Interstitial Lung Disease Events Research Articles

DESTINY-Breast07: Dose-expansion interim analysis of T-DXd monotherapy and T-DXd + pertuzumab in patients with previously untreated HER2+ mBC.

1009 Background: Trastuzumab deruxtecan (T-DXd) is approved for adult patients (pts) with HER2+ advanced/metastatic breast cancer (mBC) who received a prior anti-HER2–based regimen. DESTINY-Breast07 is a Phase 1b/2 multicenter, open-label, modular study exploring the safety, tolerability, and antitumor activity of T-DXd alone or in combination with other anticancer agents (NCT04538742). These results are from an interim analysis of the dose-expansion phase assessing T-DXd ± pertuzumab (P) as first-line (1L) treatment in HER2+ mBC. Methods: Pts had locally assessed HER2+ mBC with measurable disease and no or stable brain metastases. A disease-free interval of ≥12 months from (neo)adjuvant therapy was required; no prior therapy for mBC was allowed. Pts were stratified by hormone receptor and disease status (recurrent vs de novo), and PD-L1 expression. Pts received T-DXd 5.4 mg/kg intravenously (IV) every 3 weeks (Q3W) as monotherapy or in combination with P 420 mg IV Q3W, with an 840 mg loading dose. Primary endpoints were safety and tolerability; key secondary endpoints included objective response rate (ORR) and progression-free survival (PFS), per RECIST 1.1 by investigator. Results: Seventy-five pts were treated in the T-DXd module and 50 pts in the T-DXd + P module; median follow up was 19.2 months (range 8.7–29.2) and 20.6 months (range 13.3–26.7), respectively. Median age was 57 years in both modules. As of August 1, 2023, the most common adverse event (AE) was nausea (T-DXd, 70.7% [4.0% Grade 3]; T-DXd + P, 68.0% [0% Grade 3]). Diarrhea was reported in 34.7% (2.7% Grade 3) and 60.0% (6.0% Grade 3) of pts in the T-DXd and T-DXd + P modules, respectively. There were no Grade ≥4 nausea or diarrhea events. Adjudicated drug-related interstitial lung disease (ILD) / pneumonitis was reported in six (8.0%) and five (10.0%) pts in the T-DXd and T-DXd + P modules, respectively (all Grade ≤2). One non-treatment-related AE with outcome of death was reported in the T-DXd module (post-acute COVID-19 syndrome); none with T-DXd + P. The confirmed ORR was 77.3% (80% confidence interval [CI] 70.0, 83.6) with T-DXd and 82.0% (80% CI 73.1, 88.8) with T-DXd + P. PFS rate at 12 months was 77.3% (80% CI 69.0, 83.7) with T-DXd and 89.4% (80% CI 81.9, 93.9) with T-DXd + P. Conclusions: Safety profiles were consistent with the known profiles for T-DXd and P, with no Grade ≥3 ILD events. Early data showed promising efficacy in both modules. The DESTINY-Breast07 study is ongoing; analyses from the Phase 3 DESTINY-Breast09 clinical trial will provide definitive data on TDXd ± P in 1L HER2+ mBC. Clinical trial information: NCT04538742 . [Table: see text]

The Interplay between Cardiovascular Risk, Cardiovascular Events, and Disease Activity in Primary Sjögren's Syndrome: Is Uric Acid the Missing Link?

(1) Background: Uric acid is a well-known cardiovascular (CV) risk factor in the general population but its role in the setting of rheumatic diseases other than gout is unclear. (2) Methods: This is a retrospective study investigating a cohort of 105 pSS patients recording clinical, serological, and CV-related variables including adherence to the Mediterranean diet. (3) Results: We observed a strong relationship between disease activity, interstitial lung disease (ILD), and CV events. The association between ILD and CV events was dependent on higher SUA levels but independent of other traditional CV risk factors. All three cases of previous non-fatal stroke were reported by females aged <65 years, with higher SUA levels, and two of them also had pSS-ILD. Forty (38%) patients had a 10-year risk of fatal and non-fatal CV disease events beyond the cut-off recommended for their age, and using the correction factor of 1.5 currently applied only to rheumatoid arthritis, we could better identify patient subsets characterized by different CV risk profiles including different SUA levels. (4) Conclusions: This study is the first to investigate in depth the role of SUA in the CV scenario of pSS. Our findings underpin the importance of assessing SUA levels in pSS in addition to the other traditional CV risk factors and to consider applying the correction factor for CV risk assessment tools to achieve a better stratification of CV risk.

Interstitial lung disease associated with anti-HER2 anti-body drug conjugates: results from clinical trials and the WHO's pharmacovigilance database

ABSTRACT Background Interstitial lung disease (ILD) events associated with anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugates (ADCs) have aroused wide attention. Research design and methods In meta-analysis, we systematically reviewed literatures, and the outcomes were the proportion and risk of ILD related to anti-HER2 ADCs. A disproportionality analysis based on data from VigiBase was conducted to characterize the main features of anti-HER2 ADC-related ILD/pneumonitis. Results Two hundred and forty-five all-grade and 47 grade ≥ 3 ILD events with the proportion of 4.4% (95% confidence interval (CI) [2.0%, 6.8%]) and 0.5% (95% CI [0.3%, 0.8%]) were observed for anti-HER2 ADCs, respectively. Trastuzumab emtansine, trastuzumab deruxtecan and trastuzumab duocarmazine significantly increased the risk of all-grade and grade ≥ 3 ILD events with Peto odd ratios of 2.62 (95% CI [1.71, 4.04], P < 0.0001) and 2.82 (95% CI [1.07, 7.42], P = 0.04), respectively. In VigiBase, 271 cases of ILD/pneumonitis related to trastuzumab emtansine and trastuzumab deruxtecan were extracted. The median time to the onset of event was 86 days and 54.95% of events occurred within 3 months. Conclusions Trastuzumab emtansine, trastuzumab deruxtecan and trastuzumab duocarmazine increased the risk of ILD, which can lead to serious outcomes and tends to occur early.

Abstract CT167: Pooled analysis of drug-related interstitial lung disease (ILD) in 8 single-arm trastuzumab deruxtecan (T-DXd) studies

Abstract Introduction: T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and a membrane-permeable topoisomerase I inhibitor payload. In patients (pts) with HER2-expressing or -mutated solid tumors, T-DXd has demonstrated strong antitumor activity with a manageable safety profile and is approved for treatment (tx) of pts with HER2+ metastatic breast cancer (BC) that has progressed on ≥2 anti-HER2 therapies (US) or after chemotherapy (Japan); ILD is an important identified risk. We further characterize ILD in a pooled analysis of 8 single arm phase 1 and 2 T-DXd monotherapy studies. Methods: Pts who received ≥1 dose of T-DXd monotherapy 5.4 mg/kg or higher across 8 single-arm studies were included (between Aug 28, 2015 and the data cutoff June 08, 2020). Potential ILD cases had imaging and clinical data (baseline through the time of ILD case) retrospectively reviewed by an independent adjudication committee to assess whether the reported ILD event was study drug related; events adjudicated as study drug related are reported. Results: 879 pts were included; 510 with BC, 148 with lung cancer, 107 with colorectal cancer, 78 with gastric cancer, and 34 with other cancers (2 had missing tumor type). Median tx duration was 6.9 mo (range, 0.7-50.1 mo); 139 pts (15.8%) experienced an adjudicated ILD event, most were grade (G) 1/2 (G1/2=108 [12.3%]; G3=9 [1.0%]; G4=1 [0.1%]; G5=21 [2.4%]). Among pts treated with T-DXd 5.4 mg/kg (n=315), 48 (15.2%) experienced an ILD event (G1/2=39 [12.4%]; G3=2 [0.6%]; G4=1 [0.3%]; G5=6 [1.9%]). Additional details on ILD events by dose and tumor type will be presented. Among adjudicated ILD events (any grade), the onset date as assessed by investigator was delayed compared with the adjudication committee-assessed date in 71 cases (median difference in onset date, 49 d [range, 1-288 d]). The majority of ILD events occurred in the initial 12 mo of tx. After 12 mo the risk of new onset of ILD decreased with a conditional probability of developing ILD of 7.0% in pts treated to month 12 without ILD and 1.4% in pts treated to month 18 without ILD, which was likely driven by pts with longer tx duration in the BC cohort; however, additional follow-up is required to confirm these observations. Data on the use of steroids to manage ILD will be presented. Conclusion: Pooled analysis showed that most ILD events were low grade (78% of pts with ILD had G1/2 events) and occurred in the first 12 mo of tx, with lowered risk for pts on tx &amp;gt; 12 mo. The adjudication committee identified ILD earlier than investigators in 48% of cases suggesting opportunity for early detection and intervention. Close monitoring, prompt recognition, and proactive management of ILD using current management guidelines may help to improve ILD outcomes. Citation Format: Charles A. Powell, Shanu Modi, Hiroji Iwata, Shunji Takahashi, Egbert F. Smit, Salvatore Siena, Dwan-Ying Chang, Charles S. Fuchs, Kun Nie, Amy Qin, Jasmeet Singh, Corina Taitt, Sunil Verma, D. Ross Camidge. Pooled analysis of drug-related interstitial lung disease (ILD) in 8 single-arm trastuzumab deruxtecan (T-DXd) studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT167.

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

Using real-world Japanese postmarketing data, we characterized interstitial lung disease (ILD) development during the second- or later-line osimertinib treatment for EGFR mutation-positive NSCLC. Retrospective radiologic image evaluation of patients developing ILD was also performed. Patients who had ILD events reported as an adverse drug reaction by their physicians and who were assessed as having developed ILD as assessed by an ILD expert committee in Japan were included. Among 3578 patients, 252 ILD events were reported in 245 patients (6.8%) by their attending physicians. The median (range) time to the first onset of ILD after osimertinib treatment initiation was 63.0 (5-410) days, and 29 patients with a fatal outcome were reported. The ILD expert committee assessed 231 of 3578 patients (6.5%) as having ILD. A previous history of nivolumab therapy (adjusted OR: 2.84; 95% confidence interval: 1.98-4.07) and a history or concurrence of ILD (3.51; 2.10-5.87) were identified as factors potentially associated with ILD onset during osimertinib treatment. In patients who had received a previous nivolumab treatment, the number and proportion of patients developing ILD were highest for patients who discontinued nivolumab treatment within the first month before initiating osimertinib; trends for decreasing incidence and proportion were observed, with an increasing duration between the end of nivolumab treatment and the initiation of osimertinib treatment. The frequency of ILD was consistent with the known osimertinib safety profile in the Japanese population. A history or concurrence of ILD and history of previous nivolumab therapy are factors potentially associated with ILD onset during osimertinib treatment.

Incidence Rates of Interstitial Lung Disease Events in Tofacitinib-Treated Rheumatoid Arthritis Patients: Post Hoc Analysis From 21 Clinical Trials.

Background/ObjectiveTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Interstitial lung disease (ILD) is an extra-articular manifestation of RA. We investigated incidence rates of ILD in patients with RA, receiving tofacitinib 5 or 10 mg twice daily, and identified potential risk factors for ILD.MethodsThis post hoc analysis comprised a pooled analysis of patients receiving tofacitinib 5 or 10 mg twice daily or placebo from 2 phase (P)1, 10 P2, 6 P3, 1 P3b/4, and 2 long-term extension studies. Interstitial lung disease events were adjudicated as “probable” (supportive clinical evidence) or “possible” (no supportive clinical evidence) compatible adverse events. Incidence rates (patients with events per 100 patient-years) were calculated for ILD events.ResultsOf 7061 patients (patient-years of exposure = 23,393.7), 42 (0.6%) had an ILD event; median time to ILD event was 1144 days. Incidence rates for ILD with both tofacitinib doses were 0.18 per 100 patient-years. Incidence rates generally remained stable over time. There were 17 of 42 serious adverse events (40.5%) of ILD; for all ILD events (serious and nonserious), 35 of 42 events (83.3%) were mild to moderate in severity. A multivariable Cox regression analysis identified age 65 years or older (hazard ratio 2.43 [95% confidence interval, 1.13–5.21]), current smokers (2.89 [1.33–6.26]), and Disease Activity Score in 28 joints–erythrocyte sedimentation rate score (1.30 [1.04–1.61]) as significant risk factors for ILD events.ConclusionsAcross P1/2/3/4/long-term extension studies, incidence rates for ILD events were 0.18 following tofacitinib treatment, and ILD events were associated with known risk factors for ILD in RA.

Circulating adhesion molecules and subclinical interstitial lung disease: the Multi-Ethnic Study of Atherosclerosis.

Adhesion molecules may contribute to the development of interstitial lung disease (ILD) and have been proposed as prognostic biomarkers in idiopathic pulmonary fibrosis. Our objective was to determine whether the circulating adhesion molecules soluble intracellular adhesion molecule (sICAM)-1, soluble vascular cell adhesion molecule (sVCAM)-1 and P-selectin are associated with subclinical ILD in community-dwelling adults.The Multi-Ethnic Study of Atherosclerosis enrolled males and females aged 45-84 years from six communities in the United States in 2000-2002. High attenuation areas were defined as the percentage of imaged lung volume with attenuation -600--250 HU on cardiac computed tomography (CT). Interstitial lung abnormalities were visually assessed on full-lung CT. Spirometry was performed on a subset of individuals. ILD hospitalisations and deaths were adjudicated.In fully adjusted analyses, higher levels of sICAM-1, sVCAM-1 and P-selectin were associated with greater high attenuation areas (2.94%, 95% CI 1.80-4.07%; 1.24%, 95% CI 0.14-2.35%; and 1.58%, 95% CI 0.92-2.23%, respectively), and greater rate of ILD hospitalisations (HR 1.36, 95% CI 1.03-1.80; 1.40, 95% CI 1.07-1.85; and 2.03, 95% CI 1.16-3.5, respectively). sICAM-1 was associated with greater prevalence of interstitial lung abnormalities (OR 1.39, 95% CI 1.13-1.71). sICAM-1 and P-selectin were associated with lower forced vital capacity (44 mL, 95% CI 12-76 mL and 29 mL, 95% CI 8-49 mL, respectively). sVCAM-1 and P-selectin were associated with increased risk of ILD death (HR 2.15, 95% CI 1.26-3.64 and 3.61, 95% CI 1.54-8.46, respectively).Higher levels of circulating sICAM-1, sVCAM-1 and P-selectin are independently associated with CT and spirometric measures of subclinical ILD, and increased rate of adjudicated ILD events among community-dwelling adults.

Exploration of germline variants responsible for adverse events of crizotinib in anaplastic lymphoma kinase-positive non-small cell lung cancer by target-gene panel sequencing

ObjectivesCrizotinib is a standard treatment for advanced anaplastic lymphoma kinase (ALK)- or ROS1-fusion-gene-positive non-small cell lung cancer; however, serious adverse events (AEs), including elevated alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and interstitial lung disease (ILD), develop occasionally. Here, we evaluated relationships between clinically significant crizotinib-associated AEs and germline variations. Materials and MethodsDNA obtained from 75 patients allowed selection of 147 genes according to function, exon identification and sequencing, and determination of germline single nucleotide variants (SNVs). Correlations between clinically significant AEs and presence of germline variants were estimated by Fisher’s exact test. ResultsWe defined clinically significant AEs as grade 4 hematological toxicity, grade ≥3 non-hematological toxicity, and any grade of ILD. These AEs were observed in 26 patients (35%), with elevated AST/ALT (15%) the most common, followed by neutropenia (5%), ILD (4%), and thromboembolic events (4%). Nonsynonymous SNVs in epoxide hydrolase 1 (EPHX1) [odds ratio (OR): 3.86; p = 0.0009) and transcription factor 7-like 2 (TCF7L2) (OR: 2.51; p = 0.025) were associated with the presence of clinically significant AEs. ConclusionNonsynonymous EPHX1 and TCF7L2 SNVs might be associated with clinically significant crizotinib-associated AEs. These data indicated that target-gene sequencing could be feasible for predicting anticancer-agent toxicity, and that germline multi-gene information might be useful for predicting patient-specific AEs to promote precision medicine.

Association between chest computed tomography findings and respiratory adverse events in rheumatoid arthritis patients undergoing long-term biological therapy.

This study aimed to assess the association between chest computed tomography (CT) findings and incidence of respiratory adverse events (RAEs), and to detect risk factors for RAEs, in RA patients treated with long-term biological therapy. Clinical and radiological data of 332 RA patients who were treated with biological disease-modifying antirheumatic drugs were collected. CT data were assessed by an experienced radiologist. Patients were categorized into the interstitial lung disease (ILD) group (n=29), airway disease (AD) group (n=76), co-existing ILD and AD (Co-existing) group (n=6), and the group without detectable change (WDC, n=221) based on CT findings and scores. The incidence of RAEs was calculated for each group, and risk factors for RAEs from CT findings were explored. We identified 41 RAEs, including acute onset or exacerbation of ILD (ILD events, n=15), respiratory tract infection events (infection events, n=21), and other events (n=6). Cumulative incidences of ILD events were 20.2, 3.75, 47.2, and 1.94 (/1000 patient-years: PY) in the ILD, AD, Co-existing, and WDC groups, respectively, and those of infection events were 11.3, 17.6, 23.6, and 2.39 (/1000PY), respectively. Severity, as assessed by CT scores, was correlated with the incidence of RAEs. Risk factors for ILD events were reticular and honeycomb changes, and those for infection events were consolidation, bronchial wall thickening, bronchiectasis, bronchiolitis, air trapping, and atelectasis after adjusting for background factors. Our findings highlight particular CT findings that are associated with RAEs in RA patients undergoing long-term biological therapy.

Tolerability and antitumor activity of ASP8273 in TKI-naive Japanese subjects with EGFR mutation–positive non-small cell lung cancer.

9037 Background: EGFR-activating mutations (eg, exon 19 deletions [ex19del], L858R) occur in ~50% of East Asian patients with non-small cell lung cancer (NSCLC) and confer sensitivity to tyrosine kinase inhibitor (TKI) treatment. ASP8273, an orally administered EGFR TKI that inhibits EGFR-activating mutations, has demonstrated clinical activity in subjects with EGFR mutation-positive (EGFRmut+) NSCLC. Methods: EGFR TKI-naïve adult subjects (≥20 yr) with EGFRmut+ NSCLC were enrolled in this single arm Phase 2 study conducted in Japan (NCT02500927). Subjects received open-label ASP8273 300 mg once daily until discontinuation criteria were met. Primary endpoint was tolerability; secondary endpoint was antitumor activity defined by RECIST v1.1. Results: A total of 31 Japanese subjects (12 M/19 F; median age 64 years [range: 31–82]) were enrolled. Based on local testing, 27 subjects had an ex19del (n = 13, 42%) or a L858R (n = 14, 45%) EGFR activating mutation; 4 subjects (13%) had other EGFR activating mutations (L861Q [n = 2], G719X [n = 2]). ASP8273 300 mg had tolerable adverse events with diarrhea and peripheral neuropathy being most common; no interstitial lung disease events were reported (Table). Across all 31 subjects, based on investigator assessment, treatment with 300 mg ASP8273 was associated with an overall response rate (ORR) of 52%, disease control rate (DCR) of 94%, and a median duration of progression-free survival (PFS) of 11.3 months (95% CI: 7.2, 15.5). In subjects with ex19del, ASP8273 300 mg was associated with an ORR of 46% and DCR of 85%; median PFS was 8.3 months (95% CI: 2.9, -). In subjects with the L858R, ASP8273 300 mg was associated with an ORR of 57% and DCR of 100%; median PFS was 15.5 months (95% CI: 7.2, 15.5). Conclusions: Once-daily ASP8273 300 mg was tolerable in TKI-naïve Japanese subjects with EGFRmut+ NSCLC and demonstrated antitumor activity. Clinical trial information: NCT02500927. [Table: see text]

704P - Final Safety Analysis of Erlotinib Plus Gemcitabine in a Post-Marketing Surveillance Study (Polaris) of >800 Japanese Pancreatic Cancer Patients

ABSTRACT Aim: Erlotinib is approved in Japan for the treatment of unresectable pancreatic cancer (PC) in combination with gemcitabine (GE). This surveillance study investigated the safety and efficacy of GE in Japanese patients (pts), focusing on the incidence of interstitial lung disease (ILD), an adverse drug reaction (ADR) of particular concern in these pts. Methods: All pts receiving GE for treatment of PC in Japan between Jul 2011 and Aug 2012 were enrolled; pts with current/former ILD were excluded. Observation period: 28 wks. ADRs: adverse events where GE could not be ruled out as the cause. All ILD-like events were assessed by an independent ILD review committee (IRC). ILD: all ILD-like events excluding those deemed non-ILD by the IRC. Risk factors for ILD occurrence were analysed by multivariate Cox regression analysis. Both PFS and OS were assessed by the investigator. Results: A total of 848 pts had case report forms by the data cut-off of Dec 2013 (safety data were available for 843 pts). Baseline characteristics included: male 58.1%; median age 65 yrs; any smoking history 44.1%; lung metastases 14.0%; ECOG PS 0 69.2%; prior treatment lines 0/1/2/ ≥ 3: 80.5%/11.3%/5.1%/3.1%. ADRs were reported in 83.5% of pts; the most common were skin disorders (69.9%), including rash (63.6%), and diarrhoea (17.6%). Most ADRs were grade ≤2. ILD events were confirmed by IRC in 52 pts (6.2%), of whom 2 pts had grade 5 ILD (0.2%). This is in contrast to the higher ILD mortality rate (1.5%) previously seen in NSCLC pts. The multivariate analysis identified age ≥75 yrs and existence of any lung disease as a potential risk factor for whether pts developed ILD. Median PFS was 104 days (95% CI 92–112) and accumulated OS rate at 8, 16 and 28 wks was 95.3%, 85.0% and 68.2%, respectively. Conclusions: The safety profile from this large surveillance study was similar to previous clinical studies of GE in PC. These final data from this study in Japanese PC pts provide further information, especially on risk factors for ILD occurrence, which will be reported in more detail. Improved awareness of these risk factors will help clinicians guide GE treatment in these pts. Note: Authors Furuse, Gemma, Hatori, Okusaka attended an Independent Advisory Board for Erlotinib. Disclosure: J. Furuse: I have served on an independent erlotinib advisory board for Chugai Pharmaceutical Co., Ltd.; A. Gemma: I have served on an independent erlotinib advisory board for Chugai Pharmaceutical Co., Ltd.; T. Hatori: I have served on an advisory board for Chugai Pharmaceutical Co., Ltd.; T. Okusaka: I have served on an advisory board for Chugai Pharmaceutical Co., Ltd.; A. Seki: I am an employee of Chugai Pharmaceutical Co., Ltd. and have some stock ownership at Kissei Pharmaceutical Co., Ltd.

Potential risk of TNF inhibitors on the progression of interstitial lung disease in patients with rheumatoid arthritis

ObjectivesBiological therapy represents important advances in alleviating rheumatoid arthritis (RA), but the effect on interstitial lung disease (ILD) has been controversial. The objective of this study was to assess the...

Interstitial lung disease: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases.

Population-based, longitudinal studies spanning decades linking risk factors in childhood, adolescence and early adulthood to incident clinical interstitial lung disease (ILD) events in late adulthood have not been performed. In addition, no observational or randomized clinical trials have been conducted; therefore, there is presently no evidence to support the notion that reduction of risk factor levels in early life prevents ILD events in adult life. Primary prevention strategies are host-directed interventions designed to modify adverse risk factors (i.e., smoking) with the goal of preventing the development of ILD, whereas primordial prevention for ILD can be defined as the elimination of external risk factors (i.e., environmental pollutants). As no ILD primary prevention studies have been previously conducted, we propose that research studies that promote implementation of primary prevention strategies could, over time, make a subset of ILD preventable. Herein, we provide a number of initial steps required for the future implementation of prevention strategies; this statement discusses the rationale and available evidence that support potential opportunities for primordial and primary prevention, as well as fertile areas for future research of preventive intervention in ILD.

Risk of interstitial lung disease with gefitinib and erlotinib in advanced non-small cell lung cancer: A systematic review and meta-analysis of clinical trials

ObjectivesGefitinib and erlotinib are oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) widely used in advanced non-small cell lung cancer (NSCLC). Interstitial lung disease (ILD) events have been described with these agents, although the overall risk remains unclear. We performed a systematic review and meta-analysis to determine the incidence and the relative risk (RR) associated with the use of gefitinib and erlotinib. Materials and methodsPubMed databases were searched for articles published from January 2000 to October 2012, and abstracts presented at the American Society of Clinical Oncology and the European Society of Medical Oncology meetings held between 2000 and 2012 were searched for relevant studies. Eligible studies included randomized controlled trials with gefitinib and erlotinib in advanced NSCLC patients. Summary incidence rates, relative risks, and 95% CIs were calculated using fixed-effects or random-effects models, depending on the heterogeneity of the included studies. Results15,618 patients from 29 randomized controlled trials were selected for this meta-analysis. The overall incidence for all-grade ILD events was 1.2% (95% CI, 0.9–1.6%) among patients receiving gefitinib and erlotinib, with a mortality of 22.8% (95% CI, 14.6–31.0%). Compared with controls, the RR of all-grade ILD events associated with gefitinib and erlotinib was 1.53 (95% CI, 1.13–2.08; P=0.006) using a fixed-effects model. The RR of fatal ILD events associated with EGFR TKIs treatment was 1.96 (95% CI, 1.03–3.72, P=0.041) compared with control patients. The analysis was also stratified for drug type, study location, treatment arm, and treatment line, but no significant differences in RRs were observed. ConclusionTreatment with EGFR TKIs gefitinib and erlotinib is associated with a significant increase in the risk of developing both all-grade and fatal ILD events in advanced NSCLC.

Risk of interstitial lung disease with gefitinib and erlotinib in advanced non-small cell lung cancer: A systematic review and meta-analysis of clinical trials.

e19149 Background: Gefitinib and erlotinib are oral EGFR-TKIs widely used in advanced NSCLC. The reported incidence and risk of interstitial lung disease (ILD) events associated with gefitinib and erlotinib varies widely and has been inconsistently reported in trials. Therefore, we performed a systematic review and meta-analysis to determine the incidence and the relative risk (RR) associated with the use of gefitinib and erlotinib. Methods: PubMed databases were searched for articles published from January 2000 to October 2012, and abstracts from ASCO and ESMO meetings (2000-2012) were searched for relevant studies. Eligible studies included randomized controlled trials with gefitinib and erlotinib in advanced NSCLC patients. Summary incidence rates, RRs, and 95% CIs were calculated using fixed-effects or random-effects models, depending on the heterogeneity of the included studies. Results: 15,618 patients from 29 randomized controlled trials were selected for this meta-analysis. The overall incidence for all-grade ILD events was 1.2% (95% CI, 0.9% to 1.6%) among patients receiving gefitinib and erlotinib, with a mortality of 22.8% (95% CI, 14.6% to 31.0%). The summary incidence of fatal ILD events was 0.2% (95% CI, 0.1% to 0.3%) in 26 trials with available data. Compared with controls, the RR of all-grade and fatal ILD events was 1.53 (95% CI, 1.13 to 2.08; P = 0.006) and 1.96 (95% CI, 1.03 to 3.72, P = 0.041), respectively. After stratifying patients by study location (Asian versus non-Asian), the RR of all-grade ILD events was 2.00 (95% CI, 1.23 to 3.25) and 1.30 (95% CI, 0.88 to 1.91) for Asian studies and non-Asian studies, respectively. The analysis was also stratified for drug type, trial phase, treatment line, and studies quality, but no significant differences in RRs were observed in all subgroup analyses. Conclusions: Treatment with EGFR-TKIs gefitinib and erlotinib is associated with a significant increase in the risk of developing both all-grade and fatal ILD events in advanced NSCLC.

Risk of interstitial lung disease and other pulmonary related adverse events among patients taking EGFR inhibitors: A meta-analysis of randomized controlled trials.

e19155 Background: Epidermal growth factor receptor (EGFR) inhibitors are suspected of being a potential cause of interstitial lung disease (ILD). This speculation is based largely on case reports and series in which it is difficult to establish causality. In this meta-analysis we evaluated randomized controlled trials (RCTs) involving EGFR inhibitors to verify if a relationship exists between exposure to EGFR inhibitors and development of ILD and other pulmonary-related events. Methods: EMBASE and Medline were searched for all RCTs evaluating cetuximab, gefitinib or erlotinib in non-small cell lung cancer (NSCLC). Studies were disqualified if the control contained any EGFR inhibitor or drug known to cause ILD. Thirty-one RCTs with 15,736 patients were identified. The primary outcome was ILD incidence. ILD is poorly defined and there is overlap with other pulmonary related outcomes including pneumonia, acute respiratory failure (ARF) and pneumonitis, and these were therefore secondary outcomes of interest. For all outcomes, a fixed-effects meta-analysis was performed. Results: For the primary outcome, there is a 173% increased risk of ILD among patients given EGFR inhibitors (RR 2.73, 95% CI: 1.74-4.23, p&lt;0.001) across 15 RCTs that report on ILD incidence. Among secondary endpoints, there is an 86% increased risk of pneumonia (RR 1.86, 95% CI 1.36-2.53, p&lt;0.001), a 19% increased risk of pneumonitis (RR 1.19, 95% CI: 0.62-2.27, p=0.59) and a 33% increased risk of ARF (RR 1.33, 95% CI: 0.65-2.72, p=0.44) among patients given EGFR inhibitors. There is minimal heterogeneity across trials for all above outcomes. Conclusions: EGFR inhibitors play a direct role in causing or contributing to ILD progression in patients with NSCLC who are susceptible to alveolar damage from prior chemoradiation therapy. Additionally, EGFR inhibitors seem to be associated with an increased risk for other pulmonary related events.This research suggests that caution should be undertaken in administering EGFR inhibitors to patients with poor baseline lung function or pre-existing pulmonary disease.

O1-034 - Efficacy of Fexofenadine in Preventing Tyrosine Kinase Inhibitor (TKI)-Induced Interstitial Lung Disease

ABSTRACT Background Tyrosine kinase inhibitors (TKIs; gefitinib and erlotinib) are widely indicated in NSCLC patients, especially those harboring an active mutation of EGFR, and have shown excellent efficacy. However, severe interstitial lung disease (ILD) can occur as an adverse event with TKIs, and is sometimes fatal. Fexofenadine has been used to prevent TKI-induced skin rash in all patients, who received EGFR-TKIs, since April 2009 in our hospital, and seems to reduce the incidence of ILD. Therefore, we retrospectively analyzed the efficacy of fexofenadine in preventing TKI-induced ILD. Methods 145 NSCLC patients, in whom TKIs were administered, were analyzed in the study, comprising 54 and 91 patients with and without concomitant administration of fexofenadine, respectively. Univariate and multivariate analyses with logistic regression model were used to investigate whether fexofenadine could prevent EGFR-TKIs-induced ILD or not. Results ILD occurred in 21 patients (14.5%), and was fatal in 5 (3.4%). The number of ILD patients with/without fexofenadine was 4 out of 54 (8.5%)/17 out of 91 (18.7%), and the mortality was 1 out of 54 patients (1.9%)/4 out of 91 (4.4%), respectively. Fexofenadine appears to reduce the ILD event (P = 0.062). Interestingly, severe ILD events (grades 2, 3, 4, or 5) were significantly reduced in patients with fexofenadine compared with patients without fexofenadine (P = 0.031). Although the administration of fexofenadine was not independent predictive factor for EGFR-TKIs-induced ILD according to multivariate analysis, it seems to reduce the ILD events (P = 0.061). Conclusions Our data suggest that fexofenadine seem to reduce the incidence of TKI-induced ILD. However, the prospective study needs to be carried out to confirm our result.

Efficacy of fexofenadine in preventing tyrosine kinase inhibitor (TKI)-induced interstitial lung disease.

e18019 Background: Tyrosine kinase inhibitors (TKIs; gefitinib and erlotinib) are widely indicated in NSCLC patients, especially those harboring an active mutation of EGFR, and have shown excellent efficacy. However, severe interstitial lung disease (ILD) can occur as an adverse event with TKIs, and is sometimes fatal. Fexofenadine has been used to prevent TKI-induced skin rash in all patients, who received EGFR-TKIs, since April 2009 in our hospital, and seems to reduce the incidence of ILD. Therefore, we retrospectively analyzed the efficacy of fexofenadine in preventing TKI-induced ILD. Methods: 145 NSCLC patients, in whom TKIs were administered, were analyzed in the study, comprising 54 and 91 patients with and without concomitant administration of fexofenadine, respectively. Univariate and multivariate analyses with logistic regression model were used to investigate whether fexofenadine could prevent EGFR-TKIs-induced ILD or not. Results: ILD occurred in 21 patients (14.5%), and was fatal in 5 (3.4%). The number of ILD patients with/without fexofenadine was 4 out of 54 (8.5%)/17 out of 91 (18.7%), and the mortality was 1 out of 54 patients (1.9%)/4 out of 91 (4.4%), respectively. Fexofenadine appears to reduce the ILD event (p=0.062). Interestingly, severe ILD events (grades 2, 3, 4, or 5) were significantly reduced in patients with fexofenadine compared to patients without fexonadine (p=0.031, Table). Although the administration of fexofenadine was not independent predictive factor for EGFR-TKIs-induced ILD according to multivariate analysis, it seems to reduce the ILD events (p= 0.061). Conclusions: Our data suggest that fexofenadine seem to reduce the incidence of TKI-induced ILD. However, the prospective study needs to be performed to confirm our result. [Table: see text]

Proteomic Biomarkers for Acute Interstitial Lung Disease in Gefitinib-Treated Japanese Lung Cancer Patients

Interstitial lung disease (ILD) events have been reported in Japanese non-small-cell lung cancer (NSCLC) patients receiving EGFR tyrosine kinase inhibitors. We investigated proteomic biomarkers for mechanistic insights and improved prediction of ILD. Blood plasma was collected from 43 gefitinib-treated NSCLC patients developing acute ILD (confirmed by blinded diagnostic review) and 123 randomly selected controls in a nested case-control study within a pharmacoepidemiological cohort study in Japan. We generated ∼7 million tandem mass spectrometry (MS/MS) measurements with extensive quality control and validation, producing one of the largest proteomic lung cancer datasets to date, incorporating rigorous study design, phenotype definition, and evaluation of sample processing. After alignment, scaling, and measurement batch adjustment, we identified 41 peptide peaks representing 29 proteins best predicting ILD. Multivariate peptide, protein, and pathway modeling achieved ILD prediction comparable to previously identified clinical variables; combining the two provided some improvement. The acute phase response pathway was strongly represented (17 of 29 proteins, p = 1.0×10−25), suggesting a key role with potential utility as a marker for increased risk of acute ILD events. Validation by Western blotting showed correlation for identified proteins, confirming that robust results can be generated from an MS/MS platform implementing strict quality control.

Comparison of incidence and pattern of interstitial lung disease (ILD) during erlotinib and gefitinib treatment in Japanese pts with NSCLC

e19056 Background: Erlotinib was approved in Dec 2007 in Japan, and incidence and pattern of ILD during its therapy for Japanese pts with NSCLC has not still been determined, although we had previously reported the frequency of ILD through the gefitinib treatment [PASCO2004, #7063]. In this study, we intended to elucidate this issue in pts receiving erlotinib therapy. Methods: We reviewed the clinical records of 159 pts who had initiated erlotinib therapy last year (cohort A), and of 330 pts receiving gefitinib between 2000 and 2003 (cohort B) for comparing the incidence and pattern of ILD during the both TKI treatments. Toxicity data during the first months after the initiation of TKIs were obtained. Results: The demographics of 489 pts were as follows; M:63%, Ad:75%, and PS 0–1:69%. None of pts in the cohort B received erlotinib therapy before the gefitinib treatment, whereas 66 of the 159 cohort A pts (42%) were given gefitinib before the erlotinib therapy. In 23% and 28% of the pts in the cohorts A and B, erlotinib and gefitinb treatments were discontinued within 1 month after the initiation of TKI therapy, respectively. Two pts (1.3%) developed ILD in the cohort A during the first month of erlotinib treatment, while 8 ILD-events (2.4%) were observed in the gefitinib therapy (cohort B) during the same treatment period. Both 2 pts who developed ILD during the erlotinib therapy had not had a history of prior gefitinib treatment. The toxicity grades of ILD were as follows: grades 1 and 2 in 1 each (cohort A) and grades 3, 4 and 5 in 1, 1 and 6 pts, respectively (cohort B). Statistically significant factors affecting the occurrence of ILD by multivariate analysis were presence of prior pulmonary fibrosis (OR=37.3, p&lt;0.01) and poor PS (OR=6.4, p=0.02), but type of TKIs was not a significant risk factor for ILD. Conclusions: In this setting, the type of TKIs did not affect the incidence of ILD although its incidence after the initiation of erlotinib was somewhat low as compared with that during gefitinib therapy. In addition, the grade of ILD was less severe in the cohort A. These might be partly due to a patient selection based on the recent awareness of Japanese physicians regarding the risk factors for ILD events who learned it through the gefitinib treatment. No significant financial relationships to disclose.