Inhibitor-induced Interstitial Lung Disease Research Articles

Abstract PO1-05-04: CDK4/6 inhibitor-induced Interstitial Lung Disease (ILD) - A Case Series

Abstract Introduction: CDK4/6 inhibitors interrupt cell cycle by inhibiting intracellular and hormonal signals responsible for proliferation of malignant cells, making them an effective treatment for patients with HR+ advanced breast cancer. Pre-clinical data demonstrates that CDK4/6 inhibitors allow for inflammatory cell recruitment, inducing pulmonary inflammation and thereby increasing the risk of ILD. The overall risk of ILD was 1.6% in a meta-analysis of over 16,000 patients treated with CDK4/6 inhibitors while individual reported risk was 1%, 1.6% and 3% for palbociclib, ribociclib, and abemaciclib respectively. Objective: The aim of this case series is to add to the body of literature about this rare but possibly serious side effect of CDK4/6 inhibitor associated ILD. Early detection and prompt management are essential for improved patient outcomes. Case 1 A 61 year-old female was diagnosed with metastatic breast cancer to brain and bones after being admitted for evaluation of acute vision loss. She started on palbociclib and letrozole and subsequently had 2 hospitalizations for acute hypoxemic respiratory failure with unremarkable infectious workup. CT scan was significant for bilateral pulmonary infiltrates raising suspicion for CDK4/6 inhibitor-induced pneumonitis; subsequently palbociclib was discontinued and the patient was started on steroid taper resulting in improvement of her respiratory status. Case 2 A 71 year-old female with a remote history of left breast cancer and sarcoidosis presented with respiratory symptoms. She was found to have metastatic breast cancer with CT scan revealing hilar and mediastinal adenopathy. The patient initially received taxol with near resolution of disease on imaging. The patient was subsequently started on palbociclib + letrozole. After 9 months of treatment, the patient was admitted for pneumonia and discharged home with oxygen. PFTs at the time were suggestive of restrictive pathology related to obesity hypoventilation. Six months later, the patient was admitted for worsening respiratory failure; CT scan revealed interstitial changes likely due to multifactorial etiologies including palbociclib-induced pneumonitis. The patient subsequently passed away. Case 3 An 81 year-old female diagnosed with remote history of L. breast cancer presented with shortness of breath and weakness. CT scan revealed a nodule and lymphadenopathy; biopsy of nodule was consistent with breast primary. The patient was initially started on ribociclib which was discontinued after 4 cycles due to transaminitis. She was switched to palbociclib, however 2 months after initiation, the patient presented with flu-like symptoms. CT revealed scattered subpleural ground-glass opacities. Infectious workup was negative; pulmonary consultation believed this was likely due to drug-induced pneumonitis and palbociclib was discontinued and she was treated with a steroid taper. Patient was switched to fulvestrant; and after 9 months she was diagnosed with stage IV tongue cancer and her breast cancer therapy was discontinued. Discussion CDK4/6 inhibitors have improved survival in patients with metastatic breast cancer, however they are associated with rare but serious adverse effects like ILD. ILD is a challenging clinical diagnosis as it refers to a cluster of disorders of varying presentation and pathophysiology, and as a result can be missed. Conclusion This case series demonstrates that CDK4/6 inhibitor-associated ILD may be more prevalent than originally reported. It is important to identify early by performing a thorough workup, including a detailed history and physical exam, medication list review, infectious work-up, chest imaging, PFTs and pulmonology consultation. Publishing a set of standardized guidelines to diagnose and treat CDK4/6 inhibitor-induced ILD is necessary as more cases are identified. Citation Format: Ami Chitalia, Krishna Shah. CDK4/6 inhibitor-induced Interstitial Lung Disease (ILD) - A Case Series [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-05-04.

MO55-4 Prognostic impact and predictive biomarkers of immune checkpoint inhibitor-induced interstitial lung disease for non-small cell lung cancer

MO55-4 Prognostic impact and predictive biomarkers of immune checkpoint inhibitor-induced interstitial lung disease for non-small cell lung cancer

Molecular Mechanism-based Prediction of Interstitial Lung Disease Development Causedby Molecular Targeted Drugs: Association between Signal Transducer and Activator of Transcription 3 and Mammalian Target of Rapamycin inhibitor-induced Interstitial Lung Disease

Interstitial lung disease (ILD) is a serious adverse event common to many molecular targeted anticancer drugs. The development of ILD significantly reduces the QOL of patients and results in treatment discontinuation. Because the development of ILD is also associated with therapeutic efficacy, the establishment of prediction strategies for ILD is important. We have focused on signal transducer and activator of transcription 3 (STAT3) as an important mechanistic factor in ILD induced by molecular targeted drugs. Our study aimed to establish mechanism-based ILD prediction strategies; therefore, we investigated the hypothesis that a genetic polymorphism in STAT3 is a predictive factor of the incidence of ILD induced by mammalian target of rapamycin (mTOR) inhibitors, a class of molecular targeted drugs associated with a higher incidence of ILD. Our clinical study clearly demonstrated that the rate of ILD induced by mTOR inhibitors was significantly higher in patients with the G allele homozygous genotype of STAT3 -1697C>G compared with those with other genotypes. The cumulative incidence of ILD in patients with the G allele homozygous genotype was significantly higher compared with that in patients carrying other genotypes. Furthermore, our in vitro study indicated that the epithelial-to-mesenchymal transition (EMT), a pre-process of tissue fibrosis, was induced by an mTOR inhibitor in lung alveolar epithelial cell lines carrying the G allele homozygous genotype which was associated with a higher risk of ILD. Our study provided a novel predictive strategy for the development of ILD induced by molecular targeted drugs.

Survival and soluble immune mediators of immune checkpoint inhibitor-induced interstitial lung disease in patients with non-small cell lung cancer

BackgroundImmune checkpoint inhibitor-related interstitial lung disease (ICI-ILD) is a serious adverse event frequently observed in patients with non-small cell lung cancer (NSCLC). We investigated the clinical effects and mechanism of action of ICI-ILD in NSCLC patients treated with ICI. MethodsWe retrospectively screened patients with advanced or recurrent NSCLC who received PD-1/PD-L1 inhibitor monotherapy and examined the prognostic impact of ICI-ILD. In addition, we analyzed the levels of 72 different soluble immune mediators in pre-treatment plasma to explore possible mechanisms associated with the development of ICI-ILD. Furthermore, the relationships between soluble immune mediators associated with ICI-ILD development and survival were analyzed. ResultsOf 141 patients with NSCLC, 25 (17.7%) developed ICI-ILD. Logistic regression analysis revealed that pre-treatment CXCL9, MMP-1, IL-6, and IL-19 levels were associated with ICI-ILD development. There were no significant differences in progression-free survival (PFS) and overall survival (OS) between patients with or without ICI-ILD. In patients with ICI-ILD, patients with lower grade ICI-ILD had better OS than those with higher-grade ICI-ILD. In ICI-ILD patients, there was a trend for patients with lower-grade ICI-ILD to have better PFS and OS than those with higher-grade ICI-ILD. Among four soluble immune mediators associated with ICI-ILD, a high level of IL-19 was significantly correlated with worse OS and PFS. ConclusionThe identified soluble immune mediators, including CXCL9, MMP-1, IL-6, and IL-19, may be useful as biomarkers to associate with ICI-ILD development. Although we did not detect significant differences in PFS and OS between patients with and without ICI-ILD, PFS and OS were longer in those with lower-grade ICI-ILD than in patients with higher-grade ICI-ILD. Among biomarkers, IL-19 may be a causal and prognostic factor for ICI-ILD.

Clinical features of CDK4/6 inhibitor-related interstitial lung disease in patients with breast cancer: a case series study.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are the standard treatment for advanced hormone receptor-positive breast cancer. Although interstitial lung disease is a rare (1-3.3%) but serious adverse event associated with CDK4/6 inhibitors, the incidence of interstitial lung disease in Japanese patients in the real world and the risk factors of interstitial lung disease are not clear. We retrospectively investigated the incidence of interstitial lung disease in 224 patients with advanced breast cancer who received CDK4/6 inhibitors at our hospital between 31 January 2017 and 31 January 2021. The correlation of age (>50 vs ≤50years), presence or absence of previous history of interstitial lung disease, lung metastasis, smoking history and chest radiation with the development of interstitial lung disease was evaluated. In total, 177 cases received palbociclib, 39 cases received abemaciclib and 8 cases received both palbociclib and abemaciclib, constituting a palbociclib group (n=185) and an abemaciclib group (n=47). At a median observation period of 607days, 8.0% (18/224) cases (13 definite and 5 probable cases) had interstitial lung disease; 6.5% (12/185) of palbociclib-treated and 13% (6/47) of abemaciclib-treated cases. The median time to interstitial lung disease onset was 178 (range, 14-750) days. There was no significant correlation between the background factors studied and the development of interstitial lung disease. The frequency of CDK4/6 inhibitor-induced interstitial lung disease was higher than that reported in clinical trials. We did not identify any risk factors for the development of interstitial lung disease in this study, and thus, larger studies that include patient predisposition are required.

STAT3 Polymorphism Associates With mTOR Inhibitor-Induced Interstitial Lung Disease in Patients With Renal Cell Carcinoma.

We evaluated the association of signal transducer and activator of transcription 3 (STAT3) polymorphisms with the incidence of mammalian target of rapamycin (mTOR) inhibitor-induced interstitial lung disease (ILD) in patients with renal cell carcinoma (RCC). We also used lung-derived cell lines to investigate the mechanisms of this association. Japanese patients with metastatic RCC who were treated with mTOR inhibitors were genotyped for the STAT3 polymorphism, rs4796793 (−1697C/G). We evaluated the association of the STAT3 genotype with the incidence of ILD and therapeutic outcome. In the 57 patients included in the primary analysis, the ILD rate within 140 days was significantly higher in patients with the GG genotype compared with those with other genotypes (77.8% vs. 23.1%, odds ratio = 11.67, 95% confidential interval = 3.06–44.46). There were no significant differences in progression-free survival or time-to-treatment failure between the patients with the GG genotype and those with other genotypes. An in vitro study demonstrated that some lung-derived cell lines carrying the GG genotype exhibited an increase in the expression of mesenchymal markers, such as fibronectin, N-cadherin, and vimentin, and decreases in E-cadherin, which is an epithelial marker associated with exposure to everolimus, although STAT3 expression and activity were not related to the genotype. In conclusion, the GG genotype of the STAT3 rs4796793 polymorphism increases the risk of mTOR inhibitor-induced ILD, supporting its use as a predictive marker for RCC.

MO10-2 Association of pre-existing interstitial lung abnormalities with immune checkpoint inhibitor-induced interstitial lung disease among patients with non-lung cancers

MO10-2 Association of pre-existing interstitial lung abnormalities with immune checkpoint inhibitor-induced interstitial lung disease among patients with non-lung cancers

Association of Preexisting Interstitial Lung Abnormalities With Immune Checkpoint Inhibitor–Induced Interstitial Lung Disease Among Patients With Nonlung Cancers

Immune checkpoint inhibitor-induced interstitial lung disease (ICI-ILD) is clinically serious and life-threatening. Preexisting interstitial lung abnormalities have been shown to be risk factors for ICI-ILD in patients with lung cancer. To evaluate whether interstitial lung abnormalities are associated with ICI-ILD in patients with nonlung cancers. This cohort study was conducted between December 2015 and May 2019 at Hiroshima University Hospital. A total of 199 consecutive patients with head and neck cancer, malignant melanoma, oral cavity cancer, urological cancer, and gastrointestinal cancer who received anti-programmed cell death 1 (PD-1) antibody monotherapy were included. Data analysis was conducted from December 2015 to May 2019. The associations between potential risk factors and the development of ICI-ILD were examined. Information on patient characteristics before antibody administration, including chest computed tomography findings, was obtained. The diagnosis of ICI-ILD was defined as abnormal computed tomography shadows occurring during treatment with anti-PD-1 antibodies. A total of 199 patients were enrolled in the study. The median (range) age was 66 (20-93) years, and most patients (133 [66.8%]) were men. Nineteen patients (9.5%) developed ICI-ILD. There was no significant difference in the baseline characteristics between patients with and without ICI-ILD. The logistic regression analyses revealed that interstitial lung abnormalities were associated with increased risk of ICI-ILD (odds ratio, 6.29; 95% CI, 2.34-16.92; P < .001), and ground glass attenuation in interstitial lung abnormalities was an independently associated risk factor (odds ratio, 4.05; 95% CI, 1.29-12.71; P = .01). In this cohort study, preexisting interstitial lung abnormalities, including ground glass attenuation, were risk factors associated with ICI-ILD in patients with nonlung cancers. This observation is consistent with previously reported findings in patients with lung cancer. Therefore, we should pay more attention to the development of ICI-ILD in patients with interstitial lung abnormalities, regardless of cancer type.

Pre-existing interstitial lung abnormalities are risk factors for immune checkpoint inhibitor-induced interstitial lung disease in non-NSCLC cancers.

e15171 Background: Immune check point inhibitor (ICI) induced interstitial lung disease (ICI-ILD) is a clinically serious and life-threatening toxicity. Pre-existing ILD has been reported to be a risk factor for ICI-ILD in patients with non-small cell lung cancer (NSCLC). In addition, we have previously reported that interstitial lung abnormality (ILA) is also a risk factor for the ICI-ILD. Therefore, we investigated whether any patient characteristics, including ILA, were risk factors for ICI-ILD in patients with non-NSCLC cancers. Methods: Head and neck cancer, malignant melanoma, oral cavity cancer, renal cell carcinoma or gastric cancer patients who received anti PD-1 antibody (Nivolumab or Pembrolizumab) at Hiroshima University Hospital from December 2015 to May 2019 were enrolled. Information on patient characteristics before anti-PD-1 antibody administration, including chest CT findings and laboratory data, were obtained. Results: Two hundred patients were enrolled, and 20 (10%) developed ICI-ILD. Grade1 was observed in 15 patients, grade2 in 3, and grade3 and 5 in 1. There was no significant difference in the background factors between patients with and without ICI-ILD. On the other hand, the proportion of patients with ILA was significantly higher in the patients with ICI-ILD than those without (P &lt; 0.01). Furthermore, univariate logistic regression analysis revealed ILA was the risk factor for ICI-ILD (p &lt; 0.01), and multivariate logistic regression analysis showed that GGA or reticulation in ILA was an independent risk factor for ICI-ILD (p = 0.016, 0.011). Conclusions: Pre-existing ILA is a risk factor for ICI-ILD, and GGA or reticulation in ILA is an independent risk factor for ICI-ILD in patients with non-NSCLC cancers. Therefore, we should pay more attention to the development of ICI-ILD in patients with ILA, especially GGA or reticulation.

Epidermal growth factor receptor tyrosine kinase inhibitor rechallenge after epidermal growth factor receptor tyrosine kinase inhibitor-induced interstitial lung disease: report of one case and review of literature

目的 探索表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）致间质性肺炎（ILD）好转后成功再用同类药物的临床可行性。 方法 回顾性分析北京清华长庚医院1例肺腺癌患者应用吉非替尼致ILD治疗好转后成功再用同类药物的临床资料，并进行文献复习。 结果 该例为53岁男性患者，因转移性肺腺癌应用吉非替尼治疗50 d后出现喘憋，结合肺部CT及血气分析结果诊断为EGFR-TKI相关ILD，停用靶向药物并予激素治疗。症状明显改善后再次应用同类药物，肿瘤得到控制且未再发生ILD。 结论 EGFR-TKI致ILD症状好转后，在取得患者知情同意并密切监测的情况下，临床可尝试再用同类药物，可延长患者生存期。

Pre-existing interstitial lung abnormalities are risk factors for immune checkpoint inhibitor-induced interstitial lung disease in non-small cell lung cancer.

Approximately 5% of non-small cell lung cancer (NSCLC) patients develop immune checkpoint inhibitor (ICI)-induced interstitial lung disease (ICI-ILD), 10% of whom die. However, there are no established risk factors for its occurrence. Interstitial lung abnormalities (ILA) are areas of increased lung density on lung computed tomography (CT) in individuals with no known ILD. This study retrospectively investigated whether any patient characteristics, including ILA, were risk factors for ICI-ILD in patients with NSCLC. NSCLC patients who received anti-programmed death (PD)-1 antibody treatment at our hospital between September 2015 and December 2017 were enrolled. Information on patient characteristics before anti-PD-1 antibody administration, including chest CT findings and laboratory data, were obtained. Among 83 enrolled patients, the incidence of ICI-ILD was 16.9% (14/83). All ICI-ILD cases developed by the third line of treatment. The incidence of ICI-ILD was significantly higher in patients with pre-existing ILA than that in those without (p = 0.007). Furthermore, patients with ground glass attenuation (GGA) in ILA had a higher incidence of ICI-ILD than that in those without (p < 0.001). In univariate logistic analysis, ILA were significant risk factors for ICI-ILD (p = 0.005). Multivariate logistic analysis revealed that only GGA in ILA was a significant risk factor for ICI-ILD (p < 0.001). Pre-existing ILA are risk factors for ICI-ILD and GGA in ILA is an independent risk factor for ICI-ILD. Therefore, we should be more aware of the development of ICI-ILD in patients with ILA, especially those with GGA.

Outcome in advanced non-small cell lung cancer patients with successful rechallenge after recovery from epidermal growth factor receptor tyrosine kinase inhibitor-induced interstitial lung disease.

Several non-small cell lung cancer (NSCLC) cases of successful rechallenge with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) after recovery from gefitinib or erlotinib-induced interstitial lung disease (ILD) have been reported, but it is not clear whether the rechallenge affects the outcome. We retrospectively evaluated the difference in the outcome between advanced NCLC patients with active EGFR mutations who received EGFR-TKI rechallenge after recovery from EGFR-TKI-induced ILD and those who did not. EGFR-TKI-induced ILD occurred in 11 (10%) of 110 patients receiving gefitinib, five (7%) of 73 patients receiving erlotinib and one (8%) of 13 patients receiving afatinib. Diffuse alveolar damage pattern ILD was observed in six cases, four of which had chemotherapy-related death. Five of 13 patients who had recovered from ILD received EGFR-TKI rechallenge with concurrent oral administration of prednisolone 0.5mg/kg after the strict informed consent of the risk for the recurrence of severe ILD. All of the five patients achieved a partial response. The median overall survival from the occurrence of EGFR-TKI-induced ILD was longer in patients with EGFR-TKI rechallenge than that in patients without (15.5 vs. 3.5months, p = 0.029). The adverse events of EGFR-TKI rechallenge were tolerable, but one case receiving EGFR-TKI rechallenge with the suspected drug exhibited the recurrence of grade 3 ILD after the discontinuation of prednisolone. EGFR-TKI rechallenge with concurrent prednisolone therapy might be salvage therapy in advanced NSCLC patients with active EGFR mutations after recovery from EGFR-TKI-induced ILD.

Tyrosine Kinase Inhibitor-Induced Interstitial Lung Disease: Clinical Features, Diagnostic Challenges, and Therapeutic Dilemmas.

Since the approval of the first molecularly targeted tyrosine kinase inhibitor (TKI), imatinib, in 2001, TKIs have heralded a new era in the treatment of many cancers. Among their innumerable adverse effects, interstitial lung disease (ILD) is one of the most serious, presenting most frequently with dyspnea, cough, fever, and hypoxemia, and often treated with steroids. Of the 28 currently approved TKIs, 16 (57 %) are reported to induce ILD with varying frequency and/or severity. The interval from drug administration to onset of ILD varies between patients and between TKIs, with no predictable time course. Its incidence is variously reported to be approximately 1.6-4.3 % in Japanese populations and 0.3-1.0 % in non-Japanese populations. The mortality rate is in the range of 20-50 %. Available evidence (primarily following the use of erlotinib and gefitinib in Japan because of the unique susceptibility of that population) has identified a number of susceptibility and prognostic risk factors (male sex, a history of smoking, and pre-existing pulmonary fibrosis being the main ones). Although the precise mechanism is not understood, collective evidence suggests that immune factors may be involved. If TKI-induced ILD is confirmed by thorough evaluation of the patient and exclusion of other causes, management is supportive, and includes discontinuation of the culprit TKI and administration of steroids. Discontinuing the culprit TKI presents a clinical dilemma because the diagnosis of TKI-induced ILD in a patient with pre-existing pulmonary fibrosis can be challenging, the patient may have TKI-responsive cancer with no suitable alternative, and switching to an alternative agent, even if available, carries the risk of the patient experiencing other toxic effects. Preliminary evidence suggests that therapy with the culprit TKI may be continued under steroid cover and/or at a reduced dose. However, this approach requires careful individualized risk-benefit analysis and further clinical experience.

Clinical aspects of epidermal growth factor receptor inhibitors: Benefit and risk

Gefitinib and erlotinib are small molecules that selectively inhibit epidermal growth factor receptor (EGFR) tyrosine kinase activity. Developmental studies of either drug have failed to show synergistic effects when combined with cytotoxic drugs as the first line treatment in patients with advanced non-small cell lung cancer, but erlotinib has shown survival prolongation when compared with best supportive care in patients with recurrence. Female gender, adenocarcinoma histology and lack of smoking history are considered to be clinical factors predicting response. Being positive for EGFR mutations in exons 18-24 in cancer cells has a strong correlation with response. On the other hand, preceding idiopathic pulmonary fibrosis, male gender and history of smoking appear to be risk factors for EGFR tyrosine kinase inhibitor-induced interstitial lung disease in the Japanese population. Reports on these factors predicting response or risk for interstitial lung disease have attracted great interest in the relation between cancer genetics and drugs, as well as the relation between ethnicity and genetics. In clinical practice, EGFR tyrosine kinase inhibitor should be prescribed with careful consideration and it is essential to assess benefit and risk of the drug.