**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**

**Akira Nakao 1,**†**, Osamu Hiranuma 2,**†**, Junji Uchino 3,\*,**†**, Chikara Sakaguchi 4, Tomoyuki Araya 5, Noriya Hiraoka 6, Tamotsu Ishizuka 7, Takayuki Takeda 8, Masayuki Kawasaki 9, Yasuhiro Goto 10, Hisao Imai 11, Noboru Hattori 12, Keita Nakatomi 13, Hidetaka Uramoto 14, Kiyoaki Uryu 15, Minoru Fukuda 16, Yasuki Uchida 17, Toshihide Yokoyama 18, Masaya Akai 19, Tadashi Mio 20, Seiji Nagashima 21, Yusuke Chihara 3, Nobuyo Tamiya 3, Yoshiko Kaneko 3, Takako Mouri 3, Tadaaki Yamada 3, Kenichi Yoshimura 22, Masaki Fujita <sup>1</sup> and Koichi Takayama <sup>3</sup>**



Received: 2 May 2020; Accepted: 3 June 2020; Published: 5 June 2020

**Abstract:** 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.

**Keywords:** non-small cell lung cancer; EGFR-TKI; T790M; osimertinib

#### **1. Introduction**

Treatment for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) typically involves EGFR tyrosine kinase inhibitors (EGFR-TKIs). Gefitinib and erlotinib are the first-generation EGFR-TKIs that provide significant survival benefits compared with platinum-based chemotherapy in clinical trials [1–6]. Afatinib and dacomitinib are the second-generation EGFR-TKIs that provide significantly longer progression-free survival (PFS) compared to that of platinum-based chemotherapy and first-generation EGFR-TKIs, although the second-generation EGFR-TKIs did not significantly improve overall survival (OS) [7–11]. In addition, these drugs are associated with more severe toxicity profiles, such as skin disorders, relative to the first-generation EGFR-TKIs.

Various mechanisms are responsible for resistance to the first-generation and second-generation EGFR-TKIs, with more than one-half of the cases involving the EGFR exon 20 T790M mutation [12]. Osimertinib is a third-generation EGFR-TKI that was developed to address this issue [12], and he AURA3 study revealed that it provided significantly longer PFS compared to platinum-based chemotherapy among patients with T790M-mutated lung cancer [13]. Moreover, the FLAURA trial conducted on first-line treatment revealed that osimertinib administered as an initial treatment for EGFR-mutated cases significantly prolonged PFS and OS compared with the first-generation EGFR-TKIs, with a median OS of >3 years [14,15]. Furthermore, osimertinib is expected to have good central nervous system translocation and a limited inhibition of the wild-type EGFR, which may make it less toxic, and therefore, the first choice for EGFR-mutated NSCLC [16–18]. Nevertheless, additional evidence is needed to support this application based on various patient populations. We have performed a phase II study to investigate the efficacy and safety of osimertinib in elderly Japanese patients (≥75 years old)

with NSCLC containing the T790M mutation who progressed or experienced a relapse while receiving the first- and second- generations of EGFR-TKI treatment. In our previous report, the response rate was the primary endpoint, and the disease control rate was the secondary endpoint [19]. This report presents the results from our final analyses of PFS, OS, and safety events, which were the additional secondary endpoints in that trial.
