The development of checkpoint inhibitors has changed the treatment paradigm for cancer. Checkpoint inhibitors nivolumab, pembrolizumab, and cemiplimab target programmed death-1 (PD-1), whereas durvalumab, avelumab, and atezolizumab target PD-ligand 1. Ipilimumab targets cytotoxic T lymphocyte–associated antigen 4. Used as monotherapy or in combination, these inhibitors have shown remarkable efficacy in melanoma, lung cancer, urothelial cancer, and many other solid tumors, and indications are continuing to evolve. Checkpoint inhibitors are well tolerated when compared with traditional chemotherapy. The major adverse effect profiles are idiosyncratic immune-mediated toxicities resulting from the abnormal activation of autoreactive T cells, which can lead to inflammation in any organ system. The most commonly affected organs are bowel, lung, skin, and endocrine. Pulmonary toxicity is important to recognize, and it can be more challenging to diagnose in lung cancer patients, given the nature of the disease course and treatment. This review article focuses on all of the pulmonary adverse effects of a single PD-1 inhibitor (nivolumab) that have been described in the literature. These complications include dyspnea, pneumonitis, pleural effusion, pulmonary sarcoidosis, pulmonary tuberculosis, acute fibrinous organizing pneumonia, organizing pneumonia, eosinophilic pneumonia, adult respiratory distress syndrome, and lung cavitation. Clinicians must be aware of these toxicities and mindful when prescribing these medications in patients with known lung dysfunction due to chronic lung diseases or lung cancer.
Having trouble viewing the article content below? Click here to open it directly.
Table. Current indications of check point inhibitors.
1. Rotte A, Jin JY, Lemaire V. Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy. Ann Oncol 2017;29:71–83.
2. Wei SC, Levine JH, Cogdill AP, et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 2017;170:1120–1133.
3. Kato T, Masuda N, Nakanishi Y, et al. Nivolumab-induced interstitial lung disease analysis of two phase II studies patients with recurrent or advanced non-small-cell lung cancer. Lung Cancer 2017;104:111–118.
4. Nakahama K, Tamiya A, Taniguchi Y, et al. Severe acute interstitial lung disease after nivolumab in three non-small cell lung cancer patients with imaging findings of airway obstruction adjacent to lung tumors. J Infect Chemother 2017;23:826–829.
5. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N Engl J Med 2015;373:123–135.
6. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med 2015;373:1627–1639.
7. Kyi C, Postow MA. Checkpoint blocking antibodies in cancer immunotherapy. FEBS Lett 2014;588:368–376.
8. Koyama N, Iwase O, Nakashima E, et al. High incidence and early onset of nivolumab-induced pneumonitis: four case reports and literature review. BMC Pulm Med 2018;18:23.
9. Nishino M, Giobbie-Hurder A, Hatabu H, et al. Incidence of programmed cell death 1 inhibitor–related pneumonitis in patients with advanced cancer: a systematic review and meta-analysis. JAMA Oncol 2016;2:1607–1616.
10. Watanabe S, Kimura H, Takato H, et al. Severe pneumonitis after nivolumab treatment in a patient with melanoma. Allergol Int 2016;65:487–489.
11. Chow LQ. Exploring novel immune-related toxicities and endpoints with immune-checkpoint inhibitors in non-small cell lung cancer. Am Soc Clin Oncol Educ Book 2013; doi: 10.1200/EdBook_AM.2013.33.e280.
12. Cui P-F, Ma J-X, Wang F-X, et al. Pneumonitis and pneumonitis-related death in cancer patients treated with programmed cell death-1 inhibitors: a systematic review and meta-analysis. Ther Clin Risk Manag 2017;13:1259.
13. Suresh K, Naidoo J, Lin CT, et al. Immune checkpoint immunotherapy for non-small cell lung cancer: benefits and pulmonary toxicities. Chest 2018;154:1416–1423.
14. 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;22:6051–6060.
15. Delaunay M, Cadranel J, Lusque A, et al. Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients. Eur Respir J 2017;50:1700050.
16. Nishino M, Chambers ES, Chong CR, et al. Anti–PD-1 inhibitor–related pneumonitis in non–small cell lung cancer. Cancer Immunol Res 2016;4:289–293.
17. Sehgal S, Velcheti V, Mukhopadhyay S, et al. Focal lung infiltrate complicating PD-1 inhibitor use: A new pattern of drug-associated lung toxicity? Respir Med Case Rep 2016;19:118–120.
18. Wu J, Hong D, Zhang X, et al. PD-1 inhibitors increase the incidence and risk of pneumonitis in cancer patients in a dose-independent manner: a metaanalysis. Sci Rep 2017;7:44173.
19. Freeman-Keller M, Kim Y, Cronin H, et al. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res 2016;22:886–894.
20. Gettinger SN, Horn L, Gandhi L, et al. Overall survival and long-term safety
of nivolumab (anti–programmed death 1 antibody, BMS-936558, ONO-4538)
in patients with previously treated advanced non–small-cell lung cancer. J Clin
21. Rizvi NA, Mazières J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 2015;16:257–265.
22. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N Engl J Med 2012;366:2443–2454.
23. Gounant V, Brosseau S, Naltet C, et al. Nivolumab-induced organizing pneumonitis in a patient with lung sarcomatoid carcinoma. Lung Cancer 2016;99:162–165.
24. Sano T, Uhara H, Mikoshiba Y, et al. Nivolumab-induced organizing pneumonia in a melanoma patient. Jpn J Clin Oncol 2016;46:270–272.
25. Nakashima K, Naito T, Omori S, et al. Organizing pneumonia induced by nivolumab in a patient with metastatic melanoma. J Thorac Oncol 2016;11:432–433.
26. Ishiwata T, Ebata T, Iwasawa S, et al. Nivolumab-induced acute fibrinous and organizing pneumonia (AFOP). Intern Med 2017;56:2311–2315.
27. Montaudié H, Pradelli J, Passeron T, et al. Pulmonary sarcoid-like granulomatosis induced by nivolumab. Br J Dermatol 2017;176:1060–1063.
28. Patterson KC, Chen ES. The pathogenesis of pulmonary sarcoidosis and implications for treatment. Chest 2018;153:1432–1442.
29. Shannon VR. Pneumotoxicity associated with immune checkpoint inhibitor therapies. Curr Opin Pulm Med 2017;23:305–316.
30. Uchida N, Fujita K, Nakatani K, et al. Acute progression of aspergillosis in a patient with lung cancer receiving nivolumab. Respirol Case Rep 2018;6:
31. Fujita K, Terashima T, Mio T. Anti-PD1 antibody treatment and the development of acute pulmonary tuberculosis. J Thorac Oncol 2016;11:2238–2240.
32. Rampinelli C, Spitaleri G, Passaro A, et al. Lung tissue injury as an atypical response to nivolumab in non–small cell lung cancer. Am J Respir Crit Care Med 2017;196:1349–1350.
33. Kimura H, Sone T, Murata A, et al. Long-lasting shrinkage in tumor mass after discontinuation of nivolumab treatment. Lung Cancer 2017;108:7–8.
34. Yoshioka M, Kambe N, Yamamoto Y, et al. Case of respiratory discomfort due to myositis after administration of nivolumab. J Dermatol 2015;42:1008–1009.
35. Maeno K, Fukuda S, Oguri T, et al. Nivolumab-induced asthma in a patient with non-small-cell lung cancer. Ann Oncol 2017;28:2891.