Drug-induced pneumonitis from anti-cancer treatment is a type of interstitial lung disease (ILD) characterized by inflammation of the alveoli.1 While drug-induced pneumonitis/ILD may initially present as mild respiratory symptoms, it may progress to irreversible pulmonary fibrosis, respiratory failure, and death if left untreated.1,2 As experts on the toxicities of anti-cancer treatments, oncology pharmacists are uniquely positioned to educate patients and providers on early recognition of ILD symptoms, intervene to ensure timely interruption of the offending agent, and initiate prompt treatment for severe or progressive cases.

The exact mechanisms on how anti-cancer therapies cause ILD are unknown but are thought to include direct or indirect damage to alveolar cells, dysregulation of the immune system triggering cell-mediated lung damage, or inhibition of alveolar repair mechanisms.1,2 Different mechanisms have been proposed for various drug classes and individual agents. For example, bleomycin, a DNA damaging agent, is inactivated by the enzyme bleomycin hydrolase.3 It is hypothesized that lung tissue has a relative deficiency of bleomycin hydrolase compared to other organs, such as the liver or spleen, which could serve as a biochemical basis for how pulmonary toxicity from bleomycin occurs.3 Another agent, trastuzumab deruxtecan, may be preferentially taken up by alveolar macrophages which release the topoisomerase-I inhibitor payload into the lung environment causing cytotoxicity.4 Lastly, immune checkpoint inhibitors (ICI), such as anti-PD-1/PD-L1 agents, can promote autoimmune toxicities involving any organ, including the lungs, through overactivation of T-cells, and increasing levels of inflammatory cytokines and autoantibodies.5

The incidence of anti-cancer drug-induced ILD is difficult to estimate and varies depending on the specific agent, recent or concurrent radiation to the lungs, as well as the underlying cancer type.1,2 Pre-existing lung disease, smoking, older age, and prior radiation to the chest have been proposed as risk factors for the development of lung toxicity, but many cases of ILD are idiosyncratic and difficult to predict.6 Estimated rates of pneumonitis or ILD for selected anti-cancer agents are shown in Table 1.7-61 With the exception of select agents, overall rates of drug-induced pneumonitis or ILD are low  with an incidence <5%.7-61 For certain chemotherapy agents, such as bleomycin, cumulative dosing (>400 international units) is an important risk factor.62 Conversely, for certain targeted agents, such as osimertinib, concurrent use or recent exposure to an ICI increases the risk for developing ILD.63 It is important to note that ILD is not consistently measured in the same manner across literature. Studies may be at high risk of bias due to the limitations in study design and a lack of standardization on the definition of ILD/pneumonitis. For example, some studies defined ILD/pneumonitis by physician-reported diagnosis alone while others utilized radiological evidence without assessing clinical symptoms or excluding differential diagnoses.6

While the typical onset of drug-induced pneumonitis is within a few weeks to months after starting treatment, the timing of ILD can sometimes occur years later after exposure, such as with alkylating agents used for hematopoietic stem cell transplants. Early diagnosis and discontinuation of the offending drug are essential to prevent permanent lung damage. Common symptoms of ILD include dyspnea and cough, but patients can also present with pleuritic chest pain, fever, weight loss, and tachycardia. Pneumonitis is a diagnosis of exclusion, requiring an evaluation of infection, cardiac dysfunction, and disease progression of underlying lung metastases/lymphangitic carcinomatosis as the causes of a patient's symptoms. No definitive clinical, laboratory, radiological, or pathological features solely unique to drug-induced pneumonitis exist.1,2 Therefore, a multidisciplinary approach involving an oncologist, radiologist, and pulmonologist should be utilized for optimal diagnosis.

If pneumonitis is suspected in a patient receiving an anti-cancer agent known to cause ILD, a comprehensive workup including vital signs, imaging, and labs is warranted. Patients should be checked for hypoxia via a pulse oximeter, and a high-resolution chest CT scan should be ordered.1,2 If clinically indicated and reimbursed by insurance, expert opinion suggests that proactive CT scans of the chest every 6-12 weeks within the first 6-12 months of treatment may identify ILD/pneumonitis cases early in patients treated with trastuzumab-deruxtecan, an agent with a higher risk. If this surveillance strategy is pursued, scans of the chest should line up with disease monitoring scans to limit patient burden.64 Radiological abnormalities of ILD are vague and not confirmatory but can include ground glass opacities, infiltrates, consolidations, nodules, septal thickening, and reticular changes.65 To rule out infectious causes, a respiratory culture and viral respiratory panel should be checked. For patients that are immunosuppressed, microbiological tests for opportunistic, mycobacterial, and fungal pathogens should be added. To rule out cardiac causes of pulmonary symptoms, a pro-BNP can be checked, with consideration for an echocardiogram. In certain cases, pulmonary function tests, including a specific test called diffusing capacity of the lungs for carbon monoxide, can be performed to identify restrictive lung disease patterns consistent with ILD. While a bronchoscopy and lung biopsy may be indicated to rule out infection, bleeding, or spread of the underlying cancer, histological confirmation of ILD is not required and has a limited role for diagnosis.1,2

To help determine the severity of ILD, the common terminology criteria for adverse events (CTCAE) version 6.0 has listed descriptions for grading as shown in Table 2.66 Depending on the grade of ILD, a patient may need to interrupt administration of the drug suspected of causing pneumonitis. For grade 1, temporary holding can be considered. For grade 2 or higher, most agents should be discontinued the permanently and patients should be serially monitor for resolution of their symptoms. Depending on a patient’s clinical condition and the extent of their CT abnormalities, corticosteroid treatment may be warranted, particularly for grade 2 or higher.2 Despite a lack of randomized controlled trials demonstrating the effectiveness of corticosteroids for drug-induced ILD, expert opinion and widespread clinical practice suggest that benefits outweigh risks with treatment.1,2 Dosing of corticosteroids is not standardized, with expert opinion suggesting a grade-dependent dosing schema as seen in Table 3.

For patients with a clinical response and improvement in radiological abnormalities on repeat CT chest scan imaging (generally at least 2 weeks after initial diagnosis), corticosteroid dosing can be tapered over 4-12 weeks.2 The duration of the taper depends on the initial grading, with a longer taper favored for severe or life-threatening cases.2 Tapering of steroids is necessary to avoid recurrent symptoms but should take into account any corticosteroid toxicities a patient may experience including hyperglycemia, high blood pressure, insomnia, peripheral edema, and mood changes. If a patient develops a clinically significant toxicity to corticosteroids, a faster taper should be considered. Prophylaxis against Pneumocystis jirovecii pneumonia is required when doses of prednisone ≥20 mg are administered for over ≥4 weeks.67 Prophylaxis with a proton pump inhibitor or histamine 2 receptor antagonist can be considered to prevent gastrointestinal side effects from long-term corticosteroid therapy.

Unfortunately a subset of patients may develop refractory or persistent drug-induced ILD despite steroids, defined as a lack of symptom improvement within 48-72 hours of starting treatment.68 Treatment of steroid-refractory pneumonitis, particularly from ICI therapy, includes adding additional immunosuppressants such as infliximab, intravenous immunoglobulin (IVIG), mycophenolate mofetil, and/or tocilizumab.2,68 Data supporting the off-label use of these agents for ICI-induced pneumonitis is limited to small, non-randomized studies with data extrapolated from systemic sclerosis associated ILD. Infliximab can be administered at 5 mg/kg with consideration of subsequent dosing at least 2 weeks after the initial dose. IVIG can be dosed at 2 g/kg administered over 2-5 days depending on the patient’s ability to tolerate the drug volume and repeated every 4 weeks depending on the clinical course and resolution of symptoms. Mycophenolate mofetil can be dosed at 750-1,000 mg by mouth twice daily with consideration for a lower starting dose if there are concerns about tolerability from gastrointestinal side effects. Lastly, tocilizumab can be administered as either 162 mg subcutaneously once weekly or 8 mg/kg intravenously once every 4 weeks.68 Corticosteroids are generally tapered first before a non-steroidal immunosuppressant is stopped. Due to the high mortality associated with ILD, hospitalization and oxygen support should be given alongside immunosuppression in any grade 3 or higher case.2

The decision to rechallenge an agent suspected of causing ILD should take into account the patient’s cancer disease status, goals of treatment, and severity of the initial toxicity. Due to a high risk for recurrent ILD episodes and treatment-related mortality, rechallenging a patient who developed a grade 3 or higher drug-induced ILD should be avoided.1,2 However, case reports and pooled analysis from existing clinical trials do exist for successful rechallenges of various drugs, such as for trastuzumab deruxtecan, but mainly for patients with grade 1 ILD.69 Prescribing information of various targeted agents have individual guidance on when to rechallenge and whether a dose reduction is needed. For example with brigatinib, if grade 1 ILD develops during the first 7 days of treatment, a temporary hold until recovery is warranted before resuming the initial 90 mg dose. If grade 1 ILD develops after the first 7 days of treatment, then a temporary hold prior to resuming the 180 mg dose is reasonable.28 However, grade 2 ILD requires both temporary holding and a dose reduction. If recurrent ILD occurs after an initial hold, brigatinib treatment should be permanently discontinued.28

In conclusion, clinical oncology pharmacists need to be aware of the symptoms and management of anti-cancer drug-induced pneumonitis/ILD. Prompt identification and early discontinuation of the suspected drug is critical to ensuring optimal patient outcomes.

Table 1. Incidence of ILD/pneumonitis based on agent (rows with an incidence >5% are bolded)

Anti-cancer agent Incidence of lung toxicities (all grades)
Antibodies
Anti-HER2
Trastuzumab
0.2-0.7%
Anti-EGFR/Anti-MET
Amivantamab
2.1-3.3%
Anti-PD-1 or Anti-PD-L1
Atezolizumab
Durvalumab
Nivolumab
Pembrolizumab
3.0-13.0%
1.3-18.3%
3.1-9.0%
1.0-8.0%
Antibody Drug Conjugates
Anti-HER2
Ado-trastuzumab emtansine
Fam-trastuzumab deruxtecan
0.8-1.2%
4.4-12.0%
Anti-MET
Telisotuzumab vedotin
10.0%
Anti-Nectin-4
Enfortumab vedotin
3.0%
Anti-Tissue Factor
Tisotumab vedotin
0.9%
Anti-TROP2
Datopotamab deruxtecan
3.6-7.0%
Chemotherapy Agents
Alkylating Agents
Bleomycin
Busulfan
Carmustine
Cyclophosphamide
Mitomycin
6.8-15.0%
3.0-5.0%
3.0-6.0%
<1.0%
2.0-12.0%
Anti-metabolites
Gemcitabine
Methotrexate
1.1-3.9%
<1.0-15.0%
Taxanes
Docetaxel
Paclitaxel
<1.0%
<1.0%
Topoisomerase inhibitors
Etoposide
Irinotecan
<1.0%
<1.0%
Targeted Agents
ALK Inhibitors
Alectinib
Brigatinib
Ceritinib
Crizotinib
Ensartinib
Lorlatinib
1.3%
3.7-9.1%
2.4%
2.9%
5.0%
1.5%
BRAF & MEK Inhibitors
Dabrafenib + Trametinib
Encorafenib + Binimetinib
1.0-2.0%
0.3-1.0%
CDK4/6 Inhibitors
Abemaciclib
Palbociclib
Ribociclib
3.0-3.3%
1.0%
1.6%
EGFR Inhibitors
Afatinib
Dacomitinib
Erlotinib
Gefitinib
Osimertinib
Lazertinib
Sunvozertinib
1.6%
1.3-2.6%
1.1%
1.3%
3.3%
3.1%
1.7%
HER2 Inhibitors
Sevabertinib
Zongertinib
0.7%
2.1%
KRAS Inhibitors
Adagrasib
Sotorasib
1.1-4.1%
2.2%
MET Inhibitors
Capmatinib
Crizotinib
Tepotinib
4.8%
2.9%
2.0%
mTOR Inhibitors
Everolimus
19.0%
PARP Inhibitors
Olaparib
1.0%
PI3K Inhibitors
Alpelisib
Duvelisib
Idelalisib
1.8%
5.0%
4.0%
RET Inhibitors
Pralsetinib
Selpercatinib
12.0%
1.8%
ROS1 Inhibitors
Crizotinib
Lorlatinib
Repotrectinib
Taletrectinib

2.9%
1.5%
3.1%
2.3%
Spacer Image Spacer Image

Table 2. Pneumonitis grading based on CTCAE version 6.0

CTCAE Grade Description
Pneumonitis: A disorder characterized by inflammation focally or diffusely affecting the lung parenchyma.
1
Asymptomatic; clinical or diagnostic observations only; intervention not indicated
2
Symptomatic; medical intervention indicated; limiting instrumental activities of daily living (ADL) or mild/moderate impact on age-appropriate normal daily activity (pediatric)
3
Severe symptoms; oxygen indicated; limiting self-care ADL or severe impact on age-appropriate normal daily activity (pediatric)
4
Life-threatening respiratory compromise; urgent intervention indicated (e.g., tracheotomy or intubation)
5
Death
Spacer Image Spacer Image

Table 3. Dosing corticosteroids based on CTCAE grading for drug-induced ILD/pneumonitis

CTCAE Grade Corticosteroid Dosing
1
Not initially indicated; if treatment interruption fails to improve symptoms can consider prednisone (PO) dosed at 0.5 mg/kg/day
2
Prednisone (PO) dosed at 1-2 mg/kg.day
3
Methylprednisolone (IV) dosed at 1-2 mg/kg/day
4
Methylprednisolone (IV) dosed at 2 mg/kg/day or consider pulse-therapy for severe cases with methylprednisolone 500-1,000 mg/day for 3 days followed by prednisone dosed at 1-2 mg/kg/day

Abbreviations: CTCAE = common terminology criteria for adverse events; CT = Computed Tomography; DNA = deoxyribonucleic acid; ICI = immune checkpoint inhibitors; ILD = interstitial lung disease; IVIG = intravenous immunoglobulin; PD-1/PD-L1 = programmed cell death protein 1/programmed cell death ligand 1

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