Highlights
- •Drug-related interstitial lung disease (ILD)/pneumonitis diagnosis is challenging.
- •Careful monitoring, prompt diagnosis, and appropriate management are important.
- •Most events are low grade and can be managed safely.
- •Education is critical to ensure potential ILD/pneumonitis is proactively identified.
- •We suggest using a multidisciplinary approach.
Abstract
Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate targeting human epidermal growth factor receptor 2. Interstitial lung disease (ILD)/pneumonitis is an adverse event associated with T-DXd; in most cases, it is low grade (grade ≤ 2) and can be treated effectively but may develop to be fatal in some instances. It is important to increase patient and provider understanding of T-DXd–related ILD/pneumonitis to improve patient outcomes. Drug-related ILD/pneumonitis is a diagnosis of exclusion; other possible causes of lung injury/imaging findings must be ruled out for an accurate diagnosis. Symptoms can be nonspecific, and identifying early symptoms is challenging; therefore, diagnosis is often delayed. We reviewed characteristics of patients who developed T-DXd–related ILD/pneumonitis and its patterns, produced multidisciplinary guidelines on diagnosis and management, and described areas for future investigation. Ongoing studies are collecting data on T-DXd–related ILD/pneumonitis to further our understanding of its clinical patterns and mechanisms.
Search strategy and selection criteria
References were identified based on the guidelines used by the authors in treating interstitial lung disease and pneumonitis. Searches of the authors’ own files were also completed. A search of PubMed with the search terms (trastuzumab deruxtecan) AND (interstitial lung disease) AND (guidelines) was conducted on November 1, 2021, with no restrictions based on publication date, and the two articles yielded by the search were included.
Introduction
Background on trastuzumab deruxtecan
Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) composed of an anti–human epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody, a tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload [
[1]
]. The linker remains stable in plasma and is selectively cleaved by cathepsins that are upregulated in tumor cells [1
, 2
, 3
, 4
]. The cytotoxic payload is present at an approximately 8:1 drug-to-antibody ratio; is membrane permeable, which potentially results in a bystander effect when it is released from HER2-expressing cells and enters neighboring cells (regardless of HER2 expression); and has a short half-life, minimizing off-target effects (Fig. 1) [[2]
].
Fig. 1Mechanism of action of trastuzumab deruxtecan (T-DXd). T-DXd is composed of an anti–HER2 antibody, a linker, and a topoisomerase I inhibitor payload. The anti–HER2 antibody binds to HER2 on tumor cells, which leads to ADC internalization. The linker, which is selectively cleaved by cathepsins that are upregulated in cancer cells, is then cleaved and releases the topoisomerase I inhibitor payload. The topoisomerase I inhibitor enters the nucleus of the cell, resulting in cell death. Upon cell death, the membrane-permeable topoisomerase I inhibitor is released from the cell and can then enter neighboring cells regardless of whether they express HER2. [1–4] ADC, antibody-drug conjugate; HER2, human epidermal growth factor receptor 2; T-DXd, trastuzumab deruxtecan.
In the phase 2 DESTINY-Breast01 T-DXd trial of HER2-positive unresectable/metastatic breast cancer previously treated with trastuzumab emtansine (T-DM1), responses to T-DXd were observed in 112 (60.9%) of 184 patients [
[5]
]. Efficacy was also observed in other T-DXd trials (Table 1) [6
, 7
, 8
, 9
]. Results of DESTINY-Breast01 and the phase 2 DESTINY-Gastric01 trial informed approvals of T-DXd for unresectable/metastatic HER2-positive breast cancer that had progressed with prior therapy (accelerated approval in United States) and locally advanced/metastatic HER2-positive gastric cancer, respectively [Van Cutsem E, di Bartolomeo M, Smyth E, Chau I, Park H, Siena S, et al. Primary analysis of a phase 2 single-arm trial of trastuzumab deruxtecan (T-DXd) in western patients with HER2-positive (HER2+) unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer who progressed on or after a trastuzumab-containing regimen. Presented at: ESMO Congress; September 16-21, 2021.
8
, 10
, 11
, 12
, 13
]. T-DXd is under investigation for additional tumor types [6
, 14
, ClinicalTrials.gov. A phase 2 study of T-DXd in patients with selected HER2 expressing tumors (DPT02). https://clinicaltrials.gov/ct2/show/NCT04482309 (accessed May 25 2021).
15
, ClinicalTrials.gov. A Study of T-DXd for the treatment of solid tumors harboring HER2 activating mutations (DPT01). https://clinicaltrials.gov/ct2/show/NCT04639219 (accessed May 19 2021).
16
, ClinicalTrials.gov. Trastuzumab deruxtecan in participants with HER2-overexpressing advanced or metastatic colorectal cancer (DESTINY-CRC02). https://clinicaltrials.gov/ct2/show/NCT04744831 (accessed May 19 2021).
17
, 18
, ClinicalTrials.gov. Trastuzumab deruxtecan (DS-8201a) versus investigator's choice for HER2-low breast cancer that has spread or cannot be surgically removed [DESTINY-Breast04]. https://clinicaltrials.gov/ct2/show/NCT03734029 (accessed May 19 2021).
19
, ClinicalTrials.gov. Study of trastuzumab deruxtecan (T-DXd) vs investigator's choice chemotherapy in HER2-low, hormone receptor positive, metastatic breast cancer (DB-06). https://clinicaltrials.gov/ct2/show/NCT04494425 (accessed May 19 2021).
20
, ClinicalTrials.gov. Trastuzumab deruxtecan (T-DXd) with or without pertuzumab versus taxane, trastuzumab and pertuzumab in HER2-positive metastatic breast cancer (DESTINY-Breast09). https://clinicaltrials.gov/ct2/show/NCT04784715 (accessed June 3 2021).
21
, ClinicalTrials.gov. Ph1b/2 study of the safety and efficacy of T-DXd combinations in advanced HER2+ gastric cancer (DESTINY-Gastric03) (DG-03). https://clinicaltrials.gov/ct2/show/NCT04379596 (accessed June 10 2021).
22
].Table 1Key Trials of Trastuzumab Deruxtecan (T-DXd).
| Study | Number of Patients | Patient Population | ORR by ICR (95% CI), % | Most Common Grade ≥ 3 Adverse Events (% of Patients) | Any Grade ILD, n (%) | Grade 1 or 2 ILD, n (%) | Grade 3 ILD, n (%) | Grade 4 ILD, n (%) | Grade 5 ILD, n (%) | |
|---|---|---|---|---|---|---|---|---|---|---|
| DESTINY-Breast01 (NCT03248492) 5 , | 184 | T-DM1–treated, HER2-positive unresectable or metastatic breast cancer | 62.0 (54.5–69.0) | Decreased neutrophil count (20.7), anemia (8.7), and nausea (7.6) | 29 (15.8) | 23 (12.5) | 1 (0.5) | 0 | 5 (2.7) | |
| DESTINY-Breast03 (NCT03529110) [7] | T-DXd arm | 261 | HER2-positive unresectable or metastatic breast cancer | 79.7 (74.3–84.4) | Neutropenia (19.1), thrombocytopenia (7.0), leukopenia (6.6), and nausea (6.6) | 27 (10.5) | 25 (9.7) | 2 (0.8) | 0 | 0 |
| T-DM1 arm | 263 | HER2-positive unresectable or metastatic breast cancer | 34.2 (28.5–40.3) | Thrombocytopenia (24.9), AST increased (5.0), and ALT increased (4.6) | 5 (1.9) | 5 (1.9) | 0 | 0 | 0 | |
| DESTINY-Gastric01 (NCT03329690) [8] | T-DXd arm | 125 | HER2-positive locally advanced or metastatic gastric/GEJ cancer | 43 (34–52) | Decreased neutrophil count (51.2), anemia (37.6), and decreased white cell count (20.8) | 12 (9.6) | 9 (7.2) | 2 (1.6) | 1 (0.8) | 0 |
| Chemotherapy arm | 62 | HER2-positive locally advanced or metastatic gastric/GEJ cancer | 12 (5–24) | Decreased neutrophil count (24.2), anemia (22.6), and decreased appetite (12.9) | 0 | 0 | 0 | 0 | 0 | |
| DESTINY-Gastric02 (NCT04014075) [9] Van Cutsem E, di Bartolomeo M, Smyth E, Chau I, Park H, Siena S, et al. Primary analysis of a phase 2 single-arm trial of trastuzumab deruxtecan (T-DXd) in western patients with HER2-positive (HER2+) unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer who progressed on or after a trastuzumab-containing regimen. Presented at: ESMO Congress; September 16-21, 2021. | 79 | HER2-positive unresectable or metastatic gastric/GEJ cancer | 38 (27.3–49.6) | Anemia (7.6) and decreased neutrophil count (7.6) | 6 (7.6) | 5 (6.3) | 0 | 0 | 1 (1.3) | |
| DESTINY-Lung01 (NCT03505710) 6 , 93 | 91 | HER2-mutant unresectable or metastatic NSCLC | 55 (44–65) | Decreased neutrophil count (18.7), anemia (9.9), and nausea (8.8) | 24 (26.4) | 18 (19.8) | 4 (4.4) | 0 | 2 (2.2) | |
| 49 | HER2-overexpressing unresectable/metastatic NSCLC | 24.5 (13.3–38.9) | Decreased neutrophil count (20.4) | 8 (16.3) | 5 (10.2) | 0 | 0 | 3 (6.1) |
AC, adjudication committee; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; CTCAE, Common Terminology Criteria for Adverse Events; GEJ, gastroesophageal junction; HER2, human epidermal growth factor receptor 2; ICR, independent central review; ILD, interstitial lung disease; NSCLC, non-small cell lung cancer; ORR, objective response rate; T-DM1, trastuzumab emtansine.
a ILD/pneumonitis was adjudicated by an independent AC and was graded using the CTCAE version 5.0 for pneumonitis.
b For DESTINY-Breast01, the ORR and ILD/pneumonitis data were from the March 2021 data cutoff; the most common grade ≥ 3 adverse events were from the primary data cutoff of August 1, 2019.
c ORR was assessed by blinded ICR.
d This category includes the preferred terms neutrophil count decreased and neutropenia.
e This category includes platelet count decreased and thrombocytopenia.
f This category includes the preferred terms white blood cell count decreased and leukopenia.
g These adverse events were the most frequent grade ≥ 3 drug-related treatment-emergent adverse events among drug-related treatment-emergent adverse events with ≥ 20% overall (ie, all grades combined) incidence.
h This category includes the preferred terms hemoglobin decreased, red blood cell count decreased, anemia, and hematocrit decreased.
i These adverse events were the most frequent grade ≥ 3 drug-related treatment-emergent adverse events among drug-related treatment-emergent adverse events with ≥ 15% overall (ie, all grades combined) incidence.
The T-DXd prescribing information contains warnings for interstitial lung disease (ILD)/pneumonitis [
10
, 11
, 12
, 13
]. Diagnosis of drug-related ILD/pneumonitis can be challenging [23
, 24
]. Recommendations for ILD diagnosis and management in patients receiving anti–HER2 ADC therapies were previously reviewed [[25]
]; however, recommendations for proactively monitoring patients for anti–HER2 ADC-induced ILD/pneumonitis are lacking [[26]
]. We build on published guidelines by providing multidisciplinary clinical guidance for the proactive monitoring, diagnosis, and management of T-DXd–related ILD/pneumonitis based on expert experience and T-DXd trials.Pathophysiology and etiology of ILD
ILD, a heterogeneous group of over 200 lung disorders, manifests as inflammation and/or fibrosis in the lungs [
27
, , 29
]. These disorders are grouped based on clinical, radiographic, physiologic, and pathologic characteristics [[27]
]. ILD can present with variable pulmonary symptomatology, or asymptomatically with radiographic opacities, based on the effects on different components within the lung interstitium and other lung compartments [27
, 30
, 31
]. Radiographic disease patterns of ILD include nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia, acute interstitial pneumonia, and organizing pneumonia (OP) [27
, , 30
, 32
]. Hypersensitivity pneumonitis (HP) is a subtype of ILD, which may manifest with areas showing NSIP and/or OP patterns, among other patterns [, - Travis W.D.
- Costabel U.
- Hansell D.M.
- King T.E.
- Lynch D.A.
- Nicholson A.G.
- et al.
An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
Am J Respir Crit Care Med. 2013; 188: 733-748
30
, 32
]. Diffuse alveolar damage (DAD) is a pulmonary damage pattern associated with poor prognosis that can result from ILD [- Travis W.D.
- Costabel U.
- Hansell D.M.
- King T.E.
- Lynch D.A.
- Nicholson A.G.
- et al.
An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
Am J Respir Crit Care Med. 2013; 188: 733-748
[23]
]. ILD is becoming recognized as a category of adverse drug reactions [[33]
]. In the context of drug-related lung injury in patients with cancer, the term ILD is often used interchangeably with the term pneumonitis, which refers to disorders characterized by lung inflammation [[34]
]. In our experience, the term pneumonitis is sometimes used because patients can have a preexisting chronic ILD from other conditions, thereby complicating the use of the term ILD for acute drug reactions. In the context of this guidance document, we align our use of the terms ILD and/or pneumonitis with the cited references.ILD/pneumonitis can be idiopathic or secondary to known causes or clinical associations, including viral infections, environmental exposure to inhaled toxins or antigens, thoracic radiation, and drugs [
27
, 31
, 35
, 36
, 37
]. Because drug-related ILD/pneumonitis is a diagnosis of exclusion, extensive evaluation and testing are necessary to rule out other potential causes of lung injury or imaging findings [23
, 24
, 27
, 31
]. Diagnosis requires consideration of symptoms, physical examination findings, clinical history (including medications, prior radiation, exposures), chest imaging, pulmonary function tests, clinical laboratory findings, and exclusion of relevant alternative diagnoses (ie, infections or other causes that may lead to radiologic changes similar to ILD/pneumonitis) [31
, 38
]. Dyspnea is the most common symptom; other symptoms can include cough, malaise, chest pain, hypoxemia, and low-grade fever [27
, 31
, 38
, 39
]. Potential complications of worsening ILD/pneumonitis include development and/or progression of lung fibrosis, pulmonary hypertension, small airway disease and pulmonary emboli leading to respiratory failure, hypoxemia, and congestive heart failure [27
, 29
]. Some drug-related ILD/pneumonitis can be fulminant from the outset, resulting in life-threatening DAD and acute respiratory distress syndrome [[30]
]. ILD/pneumonitis is typically treated with steroid medications, including prednisone and methylprednisolone [, 38
].In T-DXd trials, drug-related ILD/pneumonitis severity is graded from 1 to 5 based on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) pneumonitis criteria [
8
, 23
, 34
]. Asymptomatic drug-related ILD/pneumonitis is grade 1 [12
, 23
, 34
]. Grades ≥ 2 are symptomatic (Table S1) [[34]
]. The trigger for drug-related ILD/pneumonitis onset is unknown, and numerous mechanisms likely underlie its development [30
, 40
]. Two (likely interdependent) categories of mechanisms potentially involved in drug-related ILD/pneumonitis are direct cytotoxic pulmonary injury and immune-mediated lung injury [[30]
].ILD/pneumonitis associated with anticancer treatments
Drug-related ILD/pneumonitis has been observed in association with many anticancer agents, with different patterns and incidence (Table S2) [
[38]
]. While anti–HER2 agents have changed cancer treatment and greatly improved patient outcomes, drug-related ILD/pneumonitis has been identified as an important AE [26
, 41
, 42
]. Lung epithelial cells express HER2, [[43]
] but whether this is involved in ILD/pneumonitis associated with HER2-targeting agents is unknown. Drug-related ILD has also been observed with other DXd-containing ADCs that target different proteins [, 45
].Trastuzumab [
[46]
] and the anti–HER2 ADCs T-DM1, [[47]
] trastuzumab duocarmazine (SYD985), [[48]
] ARX788, [] and T-DXd [[5]
] have been associated with ILD/pneumonitis. In a pooled analysis of eight trastuzumab trials, 162 (9.9%) of 1642 patients experienced ILD/pneumonitis; three (0.2%) had grade 5 events [[26]
]. Across three T-DM1 studies totaling 3290 patients, 15 (0.5%) patients had ILD/pneumonitis, and six (0.2%) had grade 5 events [[26]
]. In a phase 1 SYD985 trial, pneumonitis was a dose-limiting toxicity; one patient had grade 5 pneumonitis. However, pneumonitis risk was reduced at the recommended dose compared with higher doses [[48]
]. In the phase 3 TULIP trial, 291 patients were randomized to receive SYD985; 7.6% experienced ILD/pneumonitis, including two who experienced a grade 5 event []. In two separate phase 1 trials of ARX788, grade > 3 pneumonitis was reported in 4.3% of 69 patients and 2.9% of 34 patients []. The association between ILD/pneumonitis and dose may vary by agent, as dose-dependent associations have not been found with other agents [23
, 51
, 52
]. ILD/pneumonitis has also been reported with immunotherapy agents used to treat cancer (Table S2) [39
, 53
, - Okada N.
- Matsuoka R.
- Sakurada T.
- Goda M.
- Chuma M.
- Yagi K.
- et al.
Risk factors of immune checkpoint inhibitor-related interstitial lung disease in patients with lung cancer: A single-institution retrospective study.
Sci Rep. 2020; 10https://doi.org/10.1038/s41598-020-70743-2
54
, 55
, 56
, 57
]. Due to the potential for patients to experience ILD/pneumonitis with T-DXd or immunotherapy agents individually, research is needed to assess any risks with the combination of these therapies. In a trial assessing T-DXd combined with nivolumab in patients with HER2-expressing advanced/metastatic urothelial carcinoma (n = 34), adjudicated drug-related ILD/pneumonitis was reported in 23.5% (grade 1, n = 2; grade 2, n = 4; grade 3, n = 1; grade 5, n = 1) []. Additional trials of T-DXd combined with immunotherapy agents are ongoing, and results from these studies will allow for further understanding of ILD/pneumonitis with T-DXd combination therapy [21
, ClinicalTrials.gov. Ph1b/2 study of the safety and efficacy of T-DXd combinations in advanced HER2+ gastric cancer (DESTINY-Gastric03) (DG-03). https://clinicaltrials.gov/ct2/show/NCT04379596 (accessed June 10 2021).
59
, ClinicalTrials.gov. DS8201a and pembrolizumab in participants with locally advanced/metastatic breast or non-small cell lung cancer. https://clinicaltrials.gov/ct2/show/NCT04042701 (accessed February 17 2022).
60
, ClinicalTrials.gov. A phase 1b/2 study of T-DXd combinations in HER2-positive metastatic breast cancer (DB-07). https://clinicaltrials.gov/ct2/show/NCT04538742 (accessed February 17 2022).
61
, ClinicalTrials.gov. A phase 1b study of T-DXd combinations in HER2-low advanced or metastatic breast cancer (DB-08). https://clinicaltrials.gov/ct2/show/NCT04556773 (accessed February 17 2022).
62
, ClinicalTrials.gov. A study of novel anti-cancer agents in patients with metastatic triple negative breast cancer (BEGONIA). https://clinicaltrials.gov/ct2/show/NCT03742102 (accessed February 17 2022).
63
, ClinicalTrials.gov. Phase Ib study of the safety of T-DXd and durvalumab with chemotherapy in advanced or metastatic HER2+ non-squamous NSCLC (DL03). https://clinicaltrials.gov/ct2/show/NCT04686305 (accessed February 17 2022).
64
].ClinicalTrials.gov. Phase II umbrella study of novel anti-cancer agents in patients with NSCLC who progressed on an anti-PD-1/PD-L1 containing therapy (HUDSON). https://clinicaltrials.gov/ct2/show/NCT03334617 (accessed February 17 2022).
T-DXd–related ILD/pneumonitis
Preclinical data
In a cynomolgus monkey study, diffuse lymphocytic infiltrates and slight fibrosis were observed in T-DXd–related ILD/pneumonitis [
[40]
]. The inflammation and fibrosis in monkeys were similar to ILD/pneumonitis pathology patterns seen in humans, suggesting that these same mechanisms could play a role in humans [[40]
]. T-DXd was localized primarily in alveolar macrophages and not pulmonary epithelial cells, suggesting target-independent T-DXd uptake by alveolar macrophages and release of payload as a mechanism of off-target toxicity [[40]
]. T-DXd–related ILD/pneumonitis incidence and severity were dependent on T-DXd dose and administration frequency, offering additional evidence that T-DXd–related ILD/pneumonitis may result from cytotoxic lung injury [[40]
]. Further research is needed to validate these findings.Adjudication committee for clinical trials
In 2017, when the first fatal T-DXd–related ILD event was suspected during a T-DXd trial, an independent adjudication committee (AC) of ten experts was established [
65
, 66
]. This multidisciplinary committee includes oncologists, pulmonologists, and radiologists with expertise in ILD/pneumonitis, with current representation from the United States, Europe, and Japan. The AC reviews and adjudicates all suspected cases of ILD/pneumonitis and fatal ILD/pneumonitis in T-DXd studies and also determines whether they are T-DXd related based on standardized reports provided by the treating site [5
, 65
, 66
]. The AC determines date of onset, grade based on CTCAE criteria, and attribution of adjudicated ILD/pneumonitis events [[65]
]. Learnings from the AC were instrumental in identifying opportunities to improve early diagnosis and management of ILD, and these opportunities led to effective education initiatives and ILD/pneumonitis management guideline updates.Clinical data
Rates of adjudicated ILD/pneumonitis from key T-DXd trials are summarized in Table 1. In a pooled analysis of eight phase 1 or 2 T-DXd monotherapy trials including 879 heavily pretreated patients (median of 5.0 [range, 1–27] prior regimens) with different tumor types, 139 (15.8%) patients had adjudicated ILD/pneumonitis [
[66]
]. The median (range) time to first ILD/pneumonitis event was 5.5 (< 0.1–46.8) months [[66]
]. Most T-DXd–related ILD/pneumonitis was low grade [12
, 66
, 67
]; 108 of 139 patients with ILD/pneumonitis had grade 1 or 2 events, while 21 had grade 5 events (Table 2) [[66]
].Table 2Pooled Analyses of Adjudicated Interstitial Lung Disease/Pneumonitis in Single-Arm, Phase 1 or Phase 2 Trials of Trastuzumab Deruxtecan (T-DXd) Monotherapy.
| Pooled Analysis | ||
|---|---|---|
| Powell et al. 2021 [66] (N = 879) | Yin et al. 2021 [69] (N = 645) b Data cutoffs for the studies included in this analysis were February 1, 2019 for J101; December 5, 2018 for J102; September 14, 2018 for A103; September 26, 2018 for A104; and March 21, 2019 for DESTINY-Breast01. Six patients were excluded from the exposure-safety analysis for missing PK samples (n = 3) and protocol deviation for taking prohibited medication (n = 3). | |
| Studies | DS8201-A-J101, DS8201-A-J102, DS8201-A-A103, DS8201-A-A104, DESTINY-Breast01, DESTINY-CRC01, DESTINY-Lung01, and DESTINY-Gastric02 | DS8201-A-J101, DS8201-A-J102, DS8201-A-A103, DS8201-A-A104, and DESTINY-Breast01 |
| Tumor types | Multiple types of HER2-expressing or HER2-positive unresectable or metastatic tumors, including breast, gastric, lung, and colorectal; HER2-mutant lung cancer | Multiple types of HER2-expressing or HER2-positive unresectable and/or metastatic tumors, including breast and gastric |
| T-DXd doses | 5.4, 6.4, 7.4, or 8.0 mg/kg q3w | 0.8, 1.6, 3.2, 5.4, 6.4, 7.4, or 8.0 mg/kg q3w |
| Number of prior regimens, median (range) | 5.0 (1–27) | NR |
| Japanese, n (%) | 364 (41.4) | 312 (49) |
| Patients with ILD/pneumonitis, n (%) | 139 (15.8) | 70 (11) |
| Grade 1 | 40 (4.6) | NR |
| Grade 2 | 68 (7.7) | NR |
| Grade ≥ 3 | 31 (3.5) | 18 (3) |
| Grade 3 | 9 (1.0) | NR |
| Grade 4 | 1 (0.1) | NR |
| Grade 5 | 21 (2.4) | NR |
| Factors of interest potentially associated with ILD/pneumonitis | Treatment in Japan vs non-Japan countries; T-DXd dose of ≥ 7.4 vs 5.4 mg/kg; baseline SpO2 of < 95% vs ≥ 95%; moderate/severe renal impairment at baseline vs no impairment; presence of certain lung comorbidities (yes vs no: asthma, COPD, prior ILD/pneumonitis, pulmonary fibrosis, pulmonary emphysema, or radiation pneumonitis); and time since initial diagnosis (≥ 3.9 vs < 3.9) years | Asian-Japan race-country group (probability of discontinuation associated with ILD: 0.206) and T-DXd dose of 6.4 vs 5.4 mg/kg (incidence of any-grade ILD: 17.0% [90% CI, 14.8%–19.2%] vs 14.0% [90% CI, 11.5%–15.6%]) d The Asian-Japan race-country covariate group was identified by an exposure-safety analysis that used a Cox proportional hazards regression model; ILD grade ≥ 3 specifically was not found to be associated with any covariates; all-grade ILD was associated with Asian-Japan race-country covariate group. Covariates in this analysis included race (Asian vs White vs other) and country (Japan vs non-Japan), which were correlated and combined into a single race/country covariate. T-DXd dose was identified by a dose–response projection analysis that used the model developed in the exposure–response analysis. |
CI, confidence interval; COPD, chronic obstructive pulmonary disease; HER2, human epidermal growth factor receptor 2; ILD, interstitial lung disease; NR, not reported; PK, pharmacokinetic; q3w, every 3 weeks; SpO2, oxygen saturation.
a This pooled analysis had a data cutoff date of June 08, 2020.
b Data cutoffs for the studies included in this analysis were February 1, 2019 for J101; December 5, 2018 for J102; September 14, 2018 for A103; September 26, 2018 for A104; and March 21, 2019 for DESTINY-Breast01. Six patients were excluded from the exposure-safety analysis for missing PK samples (n = 3) and protocol deviation for taking prohibited medication (n = 3).
c Factors of interest were identified by a stepwise multivariate Cox regression model evaluating factors potentially associated with ILD/pneumonitis.
d The Asian-Japan race-country covariate group was identified by an exposure-safety analysis that used a Cox proportional hazards regression model; ILD grade ≥ 3 specifically was not found to be associated with any covariates; all-grade ILD was associated with Asian-Japan race-country covariate group. Covariates in this analysis included race (Asian vs White vs other) and country (Japan vs non-Japan), which were correlated and combined into a single race/country covariate. T-DXd dose was identified by a dose–response projection analysis that used the model developed in the exposure–response analysis.
In a similar pooled analysis of 245 patients (median of 7.0 [range, 2–27] prior regimens) with breast cancer treated with T-DXd 5.4 mg/kg every 3 weeks (q3w) across three trials, 15.5% experienced adjudicated ILD/pneumonitis [
[67]
]. The median (range) time to first event was 5.6 (1.1–20.8) months, with 97% occurring within the first 12 months of T-DXd treatment [[67]
]. Among the 42% of patients who remained on T-DXd after 12 months, the risk of developing new ILD/pneumonitis was low (conditional probability of 1.8%), suggesting that there is no cumulative toxicity [[67]
]. However, this analysis had limitations, including a small sample size and heterogeneous and heavily pretreated patient population [[67]
]. More data are needed to confirm these findings.In the DESTINY-Lung01 trial of heavily pretreated (up to seven prior lines of therapy) patients with metastatic HER2-mutant non-small cell lung cancer who received T-DXd 6.4 mg/kg q3w, adjudicated ILD/pneumonitis occurred in 24 (26.4%) of 91 patients (grade 1/2 in 18 patients, grade 3 in four patients, and grade 5 in two patients) [
[6]
]. In the DESTINY-Gastric02 trial of T-DXd 6.4 mg/kg q3w in HER2-positive metastatic gastric cancer, adjudicated ILD/pneumonitis occurred in six of 79 (7.6%) patients: grade 1/2 in five patients and grade 5 in one patient [[9]
].Van Cutsem E, di Bartolomeo M, Smyth E, Chau I, Park H, Siena S, et al. Primary analysis of a phase 2 single-arm trial of trastuzumab deruxtecan (T-DXd) in western patients with HER2-positive (HER2+) unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer who progressed on or after a trastuzumab-containing regimen. Presented at: ESMO Congress; September 16-21, 2021.
In the DESTINY-Breast03 trial of T-DXd 5.4 mg/kg q3w in (largely second-line) HER2-positive metastatic breast cancer, 27 (10.5%) of 257 patients experienced adjudicated ILD/pneumonitis, with no grade 4 or 5 ILD/pneumonitis events [
[7]
]. Although these data are promising, there are several factors that may potentially have led to the observed outcomes, including treating patients in earlier settings and following updated guidelines for proactive monitoring, diagnosis, and management of T-DXd–related ILD/pneumonitis. Furthermore, this trial was conducted during the COVID-19 pandemic, which may also have affected the observed findings in several ways, including delays in patients seeking care, delays in T-DXd treatment, and misdiagnosis of and delays in treatment for ILD/pneumonitis. However, the extent of any such impacts by the pandemic on ILD/pneumonitis rates in T-DXd trials is not known.In our experience, different patterns of ILD/pneumonitis with T-DXd treatment are seen based on computed tomography (CT) appearance, including OP and HP patterns; in some severe cases, DAD is observed similar to the DAD pattern seen with other agents [
31
, 68
]. Fig. 2 shows example CT images from two patients who developed T-DXd–related ILD/pneumonitis, one who developed fulminant ILD/pneumonitis with a DAD pattern and another who developed asymptomatic ILD/pneumonitis with an OP pattern. Anecdotal clinical experiences suggest that there may be temporal differences, with more severe types of damage such as DAD (possibly relating to an idiosyncratic or hypersensitivity-like reaction) seen earlier over the course of T-DXd treatment than OP. However, these general patterns are based on radiologic observations and are typically not assessed by biopsy or other evidence [[23]
]. Differentiating between these patterns could be important in making treatment decisions and when making an ILD/pneumonitis diagnosis after ruling out other possible conditions. There is an ongoing analysis of radiologic patterns of T-DXd–related ILD/pneumonitis cases in clinical trials (personal communication from AstraZeneca).
Fig. 2Radiologic images from patients who developed trastuzumab deruxtecan (T-DXd)–related interstitial lung disease/pneumonitis. CT images from 2 patients with stage 4, refractory, HER2-mutant lung adenocarcinoma who developed T-DXd–related ILD/pneumonitis during the DESTINY-Lung01 trial are shown. [6] Patient 1: Developed fulminant ILD/pneumonitis after one dose of T-DXd. (A) The baseline CT of the chest demonstrated left perihilar soft tissue lesion representing lung cancer with consolidation (asterisk, A) and nodular left pleural thickening and metastases. Two weeks after the first dose of T-DXd, the patient presented with worsening dyspnea. (B) Chest CT demonstrated a development of diffuse GGO in both lungs, indicative of ILD/pneumonitis with a DAD pattern, which tends to be the most severe type of ILD/pneumonitis. There was a decrease in left perihilar tumor burden (asterisk, B), which indicates a tumor response to T-DXd. The patient was treated with IV methylprednisolone, and the follow-up chest CT 4 weeks later (C) demonstrated near-complete resolution of diffuse GGO with minimal faint residual opacities in the right lower lobe. The left perihilar tumor further decreased (asterisk, C), and the pleural effusion and nodular metastases resolved, representing a partial response. Patient 2: The baseline CT (D, G) demonstrated a dominant mass in the right upper lobe (arrow, D), representing lung cancer. Follow-up chest CT at 3 months of T-DXd treatment demonstrated marked reduction of the dominant lesion (arrow, E), representing a partial response to therapy. However, there were new areas of consolidation and surrounding GGO in the bilateral lower lobes (arrows, H), indicative of development of grade 1 ILD/pneumonitis with an OP pattern in this asymptomatic patient. Further follow-up after 10 months of T-DXd treatment demonstrated durable tumor response to T-DXd treatment with further reduction of the right upper lobe lesion (arrow, F). The areas of previous consolidation in both lower lobes evolved into areas with more faint opacities, consisting predominantly of GGO (arrows, I). The patient subsequently received a 4-week course of prednisone, with no resultant radiologic change in the GGOs. CT, computed tomography; DAD, diffuse alveolar damage; GGO, ground-glass opacity; HER2, human epidermal growth factor receptor 2; ILD, interstitial lung disease; IV, intravenous; OP, organizing pneumonia; T-DXd, trastuzumab deruxtecan.
Characterizing patients who have developed ILD/pneumonitis
Preexisting ILD/pneumonitis has been identified as a risk factor for developing drug-related ILD/pneumonitis [
31
, 68
]. Patients with a history of noninfectious ILD/pneumonitis that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening are currently excluded from T-DXd clinical trials [6
, 8
]. Other general (ie, not T-DXd–specific) risk factors associated with drug-related ILD/pneumonitis include treatment in Japan, advanced age (≥ 60 years), other preexisting lung disease including chronic obstructive pulmonary disease and emphysema, unilateral pneumonectomy, decreased respiratory function, oxygen supplementation requirement, lung radiation exposure, existing renal impairment, smoking, and genetics [23
, 31
, 38
]. Due to limited data, it is unclear if these factors are associated with an increased risk of T-DXd–related ILD/pneumonitis.Pooled analyses of T-DXd trials have identified factors of interest potentially associated with T-DXd–related ILD/pneumonitis, including treatment in Japan, T-DXd dose, baseline oxygen saturation (SpO2), moderate/severe renal impairment, presence of certain lung comorbidities, and time since initial diagnosis (Table 2) [
66
, 69
]. These analyses should be interpreted with caution because they were performed in heavily pretreated and heterogeneous patients with different tumor types who received different doses and treatment durations [66
, 69
]. These results support the established benefit-risk profile of T-DXd and do not warrant exclusion from using T-DXd or amended T-DXd dosing for any of these factors [66
, 69
]. Further research is needed to validate these findings.While several studies have found ILD/pneumonitis to be more common in Japan, [
66
, 67
, 69
, 70
, - Suh C.H.
- Park H.S.
- Kim K.W.
- Pyo J.
- Hatabu H.
- Nishino M.
Pneumonitis in advanced non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitor: Meta-analysis of 153 cohorts with 15,713 patients: Meta-analysis of incidence and risk factors of EGFR-TKI pneumonitis in NSCLC.
Lung Cancer. 2018; 123: 60-69
71
] reasons underlying this association are uncertain. Population pharmacokinetic analyses suggested that T-DXd clearance was slightly lower in Japanese patients; however, there were no clinically meaningful differences in T-DXd steady-state exposure or released DXd based on patient race/country [[72]
]. Another possible reason is increased toxicity in general with T-DXd in Japan. In an exposure-safety analysis of T-DXd, an analysis of covariates found that modeled event rates for eight endpoints (discontinuations due to AEs, dose interruptions due to AEs, grade ≥ 3 anemia, any-grade neutropenia, grade ≥ 3 neutropenia, any-grade thrombocytopenia, grade ≥ 3 thrombocytopenia, and any-grade ILD) were significantly higher in patients in the Asian-Japan group than those in the non-Asian group [[69]
]. However, whether increased toxicity in general with T-DXd in Japanese patients can explain the increased ILD/pneumonitis rate is not known; further research is needed to address this possibility. Differences in clinical practice, including proactive patient monitoring, or genetics could be involved in the increased prevalence of ILD/pneumonitis seen in Japan compared with other countries, [65
, 73
] but further research is needed.Monitoring and diagnosis of ILD/pneumonitis in patients receiving T-DXd
In an effort to improve T-DXd–related ILD/pneumonitis management, a safe use and awareness campaign was initiated in June 2019, and new T-DXd–related ILD/pneumonitis toxicity management guidelines, including steroid recommendations, were developed based on expert consensus and published in December 2019 [
5
, 66
, 67
].Patient and provider education on T-DXd–related ILD/pneumonitis
Provider education regarding ILD/pneumonitis and patient monitoring guidelines is critical to ensure that potential ILD/pneumonitis is proactively identified. Patient education is equally important to facilitate immediate reporting of symptoms [
5
, 8
, 12
]. We suggest teaching patients how to self-monitor for new-onset cough or change in exercise tolerance. We recommend educating patients about signs/symptoms of ILD/pneumonitis; providing a T-DXd–related ILD patient guide; having dedicated nurse-led informational classes before T-DXd commencement; and asking patients to report any signs or symptoms of ILD/pneumonitis immediately to their provider. The Japan prescribing information advises educating patients about initial ILD/pneumonitis symptoms and precautions to take during treatment [[11]
].Proactive patient monitoring
Proactive patient monitoring is recommended; reports on other drugs suggest that a longer time between ILD/pneumonitis onset and drug withholding may be associated with poorer outcomes [
[38]
]. We suggest using a multidisciplinary approach, including collaboration with radiologists and pulmonologists. We recommend provider education regarding the interpretation of CT pulmonary findings, assessment of SpO2 with pulse oximetry, and use of pulmonary function testing. Patients visit their treating physician q3w for T-DXd administration. We suggest that patients on T-DXd be carefully monitored by a multidisciplinary team and have visits with their oncologist every 4–6 weeks. We suggest asking patients about symptoms of ILD/pneumonitis at each visit. Careful monitoring could facilitate early detection (eg, while grade 1) of ILD/pneumonitis, [[65]
] which is important so that T-DXd can be withheld, steroids may be started, and higher-grade or fatal ILD/pneumonitis may be avoided [27
, 38
]. The Japan prescribing information advises examining patients regularly by assessing SpO2 levels, chest X-rays, CT, and other tests [[11]
]. The US, EU, and Canada prescribing information advise promptly investigating any evidence of ILD/pneumonitis [10
, 12
, 13
].In the eight-trial pooled analysis of T-DXd–related ILD/pneumonitis, the AC retrospectively assessed 148 ILD/pneumonitis events and detected ILD/pneumonitis onset earlier than the investigator for 71 (48.0%) events [
[66]
]. For these 71 events, the median (range) difference in detection between the AC and investigators was 49.0 (1–288) days, suggesting an opportunity for optimizing ILD/pneumonitis monitoring to promote early detection [[66]
]. Further investigation is needed to determine whether early detection and management are associated with improved outcomes in patients with T-DXd–related ILD/pneumonitis.In T-DXd trials, high-resolution CT is performed every 6 weeks, [
[65]
] which can facilitate early ILD/pneumonitis detection. However, reimbursement may not be possible for CT performed every 6 weeks outside of a clinical trial. In our experience, CT is typically performed every 9–12 weeks in real-world practice for monitoring tumor response to therapy. More research is needed to determine the ideal CT frequency for ILD/pneumonitis monitoring.Pulse oximetry and pulmonary function testing can be used to assist with ILD detection [
74
, 75
]. If resting pulse oximetry is normal, exertional pulse oximetry, which assesses SpO2 levels during physical exertion, can be useful [[76]
]. Exertional hypoxemia has been observed in patients with ILD using exertional pulse oximetry, [[77]
] and dyspnea can be observed with exertion in ILD [[76]
]. In patients with symptoms of ILD/pneumonitis, reduced oxygen saturation, or other suspicion of ILD/pneumonitis, we recommend performing (1) pulmonary function testing with spirometry for forced vital capacity (FVC) and (2) diffusing capacity, and (3) an exertional pulse oximetry walk test or six-minute walk test at each regularly scheduled visit following the trend of the FVC, diffusing capacity for carbon monoxide, and lowest saturation on the walk test. These tests should also be performed at visits where shortness of breath is being assessed. No data are available regarding the use of pulse oximetry in T-DXd–related ILD/pneumonitis; therefore, future research is needed to understand its usefulness. Recently, a modified Delphi panel with three rounds of data collection (two anonymous online surveys [questionnaires with agree/disagree ratings] and one virtual meeting to facilitate expert discussion) was conducted to obtain expert clinicians’ opinions and recommendations for a functional definition of ILD as part of a larger study. The panel recommended that patients with an SpO2 decrease at rest of 2%–4% for 1–3 days measured as a continuous variable at home, or an SpO2 decrease after exertion of 2%–5% for 1–7 days, should be examined for ILD (personal communication from AstraZeneca) (Table 3). However, pulse oximetry cannot replace CT, particularly because grade 1 ILD/pneumonitis is asymptomatic with radiographic findings only [[23]
] and may not be detected with pulse oximetry.Table 3Guidance for Patient Communication and Education, Provider Education, and Proactive Patient Monitoring for Patients Receiving Trastuzumab Deruxtecan (T-DXd).
| Recommendations | |
|---|---|
| Prior to starting treatment with T-DXd [11] |
|
| Provider education |
|
| Patient education |
|
| Proactive patient monitoring |
|
CT, computed tomography; DLCO, diffusing capacity for carbon monoxide; FVC, forced vital capacity; ILD, interstitial lung disease; SpO2, oxygen saturation.
a Recommendation based on expert opinion according to a recent modified Delphi panel conducted as part of a larger study to obtain expert clinicians’ opinions and recommendations for a functional definition of ILD.
Multidisciplinary diagnosis
Per current guidelines (Fig. 3), ILD/pneumonitis must be considered if a patient develops radiographic changes potentially consistent with ILD/pneumonitis or develops an acute onset of new or worsening pulmonary signs or symptoms, including dyspnea, cough, or fever [
[5]
]. If ILD/pneumonitis is suspected, T-DXd should be interrupted until ILD/pneumonitis can be ruled out [5
, 31
]. Diagnostic criteria for T-DXd–related ILD/pneumonitis can include newly identified pulmonary parenchymal opacities with CT, temporal association of radiologic and/or symptom presentation with T-DXd commencement, and exclusion of other causes [[31]
]. An ILD/pneumonitis clinical diagnosis may be made when a patient has clinical symptoms and radiographic appearances of ILD/pneumonitis and other potential causes have been ruled out [23
, , 31
].
Fig. 3Guidelines and recommendations for the multidisciplinary diagnosis and management of interstitial lung disease/pneumonitis in patients receiving trastuzumab deruxtecan (T-DXd). These guidelines are based on guidelines published by Modi et al 2020 [5] and the US, EU, and Canada prescribing information. [10,12,13] Minor updates to the guidelines from Modi et al were published by Li et al 2021 and are included here. [6]. a KL-6, SP-A, and SP-D are used as markers in Japan but may not be used clinically in all countries. b In the event a dose reduction is needed, per the US, EU, and Canada prescribing information, dose reductions from the indicated dose of 5.4 mg/kg for patients with breast cancer are 4.4 and 3.2 mg/kg for the first and second dose-level reductions, respectively. [10,12,13] Per the US prescribing information, dose reductions from the indicated dose of 6.4 mg/kg for patients with gastric cancer are 5.4 and 4.4 mg/kg for the first and second dose-level reductions, respectively. [12] If further dose reductions are required, treatment should be discontinued. [10,12,13] c The EU and Canada prescribing information and Li et al indicate that for grade ≥ 2 ILD, steroids should be continued for ≥ 14 days or until complete resolution of clinical and chest CT findings, [6,10,13] while the US prescribing information indicates that steroids should be continued for ≥ 14 days. [12] CBC, complete blood count; CT, computed tomography; ILD, interstitial lung disease; IV, intravenous; KL-6, Krebs von den Lungen-6; PK, pharmacokinetics; SP-A, surfactant protein-A; SP-D, surfactant protein-D; SpO2, oxygen saturation; T-DXd, trastuzumab deruxtecan.
Since drug-related ILD/pneumonitis is a diagnosis of exclusion with a wide differential diagnosis, extensive evaluation and testing are required (detailed in this section and Fig. 3) [
23
, 24
, 27
]. A multidisciplinary approach, including but not limited to evaluations by the primary physician, nurse practitioner, pulmonologist, thoracic surgeon, pathologist, infectious disease specialist, and radiologist, should be taken to ensure that infections, cancer progression/metastases, pulmonary edema, pulmonary hemorrhage, prior chest radiation, and other causes are effectively ruled out [27
, 31
]. Many institutions have established multidisciplinary teams for adjudicating toxicities associated with immune checkpoint inhibitors, including ILD/pneumonitis, that work together on cases related to other agents. Such groups include a pulmonologist, oncologist, infectious disease specialist, radiologist, and pathologist for the purpose of ILD/pneumonitis diagnosis [[78]
]. Using guidelines can also streamline the diagnostic process [[27]
].High-resolution chest CT (≤ 1.5 mm slice thickness) [
[79]
] is the primary tool used for diagnosing ILD/pneumonitis [[80]
] and is recommended for all patients with suspected ILD/pneumonitis [5
, 24
, 38
]. High-resolution chest CT protocols should include inspiratory images, expiratory images, and thin-section cuts with supine and prone imaging [[79]
]. Pathologic examinations, including bronchoscopy and bronchoalveolar lavage (if clinically indicated and feasible), can be informative in assessing drug-related ILD/pneumonitis by examination of differential count and presence or absence of malignant cells, and for sending material for microbiological examination [5
, 30
, 39
]. In our experience, pathologic examinations can help exclude tumor recurrence and the presence of infection and sometimes identify histological features supportive of a drug reaction.Additional evaluations suggested in the current guidelines include pulmonologist consultation; sputum/blood culture and complete blood count; pulmonary function tests; pulse oximetry; arterial blood gases; pharmacokinetic analysis using a blood sample (if feasible); and a standard infectious disease evaluation to rule out infectious causes, [
[5]
] including viral pneumonias such as COVID-19 and influenza [[81]
]. In our experience, COVID-19 and T-DXd–related ILD/pneumonitis can have overlapping CT features. Other ILD/pneumonitis mimickers include infectious pneumonia, aspiration pneumonia, heart failure, metastatic cancer, lymphangitic carcinomatosis, and pulmonary edema [27
, 29
, 38
]. If additional blood tests are being considered, we suggest considering tests for atypical infection, such as serum beta-d-glucan and galactomannan. Serum markers, including Krebs von den Lungen-6 (KL-6), pulmonary surfactant protein-A, and pulmonary surfactant protein-D, are used in Japan and may be useful in making a diagnosis, [30
, 38
] although these markers are not used clinically in all countries. Although KL-6 can be problematic because it is also a tumor marker, [[82]
] a sudden increase in levels of these markers may be indicative of DAD [30
, 38
]. Upregulation of KL-6 has not been observed with all ILD/pneumonitis, [[38]
] so the absence of these markers is not relevant when making a diagnosis.If the AE is confirmed to have an etiology other than ILD/pneumonitis, follow routine clinical practice for that event. If another etiology cannot be identified, follow current ILD/pneumonitis management guidelines (Fig. 3) [
[5]
].Multidisciplinary management of T-DXd–related ILD/pneumonitis
A multidisciplinary team should manage the ILD/pneumonitis jointly with the medical oncologist and can include a primary care physician, nurse practitioner, pulmonologist, pathologist, pharmacist, infectious disease specialist, and radiologist [
[27]
]. The pulmonologist should be involved early to benefit from their expertise in managing lung injury [[27]
]. Patients with ILD/pneumonitis regardless of severity or seriousness should be followed up until it fully resolves, including after drug discontinuation [[6]
]. Optimized and consistent use of steroids is needed, as treatment may reduce the occurrence of or progression to high-grade ILD/pneumonitis [66
, 67
]. Similar to guidelines for immunotherapy-associated ILD/pneumonitis, [52
, 83
, 84
] current T-DXd–related ILD/pneumonitis guidelines recommend considering starting steroids promptly upon ILD/pneumonitis detection (Fig. 3). The current T-DXd–related ILD/pneumonitis guidelines also include more specific information regarding the steroid dose and duration than previous guidelines [- Puzanov I.
- Diab A.
- Abdallah K.
- Bingham C.O.
- Brogdon C.
- Dadu R.
- et al.
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; 5https://doi.org/10.1186/s40425-017-0300-z
5
, 66
].Grade 1 ILD/pneumonitis
If a patient has grade 1 ILD/pneumonitis, T-DXd must be interrupted until fully resolved to grade 0 [
[6]
]. Current guidelines recommend monitoring patients with grade 1 ILD/pneumonitis, with a follow-up in 2–7 days to evaluate for clinical symptom onset and pulse oximetry. Additionally, pulmonary function testing and pulse oximetry can be useful for disease monitoring, prognostication, and treatment decisions [27
, ]. Consider follow-up imaging in 1–2 weeks or as clinically indicated [[5]
]. In our experience, lung abnormalities on imaging may take 10–12 weeks to resolve; in some cases, fibrotic changes may remain for several months or longer, as noted in other drug-related pneumonitis. It can be challenging in clinical practice to distinguish between active ILD/pneumonitis and fibrotic changes on radiologic scans. Fibrotic changes as a sequela of lung inflammation typically represent decreasing consolidative opacities, with volume loss and architectural distortions. Resolution of any ground-glass opacities, with residual fibrotic changes without progression of other components, can be considered to be resolution of the ILD/pneumonitis if this aligns with clinical presentation. Careful examination of radiologic and clinical findings is needed in this challenging circumstance. Systemic steroids should be considered (eg, ≥ 0.5 mg/kg/day of prednisone or equivalent) until clinical improvement, followed by gradual taper over ≥ 4 weeks [[5]
]. In particular, we suggest considering steroids for select grade 1 cases that show extensive lung involvement or in patients at increased risk for progression of ILD/pneumonitis. If diagnostic observations worsen despite steroid initiation or the patient develops symptoms, follow grade 2 management guidelines (Fig. 3) [[5]
].Consistent with recommendations for ILD/pneumonitis associated with other drugs, [
52
, 83
, 84
] T-DXd can be resumed in the United States, European Union, and Canada if the grade 1 event fully resolves to grade 0 [- Puzanov I.
- Diab A.
- Abdallah K.
- Bingham C.O.
- Brogdon C.
- Dadu R.
- et al.
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; 5https://doi.org/10.1186/s40425-017-0300-z
10
, 12
, 13
]. If ILD/pneumonitis resolves ≤ 28 days from date of onset, T-DXd can be resumed at the same dose; if it takes > 28 days to resolve, the dose should be reduced by one dose level [5
, 10
, 12
, 13
]. If ILD/pneumonitis occurs beyond day 22 and has not resolved within 49 days from the last infusion, T-DXd should be permanently discontinued [5
, 12
]. Previous general drug-induced lung injury guidelines published in 2013 by Kubo et al (Fig. S1) allowed resuming drug administration to determine relatedness of ILD to the drug [[38]
]; however, current T-DXd guidelines and the US, EU, and Canada prescribing information state that the patient should not be rechallenged unless the event was grade 1 and has resolved [5
, 10
, 12
, 13
]. There are slight regional differences in T-DXd prescribing information for managing ILD/pneumonitis [10
, 11
, 12
, 13
]. In Japan, T-DXd must be permanently discontinued for grade ≥ 1 ILD/pneumonitis [[11]
].Grade 2 ILD/pneumonitis
T-DXd should be permanently discontinued for grade ≥ 2 ILD/pneumonitis, and steroids should be administered [
5
, 10
, 11
, 12
, 13
]. Per EU and Canada prescribing information, ≥ 1.0 mg/kg/day of prednisolone or equivalent should be continued for ≥ 14 days or until complete resolution of clinical and chest CT findings [10
, 13
]. Steroid treatment should then be gradually tapered over ≥ 4 weeks [6
, 10
, 11
, 12
, 13
]. Current guidelines recommend close monitoring of symptoms and repeat imaging as clinically indicated [[5]
]; high-resolution chest CT is preferable [[30]
]. If symptoms worsen or there is no clinical improvement in 5 days, consider increasing the steroid dose (eg, 2.0 mg/kg/day of prednisone or equivalent) and switching to intravenous administration, consider additional workup for other etiologies, and escalate care as clinically indicated (Fig. 3) [[5]
].Grade 3 or 4 ILD/pneumonitis
Per current guidelines, for grade 3 or 4 T-DXd–related ILD/pneumonitis, T-DXd should be permanently discontinued, and hospitalization is required [
[5]
]. A high dose of intravenous methylprednisolone (eg, 500–1000 mg/day for 3 days) should be started, followed by ≥ 1.0 mg/kg/day of prednisone (or equivalent) for ≥ 14 days or until complete resolution of clinical and chest CT findings, followed by gradual taper over ≥ 4 weeks [6
, 12
]. If there is no clinical improvement with steroids within 3–5 days, consider performing additional workup for other etiologies and treatment with immunosuppressants such as infliximab or mycophenolate mofetil and/or per local practice (Fig. 3) [[5]
].In addition, antibiotic treatment as prophylaxis can be considered if clinically indicated; for patients receiving prednisone at doses > 20 mg/day, it is recommended that trimethoprim and sulfamethoxazole be added 3 times weekly as prophylaxis [
[85]
]. More research, including randomized clinical trials, is needed to determine optimal steroid dosing and treatment for patients with T-DXd–related ILD/pneumonitis, predicted effect sizes with these treatments, and which patients would benefit most from treatment. Prospective research on rechallenging with T-DXd after ILD/pneumonitis and whether T-DXd can be reinitiated after grade ≥ 2 ILD/pneumonitis is also needed, since rechallenging with other drugs (eg, immunotherapy) after grade 2 ILD/pneumonitis is permitted [83
, 84
].- Puzanov I.
- Diab A.
- Abdallah K.
- Bingham C.O.
- Brogdon C.
- Dadu R.
- et al.
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; 5https://doi.org/10.1186/s40425-017-0300-z
Future directions
Mechanisms underlying T-DXd–related ILD/pneumonitis
HER2 protein expression in the bronchial and bronchiolar epithelium of the lung [
[43]
] or a direct cytotoxic effect of T-DXd on the lung [[30]
] may contribute to T-DXd–related ILD/pneumonitis development. As previously described, target-independent T-DXd uptake into alveolar macrophages was observed in an animal model, [[40]
] suggesting that payload release into lung tissues may be involved in T-DXd–related ILD/pneumonitis development. In this preclinical study, lung toxicity was observed with T-DXd but not with DXd monohydrate [[40]
]. Another study found that T-DXd–related ILD/pneumonitis (any grade and grade ≥ 3) was associated with intact T-DXd but not with free DXd [[69]
]. However, a risk of lung injury, including ILD/pneumonitis, with topoisomerase inhibitors has been reported in other studies [86
, 87
, 88
]. Data to support these hypotheses are lacking, and investigations into the specific lung cells that are damaged and mechanisms underlying the damage are clinically significant and warranted.Areas for future innovation
No single tool can diagnose ILD/pneumonitis. Better tools, including digital health tools, are needed to enhance early detection and diagnosis. Portable SpO2 monitoring and other remote monitoring techniques could facilitate ILD/pneumonitis detection; however, interpreting findings in patients with other comorbid lung conditions may be challenging. Innovative technologies for at-home SpO2 testing are emerging, which could prove useful coupled with close monitoring by a physician. ILD/pneumonitis detection could be facilitated by giving patients a questionnaire at each visit before T-DXd dosing, including questions on symptom development such as shortness of breath, new or worsening cough, chest pain, and fever. Questionnaires accessible through mobile applications could help monitor patients between visits. Toolkits for doctor-patient communication could facilitate closer monitoring and encourage patients to rapidly report ILD/pneumonitis signs or symptoms. Development of innovative patient-centered materials is an important future direction, particularly materials that promote patient communication and symptom reporting.
Using novel technologies, including computer-aided deep-learning approaches, in the diagnosis of ILD/pneumonitis has been proposed [
[80]
]. A study that compared the ability of a computer-aided diagnosis system that used machine learning with that of chest radiologists to classify ILD/pneumonitis into diagnostic categories using CT images found that the machine and the radiologists classified ILD/pneumonitis with similar accuracy [[89]
]. Electronic noses, which are artificial sensor systems that detect chemicals of interest and identify disease-specific patterns of volatile organic compounds in exhaled breath, have also been explored for ILD/pneumonitis diagnosis [[90]
].- Krauss E.
- Haberer J.
- Maurer O.
- Barreto G.
- Drakopanagiotakis F.
- Degen M.
- et al.
Exploring the ability of electronic nose technology to recognize interstitial lung diseases (ILD) by non-invasive breath screening of exhaled volatile compounds (VOC): A pilot study from the european IPF registry (eurIPFreg) and biobank.
Steps should also be taken to promote more granularity in reporting and better classification of ILD/pneumonitis. Clinical guidelines from groups such as the American Thoracic Society are clearer regarding fibrotic ILD than nonfibrotic ILD [
79
, 91
]; we suggest that imaging patterns would be a useful tool for classifying nonfibrotic ILD. Future research in this area, such as studies correlating image patterns with patient clinical characteristics, is necessary in order to bring about improvements in the reporting and understanding of drug-related pulmonary toxicity. In addition, the CTCAE currently includes pneumonitis but not ILD [Interstitial Lung Disease. ATS clinical practice guidelines & statements. https://www.thoracic.org/education-center/ild/resources.html (accessed February 22 2022).
[34]
]; revisions to the CTCAE should therefore be considered in order to promote more accurate reporting of these AEs.Areas for future T-DXd–related ILD/pneumonitis research
A caveat of the current T-DXd–related ILD/pneumonitis guidelines is that they are based on limited data and management practices established for ILD/pneumonitis related to other drugs [
52
, 83
, 84
]. Current data on T-DXd–related ILD/pneumonitis are exclusively clinical trial results [- Puzanov I.
- Diab A.
- Abdallah K.
- Bingham C.O.
- Brogdon C.
- Dadu R.
- et al.
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; 5https://doi.org/10.1186/s40425-017-0300-z
5
, 6
, 7
, 8
, 66
]. Real-world data on the incidence, monitoring, diagnosis, and success of managing T-DXd–related ILD/pneumonitis are needed. As more clinical trials read out, the safety profile of T-DXd will be further defined, and updates to the guidelines may be warranted. For patients who recover from ILD/pneumonitis, there is the potential risk of permanent lung fibrosis, need for oxygen therapy, and decrease in ability to function [[38]
]; follow-up studies of long-term outcomes regarding imaging abnormalities and oxygen dependence are an area of future research.Identifying biomarkers of drug-related ILD/pneumonitis onset could facilitate early detection and diagnosis. Using techniques including mass flow cytometry of exhaled breath, or blood-based assays, could facilitate biomarker identification. In the absence of accurate biomarkers or digital screening methods, improved education regarding symptoms and signs, increased awareness among radiologists and clinicians, and improved evaluation of drug-related ILD/pneumonitis may improve patient outcomes.
Conclusion
We reviewed guidelines for the multidisciplinary proactive monitoring, diagnosis, and management of T-DXd–related ILD/pneumonitis. Careful monitoring, prompt diagnosis, and appropriate management as described in these guidelines are important and may potentially help reduce the incidence of severe events [
[65]
]. In the recent DESTINY-Breast03 trial, there appeared to be a lower overall incidence of severe ILD/pneumonitis [[7]
]; several factors could potentially have contributed to this finding, including the use of T-DXd as an earlier line of therapy, patient demographics and clinical characteristics, increased awareness of and education regarding T-DXd–related ILD/pneumonitis, the use of monitoring and management guidelines, and the COVID-19 pandemic. Data from patients with other tumor types are needed to explore a potential role of these factors in reducing ILD/pneumonitis prevalence. Although T-DXd–related ILD/pneumonitis can be severe and life-threatening, [5
, 22
] most events are low grade and can be managed safely by involving a multidisciplinary team and promptly initiating steroids. Future research is needed to identify risk factors and mechanisms for T-DXd–related ILD/pneumonitis development.CRediT authorship contribution statement
Sandra M. Swain: Conceptualization, Project administration; Supervision, Visualization, Writing – original draft, Writing – review & editing. Mizuki Nishino: Conceptualization, Visualization, Writing – original draft, Writing – review & editing. Lisa H. Lancaster: Conceptualization, Writing – original draft, Writing – review & editing. Bob T. Li: Conceptualization, Data curation (computed tomography images), Writing – original draft, Writing – review & editing. Andrew G. Nicholson: Conceptualization, Writing – original draft, Writing – review & editing. Brian J. Bartholmai: Writing – original draft, Writing – review & editing. Jarushka Naidoo: Writing – original draft, Writing – review & editing. Eva Schumacher-Wulf: Writing – original draft, Writing – review & editing. Kohei Shitara: Writing – original draft, Writing – review & editing. Junji Tsurutani: Writing – original draft, Writing – review & editing. Pierfranco Conte: Writing – original draft, Writing – review & editing. Terufumi Kato: Writing – original draft, Writing – review & editing. Fabrice Andre: Writing – original draft, Writing – review & editing. Charles A. Powell: Conceptualization, Supervision, Writing – original draft, Writing – review & editing.
Declaration of Competing Interest
All authors received nonfinancial support (assistance with manuscript preparation) from ArticulateScience LLC, funded by AstraZeneca. Additional disclosures are as follows: SMS reports grants/contracts from Breast Cancer Research Foundation, Genentech/Roche, and Kailos Genetics, consulting fees from AstraZeneca, Daiichi Sankyo, Molecular Templates, Silverback Therapeutics, Eli Lilly, Merck, Natera, Exact Sciences, Athenex, Biotheranostics, and Genentech/Roche, honoraria from Genentech/Roche, Daiichi Sankyo, and Beijing Medical Foundation, 3rd party writing in kind Genentech/Roche travel support from Genentech/Roche, Caris, and Daiichi Sankyo, serving on Data and Safety Monitoring Committee for AstraZeneca, and leadership or a fiduciary role for ASCO Conquer Cancer Foundation and The National Surgical Adjuvant Breast and Bowel Project Foundation, outside of the submitted work; MN reports grants/contracts to the institution from Canon Medical Systems, AstraZeneca, and Daiichi Sankyo, and consulting fees from AstraZeneca and Daiichi Sankyo, outside of the submitted work; LHL reports grants/contracts from FibroGen, Novartis, Celgene, Biogen, Pliant, Galecto, Boehringer Ingelheim, Respivant, Bristol Myers Squibb, Genentech, and Galapagos, consulting fees from AstraZeneca, Boehringer Ingelheim, Genentech, Galapagos, Veracyte, and DevPro Biopharma, honoraria from Genentech, Boehringer Ingelheim, and Veracyte, serving on advisory/data safety monitoring boards or steering committees for Senhwa, Bellerophon, and United Therapeutics, and leadership or a fiduciary role for Pulmonary Fibrosis Foundation Registry Steering Committee, outside of the submitted work; BTL reports grants/contracts from the National Institutes of Health, AstraZeneca, and Daiichi Sankyo, during the submitted work, and grants/contracts from Amgen, Eli Lilly, Genentech/Roche, Hengrui USA, and Bolt Biotherapeutics, royalties or licenses from Karger Publishers and Shanghai Jiao Tong University Press, travel support from MORE Health and Jiangsu Hengrui Medicine, and two institutional patents at Memorial Sloan Kettering Cancer Center (US62/685,057, US62/514,661), outside of the submitted work; AGN reports consulting fees from Galapagos, Boehringer Ingelheim, Roche, and Medical Quantitative Image Analysis, and honoraria from UpToDate and Boehringer Ingelheim, outside of the submitted work; BJB reports grants/contracts from the National Institutes of Health/National Cancer Institute and Hurvis Foundation, royalties from Imbio, consulting fees from AstraZeneca, and two patents (patent number: 11026641; publication number: 20180061049), outside of the submitted work; JN reports grants/contracts from Merck, AstraZeneca, and Bristol Myers Squibb, consulting fees from Merck, AstraZeneca, Bristol Myers Squibb, Pfizer, Daiichi Sankyo, Takeda, and Roche/Genentech, honoraria from Merck, AstraZeneca, Bristol Myers Squibb, Pfizer, Takeda, and Roche/Genentech, travel support from Merck, and serving on advisory boards for Daiichi Sankyo, outside of the submitted work; KS reports grants/contracts from Astellas, Eli Lilly, Ono, Sumitomo Dainippon, Daiichi Sankyo, Taiho, Chugai, MSD, Medi Science, and Eisai, consulting fees from Astellas, Eli Lilly, Bristol Myers Squibb, Takeda, Pfizer, Ono, MSD, Taiho, Novartis, AbbVie, GlaxoSmithKline, Daiichi Sankyo, Amgen, and Boehringer Ingelheim, and honoraria from Novartis, AbbVie, and Yakult, outside of the submitted work; JT reports travel support and honoraria from Daiichi Sankyo, and serving on advisory boards for Daiichi Sankyo, outside of the submitted work; TK reports grants/contracts from Regeneron, AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Chugai, Eli Lilly, Merck Biopharma, MSD, Novartis, Ono, Pfizer, and Taiho, payment or honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Merck Biopharma, MSD, Novartis, Ono, Pfizer, and Roche, serving on advisory/data safety monitoring boards with honoraria for AbbVie, Amgen, AstraZeneca, Chugai, Daiichi-Sankyo, Eli Lilly, Merck Biopharma, MSD, Nippon Kayaku, Novartis, Ono, Pfizer, Taiho, and Takeda, and spousal employment at Eli Lilly, outside of the submitted work; FA reports grants/contracts from AstraZeneca, Daiichi Sankyo, Novartis, Sanofi, Roche Genentech, Lilly, and Pfizer, travel support from Pfizer, and serving on advisory boards for AstraZeneca, Daiichi Sankyo, Novartis, Sanofi, Roche/Genentech, Eli Lilly, and Pfizer, outside of the submitted work; and CAP reports personal fees from Daiichi Sankyo, AstraZeneca, Voluntis, Bristol Meyers Squibb, Senhwa Biosciences, and Eisai, outside of the submitted work. ES-W and PC do not have any disclosures to report.
Disclaimers.
The authors did not receive any financial compensation for this work. Financial support for medical writing was provided by AstraZeneca. In March 2019, AstraZeneca entered into a global development and commercialization collaboration agreement with Daiichi Sankyo for trastuzumab deruxtecan (T-DXd; DS-8201).
Acknowledgments
Medical writing support was provided by Samantha Keller, PhD, of ArticulateScience LLC, and funded by AstraZeneca in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). The manuscript was reviewed for medical accuracy by AstraZeneca and Daiichi Sankyo; however, the authors retained full control of the content and made the final decisions for all aspects of this article. Bob T. Li was supported by the Memorial Sloan Kettering Cancer Center Support Grant P30 CA008748 and Research Project Grant 1R01CA249666-01A1 from the National Institutes of Health.
Appendix A. Supplementary material
The following are the Supplementary data to this article:
- Supplementary data 1
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Article Info
Publication History
Published online: March 11, 2022
Accepted:
March 8,
2022
Received in revised form:
March 7,
2022
Received:
January 12,
2022
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