumor immune response. In clinical practice, immune checkpoint inhibitors that block the activity of the programmed death 1 (PD-1) molecule (nivolumab, pembrolizumab, avelumab) and its ligand, programmed death ligand 1 (PD-L1; atezolizumab, durvalumab) are now approved by the US Food and Drug Administration for multiple solid tumors and hematologic malignancies, based on improvements in survival outcomes and tumor response in cancers such as melanoma, non–small-cell lung cancer (NSCLC),[4,5] renal cell carcinoma, urothelial carcinoma, head and neck cancer, Merkel cell carcinoma, microsatellite-unstable cancers, and Hodgkin lymphoma.[11,12]
Although clearly efficacious, immune checkpoint inhibitors are associated with the development of certain adverse events, termed immune-related adverse events (irAEs), that occur as a result of inflammation in nontarget areas of the body. Of these irAEs, pneumonitis is an uncommon but potentially fatal toxicity of anti–PD-1/PD-L1 immune checkpoint inhibitors.
Pneumonitis is defined as a focal or diffuse inflammation of the lung parenchyma. The grading system used for pneumonitis is based on criteria listed in the Common Terminology Criteria for Adverse Events (CTCAE; version 4.03). Patients with pneumonitis secondary to PD-1/PD-L1 immune checkpoint inhibitors may present clinically with dyspnea, cough, fever, and chest pain; or patients may be asymptomatic, with radiologic findings alone. The mechanism of development of pneumonitis secondary to anti–PD1/PD-L1 immune checkpoint inhibitors is unknown. The incidence rate of pneumonitis in advanced solid cancers and melanoma following anti–PD-1/PD-L1 immune checkpoint inhibitor therapy is estimated at 5%. This estimate was confirmed in a meta-analysis of patients diagnosed with NSCLC and treated with anti–PD-1 immune checkpoint inhibitors, where the incidence rate for all grades of pneumonitis was 4.1%, that for grade 3+ events was 1.8%, and the rate of pneumonitis-related deaths was 0.4%. Combination immune checkpoint inhibitor therapy utilizing anti–PD-1/PD-L1 and anti–cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) agents is associated with a higher incidence of pneumonitis, with shorter time to onset, compared with anti–PD-1/PD-L1 monotherapy. Additionally, the incidence rate of pneumonitis is reported to be higher in patients treated with anti–PD-1/PD-L1 immune checkpoint inhibitors than in those treated with anti–CTLA-4 agents. While the incidence of irAEs is relatively low, the absolute number of patients receiving immune checkpoint inhibitors is steadily increasing. Thus, it is likely that, with time, larger numbers of patients will develop irAEs, including pneumonitis.
A 73-year-old man with a 30 pack-year history of cigarette smoking and stage IV NSCLC was treated with 6 cycles of first-line carboplatin/nab-paclitaxel combination chemotherapy (Figure 1A). He then developed progressive NSCLC, and commenced second-line, standard-of-care nivolumab (3 mg/kg). After 2 cycles of nivolumab, the patient presented to the outpatient oncology clinic with a new dry cough, shortness of breath, and dyspnea on exertion, but was noted to have normal oxygen saturation on room air. A contrast-enhanced CT scan of the chest performed the same day demonstrated new peribronchial nodularity in the right lower lobe and a mild increase in size of the primary right lower lobe mass (Figure 1B). At that time, it was thought likely that the patient’s acute presentation was due to anti–PD-1–induced pneumonitis, of grade 2 severity. A pan-culture performed at that time (sputum, blood, and urine cultures) did not reveal any causative organisms, and the patient declined a suggested bronchoscopy (Table). He was thus started on a 7-day course of oral prednisone at a dose of 1 mg/kg (50 mg daily) and nivolumab therapy was held. A week later, the patient noted near-complete resolution of his symptoms. He then began a prednisone taper over 4 weeks, starting at 50 mg/daily, with the dose reduced by 10 mg per week over 4 weeks. He returned to the outpatient clinic 2 weeks later with a reported recrudescence of symptoms. A slower prednisone taper was prescribed, starting with 20 mg/daily, and reducing the dose by 5 mg every 2 weeks for 8 weeks—and nivolumab was permanently discontinued. A repeat CT scan at this time demonstrated progressive disease, and systemic chemotherapy was commenced. Two weeks later, he presented to the emergency department with dyspnea on exertion and a worsening, nonproductive cough, and was admitted to the medical intensive care unit for likely progressive NSCLC and possible persistent pneumonitis.
The patient received a high dose of prednisone (2 mg/kg) and was managed with 6 L of supplemental oxygen via nasal cannula. He began to desaturate (80% oxygen saturation) with movement, and was treated with ipratropium bromide/albuterol nebulizers twice daily. A bronchoscopy was not performed upon admission as the patient was not stable enough to undergo the procedure. A pan-culture was performed at this time (sputum, peripheral blood, and methicillin-resistant Staphylococcus aureus surveillance culture; see Table); results did not reveal a causative microbial organism. The patient’s symptoms improved once again after 48 hours of high-dose corticosteroids and oxygen supplementation; thus, while additional immunosuppression had been considered, it was not administered at that time. A course of trimethoprim/sulfamethoxazole was started as prophylaxis for Pneumocystis jirovecii pneumonia. The patient was successfully discharged on a 1.5-mg/kg dose of prednisone (45 mg/daily) and was held at that dosage for 4 weeks, with plans to evaluate the duration of the steroid taper at the next outpatient appointment in 1 month’s time. At the 1-month follow-up visit, the patient was readmitted for worsening dyspnea. Follow-up chest CT scan demonstrated progression of NSCLC, with enlarging mediastinal and hilar adenopathy despite improved changes from prior pneumonitis (Figures 1C and 1D). He was subsequently discharged to inpatient palliative care services and died 2 weeks later.
A 70-year-old woman with a 50 pack-year history of cigarette smoking and recurrent small-cell lung cancer (SCLC) was treated with a right upper lobectomy for stage I resectable SCLC, followed by 4 cycles of adjuvant carboplatin/etoposide chemotherapy (Figure 2A). Three months after completion of chemotherapy, the patient developed progressive SCLC with new bony metastases, as well as a right adrenal metastasis. Second-line, standard-of-care nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) was started. Three days after receiving her first cycle of therapy, the patient experienced new-onset fever, fatigue, generalized weakness, and nausea, which were managed supportively. One week later, she presented to her local emergency department with a 1-day history of acute onset shortness of breath. At that time, she was found to be hypoxic on room air (oxygen saturation, 80%). Her diagnostic evaluation included a CT scan of the chest without contrast (Figure 2B), which revealed new patchy ground-glass opacities in the right lower lobe and small bilateral pleural effusions. Blood cultures and a respiratory virus panel were ordered, neither of which revealed a causative microbial organism (Table). Due to the patient’s hypoxia, she was not deemed suitable for bronchoscopy on admission. Her clinical presentation was thus thought to be consistent with anti–PD-1–related pneumonitis, of grade 3 severity.
The patient was started on intravenous prednisone (100 mg; 2mg/kg) and high-flow oxygen to maintain oxygen saturation > 92%. She reported symptomatic improvement within 48 hours and was discharged 4 days later with supplemental oxygen and a 4-week taper of prednisone; the initial prednisone dose was 40 mg daily, which was to be reduced by 10 mg per week. Following 2 weeks of corticosteroid treatment, she presented for outpatient follow-up with her oncologist and demonstrated both clinical and radiologic improvement (Figure 2C). Her oxygen saturation was > 93% on room air at that time, and also at a subsequent visit 2 weeks later. A follow-up CT scan performed 9 weeks after the initial presentation of pneumonitis (Figure 2D) demonstrated almost complete resolution of the ground-glass opacities and resolution of the pleural effusions. Unfortunately, near the completion of the prednisone taper, the patient experienced another episode of dyspnea, and, after discussion with the pulmonary medicine service, prednisone was increased to 20 mg daily, with a slower taper of 5 mg per week to allow for a 4-week taper, which successfully alleviated her symptoms. Ipilimumab and nivolumab were permanently discontinued, and the patient’s next line of systemic therapy for SCLC was begun after a subsequent CT scan demonstrated progressive disease in the adrenal glands and a new liver lesion.
1. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;25:1565-70.
2. Naidoo J, Page D, Wolchok J. Immune checkpoint blockade. Hematol Oncol Clin N Am. 2014;28:585-600.
3. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23-34.
4. Kazandjian D, Suzman DL, Blumenthal G, et al. FDA approval summary: nivolumab for the treatment of metastatic non-small cell lung cancer with progression on or after platinum-based chemotherapy. Oncologist. 2016;21:634-42.
5. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomized, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17:1497-1508.
6. Cella D, Grünwald V, Nathan P, et al. Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomized, open-label, phase 3 trial. Lancet Oncol. 2016;17:994-1003.
7. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376:1015-26.
8. Ferris RL, Blumenschein G, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375:1856-67.
9. Kaufman H, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicenter, single-group, open-label, phase 2 trial. Lancet Oncol. 2016;17:1374-85.
10. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509-20.
11. Raval R, Sharabi A, Walker A, et al. Tumor immunology and cancer immunotherapy: summary of the 2013 SITC primer. J Immunother Cancer. 2014;2:1-11.
12. Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicenter, multicohort, single-arm phase 2 trial. Lancet Oncol. 2016;17:1283-94.
13. Naidoo J, Page D, Li B, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26:2375-91.
14. Marrone KA, Naidoo J, Brahmer J. Immunotherapy for lung cancer: no longer an abstract concept. Semin Respir Crit Care Med. 2016;37:771-82.
15. US Dept of Health and Human Services. Common terminology criteria for adverse events (CTCAE). Version 4.03. US Dept of Health and Human Services. 2010 Jun 14. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed September 19, 2017.
16. Naidoo J, Wang X, Woo K, et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J Clin Oncol. 2016;35:709-19.
17. Nishino M, Giobbe-Hurder A, Hatabu H. Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer: a systematic review and meta-analysis. JAMA Oncol. 2016;2:1607-16.
18. Friedman C, Proverbs-Singh T, Postow M. Treatment of the immune-related adverse effects of immune checkpoint inhibitors. JAMA Oncol. 2016;2:1346-53.
19. Nishino M, Ramaiya NH, Awad MM, et al. PD-1 inhibitor–related pneumonitis in advanced cancer patients: radiographic patterns and clinical course. Clin Cancer Res. 2016;22:6051-60.
20. Postow M, Wolchok J. Toxicities associated with checkpoint inhibitor immunotherapy. UpToDate. https://www.uptodate.com/contents/toxicities-associated-with-checkpoint-inhibitor-immunotherapy/contributors. Accessed September 19, 2017.
21. Hamada-Ode K, Taniguchi Y, Kimata T, et al. High-dose intravenous immunoglobulin therapy for rapidly progressive interstitial pneumonitis accompanied by anti-melanoma differentiation-associated gene 5 antibody-positive amyopathic dermatomyositis. Eur J Rheumatol. 2015;2:83-5.
22. O’Kane GM, Labbe C, Doherty MK, et al. Monitoring and management of immune-related adverse events associated with programmed cell death protein-1 axis inhibitors in lung cancer. Oncologist. 2017;22:70-80.
23. Fischer A, Brown KK, Du Bois RM, et al. Mycophenolate mofetil improves lung function in connective tissue disease-associated interstitial lung disease. J Rheumatol. 2013;40:640-6.
24. National Comprehensive Cancer Network. Immunotherapy teaching/monitoring tool. https://www.nccn.org/immunotherapy-tool/pdf/NCCN_Immunotherapy_Teaching_Monitoring_Tool.pdf. Accessed August 14, 2017.