Rationale and design of a phase II trial of osimertinib as first-line treatment for elderly patients with epidermal growth factor receptor mutation-positive advanced non-small cell lung cancer (SPIRAL-0 study)
Study Protocol

Rationale and design of a phase II trial of osimertinib as first-line treatment for elderly patients with epidermal growth factor receptor mutation-positive advanced non-small cell lung cancer (SPIRAL-0 study)

Yusuke Chihara1, Tadaaki Yamada1, Junji Uchino1, Nobuyo Tamiya1, Yoshiko Kaneko1, Junji Kishimoto2, Koichi Takayama1

1Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan; 2Department of Research and Development of Next Generation Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan

Contributions: (I) Conception and design: J Uchino, Y Chihara; (II) Administrative support: None; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: None; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Dr. Junji Uchino. Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, kawaramachi-dori, Kamigyo-ku, Kyoto, Kyoto 602-0857, Japan. Email: uchino@koto.kpu-m.ac.jp.

Background: Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has a potent inhibitory effect against both T790M resistance mutations and EGFR-TKI sensitizing in EGFR, with a relatively low affinity for wild-type EGFR. Osimertinib has been approved as a therapeutic agent for patients with T790M-mutation positive advanced non-small cell lung cancer. As a first-line treatment, osimertinib may significantly prolong progression-free survival (PFS) in comparison with the earlier generation first-line standard treatment. Osimertinib has been reported to provide survival benefits to EGFR mutation-positive patients. However, the efficacy and safety of osimertinib as a first-line treatment for patients aged ≥75 years remains to be established.

Methods: In this single arm, prospective, open-label, multicenter, phase II trial, 40 subjects aged ≥75 years with EGFR mutation-positive advanced non-small-cell-lung cancer will be recruited. Patients will be treated with osimertinib 80 mg/day until disease progresses or until the patient meets a discontinuation criterion. The primary endpoint is 1-year PFS. Secondary endpoints are overall response rate, PFS, overall survival, and safety. Thirty-seven patients are required for the present study, as calculated based on normal approximation with a one-sided α level of 5% and 80% power, assuming that the expected 1-year PFS is 70% and the 1-year PFS threshold is 50%.

Discussion: We are conducting an intervention study to investigate the safety and efficacy of osimertinib as a first-line treatment agent for EGFR mutation-positive NSCLC in patients aged ≥75 years.

Trial registration number: jRCTs071180007

Keywords: Osimertinib; elderly patients; progression-free survival (PFS); phase II study


Submitted Sep 15, 2019. Accepted for publication Oct 31, 2019.

doi: 10.21037/tlcr.2019.11.19


Introduction

Due to population ageing, the incidence of lung cancer is increasing. The highest incidence rates of lung cancer in the US have been observed in the 80–89-year age group in men and 80–84-year age group in women (1). Moreover, 14% of lung cancer patients in the US are aged ≥80 years (2). In Japan, 45,000 individuals aged ≥75 years were estimated to have died of lung cancer in 2016 (3). Thus, the development of a treatment strategy for elderly patients with NSCLC is an important issue.

Gefitinib, erlotinib are first-generation, and afatinib is a second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), which have been approved for the treatment of EGFR mutation-positive advanced NSCLC. A meta-analysis of randomized control trials (RCTs) showed that EGFR-TKIs demonstrated a significantly longer median progression-free survival (PFS) than chemotherapy (11 versus 5.6 months) (4). The third-generation EGFR-TKI, osimertinib, has been shown to have a potent inhibitory effect against both sensitizing mutations and resistance by T790M mutations in EGFR, with a relatively low affinity for wild-type EGFR. Osimertinib has been approved for patients with T790M mutation. As a first-line treatment, osimertinib significantly prolonged PFS in comparison with the standard EGFR-TKIs in the FLAURA study [18.9 versus 10.2 months; hazard ratio (HR): 0.46] (5).

A phase II trial demonstrated that the efficacy of gefitinib is similar in younger (<75 years) and elderly (≥75 years) patients with EGFR-positive patients (6). Osimertinib is well-tolerated compared with first-generation EGFR-TKIs (7). The major adverse events observed in the FLAURA study were diarrhea (58% at all Grades, 2% at ≥ Grade 3) and acneiform rash (58% at all Grades, 1% at ≥ Grade 3) in the osimertinib group, and, in a similar manner, diarrhea (57% at all Grades, 2% at ≥ Grade 3) and acneiform rash (78% at all Grades, 7% at ≥ Grade 3) in the first-generation EGFR-TKIs group. The incidence of adverse events of ≥ Grade 3 was reported to be lower in the osimertinib group (33.7%) compared with the first-generation EGFR-TKIs group (44.8%) (5).

Based on these findings, osimertinib is considered to potentially provide benefits to EGFR mutation-positive patients. In Japan, lung cancer clinical practice guidelines define patients aged ≥75 years as ‘elderly’; furthermore, based on the results of some clinical studies in Japan, gefitinib and erlotinib are recommended in patients aged ≥75 years (6,8). Although a subset analysis of the data of patients aged ≥65 years was performed in the FLAURA trial, the data obtained for patients aged ≥75 years is highlighted in the elderly patients. In this study, we aim to investigate the efficacy and safety of osimertinib as a first-line treatment for EGFR mutation-positive NSCLC in patients aged ≥75 years.


Methods

Study design

This is a single arm, prospective, open-label, multicenter, phase II trial. The present study begun in November 2018 and is currently in progress.

End points

The primary endpoint is one-year progression-free survival (PFS). Secondary endpoints are response rate (RR), progression-free survival (PFS), overall survival (OS), and safety.

Eligibility criteria

The inclusion and exclusion criteria are shown in Table 1.

Table 1
Table 1 Eligibility criteria
Full table

ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; AST, aspartate amino transferase; ALT, alanine aminotransferase; SpO2, peripheral capillary oxygen saturation.

Dose and treatment regimen

Osimertinib will be administered at a dose of 80 mg orally once daily, at the same time, with or without food. If a scheduled dose is missed, it will be recommended to take osimertinib as soon as possible; however, if it is less than 12 hours until the next scheduled dose, the missed dose of osimertinib will be omitted. Patients will continue to receive oral osimertinib until disease progression or until a discontinuation criterion (Table 2) is met. A schema of the study is shown in Figure 1.

Table 2
Table 2 Discontinuation criteria for treatment protocol
Full table
Figure 1 Study profile. EGFR, epidermal growth factor receptor; PD, progressive disease.

Rationale for the setting of the number of enrolled subjects

In the FLAURA study, 1-year PFS for EGFR mutation-positive patients treated with osimertinib was approximately 70% and the median PFS was 18.9 months (5). In addition, the 1-year PFS for EGFR mutation-positive elderly patients who received gefitinib in Japan was reported to be approximately 50% and the median PFS to be 12.1 months (6). Therefore, 37 patients are required for the present study, when calculated based on normal approximation with a one-sided α level of 5% and 80% power, assuming that the expected 1-year PFS is 70% and the 1-year PFS threshold is 50%. Thus, to account for possible dropouts, the study sample size has been set to 40.

Population to be analyzed

Patients enrolled in this study, excluding those with serious protocol violation, will be included in the full analysis set (FAS). The per-protocol set (PPS) will include the remaining subjects from the FAS, after excluding those with violation of inclusion/exclusion criteria or violation for prohibited concomitant drugs/therapies. The safety analysis set (SAF) will include patients who received ≥1 dose of osimertinib.

Statistical analysis

The 1-year PFS will be estimated by the Kaplan-Meier method, and the confidence interval (CI) calculated using the Greenwood method. If the lower limit of the estimated 90% CI exceeds the threshold of 50%, it will be considered statistically significant. As for PFS and OS, the Kaplan-Meier method will be used to estimate the survival curve, median, and annual rate. The Brookmeyer and Crowley method will be used to estimate the median CI, and Greenwood’s method will be used to estimate the standard error of the annual rate. The RR and 95% CI (two-sided) will be estimated via the Wilson method. The severity and incidence of each adverse event will be recorded.


Discussion

Osimertinib is expected to provide well-tolerated treatment for elderly EGFR mutation-positive patients with fewer serious adverse drug reactions and longer survival benefit compared with first and second generation EGFR-TKIs. To our knowledge, this study is the first prospective trial to investigate the efficacy and safety of osimertinib as a first-line treatment for EGFR mutation-positive lung cancer in patients aged ≥75 years.


Acknowledgments

We would like to thank Editage (www.editage.jp) for English language editing.

Funding: This work was supported by “Externally sponsored scientific research” in AstraZeneca (ESR-17-13222).


Footnote

Conflicts of Interest: J Uchino reports grants from Eli Lilly Japan K.K. that are outside of the submitted work. T Yamada reports grants from Nippon Boehringer Ingelheim and Ono Pharmaceutical Company that are outside of the submitted work. K Takayama reports grants from Chugai-Roche and Ono Pharmaceutical Company, personal fees from AstraZeneca K.K., Chugai-Roche, MSD-Merck, Eli Lilly, Boehringer-Ingelheim, and Daiichi-Sankyo that are outside of the submitted work. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study protocol and informed consent documents were approved by the ethical committees of the participating institutions, Clinical Research Network Fukuoka Certified Review Board (No. 18-C06), and informed consent was obtained from all patients.


References

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Cite this article as: Chihara Y, Yamada T, Uchino J, Tamiya N, Kaneko Y, Kishimoto J, Takayama K. Rationale and design of a phase II trial of osimertinib as first-line treatment for elderly patients with epidermal growth factor receptor mutation-positive advanced non-small cell lung cancer (SPIRAL-0 study). Transl Lung Cancer Res 2019;8(6):1086-1090. doi: 10.21037/tlcr.2019.11.19