Observational study of the efficacy and safety of first-line osimertinib and later treatments for uncommon epidermal growth factor receptor-activating mutation-positive advanced non-small cell lung cancer.

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is a first-line therapy for advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR mutations, including both sensitizing and T790M resistance mutations. Its real-world efficacy against uncommon EGFR mutations remains under-researched. The REIWA study, a multicentric, prospective, observational study conducted in Japan from September 2018 to August 2020, enrolled patients with advanced or recurrent EGFR mutation-positive NSCLC receiving osimertinib. Data on clinical outcomes, safety, disease progression, and subsequent treatments were collected for patients with uncommon EGFR mutations. Of 583 patients receiving osimertinib, 39 (6.7%) had an uncommon EGFR mutation. The present study included 32 of these patients after excluding seven patients with an exon 20 insertion mutation. The overall objective response rate was 53.1% [95% confidence interval (CI): 36.4-69.1], and the disease control rate was 78.1% (95% CI: 61.0-89.3). The median progression-free survival was 9.4 months (95% CI: 5.0-20.0), and the median overall survival (OS) was 21.8 (95% CI: 14.4-NA) months. Notably, patients with an exon21 L861Q mutation had a significantly longer OS than those with an exon18 G719X mutation, the respective values being 37.8 and 9.7 months (hazard ratio: 0.29; 95% CI: 0.10-0.85; P = 0.02). The rate of grade 3 or worse adverse events was 10.3%. Seven out of 32 (21.9%) patients showed progression involving only the central nervous system. Osimertinib demonstrated efficacy and tolerability in the clinical setting in patients with uncommon EGFR mutation-positive NSCLC.

Hirata T ，Watanabe K ，Hosomi Y ，Yoh K ，Usui K ，Kishi K ，Naka G ，Tamano S ，Uemura K ，Kunitoh H ... -  《-》

Clinical outcomes of patients with EGFR-mutated NSCLC developing interstitial lung disease during first-line osimertinib therapy: a sub-analysis of the Reiwa study.

Osimertinib-induced interstitial lung disease in untreated EGFR-mutated, advanced non-small cell lung cancer is being reported at a higher rate in Japan than elsewhere. However, data on the interstitial lung disease incidence during first-line osimertinib therapy and the course of lung cancer treatments administered after interstitial lung disease onset in the real-world setting are scarce. The present study reviewed the data from the Reiwa study, a multicentric, observational study examining the efficacy and safety of first-line osimertinib therapy in the clinical setting. Patients with EGFR-mutated non-small cell lung cancer who began osimertinib therapy between September 2018 and August 2020 were enrolled and followed until August 2022. Among 583 patients receiving first-line osimertinib therapy, 75 (12.8%) had interstitial lung disease development, and 18 (3.0%) had at least grade 3 interstitial lung disease. Fifty-nine patients (78%) received some form of treatment following interstitial lung disease onset. An epidermal growth factor receptor-tyrosine kinase inhibitor rechallenge was performed in 31 patients (41%), with 18 (24%) receiving osimertinib again. Interstitial lung disease recurred in five (28%) of these 18 patients, none of 13 patients receiving another type of tyrosine kinase inhibitor, and seven (25%) of 28 patients receiving chemotherapy and/or immune checkpoint inhibitor therapy. The median overall survival after the initial osimertinib therapy was 38.4 months and 12.2 months for patients with interstitial lung disease grade 1-2 and grade 3-4, respectively (hazard ratio: 0.37; 95% confidence interval: 0.20-0.70; P = 0.002). Patients with interstitial lung disease grade 3-4 had poorer survival during the first-line osimertinib therapy. A substantial risk of interstitial lung disease recurrence was associated with post-osimertinib therapy. Trial registration code: UMIN000038683.

Kobayashi T ，Watanabe K ，Hosomi Y ，Yoh K ，Usui K ，Kishi K ，Naka G ，Tamano S ，Uemura K ，Kunitoh H ... -  《-》

First-Line Osimertinib for Previously Untreated Patients With NSCLC and Uncommon EGFR Mutations: The UNICORN Phase 2 Nonrandomized Clinical Trial.

Okuma Y ，Kubota K ，Shimokawa M ，Hashimoto K ，Kawashima Y ，Sakamoto T ，Wakui H ，Murakami S ，Okishio K ，Hayashihara K ，Ohe Y ，Tokyo Cooperative Oncology Group (TCOG) ... -  《-》

Phase II Efficacy and Safety of 80 mg Osimertinib in Patients With Leptomeningeal Metastases Associated With Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer (BLOSSOM).

Park S ，Baldry R ，Jung HA ，Sun JM ，Lee SH ，Ahn JS ，Kim YJ ，Lee Y ，Kim DW ，Kim SW ，Lee KH ，Lee WJ ，Choi JW ，Chong K ，Lee JI ，Gwon SH ，Son NH ，Ahn MJ ... -  《-》

Efficacy and Safety of Chemotherapy or EGFR-TKIs as First-Line Therapy in NSCLC Patients Harboring Non-Ex 20 Ins Uncommon EGFR Mutations: A Retrospective Study in China.

Uncommon EGFR mutations are a kind of heterogeneous group of mutations with various responses to EGFR-TKIs and are often excluded from most prospective clinical trials. In this real-world retrospective study, we retrospectively compared the efficacy and safety of chemotherapy or various generations of EGFR-TKIs as first-line therapy in NSCLC Chinese patients harboring non-ex 20 ins uncommon EGFR mutations. We enrolled 139 NSCLC patients with non-ex 20 ins uncommon EGFR mutations in this study retrospectively. Patients' clinical characteristics and the efficacy and safety of different first-line therapies were analyzed and compared. Our data reviewed that for first-line therapy, NSCLC patients harboring non-ex 20 ins uncommon EGFR mutations benefited more from EGFR-TKIs compared with chemotherapy. Afatinib performed with great efficacy for the majority of non-ex 20 ins uncommon EGFR mutations (N = 43, ORR = 41.86%, mPFS = 13.5 months, mOS = 20.8 months), especially in L861Q mutation (mPFS = 18.4 months). Osimertinib also demonstrated efficacy in patients harboring non-ex 20 ins uncommon EGFR mutations (N = 36, ORR = 27.78%, mPFS = 10.0 months, mOS = 21.0 months), especially in those without L861Q and G719X mutations (mPFS = 12.1 months). When treated with afatinib, patients harboring non-ex 20 ins uncommon EGFR mutations should pay attention to the management of safety, especially for gastrointestinal-related AE and rash, while osimertinib was safer. Taking into account both efficacy and safety, afatinib and osimertinib are better choices than chemotherapy and first-generation EGFR-TKIs for NSCLC patients with non-ex 20 ins uncommon EGFR mutations. L861Q showed a trend toward a better response to afatinib, while in those without L861Q and G719X mutations, osimertinib might be a better choice. Safety also should be a concern when choosing EGFR-TKI for treatment, patients should pay attention to the management of safety when using afatinib while osimertinib is safer.

Liao C ，Bai L ，He T ，Liang Q ，Hu D ，Lei S ，He Y ，Wang Y ... -  《Cancer Medicine》