Overview and Management of Drug-Induced Interstitial Lung Disease With Novel Treatments in HER2+ Breast Cancer, Lung Cancers, and Gastrointestinal Cancers

Recently developed treatments for human epidermal growth factor receptor 2 (HER2)-positive (HER2+) breast cancer, lung cancers, and gastrointestinal (GI) cancers include antibody-drug conjugates (ADCs), cyclin-dependent kinase (CDK) 4/6 inhibitors, and immuno-oncology agents (eg, immune checkpoint inhibitors).^1-4

An ADC is composed of a monoclonal antibody linked to a cytotoxic chemotherapy drug via specialized linker proteins.² An ADC delivers and releases cytotoxic agents at the tumor site with reduced systemic toxicity. ADCs approved for HER2+ breast cancer include trastuzumab emtansine and trastuzumab deruxtecan.^5,6 Trastuzumab emtansine is indicated for patients with HER2+ early breast cancer who have residual invasive disease or HER2+ metastatic breast cancer who previously received trastuzumab and a taxane.⁵ Trastuzumab deruxtecan is indicated for adult patients with unresectable HER2+ breast cancer or metastatic HER2+ breast cancer who received 2 or more anti–HER2-based therapies in the metastatic setting.⁶ Trastuzumab deruxtecan is also under investigation for gastric cancer.⁷

The CDK 4/6 inhibitors palbociclib, ribociclib, and abemaciclib are approved for HER2-negative breast cancer.^8-10 These agents are also in various phases of development as part of combination therapy for the treatment of patients with HER2+ breast cancer.^11-13

The immuno-oncology agents that are PD-1/PD-L1 inhibitors belong to a class of agents called immune checkpoint inhibitors; they target regulatory immune cell checkpoints.⁴ The PD-1 inhibitors nivolumab and pembrolizumab are approved for use in a variety of solid tumors, including lung cancer, and PD-L1 inhibitors, such as atezolizumab and durvalumab, are indicated for the treatment of several cancers, including those of the breast and lung.^14-18

The ADCs, CDK 4/6 inhibitors, and immuno-oncology agents were approved for these indications based on efficacy and safety results from clinical trials. This article provides an overview of adverse events (AEs) associated with these treatments and discusses strategies for their management, with a particular focus on interstitial lung disease (ILD) or pneumonitis.

Overview and Management of AEs

ADCs

In clinical trials, AEs that occurred in at least 25% of patients with HER2+ metastatic breast cancer who were given trastuzumab emtansine were fatigue, nausea, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, increased transaminases, constipation, and epistaxis.⁵ The most common AEs (incidence >25%) in patients with early breast cancer who were given trastuzumab emtansine in the KATHERINE trial were fatigue, nausea, increased transaminases, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, peripheral neuropathy, and arthralgia.⁵ Nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, cough, and thrombocytopenia were the most frequent AEs (incidence ≥20%) in patients given trastuzumab deruxtecan.⁶

Infusion-related reactions (IRRs) are often observed with ADCs and can range from mild allergic reactions to anaphylaxis.¹ To prevent IRRs, premedication with a corticosteroid, antihistamine, and acetaminophen is recommended 1 hour prior to ADC infusion.¹ Treatment discontinuation should be considered for patients who develop signs or symptoms of anaphylaxis (eg, severe respiratory symptoms or clinically significant hypotension).¹

Serious AEs with trastuzumab emtansine can include liver toxicity and reductions in left ventricular ejection fraction.⁵ ILD or pneumonitis, left ventricular dysfunction, and neutropenia are possible serious AEs with trastuzumab deruxtecan.6 Patients should be monitored for potential drug reactions, and dose modifications or treatment discontinuation should be instituted as appropriate.^5,6

CDK 4/6 Inhibitors

AEs that are commonly reported in phase 3 trials of CDK 4/6 inhibitors include fatigue, nausea, vomiting, stomatitis, alopecia, rash, diarrhea, decreased appetite, infections, and neutropenia.¹⁹ The most frequent AEs (incidence ≥10%) observed with palbociclib were neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anemia, alopecia, diarrhea, thrombocytopenia, rash, vomiting, decreased appetite, asthenia, and pyrexia.⁸ Neutropenia, nausea, infections, fatigue, diarrhea, leukopenia, vomiting, alopecia, headache, constipation, rash, and cough were the most common AEs (incidence ≥20%) in clinical trials with ribociclib.⁹ The most frequent AEs (incidence ≥20%) in clinical studies of abemaciclib were diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia.¹⁰

Most AEs are mild and can be managed with dose modification or supportive care measures.¹⁹ Although rare, CDK 4/6 inhibitors can cause serious inflammation in the lungs.²⁰ Patients receiving a CDK 4/6 inhibitor should be monitored for signs and symptoms of ILD or pneumonitis.^8-10

Immuno-Oncology Agents

Immuno-oncology agents are associated with immune-related AEs (irAEs), which can occur due to nonspecific activation of the immune system by immunotherapeutic agents.⁴ irAEs can affect any organ system, but those of the skin, GI tract, endocrine system, lungs, and the musculoskeletal system are most common.⁴ Dermatologic reactions (eg, rash, pruritus, psoriasiform eruptions, and vitiligo) are the most frequently observed irAEs, followed by GI toxicities (eg, diarrhea, colitis, hepatitis, and pancreatitis).²¹

In clinical trials, the most common AEs (occurring in ≥20%) in patients given nivolumab included fatigue, rash, musculoskeletal pain, pruritus, diarrhea, and nausea.¹⁴ The most frequent AEs (incidence >20%) in patients given pembrolizumab were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, and peripheral neuropathy were the most common AEs in patients given pembrolizumab and chemotherapy.¹⁵

AEs occurring in at least 20% of patients given atezolizumab monotherapy in clinical trials were fatigue/asthenia, nausea, cough, dyspnea, and decreased appetite. The most common AEs (incidence ≥20%) in patients with non–small cell lung cancer (NSCLC) and small cell lung cancer who were given atezolizumab plus other antineoplastic drugs were fatigue/asthenia, nausea, alopecia, constipation, diarrhea, and decreased appetite. In patients with triple-negative breast cancer, the most frequent AEs with atezolizumab plus protein-bound paclitaxel were alopecia, peripheral neuropathies, fatigue, nausea, diarrhea, anemia, constipation, cough, headache, neutropenia, vomiting, and decreased appetite.¹⁷ The most frequent AEs occurring in at least 20% of patients with unresectable stage III NSCLC who were given durvalumab were cough, fatigue, pneumonitis/radiation pneumonitis, upper respiratory tract infections, dyspnea, and rash. In those with extensive-stage small cell lung cancer, the most common AEs with durvalumab were nausea, fatigue/asthenia, and alopecia.¹⁸

Pneumonitis is the most common fatal irAE associated with PD-1/PD-L1 inhibitors. It accounts for approximately one-third of deaths related to anti–PD-1/PD-L1 agents.²²

Potential Lung-Related AEs Associated With ADCs and Other Targeted Agents

ILD is a term used for a group of lung disorders that includes drug-induced pneumonitis, a potential lung-related AE associated with ADCs and other targeted agents. The diagnosis of ILD may be supported by the patient’s clinical history, physical examination, chest x-ray, and other appropriate laboratory testing (eg, peripheral blood tests and lung physiologic testing).²³ In a retrospective analysis of patients receiving anti–PD-1/PD-L1 agents, the most commonly reported symptoms of ILD were dyspnea (53%), cough (35%), fever (12%), and chest pain (7%).²⁴ Up to one-third of patients given PD-1/PD-L1 inhibitors who develop pneumonitis are asymptomatic.²⁵ The signs and symptoms of ILD or pneumonitis are nonspecific, and other causes (eg, bacterial or viral infection) must be excluded.²⁴ The onset of pneumonitis can occur within days or up to 24 months after treatment initiation.²⁵

Patients presenting with signs and symptoms of ILD or pneumonitis are routinely assessed using CT of the chest, which may show diffuse, patchy ground-glass attenuation and centrilobular nodules with areas of air-trapping.^26,27 Highresolution CT is useful in diagnosing and evaluating patients with suspected pneumonitis.²³ Characteristic findings can include radiologic patterns such as cryptogenic organizing pneumonia, acute interstitial pneumonia/acute respiratory distress syndrome, nonspecific interstitial pneumonia, and hypersensitivity pneumonitis.²² Patients with radiographic or clinical evidence of pneumonitis (eg, new pulmonary infiltrates on lung imaging, or new or worsened hypoxemia, dyspnea, or cough) should be referred to a pulmonologist for further evaluation.⁴

The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) are used to document the incidence and severity of AEs.²⁸ Management of irAEs, such as ILD or pneumonitis, is guided by the NCI-CTCAE grade.²⁸ Grade 1 (mild) pneumonitis is asymptomatic, confined to 1 lobe of the lung or less than 25% of lung parenchyma.²⁸ Grade 2 (moderate) pneumonitis involves the presence of new or worsening symptoms, including shortness of breath, cough, chest pain, fever, and increased oxygen requirement.²⁸ To monitor for signs and symptoms, patients should have a history and physical examination and pulse oximetry performed every 1 to 2 weeks in those with mild pneumonitis and every 3 to 7 days in those with moderate pneumonitis.²⁶ Grade 3/4 (severe) pneumonitis involves severe symptoms, affects all lung lobes or greater than 50% of lung parenchyma, and limits self-care activities of daily living.28,29 Patients with grade 3/4 pneumonitis should be admitted to the hospital or intensive care unit.29 In patients with grade 2 or higher pneumonitis, immunotherapy should be held (grade 2) or permanently discontinued (grade 3/4) and corticosteroid treatment initiated.28 Antibiotics should be considered if infection has not been excluded.²⁸

In patients with metastatic breast cancer participating in the EMILIA trial, the incidence of ILD or pneumonitis was low (0.8% [7/884 cases], with one case of grade 3 pneumonitis). The overall incidence of ILD or pneumonitis was 1.2% in EMILIA.⁵ In clinical studies of patients with unresectable or metastatic HER2+ breast cancer given trastuzumab deruxtecan (n = 234), ILD occurred in 9% of patients.⁶ However, clinical experience suggests that the incidence of pulmonary toxicity may be higher than reported in the clinical trials and possibly influenced by type of malignancy (ie, a higher rate in NSCLC than melanoma).^22,30

Pulmonary toxicity (eg, ILD or pneumonitis) is listed under warnings and precautions in the trastuzumab emtansine prescribing information.⁵ Some cases of ILD or pneumonitis leading to acute respiratory distress syndrome or death were reported in clinical trials with trastuzumab emtansine.⁵ If ILD or pneumonitis occurs, trastuzumab emtansine should be permanently discontinued.⁵ The risk of pulmonary toxicity is increased in patients with dyspnea at rest due to complications of advanced malignancy, comorbidities, and concurrent pulmonary radiation therapy.⁵

Trastuzumab deruxtecan has a boxed warning for ILD and pneumonitis; fatal outcomes of ILD or pneumonitis were reported in 2.6% of patients given trastuzumab deruxtecan.⁶ Patients receiving trastuzumab deruxtecan should be advised of the risk of ILD and monitored for signs and symptoms of ILD (eg, cough, dyspnea, fever, and other new or worsening respiratory symptoms).⁶ Patients should be instructed to immediately report symptoms, and these symptoms must be promptly investigated if ILD is suspected.⁶ In grade 1 (asymptomatic) pneumonitis, treatment with trastuzumab deruxtecan should be interrupted until resolution of the adverse reaction to grade 0.6 The dose of trastuzumab deruxtecan can be maintained if pneumonitis resolves in 28 days or less, or reduced if pneumonitis resolves in more than 28 days. Corticosteroid treatment can be considered as soon as ILD or pneumonitis is suspected.⁶ In grade 2 or higher (symptomatic) pneumonitis, treatment with trastuzumab deruxtecan should be permanently discontinued and corticosteroid therapy initiated as soon as ILD or pneumonitis is suspected.⁶

CDK 4/6 inhibitors, like ADCs, are associated with ILD or pneumonitis. The prescribing information for palbociclib, ribociclib, and abemaciclib include a warning about the potential for severe, life-threatening, or fatal ILD or pneumonitis. Patients should be monitored for the signs and symptoms of ILD or pneumonitis, and treatment should be interrupted in suspected cases and permanently discontinued in severe cases.^8-10

The prescribing information for the PD-1/PD-L1 inhibitors nivolumab, pembrolizumab, atezolizumab, and durvalumab include warnings about the risk of immune-mediated pneumonitis, defined as requiring the use of systemic corticosteroids. Some cases have been fatal. Patients should be monitored for the signs and symptoms of pneumonitis, and these agents should be withheld or discontinued based on its severity.^14,15,17,18

Conclusions

ILD or pneumonitis is a potentially fatal immune-related adverse reaction that can occur in patients treated with ADCs, CDK 4/6 inhibitors, and immuno-oncology agents. Immune- related AEs observed with these therapies may involve the skin, GI system, and other organ systems. Patients treated with these agents should be monitored for ILD or pneumonitis and other immune-related toxicities. Successful resolution of ILD or pneumonitis requires prompt diagnosis and appropriate management using dose reductions, treatment discontinuation, and corticosteroid therapy as needed.

References:

1. Wolska-Washer A, Robak T. Safety and tolerability of antibody-drug conjugates in cancer. Drug Saf. 2019;42(2):295-314. doi:10.1007/s40264-018-0775-7
2. Chau CH, Steeg PS, Figg WD. Antibody–drug conjugates for cancer. Lancet. 2019;394(10200):793-804. doi:10.1016/S0140-6736(19)31774-X
3. Pernas S, Tolaney SM. HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance. Ther Adv Med Oncol. 2019;11:1758835919833519. doi:10.1177/1758835919833519
4. Puzanov I, Diab A, Abdallah K, et al; Society for Immunotherapy of Cancer Toxicity Management Working Group. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5(1):95. doi:10.1186/s40425-017-0300-z
5. Kadcyla. Prescribing information. Genentech; 2020. Accessed June 28, 2020. https://www.gene.com/download/pdf/kadcyla_prescribing.pdf
6. Enhertu. Prescribing information. Daiichi Sankyo; 2019. Accessed June 28, 2020. https://dsi.com/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true
7. Shitara K, Bang Y-J, Iwasa S, et al; DESTINY-Gastric01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med. 2020;382(25):2419-2430. doi:10.1056/NEJMoa2004413
8. Ibrance. Prescribing information. Pfizer; 2019. Accessed June 28, 2020. http://labeling.pfizer.com/ShowLabeling.aspx?id=2191
9. Kisqali. Prescribing information. Novartis; 2020. Accessed June 28, 2020. https://www.novartis.us/sites/www.novartis.us/files/kisqali.pdf
10. Verzenio. Prescribing information. Lilly USA; 2020. Accessed June 28, 2020. https://uspl.lilly.com/verzenio/verzenio.html#pi
11. Loibl S, Metzger O, Mandrekar SJ, et al. PATINA: a randomized, open label, phase III trial to evaluate the efficacy and safety of palbociclib + anti-HER2 therapy + endocrine therapy (ET) vs. anti-HER2 therapy + ET after induction treatment for hormone receptor positive (HR+)/HER2-positive metastatic breast cancer (MBC). Ann Oncol. 2018;29 (suppl 8):viii121. doi:10.1093/annonc/mdy272.357
12. Goel S, Pernas S, Tan-Wasielewski Z, et al. Ribociclib plus trastuzumab in advanced HER2-positive breast cancer: results of a phase 1b/2 trial. Clin Breast Cancer. 2019;19(6):399-404. doi:10.1016/j.clbc.2019.05.010
13. A Study of Abemaciclib (LY2835219) in Women with HR+, HER2+ Locally Advanced or Metastatic Breast Cancer (monarcHER). ClinicalTrials.gov. Updated May 26, 2020. Accessed June 28, 2020. https://clinicaltrials.gov/ct2/show/NCT0267523114. Opdivo. Prescribing information. Bristol-Myers Squibb; 2020. Accessed June 28, 2020. https://packageinserts.bms.com/pi/pi_opdivo.pdf
14. Keytruda. Prescribing information. Merck; 2020. Accessed June 28, 2020. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
15. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2018;36(17):1714-1768. doi:10.1200/JCO.2017.77.6385
16. Tecentriq. Prescribing information. Genentech; 2020. Accessed June 28, 2020. https://www.gene.com/download/pdf/tecentriq_prescribing.pdf
17. Imfinzi. Prescribing information. AstraZeneca; 2020. Accessed June 28, 2020. https://www.azpicentral.com/imfinzi/imfinzi.pdf#page=1
18. Spring LM, Wander SA, Zangardi M, Bardia A. CDK 4/6 inhibitors in breast cancer: current controversies and future directions. Curr Oncol Rep. 2019;21(3):25. doi:10.1007/s11912-019-0769-3
19. FDA warns about rare but severe lung inflammation with Ibrance, Kisqali, and Verzenio for breast cancer. FDA Drug Safety Communication. FDA; September 13, 2019. Accessed June 28, 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-severe-lung-inflammationibrance-kisqali-and-verzenio-breast-cancer
20. Stucci S, Palmirotta R, Passarelli A, et al. Immune-related adverse events during anticancer immunotherapy: pathogenesis and management. Oncol Lett. 2017;14(5):5671-5680. doi:10.3892/ol.2017.6919
21. Sears CR, Peikert T, Possick JD, et al. Knowledge gaps and research priorities in immune checkpoint inhibitor–related pneumonitis. an official American Thoracic Society research statement. Am J Respir Crit Care Med. 2019;200(6):e31-e43. doi:10.1164/rccm.201906-1202ST
22. Meyer KC. Diagnosis and management of interstitial lung disease. Transl Respir Med. 2014;2:4. doi:10.1186/2213-0802-2-4
23. Naidoo J, Wang X, Woo KM, et al. Pneumonitis in patients treated with anti–programmed death-1/programmed death ligand 1 therapy. J Clin Oncol. 2017;35(7):709-717. doi:10.1200/JCO.2016.68.2005
24. Bala-Hampton JE, Bazzell AF, Dains JE. Clinical management of pneumonitis in patients receiving anti–PD-1/PD-L1 therapy. J Adv Pract Oncol. 2018;9(4):422-428.
25. Thompson JA, Schneider BJ, Brahmer J, et al. NCCN Guidelines Insights: Management of Immunotherapy-Related Toxicities, version 1.2020. J Natl Compr Canc Netw. 2020;18(3):230-241. doi:10.6004/jnccn.2020.0012
26. Hassel JC, Heinzerling L, Aberle J, et al. Combined immune checkpoint blockade (anti–PD-1/anti–CTLA-4): evaluation and management of adverse drug reactions. Cancer Treat Rev. 2017;57:36-49. doi:10.1016/j.ctrv.2017.05.003
27. Naidoo J, Nishino M, Patel SP, et al. Immune-related pneumonitis after chemoradiotherapy and subsequent immune checkpoint blockade in unresectable stage III non–small-cell lung cancer. Clin Lung Cancer. Published online March 9, 2020. doi:10.1016/j.cllc.2020.02.025
28. Chuzi S, Tavora F, Cruz M, et al. Clinical features, diagnostic challenges, and management strategies in checkpoint inhibitor–related pneumonitis. Cancer Manag Res. 2017;9:207-213. doi:10.2147/CMAR.S136818
29. Egloff H, Kidwell KM, Schott A. Ado-trastuzumab emtansine–induced pulmonary toxicity: a single-institution retrospective review. Case Rep Oncol. 2018;11(2):527-533. doi:10.1159/000491574