Osimertinib versus standard-of-care EGFR-TKI as first-line treatment for EGFRm advanced NSCLC: FLAURA Japanese subset

Ohe, Yuichiro; Imamura, Fumio; Nogami, Naoyuki; Okamoto, Isamu; Kurata, Takeshi; Kato, Terufumi; Sugawara, Shunichi; Ramalingam, Suresh S.; Uchida, Hirohiko; Hodge, Rachel; Vowler, Sarah L.; Walding, Andrew; Nakagawa, Kazuhiko

doi:10.1093/jjco/hyy179

Cited by 133 publications

(120 citation statements)

References 22 publications

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“…There is a significant difference in the composition ratio of patients with multiple CNS metastases in each group, possibly resulting from variability in the response to the EGFR-TKI in diverse reports [19,29]. In the present study, the survival benefits of OSI over AFA were consistent with prospective randomized trials [22,25,30,31]in which the composition ratio of multiple CNS metastases was assessed in subgroup analyses. Consequently, the betweengroup differences in survival benefits might be attributed to drug mechanistic differences [22,32].…”

Section: Discussionsupporting

confidence: 82%

Osimertinib versus afatinib in patients with T790M-positive, non-small-cell lung cancer and multiple central nervous system metastases after failure of initial EGFR-TKI treatment

Chen

Hua

et al. 2019

Preprint

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Background The purpose of this study was to compare the efficacy of osimertinib (OSI) versus afatinib (AFA) in patients with T790M-positive, non-small-cell lung cancer (NSCLC) and multiple central nervous system (CNS) metastases after failure of initial epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. Methods The cohort consisting of 124 patients (OSI: n=60, median age=64.24 years [range, 51.91 to 76.57]; AFA: n=64, median age=64.13 years [range, 50.41 to 77.85]) with T790M-positive NSCLC and multiple CNS metastases after failure of initial EGFR-TKI treatment were consecutively identified at the Cancer Medical Center, Sun Yat-Sen University between March 2017 and July 2017; patients underwent either oral OSI (80 mg/day) or oral AFA (40 mg/day) until the occurrence of disease progression, intolerable adverse events (AEs), or death. The co-primary endpoints were overall survival (OS) and progression-free survival (PFS). Results After a median follow-up of 24 months (range, 6 to 26), a significant improvement in OS was observed in the OSI group compared with the AFA group (hazard ratio [HR] 0.30, 95% confidence interval [CI] 0.23 - 0.41; p = 0.009; median, 13.0 versus 9.2 months). The median duration of PFS was significantly longer with OSI than with AFA (HR 0.25, 95% CI 0.11 - 0.34; p = 0.001; median, 5.4 versus 4.3 months). The proportion of grade 3 or higher AEs was lower with OSI (22.4%) than with AFA (39.4%). Conclusion In patients with T790M-positive NSCLC and multiple CNS metastases after failure of initial EGFR-TKI treatment, OSI was associated with significantly improved survival benefit compared with AFA, and OSI exhibited a controllable tolerability profile.

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Section: Discussionsupporting

confidence: 82%

Osimertinib versus afatinib in patients with T790M-positive, non-small-cell lung cancer and multiple central nervous system metastases after failure of initial EGFR-TKI treatment

Chen

Hua

et al. 2019

Preprint

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“…In contrast, third-generation EGFR-TKIs have been designed to inhibit mutated EGFR and are rarely associated with dermatologic AEs. Although ethnic differences in skin toxicities have not been observed in phase III trials of first-, second-and third-generation EGFR-TKIs, Japanese patients tend to develop a rash more frequently compared to their global, European and non-Japanese Asian counterparts [5,13,14]. However, only a few SJS/TEN cases associated with EGFR-TKIs have been reported [7][8][9][10][11].…”

Section: Discussionmentioning

confidence: 99%

Osimertinib-Associated Toxic Epidermal Necrolysis in a Lung Cancer Patient Harboring an EGFR Mutation—A Case Report and a Review of the Literature

et al. 2020

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Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are life-threatening dermatologic adverse events in the same category, caused by a delayed-type drug hypersensitivity reaction. Although skin toxicity is common during treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), osimertinib-associated TEN is quite rare—thus far, only one report has been published from China. We report a case of an 80-year-old Japanese woman with lung adenocarcinoma harboring an EGFR-sensitizing mutation who was treated with osimertinib as the first-line treatment. Forty-six days after osimertinib induction, diffuse erythematous rash rapidly spread over the patient’s trunk along with vesicles and purpuric macules; furthermore, she developed targetoid erythema on the face. Despite osimertinib discontinuation and corticosteroid treatment, diffuse erythema with Nikolsky’s sign, general epidermal detachment, erosion and loose blisters developed over her entire body including the face. Based on her symptoms, TEN was diagnosed and thus, intravenous immunoglobulin was immediately administered for 4 days. The treatment ameliorated TEN-associated skin toxicity and caused epithelialization. Reports on osimertinib-associated SJS/TEN are scarce and only one report each on SJS and TEN from China is available. This is the first report of osimertinib-associated TEN from Japan. Cases of EGFR-TKI-associated SJS/TEN have been reported predominantly from Asian countries, suggesting ethnicity and genetic linkage play a role in the underlying mechanism.

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“…In addition, the Japanese subset of the FLAURA study population had a higher frequency of pulmonary disorders (all grades: 12%, Grade 3 or higher: 2%); it should be noted that this is a first-line trial. Other reports have also suggested that osimertinib may be associated with an increased incidence of pulmonary disorders relative to other EGFR-TKIs [32]. Nevertheless, the odds ratio for pulmonary disorders after gefitinib treatment was 1.92-fold higher among Japanese patients who were ≥55 years old, which suggests that careful follow-up is required for patients who are ≥75 years old [35].…”

Section: Discussionmentioning

confidence: 94%

“…Osimertinib has also been reported to be more frequently myelosuppressed than in other EGFR-TKI in a pivotal study [13,14]. In addition, myelosuppression was reported to be stronger in the analysis of the Japanese population [32]. Although the obvious mechanism was unclear, it was suggested that racial differences might be involved.…”

Section: Discussionmentioning

confidence: 99%

Final Results from a Phase II Trial of Osimertinib for Elderly Patients with Epidermal Growth Factor Receptor t790m-Positive Non-Small Cell Lung Cancer That Progressed during Previous Treatment

Nakao

Hiranuma

Uchino

et al. 2020

JCM

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Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used for treating EGFR-mutated lung cancer, and osimertinib is effective in cases that acquired T790M mutations after treatment with the first- and second-generation EGFR-TKIs. However, no study has evaluated its safety and efficacy in older patients. This phase II trial (jRCTs071180002) evaluated osimertinib in T790M mutation-positive Japanese patients who were ≥75 years old and had experienced relapse or progression after previous EGFR-TKI treatment. Our previous report that enrolled 36 patients showed the overall response rate (58.3%) and disease control rate (97.2%), while this report describes the results for the progression-free survival (PFS), overall survival (OS), and safety analyses. The median PFS was 11.9 months (95% confidence interval (CI): 7.9–17.5), and the median OS was 22.0 months (95% CI: 16.0 months–not reached). The most frequent adverse events were anemia/hypoalbuminemia (27 patients, 75.0%), thrombocytopenia (21 patients, 58.3%), and paronychia/anorexia/diarrhea/neutropenia (15 patients, 41.7%). Pneumonitis was observed in four patients (11.1%), including two patients (5.6%) with Grade 3–4 pneumonitis. These results suggest that osimertinib was relatively safe and effective for non-small cell lung cancer that acquired T790M mutations after previous EGFR-TKI treatment, even among patients who were ≥75 years old.

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Osimertinib versus standard-of-care EGFR-TKI as first-line treatment for EGFRm advanced NSCLC: FLAURA Japanese subset

Abstract: In the FLAURA trial Japanese subset, osimertinib significantly improved median PFS versus standard-of-care (gefitinib) in patients with previously untreated EGFR (exon 19 deletion or L858R) mutation-positive advanced or metastatic NSCLC.

Cited by 133 publications

References 22 publications

Osimertinib versus afatinib in patients with T790M-positive, non-small-cell lung cancer and multiple central nervous system metastases after failure of initial EGFR-TKI treatment

Osimertinib versus afatinib in patients with T790M-positive, non-small-cell lung cancer and multiple central nervous system metastases after failure of initial EGFR-TKI treatment

Osimertinib-Associated Toxic Epidermal Necrolysis in a Lung Cancer Patient Harboring an EGFR Mutation—A Case Report and a Review of the Literature

Final Results from a Phase II Trial of Osimertinib for Elderly Patients with Epidermal Growth Factor Receptor t790m-Positive Non-Small Cell Lung Cancer That Progressed during Previous Treatment

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