A multicenter, prospective phase II trial of first-line osimertinib treatment for patients with poor performance status and EGFR mutation–positive non-small cell lung cancer (OPEN/TORG2040).
Authors: Mamesaya Nobuaki , Fukui Tomoya , Takahashi Toshiaki , Kishi Kazuma , Yoshizawa Takahiro , Tokito Takaaki , Azuma Koichi , Morikawa Kei , Okuma Yusuke , Yoshioka Hiroshige , Hosokawa Shinobu , Kasai Takashi , Masubuchi Ken , Nakamichi Shinji , Aga Masaharu , Sasaki Jiichiro , Igawa Satoshi , Kada Akiko , Naoki Katsuhiko , Okamoto Hiroaki 
Published: June 2024

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Background: EGFR tyrosine kinase inhibitors (TKIs) are the standard first-line treatment for patients with advanced EGFR mutation-positive non-small cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR-TKI, is the preferred first-line treatment for EGFR mutation-positive NSCLC patients with good performance status (PS) because of its survival benefit. However, NSCLC patients with poor PS have historically been excluded from clinical trials due to their poor prognosis and first-generation EGFR-TKIs such as gefitinib are limited treatment options for these EGFR mutation-positive patients. Although clinical data on treatment with osimertinib have accumulated, there is limited evidence regarding efficacy and safety in EGFR mutation-positive patients with poor PS. Therefore, we conducted a multicenter, prospective phase II trial to evaluate the efficacy and safety of osimertinib treatment in EGFR mutation-positive NSCLC patients with poor PS (OPEN/TORG2040). Methods: Patients withpreviously untreated advanced NSCLC harboring EGFR-sensitive mutations consisting of deletion of exon 19 (DEL), L858R, G719X, and L861Q and ECOG PS 2–4 were enrolled. Eligible patients were treated with osimertinib until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). With a threshold value of 45%, an expected value of 70% for ORR, a one-sided significance level of 5%, a statistical power of 80% and ineligible patients, the sample size was set at 30. The follow-up period was 18 months from the last enrollment, and progression-free survival (PFS), overall survival (OS), PS improvement rate, and safety were also evaluated (jRCTs041200100). Results: Thirty patients with poor PS (22 with PS 2, 6 with PS 3, and 2 with PS 4) were enrolled between February 2021 and February 2022, with a median age of 75 years (range 41–92), 9 men and 21 women, all with adenocarcinoma, 12 with DEL and 18 with L858R, and 18 with central nervous system metastases. The ORR was 63.3% (n = 19/30, 90% confidence interval [CI], 46.7–77.9; one-sided exact p = .033), meeting the primary endpoint. The PS improvement rate was 63.3% (n = 19/30) and PS improved (Wilcoxon signed-rank test p < .001). Median PFS was 8.0 months (95% CI, 5.6–20.4) and OS was 25.4 months (95% CI, 15.6–not available). Serious adverse events leading to discontinuation were observed in 8 (27%) patients: 6 (20%) patients with any grade of interstitial lung disease (ILD) (2 with grade 3 and 1 with grade 5), 1 (3%) each with grade 4 AST/ALT increased, grade 3 diarrhea, grade 3 nausea, and grade 3 rash. Conclusions: Osimertinib treatment is effective in patients with EGFR mutation-positive NSCLC, even those with poor PS and limited treatment options, but the risk of adverse events must be adequately managed, especially ILD. Clinical trial information: jRCTs041200100 .