Safety Of Afatinib Research Articles

Clinical efficacy and identification of factors confer resistance to afatinib (tyrosine kinase inhibitor) in EGFR-overexpressing esophageal squamous cell carcinoma

Epidermal growth factor receptor (EGFR) is reportedly overexpressed in most esophageal squamous cell carcinoma (ESCC) patients, but anti-EGFR treatments offer limited survival benefits. Our preclinical data showed the promising antitumor activity of afatinib in EGFR-overexpressing ESCC. This proof-of-concept, phase II trial assessed the efficacy and safety of afatinib in pretreated metastatic ESCC patients (n = 41) with EGFR overexpression (NCT03940976). The study met its primary endpoint, with a confirmed objective response rate (ORR) of 39% in 38 efficacy-evaluable patients and a median overall survival of 7.8 months, with a manageable toxicity profile. Transcriptome analysis of pretreatment tumors revealed that neurotrophic receptor tyrosine kinase 2 (NTRK2) was negatively associated with afatinib sensitivity and might serve as a predictive biomarker, irrespective of EGFR expression. Notably, knocking down or inhibiting NTRK2 sensitized ESCC cells to afatinib treatment. Our study provides novel findings on the molecular factors underlying afatinib resistance and indicates that afatinib has the potential to become an important treatment for metastatic ESCC patients.

The ASCENT Trial: a phase 2 study of induction and consolidation afatinib and chemoradiation with or without surgery in stage III EGFR-mutant NSCLC.

The role of tyrosine kinase inhibitors (TKIs) in early-stage and metastatic oncogene-driven non-small cell lung cancer (NSCLC) is established, but it remains unknown how best to integrate TKIs with concurrent chemoradiotherapy (cCRT) in locally advanced disease. The phase 2 ASCENT trial assessed the efficacy and safety of afatinib and cCRT with or without surgery in locally advanced epidermal growth factor receptor (EGFR)-mutant NSCLC. Adults ≥18 years with histologically confirmed stage III (AJCC 7th edition) NSCLC with activating EGFR mutations were enrolled at Mass General and Dana-Farber/Brigham Cancer Centers, Boston, Massachusetts. Patients received induction afatinib 40 mg daily for 2 months, then cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 IV every 3 weeks during RT (definitive or neoadjuvant dosing). Patients with resectable disease underwent surgery. All patients were offered consolidation afatinib for 2 years. The primary endpoint was the objective response rate (ORR) to induction TKI. Secondary endpoints were safety, conversion to operability, progression-free survival (PFS), and overall survival (OS). Analyses were performed on the intention-to-treat population. Nineteen patients (median age 56 years; 74% female) were enrolled. ORR to induction afatinib was 63%. Seventeen patients received cCRT; 2/9 previously unresectable became resectable. Ten underwent surgery; 6 had a major or complete pathological response. Thirteen received consolidation afatinib. With a median follow-up of 5.0 years, median PFS and OS were 2.6 (95% CI, 1.4-3.1) and 5.8 years (2.9-NR), respectively. Sixteen recurred or died; 6 recurrences were isolated to CNS. The median time to progression after stopping consolidation TKI was 2.9 months (95% CI, 1.1-7.2). Four developed grade 2 pneumonitis. There were no treatment-related deaths. We explored the efficacy of combining TKI with cCRT in oncogene-driven NSCLC. Induction TKI did not compromise subsequent receipt of multimodality therapy. PFS was promising, but the prevalence of CNS-only recurrences and rapid progression after TKI discontinuation speak to unmet needs in measuring and eradicating micrometastatic disease.

The difference between dacomitinib and afatinib in effectiveness and safety in first-line treatment of patients with advanced EGFR-mutant non-small cell lung cancer: a real-world observational study

ObjectivesThe irreversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) afatinib and dacomitinib are approved for first-line treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and dacomitinib in this setting.Materials and methodsBetween September 2020 and March 2023, we retrospectively recruited patients diagnosed with advanced-stage EGFR-mutant NSCLC who were treated with first-line irreversible EGFR-TKIs. The enrolled patients were assigned to two groups based on whether they received afatinib or dacomitinib.ResultsA total of 101 patients were enrolled in the study (70 to afatinib and 31 to dacomitinib). The partial response rates (PR) for first-line treatment with afatinib and dacomitinib were 85.7 and 80.6% (p = 0.522). The median progression-free survival (PFS) (18.9 vs. 16.3 months, p = 0.975) and time to treatment failure (TTF) (22.7 vs. 15.9 months, p = 0.324) in patients with afatinib and dacomitinib treatment were similar. There was no significant difference observed in the median PFS (16.1 vs. 18.9 months, p = 0.361) and TTF (32.5 vs. 19.6 months, p = 0.182) between patients receiving the standard dose and those receiving the reduced dose. In terms of side effects, the incidence of diarrhea was higher in the afatinib group (75.8% vs. 35.5%, p < 0.001), while the incidence of paronychia was higher in the dacomitinib group (58.1% vs. 31.4%, p = 0.004). The PFS (17.6 vs. 24.9 months, p = 0.663) and TTF (21.3 vs. 25.1 months, p = 0.152) were similar between patients younger than 75 years and those older than 75 years.ConclusionThis study showed that afatinib and dacomitinib had similar effectiveness and safety profiles. However, they have slightly different side effects. Afatinib and dacomitinib can be safely administered to patients across different age groups with appropriate dose reductions.

Effectiveness and safety of afatinib, gefitinib, and erlotinib for treatment-naïve elderly patients with epidermal growth factor receptor-mutated advanced non-small-cell lung cancer: a multi-institute retrospective study.

In real-world practice, most patients with lung cancer are diagnosed when they are aged ≥65 years. However, clinical trials tend to lack data for the elderly population. Therefore, we aimed to describe the effectiveness and safety of afatinib, gefitinib, and erlotinib for elderly patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC). Treatment-naïve patients with EGFR-mutated advanced NSCLC were enrolled at many hospitals in Taiwan. Patient characteristics and the effectiveness and safety of afatinib, gefitinib, and erlotinib were compared. This study enrolled 1,343 treatment-naïve patients with EGFR-mutated advanced NSCLC, of whom 554 were aged <65 years, 383 were aged 65-74 years, 323 were aged 75-84 years, and 83 were aged ≥85 years. For elderly patients, afatinib was more effective, with a median progression-free survival (PFS) of 14.7 months and overall survival (OS) of 22.2 months, than gefitinib (9.9 months and 17.7 months, respectively) and erlotinib (10.8 months and 18.5 months, respectively; PFS: p = 0.003; OS: p = 0.026). However, grade ≥3 adverse events, including skin toxicities, paronychia, mucositis, and diarrhea, were more frequently experienced by patients receiving afatinib than those receiving gefitinib or erlotinib. This large retrospective study provides real-world evidence of the effectiveness and safety of EGFR-TKIs for elderly patients with EGFR-mutated advanced NSCLC, a population that is often underrepresented in clinical trials and real-world evidence. Afatinib was more effective as a first-line treatment than gefitinib or erlotinib for elderly patients with EGFR-mutated advanced NSCLC.

Real-World Treatment Outcomes and Safety of Afatinib in Advanced Squamous Cell Lung Cancer Progressed after Platinum-Based Doublet Chemotherapy and Immunotherapy (SPACE Study)

Real-World Treatment Outcomes and Safety of Afatinib in Advanced Squamous Cell Lung Cancer Progressed after Platinum-Based Doublet Chemotherapy and Immunotherapy (SPACE Study)

The Efficacy and Safety of Afatinib in Non-Small Cell Lung Cancer Patients with Brain Metastasis: A Meta-Analysis.

The aim of this study is to evaluate the efficacy and safety of afatinib in the treatment of non-small cell lung cancer (NSCLC) patients with brain metastasis based on meta-analysis. Related literatures were searched in the following databases: EMbase, PubMed, China Knowledge Network (CNKI), Wanfang, Weipu, Google Scholar, the China Biomedical Literature Service System, and other databases. Clinical trials and observational studies that met the requirements were selected for meta-analysis using Revman 5.3. The hazard ratio (HR) was used as an indicator of the impact of afatinib. A total of 142 related literatures were acquired, but after screening, five literatures were selected for data extraction. The following indices were compared: the progression-free survival (PFS), overall survival (OS), and common adverse reactions (ARs) of grade 3 and above. A total of 448 patients with brain metastases were included and were divided into two groups: the control group (no afatinib treatment, with chemotherapy alone and the first-generation EGFR-TKIs) and the afatinib group. The results showed that afatinib could improve PFS (HR: 0.58, 95% CI: 0.39-0.85, P < 0.05) and ORR (OR = 2.86, 95% CI: 1.45-2.57, P < 0.05), but had no benefit on OS (HR: 1.13, 95% CI: 0.15-8.75, P > 0.05) and DCR (OR = 2.87, 95% CI: 0.97-8.48, P > 0.05). For the safety of afatinib, the incidence of grade-3-and-above ARs was low (HR: 0.01, 95% CI: 0.00-0.02, P < 0.05). Afatinib improves the survival of NSCLC patients with brain metastases and shows satisfactory safety.

CNS efficacy of afatinib as first-line treatment in advanced non-small cell lung cancer patients with EGFR mutations.

Afatinib is a potent, irreversible second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor which has demonstrated efficacy in advanced non-small cell lung cancer (NSCLC) patients harboring either common or uncommon EGFR mutations. However, data on its activity against brain metastases are limited. This study aimed to retrospectively evaluate the efficacy and safety of afatinib as first-line treatment for EGFR-mutant NSCLC patients with brain metastases. Treatment-naive advanced NSCLC patients harboring EGFR mutations and brain metastases treated with afatinib were retrospectively reviewed to assess the central nervous system (CNS) efficacy and also the systematic benefits. Totally 43 patients with measurable or non-measurable brain metastases were enrolled in the CNS full analysis (cFAS) set. Among them, 23 patients with measurable brain metastases were included in the CNS evaluable for response (cEFR) set. The CNS ORR was 48.8% (95% CI, 33.3 - 64.5%) in the cFAS set and 82.6% (95% CI, 61.2 - 95.0%) in the cEFR set, respectively. CNS mDoR was 8.9 months (95% CI, 4.7 - 13.1 months) and CNS mPFS was 12.7 months (95% CI, 6.9 - 18.5 months) in the cFAS set. In the subgroup analysis stratified by EGFR mutation types, CNS ORR of cEFR set in the common mutation cohort was 100% (95% CI, 75.3 - 100%) and 60% (95% CI, 26.2 - 87.8%) in the uncommon mutation cohort (p = 0.024); CNS ORR of cFAS set was 57.7% (95% CI, 36.9 - 76.6%) and 35.3% (95% CI, 14.2 - 61.7%), respectively (p = 0.151). CNS mPFS was 14.4 months in patients with common mutations and 6.1 months in patients with uncommon mutations (hazard ratio, 0.47; 95% CI, 0.22 - 1.00; p = 0.045). Patients with common mutations showed a significantly lower cumulative incidence of CNS failure than uncommon mutation cohort (p = 0.0026). Most of patients experienced grade 1/2 treatment-related adverse events. First-line afatinib demonstrated encouraging efficacy on brain metastases in NSCLC patients harboring either common or major uncommon EGFR mutations in a real-world setting, with manageable toxicities. Patients with common mutations showed better CNS outcomes than those with uncommon mutations.

Efficacy and Safety of Afatinib in the Treatment of Advanced Non-Small-Cell Lung Cancer with EGFR Mutations: A Meta-Analysis of Real-World Evidence

Introduction The purpose of this study was to explore the efficacy and safety of afatinib in advanced non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations based on real-world evidence. Materials and Methods Eligible real-world studies were identified from PubMed, Cochrane Library, and Embase. Cochrane guidelines were used to assess the quality of included studies. Cochran's Q test and I2 statistics were used for the heterogeneity analysis. Results Twenty-five studies were included in this meta-analysis; nine studies were included in the qualitative descriptive analysis. The summarized disease control rate (DCR) was 87.6% (81.5%, 92.7%), and the overall response rate (ORR) was 58.9% (48.8%, 68.7%). The pooled median progression-free survival (PFS) was 12.4 (10.3, 14.5) months, mean time to failure (TTF) was 15.4 (13.6, 17.2) months, and median overall survival (OS) was 31.6 (26.7, 36.5) months. The total incidences of adverse events (AEs) for skin rashes, diarrhea, paronychia, and mucositis were 71.4% (64.4%, 77.9%), 70.4% (60.1%, 79.8%), 52.1% (41.9, 62.3%), and 36.5% (29.5%, 43.8%), respectively. The incidences of severe adverse events (SAEs, Grade ≥3) for diarrhea, skin rashes, paronychia, and mucositis were 9.7% (6.8%, 13.1%), 5.8% (4.5%, 7.2%), 3.8% (2.0%, 6.2%), and 2.1% (1.0%, 3.6%), respectively. Differences in PFS and OS between the afatinib non-full-dose (<40 mg) and full-dose (>40 mg) groups were not significant (P > 0.05). However, the ORR in the full-dose group was 78.5% (66.7%, 88.4%), which was significantly higher than that in the non-full-dose group (67.8% [56.8%, 77.9%]). Conclusion The efficacy and safety of afatinib has been confirmed by real-world evidence in advanced NSCLC with EGFR mutation, consistent with randomized controlled trial results. In real-world setting, tolerability-guided dose adjustment might not affect the afatinib efficacy.

1230P Elderly patients treated with afatinib in clinical practice: Final results of the GIDEON study in EGFR mutated NSCLC in Germany

Despite the high prevalence of lung cancer among older adults, these are often under-represented in clinical trials, leading to uncertainties in the treatment of these patients in the clinical routine. With 43%, the German prospective non-interventional study (NIS) GIDEON enrolled a high proportion of patients aged ≥70 years, providing an opportunity to study the efficacy and safety of afatinib in this subcohort in routine clinical practice.

Efficacy and safety of afatinib in advanced non-small cell lung cancer with EGFR mutations: A real-world study based meta-analysis.

e21134 Background: This study aimed to explore the efficacy and safety of Afatinib in advanced EGFR mutation NSCLC patients based on real-world evidence. We also explore the effectiveness of tolerability-guided dose reduction on outcomes in the real-world setting. Methods: Eligible real-world studies from Pubmed, Emabse and Cochrane Library were included in this study. The quality assessment of the included studies was based on the guidelines of Cochrane. Then heterogeneity analysis was performed based on Cochran’s Q test and I2 statistics. Results: A total of twenty-five studies were enrolled for this meta-analysis. Meanwhile, nine studies were included in qualitative descriptive analysis. The efficacy of DCR and ORR were 87.6 % (81.5, 92.7) and 58.9 % (48.8, 68.7). The pooled medium PFS was 12.45 months (10.36, 14.54), medium TTF was 15.42 months (13.62, 17.22) and medium OS was 31.67 (26.78, 36.56) months. The efficacy of afatinib in first-line only group was superior than those in second-line. The total incidence of adverse events for diarrhea, mucositis and skin rashes were 70.4 (60.1, 79.8)%, 36.5 (29.5, 43.8)% and 71.4 (64.4, 77.9)%, respectively. Meanwhile, the serious adverse reactions (Grade ≥3) for diarrhea, mucositis and skin rashes were 9.7 (6.8, 13.1)%, 2.1 (1.0, 3.6)% and 5.8 (4.5, 7.2)%, respectively. Furthermore, the different for PFS and OS between afatinib non-full dose group ( &lt; 40mg) and full dose group ( &gt; 40mg) was not significant (P &lt; 0.05). however, the ORR in full dose group was 78.5 % (66.7, 88.4), which was significantly higher in the non-full dose group 67.8 % (56.8, 77.9). Conclusions: Afatinib was a safe and effective TKI for real-world EGFR-mutated NSCLC patients, which was consistent with the results of RCT. Tolerability-guided dose adjustment might affect the efficacy of afatinib in real-world setting.

Treatment outcomes and safety of afatinib in advanced squamous cell lung cancer progressed after platinum-based doublet chemotherapy and immunotherapy (SPACE study).

Afatinib is an ErbB family blocker approved for the treatment of epidermal growth factor receptor mutation‐positive nonsmall‐cell lung cancer. A pivotal trial demonstrated significant clinical benefits with manageable toxicity of afatinib as a second‐line treatment option in squamous cell carcinoma of the lung (SCC) which led to approval in >60 countries. However, these results were derived from a controlled study conducted in selected patients and are not necessarily representative of the real‐world use of this drug. In addition, data on afatinib use after immunotherapy in this clinical setting are lacking. The aim of this study is to evaluate the treatment outcomes and safety of afatinib as a second‐ or later‐line treatment for SCC and to identify potential predictive biomarkers. As a real‐world observational study, 130 eligible patients with advanced SCC, who progressed after platinum‐based chemo‐ and immunotherapy, will be enrolled. Treatment outcomes and safety data will be collected for both the retrospective and prospective cohorts, and molecular profiling using tissue and plasma will be performed for the prospective cohort. The primary endpoint is time to treatment failure, and the secondary endpoints are objective response rate, progression‐free survival, overall survival, and safety. Comparison of clinical outcomes with respect to the different programmed death‐ligand 1 expression and molecular characteristics will also be carried out. This study will provide additional evidence on the usefulness of afatinib as a subsequent treatment, as well as feasible molecular biomarkers to predict its efficacy in this clinical setting.

MO01.14 Real-World Effectiveness and Safety of Afatinib Following Immunotherapy (IO) in the Treatment of Metastatic, Squamous Cell/Mixed Histology Carcinoma of the Lung: A Multi-Site Retrospective Chart Review Trial in the US

MO01.14 Real-World Effectiveness and Safety of Afatinib Following Immunotherapy (IO) in the Treatment of Metastatic, Squamous Cell/Mixed Histology Carcinoma of the Lung: A Multi-Site Retrospective Chart Review Trial in the US

Afatinib in patients with advanced non-small cell lung cancer harboring HER2 mutations, previously treated with chemotherapy: A phase II trial

BackgroundDespite 1–4 % of NSCLC tumors harboring mutations in the HER2 gene, there are no approved HER2-pathway-targeted treatments available. We report an open-label, single-arm, multicenter phase II study investigating the efficacy and safety of afatinib in Asian patients with HER2-mutation positive (HER2m+) NSCLC. MethodsEligible patients for Part A had confirmed stage IIIb/IV HER2m + NSCLC, had failed one or two prior lines of chemotherapy, and were EGFR/HER2-inhibitor naïve. Patients received oral afatinib 40 mg/day in continuous 28-day cycles, until disease progression or intolerable adverse events (AEs). Patients qualified for Part B if they had > 12 weeks’ clinical benefit and Eastern Cooperative Oncology Group performance status ≤ 2. In Part B, patients were to receive afatinib at the last received dose, plus paclitaxel 80 mg/m2 weekly, until disease progression or intolerable AEs. The primary endpoint in Part A was objective response (OR); secondary endpoints included disease control (DC), progression-free survival (PFS), and overall survival (OS). Further exploratory endpoints were OR, DC, and PFS in Part B. ResultsEighteen patients received afatinib in Part A. No patient achieved an OR; 11 patients (61.1 %) achieved stable disease, and six patients (33.3 %) had progressive disease. DC rate was therefore 61.1 % (95 % confidence interval [CI]: 35.7, 82.7). A decrease in tumor size from baseline of > 0 to < 30 % was observed in eight patients. At the time of analysis, 16 patients (88.9 %) had progressed or died. Median PFS was 2.76 months (95 % CI: 1.87, 4.60) and median OS was 10.02 months (95 % CI: 8.47, 10.08). All patients experienced ≥ 1 AE, most commonly diarrhea (66.7 %) and rash (33.3 %). No patients met the inclusion criteria for Part B, and recruitment was slow; therefore, the study was terminated. ConclusionsThis study found no clinical benefit of afatinib for EGFR TKI-naïve patients with HER2m + NSCLC.

Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors represent the standard of care in patients with EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). The availability of several EGFR tyrosine kinase inhibitors approved for use in the first-line or later settings in NSCLC warrants an in-depth understanding of the pharmacological properties of, and clinical data supporting, these agents. The second-generation, irreversible ErbB-family blocker, afatinib, has been extensively studied in the context of EGFRm+ NSCLC. Results from the LUX-Lung 3 and 6 studies showed that afatinib was more active and better tolerated than chemotherapy in patients with tumors harboring EGFR mutations. Subanalysis of these trials, along with real-world data, indicates that afatinib is active in patients with certain uncommon EGFR mutations (S768I/G719X/L861Q) as well as common mutations (Del19/L858R), and in patients with active brain metastases. In LUX-Lung 7, a head-to-head phase IIb trial, afatinib improved progression-free survival and time-to-treatment failure versus the first-generation reversible EGFR tyrosine kinase inhibitor, gefitinib, albeit with a higher incidence of serious treatment-related adverse events. Nevertheless, afatinib is generally well tolerated, and adverse events are manageable through supportive care and a well-defined tolerability-guided dose adjustment scheme. In this review, we provide a detailed overview of the pharmacology, efficacy, and safety of afatinib, discuss treatment sequencing strategies following emergence of different resistance mechanisms, and shed light on the economic impact of afatinib. We also provide a comparison of afatinib with the available EGFR tyrosine kinase inhibitors and discuss its position within treatment strategies for patients with EGFRm+ NSCLC.

Efficacy and safety of afatinib for non-small-cell lung cancer: state-of-the-art and future perspectives

ABSTRACT Introduction Afatinib is a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, acting as an irreversible and multitarget blocker of ErbB family members. Afatinib is currently approved for advanced non-small-cell lung cancer (NSCLC) harboring common and uncommon sensitizing EGFR mutations and for squamous NSCLC patients progressing after first-line platinum-based chemotherapy. Areas covered This review summarizes the efficacy and safety profile of afatinib compared with chemotherapy and other EGFR TKIs, in order to evaluate its characteristics and potential role in the increasingly complex treatment landscape of EGFR-mutant lung cancer. Future perspectives and innovative drug combinations are also discussed. Expert opinion Afatinib has been demonstrated to improve efficacy and quality of life compared with chemotherapy with a managed toxicity profile. However, in recent years, the increasing availability of different treatment options for advanced EGFR-mutant NSCLC has made the current treatment scenario more complicated, with an increasing need of new and deeper scientific data. In this light, the identification and validation of potential clinicopathological and/or molecular predictors of benefit, as well as the clarification of resistance mechanisms, may help to clarify the most appropriate treatment strategies and sequences for EGFR-mutant patients.

The efficacy of afatinib in patients with HER2 mutant non-small cell lung cancer: a meta-analysis.

BackgroundErb-b2 receptor tyrosine kinase 2 (ErbB2/HER2) mutation has been found in approximately 2–4% of non-small cell lung cancer (NSCLC) patients and has been identified as one of carcinogenic mutations. Afatinib, a member of irreversible HER family inhibitor, has been investigated by a number of literatures, yet whose therapeutic efficiency remains uncertain in NSCLC with HER2 mutation. To elucidate the clinical efficacy and safety of afatinib in treating HER2 mutant NSCLC, we integrated and reanalyzed the data from current available studies.MethodsWe conducted a systematic literature search for published articles regarding afatinib treating HER2-mutant lung cancer. Eight studies met the inclusion and exclusion criteria. The main outcomes were the objective response rate (ORR) and disease control rate (DCR).ResultsNinety-five patients with HER2 mutations were identified from eight studies. The pooled ORR was 21% (95% CI: 11–34%) and the pooled DCR was 66% (95% CI: 57–76%). The patients harboring A775-G776ins YVMA mutation, the most common subtype of HER2 exon 20 mutation, derived greater clinical benefit. Most adverse events were grade 1–2, except a case of fatal acute renal injury, possibly related to afatinib.ConclusionsAfatinib monotherapy demonstrated frustrating anti-tumor activity with tolerable toxicity in HER2 mutant NSCLC. Based on current available data, we do not recommend the regular application of afatinib in NSCLC with HER2 mutations unless the response heterogeneity with specific genomic variant of HER2 mutation was further clarified.

63O - NRG1-fusion-driven solid tumours: A case series indicating the therapeutic potential of afatinib

63O - NRG1-fusion-driven solid tumours: A case series indicating the therapeutic potential of afatinib

P1.14-36 Phase II Trial of Afatinib in Elderly Patients Aged Over 75 Years with EGFR Mutation Positive Non-Small Cell Lung Cancer

Although reports on the use of gefitinib or erlotinib in elderly patients were occasionally found, those on afatinib were rare. According to the analysis of 54 Japanese patients in the LUX-Lung3 study, the dose reduction of afatinib from 40 mg/day was necessary for 76.0% of patients. However, the prolonged administration was possible after a dose reduction to 30 or 20 mg/day, and antitumor effects were maintained with the reduced dose. The efficacy and safety of afatinib at 30 mg/day in PS 0-1 patients who were aged 75 years with EGFR mutation positive chemotherapy-naïve non-small cell lung cancer were studied. The primary endpoint was the response rate (RR), and the planned number of registered cases was set at 35, with a threshold RR of 50%, an expected RR of 75%, α of 0.05, and β of 0.1. The secondary endpoints were progression-free survival (PFS), overall survival (OS), the incidence rate of adverse events (AEs), QOL survey (FACT-L), and trough plasma concentration of afatinib at steady state (PK, collected between the 8th to 15th day after the start of oral administration). The data of 35 patients were collected from May 2015 to August 2017. Patient background was, median age of 79 years (75-92), male/female: 8/27, PS 0/1: 8/27, adenocarcinoma/NSCLC: 30/5, IIIA/IIIB/IV/postoperative recurrence (TNM 7th edition): 2/2/22/9, and exon19del/exon21L858R/exon19del+exon21L858R: 15/19/1. The best overall efficacy was PR/SD/PD/NE: 28/4/1/2, and the RR was 80.0% (95% CI, 63.1-91.6). The median PFS and OS were 16.3 months (95% CI, 11.8-27.0) and not reached, respectively. The main AEs were rash 69%, diarrhea 60%, and paronychia 51%. While the initial afatinib dose was 30 mg, nine (26%) patients continued with 30 mg, 23 (66%) were reduced to 20 mg, and 3 (8%) discontinued due to AEs (2 ILD and 1 stomatitis). Treatment-related death was not observed. There were no significant change of QOL at baseline, after 4, 8, and 12 weeks. PK analyses showed steady state plasma concentration as 22.8 ng/mL which was comparable to reported plasma concentration of 40 mg afatinib in LUX-LUNG3 and 6 (24.3 ng/mL). No obvious PK differences were found according to dose reduction, adverse event, and response. Afatinib at 30 mg/day could be an effective treatment option for elderly patients, over 75 years of age, with good PS. (UMIN 0000177050)

Abstract 3998: Phase II trial of afatinib in elderly patients over 75 years of age withEGFR mutation positive non-small cell lung cancer

Abstract Background: Although reports on the use of gefitinib and erlotinib in elderly patients are occasionally found, reports on afatinib are rare. According to the analysis of 54 Japanese patients in the LUX-Lung3 study, an afatinib dose reduction from 40 mg/day, was necessary for 76.0%. However, the prolonged administration was possible after a dose reduction to 20 mg/day, and antitumor effects were maintained with the reduced dose. Material and methods: The efficacy and safety of afatinib at 30 mg/day in PS0-1 patients who were over 75 years of age with EGFR mutation positive non-small cell lung cancer were studied. The primary endpoint was the response rate (RR), and the planned number of registered cases was set at 35, with a threshold RR of 50%, an expected RR of 75%, α of 0.05, and β of 0.1. The secondary endpoints were progression-free survival (PFS), overall survival (OS), the incidence rate of adverse events (AE), QOL survey (FACT-L), and trough plasma concentration of afatinib at steady state (PK, collected between 8th to 15th day of oral administration). Results: The data of 35 patients were collected from May 2015 to August 2017. Patient background was, median age of 79 years (75-92), male/female: 8/27, PS 0/1: 8/27, adenocarcinoma/NSCLC: 30/5, IIIA/IIIB/IV/postoperative recurrence (TNM 7th edition): 2/2/22/9, and exon19del/exon21L858R/exon19del+exon21L858R: 15/19/1. The best overall efficacy was PR/SD/PD/NE: 28/4/1/2, and the RR was 80.0% (95% CI, 63.1-91.6). The median PFS and OS were 16.3 months (95% CI, 11.8-27.0) and not reached. The main AEs were rash 69%, diarrhea 60%, and paronychia 51%. While the initial afatinib dose was 30 mg, nine (26%) patients continued with 30 mg, 23 (66%) were reduced to 20 mg, and three (8%) discontinued due to AEs (2 ILD and 1 stomatitis). Treatment-related death was not observed. There is no significant change of QOL at baseline, after 4, 8, and 12 weeks. PK analyses showed steady state plasma concentration as 22.8 ng/mL which was comparable to reported plasma concentration of 40 mg afatinib in LUX-LUNG3 and 6 trials (24.3 ng/mL). No obvious PK differences were found according to dose reduction, adverse event, and response. Conclusions: Afatinib at 30 mg/day could be an effective treatment option for elderly patients, over 75 years of age, with good PS. (UMIN 0000177050) Citation Format: Kageaki Watanabe, Satoshi Oizumi, Hidenori Mizugaki, Yuka Fujita, Toshiyuki Harada, Taichi Takashina, Satoshi Igawa, Ryo Ko, Takamasa Hotta, Hiroyuki Minemura, Sho Saeki, Shigehiro Yagishita, Akinobu Hamada. Phase II trial of afatinib in elderly patients over 75 years of age withEGFR mutation positive non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3998.

Afatinib in the treatment of advanced NSCLC with EGFR mutation: An observational real-world study.

e20518 Background: Compared with the first generation of EGFR-TKI, Afatinib has a broader spectrum of activity and can better inhibit tumor growth. At present, the therapeutic effects of Afatinib varies on patients with different EGFR mutations and studies on the mechanism of acquired Afatinib resistance are limited. The aim of this study was to evaluate the efficacy and safety of Afatinib in the treatment of EGFR-mutation NSCLC who hadn’t received EGFR-TKI in the past. Methods: 88 patients with advanced NSCLC who had EGFR mutations were enrolled and given oral 40 mg Afatinib daily until disease progression or adverse events that could not be handled by dosage reduction. Efficacy and safety in different subgroups were analyzed. Results: Among 88 patients, the common mutation rate of EGFR was 79.5%, and the rare mutation rate was 20.5%. The objective remission rate (ORR) was 54.5%, and the disease control rate (DCR) was 92.0%. The median progression-free survival (PFS) was 14.2 months (95% CI 11.4-18.5), 27 patients (30.7%) continued Afatinib treatment after tumor progression, and the median time to progression of clinical symptoms (TTSP) was 16.3 months (95% CI 12.7-19.3). A total of 13 patients (14.8%) reduced Afatinib dosage of due to adverse events. Subgroup analysis showed that Afatinib had better effect on patients harboring common EGFR mutation but not exon 20 mutation, and was not affected by brain metastasis, dosage and lines of therapy. Among patients who progressed on Afatinib, 65.4% harbored T790M mutation. Most T790M patients received the third generation EGFR-TKI including AZD9291 and oxetinib treatment. The most common adverse reactions were diarrhea, rash, paronychia and stomatitis. Conclusions: Afatinib showed good efficacy and tolerance in advanced NSCLC patients with EGFR mutations. Continuation of Afatinib treatment after cancer progression could delay the progression of disease symptoms. The third generation EGFR-TKI could become a treatment option after Afatinib resistance. These findings reflected the real-world clinical practice of Afatinib.