Management of Lung Toxicity with T-DXd in Canada: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Jan-Willem Henning.

Ongoing advances in precision cancer therapy have increased the number of molecularly targeted and immuno-oncology agents for a variety of cancers, many of which have been associated with a risk of pulmonary complications, among the most concerning being drug-induced interstitial lung disease/pneumonitis (DI-ILD). As the number of patients undergoing treatment with novel anticancer agents continues to grow, DI-ILD is expected to become an increasingly significant clinical challenge. Trastuzumab deruxtecan (T-DXd) is an antibody–drug conjugate targeting human epidermal growth factor receptor 2 that is gaining widespread use in the metastatic breast cancer setting and is undergoing exploration for other oncologic indications. ILD/pneumonitis is an adverse event of special interest associated with T-DXd, which has potentially fatal consequences if left untreated and allowed to progress. When identified in the asymptomatic stage (grade 1), T-DXd-related ILD can be monitored and treated effectively with the possibility of treatment continuation. Delayed diagnosis and/or treatment, however, results in progression to grade 2 or higher toxicity and necessitates immediate and permanent discontinuation of this active agent. Strategies are, therefore, needed to optimize careful monitoring during treatment to ensure patient safety and optimize outcomes.

  • trastuzumab deruxtecan
  • metastatic breast cancer
  • interstitial lung disease
  • pneumonitis

1. Introduction

A number of systemic agents used for the treatment of cancer have been associated with pulmonary toxicities, one of the most concerning of which is drug-induced interstitial lung disease (ILD)/pneumonitis (DI-ILD). Many novel therapies, including molecularly targeted agents, immune checkpoint inhibitors, and antibody–drug conjugates (ADCs) have been associated with a risk of DI-ILD. As the number of anticancer agents continues to grow, DI-ILD is expected to become an increasingly significant clinical challenge across all types of cancers. The recent approval of trastuzumab deruxtecan (T-DXd), a novel ADC targeting human epidermal growth factor receptor 2 (HER2), for various lines of therapy and indications in breast cancer has highlighted this issue and is the focus of this revisewarch.
ILD has been identified as an adverse event of special interest with T-DXd and occurs in approximately 10% to 14% of breast cancer patients treated with the drug [1,2,3,4][1][2][3][4]. If not effectively identified and treated, T-DXd-related ILD can be fatal. While asymptomatic (grade 1) DI-ILD caused by most drugs does not require specific therapy, T-DXd-related ILD is unique because of the high risk of evolution to serious illness (grades 3–4 ILD) and because early identification of grade 1 ILD may allow for ongoing treatment, whereas progression to grade 2 or higher ILD necessitates permanent discontinuation of T-DXd.

2. Indications for T-DXd in Canada

T-DXd is approved in Canada for the treatment of adult patients with unresectable or metastatic HER2+ breast cancer as a third-line therapy after disease progression following taxanes, trastuzumab + pertuzumab, and trastuzumab-emtansine, as well as for early disease recurrence in the neoadjuvant or adjuvant setting, and for second-line therapy in patients previously treated with taxanes and trastuzumab + pertuzumab [1,2,7][1][2][5]. In 2023, T-DXd was also approved for the treatment of adult patients with unresectable or metastatic HER2-low breast cancer who have received at least two prior lines of endocrine therapy in addition to one line of chemotherapy in the metastatic setting or following disease recurrence during or within 6 months of completion of adjuvant chemotherapy. HER2-low is defined as a score of 1+ on immunohistochemistry (IHC) or an IHC score of 2+ with no HER2 amplification on in situ hybridization [4]. Approvals for these indications were based on significant improvements in all relevant efficacy endpoints compared to standard of care therapy observed in the DESTINY-Breast01 [1[1][6],8], DESTINY-Breast02 [2], DESTINY-Breast03 [3], and DESTINY-Breast04 [4] trials. In addition to the indications for metastatic breast cancer, T-DXd is approved in the United States for locally advanced/metastatic HER2-positive gastric cancer, based on the positive results of the DESTINY-Gastric01 and DESTINY-Gastric02 trials [9,10][7][8]; for metastatic HER2-positive nonsmall cell lung cancer (NSCLC), based on the DESTINY-Lung01 and DESTINY-Lung02 trials [11,12,13][9][10][11]; and is under investigation for various additional tumor types, including colorectal and other cancers [14,15][12][13].

3. Known Risk Factors for DI-ILD

The term “ILD/pneumonitis” is broadly used to describe a diverse group of inflammatory lung disorders affecting alveolar structures, pulmonary interstitium, and small airways and is characterized by the presence of inflammation or scarring of lung parenchyma [16][14]. Identifiable causes include exposure to organic materials, drugs, or toxins that trigger hypersensitivity pneumonitis; exposure to inorganic dusts and other compounds causing pneumoconiosis; autoimmune conditions such as rheumatoid arthritis and scleroderma; uncommon or rare genetic abnormalities (mutations in telomerase enzymes, mucin genes, surfactant proteins, etc.); and exposure to certain drugs [16][14]. A number of drug classes have been implicated in DI-ILD, including disease-modifying antirheumatic drugs (DMARDs), antiarrhythmics, antimicrobials, and antineoplastic agents [17,18][15][16]. Key risk factors that predict for an increased risk of developing DI-ILD include a history of pre-existing lung disease and reduced lung function [18,19,20,21][16][17][18][19]; poor performance status [22][20]; smoking [18][16]; age older than 60 years [18,19,21][16][17][19]; Japanese or African American ethnicity [21,23][19][21]; and male sex [18,19][16][17]. Specifically related to oncology, prior treatment with multiple chemotherapy regimens or thoracic radiotherapy; history of radiation recall pneumonitis; presence of lung cancer, lung metastases, or other drug-induced pneumonitides; ongoing therapy with multiple molecularly targeted agents; and treatment with a combination of molecularly targeted and cytotoxic agents have all been identified as risk factors predisposing to DI-ILD [18,21,22][16][19][20]. Factors that increase the risk of poor outcomes and/or mortality from DI-ILD include acute symptomatic disease with rapid symptom onset, hypoxemia, need for mechanical ventilation (associated with a mortality rate > 60%), pre-existing ILD, male sex, age over 65 years, and a diagnosis of nonsmall cell lung cancer [24,25,26,27,28,29][22][23][24][25][26][27]. However, it is important to note that many people who develop DI-ILD have no identifiable pre-existing risk factors, which highlights the need for vigilance. The identification and monitoring of patients at risk of DI-ILD are crucial for timely intervention; however, there are currently no effective strategies for identifying and monitoring DI-ILD in clinical practice beyond CT imaging and monitoring of oxygen saturation. Prospective clinical trials are on the horizon to determine if there are any helpful screening tools. The authors of this preseaperrch encourage Canadian clinicians to collect real-world data on the incidence of T-DXd-related ILD and other potential adverse events.

4. DI-ILD with Specific Anticancer Treatments

DI-ILD has been recognized as an important toxicity associated with a number of chemotherapeutic and targeted antineoplastic therapies. Bleomycin is the historical example, with a reported incidence of up to 45% and up to a 3% mortality rate [5,30,31][28][29][30]. Contemporary examples include agents targeting mammalian target of rapamycin (mTOR) [32[31][32],33], tyrosine kinase/anti-epidermal growth factor receptor (EGFR) inhibitors [34[33][34][35][36][37][38][39][40],35,36,37,38,39,40,41], anti-HER2 agents [42[41][42][43][44][45],43,44,45,46], BRAF inhibitors [47][46], cyclin-dependent kinase 4/6 inhibitors [48[47][48][49],49,50], and poly (ADP-ribose) polymerase (PARP) inhibitors [51][50], as well as immune checkpoint inhibitors [52,53,54,55,56,57][51][52][53][54][55][56] and ADCs [5][28], with case-fatality rates ranging from 0% to 51.3% depending on the drug [18][16]. DI-ILD has been reported, to a lesser extent, with other widely used conventional chemotherapeutic agents, such as taxanes and gemcitabine, with an incidence of DI-ILD of up to 5% [58,59][57][58], and rare but serious events can arise with oxaliplatin [60][59]. The pathogenesis of DI-ILD is poorly understood, but several mechanisms—both cytotoxic and immune related—may be involved, either alone or in combination, depending on the drug. Direct damage to pneumocytes or alveolar endothelial cells, cell-mediated lung injury, oxidative stress, and systemic cytokine release may all contribute to DI-ILD [61][60]. In patients treated with immune checkpoint inhibitors, these mechanisms may be compounded by amplified auto-immune processes triggered by the therapy [57][56]. Further studies are needed to investigate further the cytotoxic and immune-related mechanisms involved in DI-ILD to provide a better understanding of the underlying processes involved and potentially aid in the development of preventive strategies.

5. T-DXd and the Risk of ILD

ILD was first identified as an adverse event of special interest in the DESTINY-Breast01 trial, where 13.6% of patients experienced independently adjudicated ILD and 2.2% died because of this complication [1]. Subsequently, guidelines for the identification and management of ILD were incorporated into the DESTINY clinical trial program with a focus on close monitoring and active management including corticosteroids, along with dose interruption/modification and mandatory discontinuation of T-DXd for grade 2 or higher ILD events. In a pooled analysis of heavily treated patients across 9 phase 1 and 2 T-DXd clinical trials, the incidence of T-DXd-related ILD was 15.4%, with 11.9% experiencing grade 1 or 2 events and a 2.2% incidence of grade 5 events [62][61]. Rates of ILD ranged from 10.1% in DESTINY-Gastric02 [10][8] to 26.4% in DESTINY-Lung01 [11][9]. Most events (87%) occurred during the first 12 months of treatment, with a median time to onset of 5.4 months (range < 0.1 to 46.8 months) overall and of 3.2 months for grade 5 events (range < 0.1 to 20.8 months) [62][61]. Potential risk factors for DI-ILD in the pooled analysis included baseline oxygen saturation (SpO2) < 95%, T-DXd dose > 6.4 mg/kg q3w, >4 years since initial disease diagnosis, renal dysfunction, age < 65 years, and baseline or prior lung comorbidities (asthma, chronic obstructive pulmonary disease (COPD), prior ILD/pulmonary fibrosis, and radiation pneumonitis) [62][61]. Treatment in Japan was also identified as a risk factor for DI-ILD in the pooled analysis [62][61]; however, T-DXd was initially studied in Japan without the monitoring protocols implemented in later trials, which may account for the higher incidence in this population. As with other anticancer agents, the underlying mechanisms of T-DXd-related DI-ILD are unclear, but the proposed pathogenesis includes target-dependent and/or -independent uptake and catabolism of the ADC or a bystander effect of the cytotoxic payload released from cells following ADC catabolism [63][62]. Lung epithelial cells express HER2 protein, and off-cancer target mechanisms have been suggested on the basis of animal studies which observed localization of T-DXd in alveolar macrophages rather than pulmonary epithelial cells [64][63]. The release of the chemotherapy payload and subsequent bystander effect resulting in cytotoxic lung injury is currently the leading hypothesis in the understanding of T-DXd-related ILD [5][28].

6. Diagnosis and Monitoring of T-DXd-Related ILD

Current published recommendations for the early identification and management of T-DXd-related ILD in other jurisdictions do not necessarily fully apply to the Canadian health care environment, with variable timely access to pulmonary function tests (PFTs), high-resolution computed tomography (HRCT), and subspecialty respirology expertise. The steering committee therefore sought to tailor existing recommendations and create a practical approach for the Canadian health care landscape. Diagnosis of DI-ILD requires timely investigation and multidisciplinary collaboration among the oncologist, respirologist, radiologist, and other allied health care providers. In the case of reasonable causality between T-DXd and development of ILD/pneumonitis, prompt diagnosis and therapeutic intervention is key. Other diagnoses (e.g., bacterial, viral, and fungal infections; alveolar hemorrhage; metastases; heart failure; aspiration pneumonia; radiation-induced lung injury; and pulmonary embolism with infarction [65][64]) should be kept under consideration for atypical cases and nonresponding patients. Opportunistic infections such Pneumocystis jirovecii (PJP) should be strongly considered for patients on systemic corticosteroids or other immunosuppressive therapies. While the risk of T-DXd-related ILD appears to plateau after 12 months [62][61], it can occur at any time, and long-term monitoring and vigilance are essential.

7. Management of T-DXd—Related ILD

Because of the possibility of rapid ILD/pneumonitis progression and because holding treatment is critical in cases of T-DXd-related events, it is important not to delay implementation of the following management steps even when diagnosis may be uncertain.

7.1. Grade 1/Asymptomatic ILD

ILD can be fatal if it is left untreated, and progression to grade 2 or higher ILD precludes continued and future treatment with T-DXd [7][5]. Grade 1 disease will generally be diagnosed and managed by the oncologist or oncology delegate without the need for higher-level investigation or consultation. However, if the patient has a history of previous lung disease or if there is diagnostic uncertainty, assessment by respirology may be warranted. Grade 1 ILD requires that T-DXd be withheld until recovery to grade 0 (normalization of CT abnormalities), at which point treatment may be resumed, with the dose depending on time to resolution [7][5]. If resolution occurs in 28 days or fewer from onset, the original dose of T-DXd can be maintained (5.4 mg/kg–6.4 mg/kg for gastric cancer), but dose escalation is not recommended, and some clinicians may choose to dose-reduce out of an abundance of caution. If resolution takes more than 28 days, the dose is reduced to 4.4 mg/kg after a first occurrence (5.4 mg/kg for gastric cancer). If there is a second occurrence, the dose is reduced to 3.2 mg/kg (4.4 mg/kg for gastric cancer). If there is a third occurrence of pneumonitis, or if the grade 1 ILD/pneumonitis event has not resolved within 18 weeks (126 days) from the last infusion, T-DXd must be permanently discontinued. The Canadian Product Monograph for T-DXd recommends considering corticosteroid treatment for grade 1 DI-ILD (e.g., >0.5 mg/kg/day prednisolone or equivalent until improvement, with a gradual taper over 4 weeks or longer) [7][5]. Until there are further data to clarify the role of steroids for grade 1 events, the steering committee recommends following this guidance, especially if any DI-ILD-related risk factors are identified. Repeat HRCT should be considered prior to each of the next two doses of T-DXd to ensure no recurrence, after which conventional chest CT scans can resume at an interval of every 9 to 12 weeks.

7.2. Grade 2 ILD

Symptomatic ILD that does not interfere with activities of daily living (grade 2) requires permanent discontinuation of T-DXd and prompt initiation of systemic corticosteroid treatment (e.g., ≥1 mg/kg/day prednisolone or equivalent for at least 14 days followed by a gradual taper over at least a 4-week period) [7][5]. PJP prophylaxis with trimethoprim/sulfamethoxazole (TMP-SMX) should be considered for all cases and is recommended for patients who are expected to be on corticosteroids at a dose of ≥20 mg for ≥1 month [74][65]. The patient’s symptoms should be monitored closely, with re-imaging conducted as clinically indicated. The steering committee recommends clinical reassessment 7 days after initiation of steroids and early, repeat imaging with low-dose CT scan 7 to 14 days after initiation of steroids for those with nonimproving or worsening symptoms. Precise timing of repeat chest imaging for those who are clearly responding to steroids can be determined by the treating oncologist but should occur within 4 to 6 weeks. If there is clinical or radiographic worsening (especially within 5 days of initiation of therapy), consideration should be given to increasing the dose of steroids (e.g., 2 mg/kg/day of prednisolone or equivalent) or switching to IV administration (e.g., methylprednisolone). A multidisciplinary approach to the management of these patients is indicated. At this point, additional work-up for alternative etiologies and referral to respirology should be considered.

7.3. Grade 3 or 4 ILD

Patients with grade 3 or higher ILD need to be hospitalized because of supplemental oxygen requirements and ventilator support. Empiric high-dose methylprednisolone IV should be promptly initiated (e.g., 500 to 1000 mg/day for 3 days), followed by at least 1.0 mg/kg/day of prednisolone (or equivalent) for at least 14 days, followed by a gradual taper over at least 4 weeks. PJP prophylaxis with TMP-SMX should be considered for all cases and is recommended for patients who are expected to be on corticosteroids at a dose of ≥20 mg for ≥1 month [74][65]. A multidisciplinary approach to the management of these patients is indicated. In-patient respirology consultation along with involvement of other relevant specialists should be considered, including but not limited to radiologists, intensivists, internists, and infectious disease specialists. The patient’s symptoms should be monitored closely, with re-imaging conducted as clinically indicated. The steering committee recommends daily clinical reassessment after initiation of steroids and early, repeat imaging with low-dose CT scan 7 to 14 days after initiation of steroids for those with nonimproving or worsening symptoms. Precise timing of repeat chest imaging for those who are clearly responding to steroids can be determined by the treating oncologist but should occur within 4 to 6 weeks. If there is clinical or radiographic worsening (especially within 5 days of initiation of therapy), additional work-up should be considered to explore alternative etiologies. Consider other immunosuppressants and/or treat per local practice.
  • Summary: Management of T-DXd-Related DI-ILD
  • Grade 1 DI-ILD
●
Interrupt T-DXd until resolved to grade 0 (resolution of CT abnormalities), then:
⚬
If resolved in ≤28 days from date of onset, maintain dose (starting dose is 5.4 mg/kg (6.4 mg/kg for gastric cancer));
⚬
If resolved in >28 days from date of onset, reduce dose one level:
●
Dose reduction with first occurrence: 4.4 mg/kg (5.4 mg/kg for gastric cancer);
●
Dose reduction with second occurrence: 3.2 mg/kg (4.4 mg/kg for gastric cancer).
⚬
Permanently discontinue T-DXd if there is a third recurrence;
⚬
Permanently discontinue T-DXd if the grade 1 ILD/pneumonitis event has not resolved within 18 weeks (126 days) from the last infusion.
●
Consider prednisolone ≥ 0.5 mg/kg/day or equivalent with a gradual taper over ≥4 weeks, until improvement; *
●
Monitor and closely follow up in 2–7 days for onset of clinical symptoms and SpO2;
●
Consider follow-up imaging in 1–2 weeks or as clinically indicated.
  • Grade 2 DI-ILD
●
Permanently discontinue T-DXd;
●
Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected: *
⚬
A total of 1 mg/kg/day of prednisolone or equivalent for ≥14 days;
⚬
Gradually taper over ≥4 weeks.
●
Monitor symptoms closely;
●
Re-image with HRCT within 7–14 days to confirm improvement and then re-image as clinically indicated;
●
If clinical or radiographic worsening or still no improvement (especially within 5 days):
⚬
Consider increasing dose of steroids (e.g., 2 mg/kg/day of prednisolone or equivalent), switching administration to i.v. (e.g., methylprednisolone); *
⚬
Reconsider additional work-up for alternative etiologies, as described above;
⚬
Escalate care as clinically indicated.
  • Grade 3+ DI-ILD
●
Permanently discontinue T-DXd;
●
Hospitalization required;
●
Promptly initiate empirical high-dose methylprednisolone IV treatment: *
⚬
Give 500–1000 mg/day for 3 days followed by ≥1 mg/kg/day of prednisolone (or equivalent) for ≥14 days;
⚬
Gradually taper over ≥4 weeks
●
Re-image with HRCT within 7–14 days to confirm improvement and then re-image as clinically indicated;
●
If clinical or radiographic worsening or still no improvement (especially within 5 days):
⚬
Reconsider additional work-up for alternative etiologies, as described above;
⚬
Consider other immunosuppressants and/or treat per local practice.
●
Consider involvement of respirology or internal medicine.
* Consider PJP prophylaxis with TMP-SMX for all patients—recommended for patients who are expected to be on corticosteroids at a dose of ≥20 mg for ≥1 month.

References

  1. Modi, S.; Saura, C.; Yamashita, T.; Park, Y.H.; Kim, S.B.; Tamura, K.; Andre, F.; Iwata, H.; Ito, Y.; Tsurutani, J.; et al. DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated Her2-positive breast cancer. N. Engl. J. Med. 2020, 382, 610–621.
  2. André, F.; Hee Park, Y.; Kim, S.B.; Takano, T.; Im, S.A.; Borges, G.; Lima, J.P.; Aksoy, S.; Gavila Gregori, J.; De Laurentiis, M.; et al. Trastuzumab deruxtecan versus treatment of physician’s choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): A randomised, open-label, multicentre, phase 3 trial. Lancet 2023, 401, 1773–1785.
  3. Hurvitz, S.A.; Hegg, R.; Chung, W.P.; Im, S.A.; Jacot, W.; Ganju, V.; Chiu, J.W.Y.; Xu, B.; Hamilton, E.; Madhusudan, S.; et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: Updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet 2023, 401, 105–117.
  4. Modi, S.; Jacot, W.; Yamashita, T.; Sohn, J.; Vidal, M.; Tokunaga, E.; Tsurutani, J.; Ueno, N.T.; Prat, A.; Chae, Y.S.; et al. DESTINY-Breast04 Trial Investigators. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N. Engl. J. Med. 2022, 387, 9–20.
  5. Enhertu (Trastuzumab Deruxtecan for Injection) Product Monograph; AstraZeneca Canada Inc.: Mississauga, ON, Canada, 2023.
  6. Manich, S.C.; Modi, S.; Krop, I.; Park, Y.H.; Kim, S.; Tamura, K.; André, F.; Iwata, H.; Ito, Y.; Tsurutani, J.; et al. Trastuzumab deruxtecan (T-DXd) in patients with HER2-positive metastatic breast cancer (MBC): Updated survival results from a phase II trial (DESTINY-Breast01). Ann. Oncol. 2021, 32 (Suppl. S5), S486.
  7. Shitara, K.; Bang, Y.J.; Iwasa, S.; Sugimoto, N.; Ryu, M.H.; Sakai, D.; Chung, H.C.; Kawakami, H.; Yabusaki, H.; Lee, J.; et al. DESTINY-Gastric01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N. Engl. J. Med. 2020, 382, 2419–2430.
  8. Ku, G.Y.; Di Bartolomeo, M.; Smyth, E.; Chau, I.; Park, H.; Siena, S.; Lonardi, S.; Wainberg, Z.A.; Ajani, J.A.; Chao, J.; et al. 1205MO Updated analysis of DESTINY-Gastric02: A phase II single-arm trial of trastuzumab deruxtecan (T-DXd) in western patients (Pts) with HER2-positive (HER2+) unresectable/metastatic gastric/gastroesophageal junction (GEJ) cancer who progressed on or after trastuzumab-containing regimen. Ann. Oncol. 2022, 33, S1100.
  9. Li, B.T.; Smit, E.F.; Goto, Y.; Nakagawa, K.; Udagawa, H.; Mazières, J.; Nagasaka, M.; Bazhenova, L.; Saltos, A.N.; Felip, E.; et al. DESTINY-Lung01 Trial Investigators. Trastuzumab deruxtecan in Her2-mutant non-small-cell lung cancer. N. Engl. J. Med. 2022, 386, 241–251.
  10. Smit, E.F.; Nakagawa, K.; Nagasaka, M.; Felip, E.; Goto, Y.; Li, B.T.; Pacheco, J.M.; Murakami, H.; Barlesi, F.; Saltos, A.N.; et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): Interim results of DESTINY-Lung01. J. Clin. Oncol. 2020, 38 (Suppl. S15), 9504.
  11. ClinicalTrials.gov. Trastuzumab Deruxtecan in Participants with HER2-Mutated Metastatic Non-Small Cell Lung Cancer (NSCLC) (DESTINY-LUNG02). Available online: https://clinicaltrials.gov/ct2/show/NCT04644237 (accessed on 12 May 2023).
  12. ClinicalTrials.gov. A Phase 2 Study of T-DXd in Patients With Selected HER2 Expressing Tumors (DPT02). Available online: https://clinicaltrials.gov/ct2/show/NCT04482309 (accessed on 9 February 2023).
  13. ClinicalTrials.gov. Trastuzumab Deruxtecan in Participants with HER2-Overexpressing Advanced or Metastatic Colorectal Cancer (DESTINY-CRC02). Available online: https://clinicaltrials.gov/ct2/show/NCT04744831 (accessed on 9 February 2023).
  14. Kreuter, M.; Herth, F.J.; Wacker, M.; Leidl, R.; Hellmann, A.; Pfeifer, M.; Behr, J.; Witt, S.; Kauschka, D.; Mall, M.; et al. Exploring clinical and epidemiological characteristics of interstitial lung diseases: Rationale, aims, and design of a nationwide prospective registry—The EXCITING-ILD Registry. Biomed. Res. Int. 2015, 2015, 123876.
  15. Camus, P.; Bonniaud, P.; Fanton, A.; Camus, C.; Baudaun, N.; Foucher, P. Drug-induced and iatrogenic infiltrative lung disease. Clin. Chest Med. 2004, 25, 479–519.
  16. Skeoch, S.; Weatherley, N.; Swift, A.J.; Oldroyd, A.; Johns, C.; Hayton, C.; Giollo, A.; Wild, J.M.; Waterton, J.C.; Buch, M.; et al. Drug-induced interstitial lung disease: A systematic review. J. Clin. Med. 2018, 7, 356.
  17. Osawa, M.; Kudoh, S.; Sakai, F.; Endo, M.; Hamaguchi, T.; Ogino, Y.; Yoneoka, M.; Sakaguchi, M.; Nishimoto, H.; Gemma, A. Clinical features and risk factors of panitumumab-induced interstitial lung disease: A postmarketing all-case surveillance study. Int. J. Clin. Oncol. 2015, 20, 1063–1071.
  18. Sakurada, T.; Kakiuchi, S.; Tajima, S.; Horinouchi, Y.; Okada, N.; Nishisako, H.; Nakamura, T.; Teraoka, K.; Kawazoe, K.; Yanagawa, H.; et al. Characteristics of and risk factors for interstitial lung disease induced by chemotherapy for lung cancer. Ann. Pharmacother. 2015, 49, 398–404.
  19. Schwaiblmair, M.; Behr, W.; Haeckel, T.; Märkl, B.; Foerg, W.; Berghaus, T. Drug induced interstitial lung disease. Open Respir. Med. J. 2012, 6, 63–74.
  20. Yonemori, K.; Hirakawa, A.; Kawachi, A.; Kinoshita, F.; Okuma, H.; Nishikawa, T.; Tamura, K.; Fujiwara, Y.; Takebe, N. Drug induced interstitial lung disease in oncology phase I trials. Cancer Sci. 2016, 107, 1830–1836.
  21. Vansteenkiste, J. Nivolumab for NSCLC in Japanese patients: Similar benefits, but beware of pneumonitis. ESMO Open 2017, 2 (Suppl. S1), e000119.
  22. Vial-Dupuy, A.; Sanchez, O.; Douvry, B.; Guetta, L.; Juvin, K.; Wermert, D.; Guérot, E.; Israël-Biet, D. Outcome of patients with interstitial lung disease admitted to the intensive care unit. Sarcoidosis Vasc. Diffuse Lung Dis. 2013, 30, 134–142.
  23. Park, S.Y.; Lim, S.Y.; Um, S.W.; Koh, W.J.; Chung, M.P.; Kim, H.; Kwon, O.J.; Park, H.K.; Kim, S.J.; Im, Y.H.; et al. Outcome and predictors of mortality in patients requiring invasive mechanical ventilation due to acute respiratory failure while undergoing ambulatory chemotherapy for solid cancers. Support. Care Cancer 2013, 21, 1647–1653.
  24. Chikura, B.; Lane, S.; Dawson, J.K. Clinical expression of leflunomide-induced pneumonitis. Rheumatology 2009, 48, 1065–1068.
  25. Mankikian, J.; Favelle, O.; Guillon, A.; Guilleminault, L.; Cormier, B.; Jonville-Béra, A.P.; Perrotin, D.; Diot, P.; Marchand-Adam, S. Initial characteristics and outcome of hospitalized patients with amiodarone pulmonary toxicity. Respir. Med. 2014, 108, 638–646.
  26. Sato, T.; Inokuma, S.; Sagawa, A.; Matsuda, T.; Takemura, T.; Otsuka, T.; Saeki, Y.; Takeuchi, T.; Sawada, T.; Study Committee for Leflunomide-induced Lung Injury; et al. Factors associated with fatal outcome of leflunomide-induced lung injury in Japanese patients with rheumatoid arthritis. Rheumatology 2009, 48, 1265–1268.
  27. Yoshii, N.; Suzuki, T.; Nagashima, M.; Kon, A.; Kakihata, K.; Gemma, A. Clarification of clinical features of interstitial lung disease induced by irinotecan based on postmarketing surveillance data and spontaneous reports. Anti-Cancer Drugs 2011, 22, 563–568.
  28. Swain, S.M.; Nishino, M.; Lancaster, L.H.; Li, B.T.; Nicholson, A.G.; Bartholmai, B.J.; Naidoo, J.; Schumacher-Wulf, E.; Shitara, K.; Tsurutani, J.; et al. Multidisciplinary clinical guidance on trastuzumab deruxtecan (T-DXd)-related interstitial lung disease/pneumonitis-Focus on proactive monitoring, diagnosis, and management. Cancer Treat. Rev. 2022, 106, 102378.
  29. Kubo, K.; Azuma, A.; Kanazawa, M.; Kameda, H.; Kusumoto, M.; Genma, A.; Saijo, Y.; Sakai, F.; Sugiyama, Y.; Tatsumi, K.; et al. Japanese Respiratory Society Committee for formulation of Consensus statement for the diagnosis and treatment of drug-induced lung injuries. Consensus statement for the diagnosis and treatment of drug-induced lung injuries. Respir. Investig. 2013, 51, 260–277.
  30. Sleijfer, S. Bleomycin-induced pneumonitis. Chest 2001, 120, 617–624.
  31. Dabydeen, D.A.; Jagannathan, J.P.; Ramaiya, N.; Krajewski, K.; Schutz, F.A.; Cho, D.C.; Pedrosa, I.; Choueiri, T.K. Pneumonitis associated with mTOR inhibitors therapy in patients with metastatic renal cell carcinoma: Incidence, radiographic findings and correlation with clinical outcome. Eur. J. Cancer 2012, 48, 1519–1524.
  32. Baselga, J.; Campone, M.; Piccart, M.; Burris, H.A., 3rd; Rugo, H.S.; Sahmoud, T.; Noguchi, S.; Gnant, M.; Pritchard, K.I.; Lebrun, F.; et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 2012, 366, 520–529.
  33. Akamatsu, H.; Inoue, A.; Mitsudomi, T.; Kobayashi, K.; Nakagawa, K.; Mori, K.; Nukiwa, T.; Nakanishi, Y.; Yamamoto, N. Interstitial lung disease associated with gefitinib in Japanese patients with EGFR-mutated non-small-cell lung cancer: Combined analysis of two phase III trials (NEJ 002 and WJTOG 3405). Jpn. J. Clin. Oncol. 2013, 43, 664–668.
  34. Hotta, K.; Kiura, K.; Takigawa, N.; Yoshioka, H.; Harita, S.; Kuyama, S.; Yonei, T.; Fujiwara, K.; Maeda, T.; Aoe, K.; et al. Comparison of the incidence and pattern of interstitial lung disease during erlotinib and gefitinib treatment in Japanese Patients with non-small cell lung cancer: The Okayama Lung Cancer Study Group experience. J. Thorac. Oncol. 2010, 5, 179–184.
  35. Nakagawa, K.; Kudoh, S.; Ohe, Y.; Johkoh, T.; Ando, M.; Yamazaki, N.; Seki, A.; Takemoto, S.; Fukuoka, M. Postmarketing surveillance study of erlotinib in Japanese patients with non-small-cell lung cancer (NSCLC): An interim analysis of 3488 patients (POLARSTAR). J. Thorac. Oncol. 2012, 7, 1296–1303.
  36. Pellegrino, B.; Facchinetti, F.; Bordi, P.; Silva, M.; Gnetti, L.; Tiseo, M. Lung toxicity in non-small-cell lung cancer patients exposed to ALK inhibitors: Report of a peculiar case and systematic review of the literature. Clin. Lung Cancer 2018, 19, e151–e161.
  37. Nakano, K.; Seto, A.; Sasaki, T.; Shimbashi, W.; Fukushima, H.; Yonekawa, H.; Mitani, H.; Takahashi, S. Incidence and risk factors of interstitial lung disease of patients with head and neck cancer treated with cetuximab. Head Neck 2019, 41, 2574–2580.
  38. Gemma, A.; Kusumoto, M.; Sakai, F.; Endo, M.; Kato, T.; Saito, Y.; Baba, T.; Sata, M.; Yamaguchi, O.; Yabuki, Y.; et al. Real-world evaluation of factors for interstitial lung disease incidence and radiologic characteristics in patients with EGFR T790M-positive NSCLC treated with osimertinib in Japan. J. Thorac. Oncol. 2020, 15, 1893–1906.
  39. Suh, C.H.; Kim, K.W.; Pyo, J.; Hatabu, H.; Nishino, M. The incidence of ALK inhibitor-related pneumonitis in advanced non-small-cell lung cancer patients: A systematic review and meta-analysis. Lung Cancer 2019, 132, 79–86.
  40. 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.
  41. Hackshaw, M.D.; Danysh, H.E.; Singh, J.; Ritchey, M.E.; Ladner, A.; Taitt, C.; Camidge, D.R.; Iwata, H.; Powell, C.A. Incidence of pneumonitis/interstitial lung disease induced by HER2-targeting therapy for HER2-positive metastatic breast cancer. Breast Cancer Res. Treat. 2020, 183, 23–39.
  42. Banerji, U.; van Herpen, C.M.L.; Saura, C.; Thistlethwaite, F.; Lord, S.; Moreno, V.; Macpherson, I.R.; Boni, V.; Rolfo, C.; de Vries, E.G.E.; et al. Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: A phase 1 dose-escalation and dose-expansion study. Lancet Oncol. 2019, 20, 1124–1135.
  43. Manich, C.S.; O’Shaughnessy, J.; Aftimos, P.G.; van den Tweel, E.; Oesterholt, M.; Escrivá-de-Romaní, S.I.; Quenel Tueux, N.; Tan, T.J.; Lim, J.S.; Ladoire, S.; et al. Primary outcome of the phase III SYD985.002/TULIP trial comparing trastuzumab duocarmazine to physician’s choice treatment in patients with pre-treated HER2-positive locally advanced or metastatic breast cancer. Ann. Oncol. 2021, 32, S1288.
  44. Zhang, Y.; Qiu, M.; Wang, J.; Zhang, Y.Q.; Shen, A.; Yuan, X.L.; Zhang, T.; Wei, X.L.; Zhao, H.Y.; Wang, D.S.; et al. A phase 1 multicenter, dose expansion study of ARX788 as monotherapy in patients with HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma (ACE-Gastric-01). J. Clin. Oncol. 2021, 39, e16059.
  45. Hurvitz, S.A.; Park, H.; Frentzas, S.; Shannon, C.M.; Cuff, K.; Eek, R.W.; Budd, G.T.; McCartney, A.; O’Shaughnessy, J.; Lu, J.M.; et al. Safety and unique pharmacokinetic profile of ARX788, a site-specific ADC, in heavily pretreated patients with HER2-overexpresing solid tumors: Results from two phase 1 clinical trials. J. Clin. Oncol. 2021, 39, 1038.
  46. Flaherty, K.T.; Robert, C.; Hersey, P.; Nathan, P.; Garbe, C.; Milhem, M.; Demidov, L.V.; Hassel, J.C.; Rutkowski, P.; Mohr, P.; et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. M. Engl. J. Med. 2012, 367, 107–114.
  47. Verzanio (Abemaciclib) Product Monograph; Eli Lilly Canada: Toronto, ON, Canada, 2019.
  48. Finn, R.S.; Rugo, H.S.; Gelmon, K.A.; Cristofanilli, M.; Colleoni, M.; Loi, S.; Schnell, P.; Lu, D.R.; Theall, K.P.; Mori, A.; et al. Long-term pooled safety analysis of palbociclib in combination with endocrine therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Updated analysis with up to 5 years of follow-up. Oncologist 2021, 26, e749–e755.
  49. Kisqali (Ribociclib) Product Monograph; Novartis Pharmaceuticals Canada Inc.: Dorval, QC, Canada, 2012.
  50. Ma, Z.; Sun, X.; Zhao, Z.; Lu, W.; Guo, Q.; Wang, S.; You, J.; Zhang, Y.; Liu, L. Risk of pneumonitis in cancer patients treated with PARP inhibitors: A meta-analysis of randomized controlled trials and a pharmacovigilance study of the FAERS database. Gynecol. Oncol. 2021, 162, 496–505.
  51. Okada, N.; Matsuoka, R.; Sakurada, T.; Goda, M.; Chuma, M.; Yagi, K.; Zamami, Y.; Nishioka, Y.; Ishizawa, K. Risk factors of immune checkpoint inhibitor-related interstitial lung disease in patients with lung cancer: A single-institution retrospective study. Sci. Rep. 2020, 10, 13773.
  52. Khunger, M.; Rakshit, S.; Pasupuleti, V.; Hernandez, A.V.; Mazzone, P.; Stevenson, J.; Pennell, N.A.; Velcheti, V. Incidence of pneumonitis with use of programmed death 1 and programmed death-ligand 1 inhibitors in non-small cell lung cancer: A systematic review and meta-analysis of trials. Chest 2017, 152, 271–281.
  53. Suzuki, Y.; Karayama, M.; Uto, T.; Fujii, M.; Matsui, T.; Asada, K.; Kusagaya, H.; Kato, M.; Matsuda, H.; Matsuura, S.; et al. Assessment of immune-related interstitial lung disease in patients with NSCLC treated with immune checkpoint inhibitors: A multicenter prospective study. J. Thorac. Oncol. 2020, 15, 1317–1327.
  54. Kato, T.; Masuda, N.; Nakanishi, Y.; Takahashi, M.; Hida, T.; Sakai, H.; Atagi, S.; Fujita, S.; Tanaka, H.; Takeda, K.; et al. Nivolumab-induced interstitial lung disease analysis of two phase II studies patients with recurrent or advanced non-small-cell lung cancer. Lung Cancer 2017, 104, 111–118.
  55. Nishino, M.; Giobbie-Hurder, A.; Hatabu, H.; Ramaiya, N.H.; Hodi, F.S. Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer: A systematic review and meta-analysis. JAMA Oncol. 2016, 2, 1607–1616.
  56. Delaunay, M.; Cadranel, J.; Lusque, A.; Meyer, N.; Gounant, V.; Moro-Sibilot, D.; Michot, J.M.; Raimbourg, J.; Girard, N.; Guisier, F.; et al. Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients. Eur. Respir. J. 2017, 50, 1700050.
  57. Barlési, F.; Villani, P.; Doddoli, C.; Gimenez, C.; Kleisbauer, J.P. Gemcitabine-induced severe pulmonary toxicity. Fundam. Clin. Pharmacol. 2004, 18, 85–91.
  58. Singavi, A.K.; Ramalingam, V.; George, B. Etanercept for treatment of taxane-induced pneumonitis. J. Oncol. Pract. 2019, 15, 556–557.
  59. Suthar, K.H.; Al Mutar, S.; Venkatesan, R. Oxaliplatin-induced pulmonary toxicity: A rare but serious complication. Cureus 2020, 12, e7483.
  60. Matsuno, O. Drug-induced interstitial lung disease: Mechanisms and best diagnostic approaches. Respir. Res. 2012, 13, 39.
  61. Powell, C.A.; Modi, S.; Iwata, H.; Takahashi, S.; Smit, E.F.; Siena, S.; Chang, D.Y.; Macpherson, E.; Qin, A.; Singh, J.; et al. Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies. ESMO Open 2022, 7, 100554.
  62. Conte, P.; Ascierto, P.A.; Patelli, G.; Danesi, R.; Vanzulli, A.; Sandomenico, F.; Tarsia, P.; Cattelan, A.; Comes, A.; De Laurentiis, M.; et al. Drug-induced interstitial lung disease during cancer therapies: Expert opinion on diagnosis and treatment. ESMO Open 2022, 7, 100404.
  63. Kumagai, K.; Aida, T.; Tsuchiya, Y.; Kishino, Y.; Kai, K.; Mori, K. Interstitial pneumonitis related to trastuzumab deruxtecan, a human epidermal growth factor receptor 2-targeting Ab-drug conjugate, in monkeys. Cancer Sci. 2020, 111, 4636–4645.
  64. Müller, N.L.; White, D.A.; Jiang, H.; Gemma, A. Diagnosis and management of drug-associated interstitial lung disease. Br. J. Cancer 2004, 91 (Suppl. S2), S24–S30.
  65. Limper, A.H.; Knox, K.S.; Sarosi, G.A.; Ampel, N.M.; Bennett, J.E.; Catanzaro, A.; Davies, S.F.; Dismukes, W.E.; Hage, C.A.; Marr, K.A.; et al. American Thoracic Society Fungal Working Group. An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients. Am. J. Respir. Crit. Care Med. 2011, 183, 96–128.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback