Elsevier

Clinical Lung Cancer

Volume 22, Issue 2, March 2021, Pages 147-151
Clinical Lung Cancer

Current Trial Report
A Phase II Study of Osimertinib Combined With Platinum Plus Pemetrexed in Patients With EGFR-Mutated Advanced Non–Small-cell Lung Cancer: The OPAL Study (NEJ032C/LOGIK1801)

https://doi.org/10.1016/j.cllc.2020.09.023Get rights and content

Abstract

Background

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is now a standard treatment of previously untreated EGFR-mutated advanced non–small-cell lung cancer (NSCLC). However, disease progression occurs within 19 months of treatment. In the NEJ009 study, gefitinib plus carboplatin plus pemetrexed demonstrated significantly better progression-free and overall survival compared with gefitinib monotherapy. Furthermore, the Lung Oncology Group in Kyushu and North East Japan Study Group, major clinical trial groups in Japan, conducted a randomized phase II study to evaluate the efficacy and safety of second-line osimertinib plus carboplatin plus pemetrexed versus osimertinib monotherapy for patients with disease progression during first-line EGFR tyrosine kinase inhibitor therapy and the EGFR T790M resistance mutation (TAKUMI trial; trial registration no., jRCTs071180062). In the first treatment course for the initial 24 patients, no safety issues were reported in the combination arm. Thus, we have planned this phase II study to evaluate the safety and preliminary efficacy of osimertinib plus cisplatin/carboplatin plus pemetrexed therapy for patients with previously untreated EGFR-mutated NSCLC.

Patients and Methods

A total of 66 patients will be enrolled, because this sample size will be adequate for assessing treatment safety and efficacy. The co-primary endpoints include safety and the objective response rate, and the secondary endpoints include the complete response rate, disease control rate, and progression-free survival.

Conclusions

This is the first study to explore the efficacy and safety of osimertinib combined with platinum-based chemotherapy in previously untreated NSCLC patients with EGFR-sensitizing mutations. Our findings could provide valuable information for phase III studies such as FLAURA2 and for developing treatment strategies for EGFR-mutated NSCLC.

Introduction

The recent development of non–small-cell lung cancer (NSCLC) therapies that specifically target driver mutations such as epidermal growth factor receptor (EGFR)-sensitizing mutations has changed the standard of care and prognosis of patients with advanced NSCLC. The prevalence of EGFR-sensitizing mutations in NSCLC patients is ∼30% to 40% in East Asia and 10% to 15% in Western countries.1

First- and second-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, and afatinib have significantly improved the treatment of NSCLC. In several randomized studies, first-line treatment with EGFR-TKIs significantly prolonged progression-free survival (PFS) compared with platinum-based chemotherapy for NSCLC patients with EGFR-sensitizing mutations.2, 3, 4, 5, 6, 7 These EGFR-TKIs are now the standard first-line treatments for these patients.

Osimertinib is a third-generation, central nervous system–active EGFR-TKI that potently and selectively inhibits both EGFR-sensitizing mutations and T790M resistance mutations. Preclinical and early clinical data have suggested that osimertinib might also be an effective first-line treatment of NSCLC patients with EGFR-sensitizing mutations.8,9 Recently, in the phase III FLAURA (AZD9291 vs. gefitinib or erlotinib in patients with locally advanced or metastatic non-small cell lung cancer) trial, osimertinib showed statistically significant and clinically meaningful PFS and overall survival (OS) benefits compared with first-generation EGFR-TKIs (erlotinib or gefitinib) in patients with previously untreated EGFR-sensitizing mutation-positive NSCLC. The median PFS was 18.9 months in the osimertinib group and 10.2 months in the standard EGFR-TKI (gefitinib/erlotinib) group (hazard ratio [HR] for disease progression or death, 0.46; 95% confidence interval [CI], 0.37-0.57; P < .001).10 The median OS was 38.6 months in the osimertinib group and 31.8 months in the comparator group (HR for death, 0.80; 95% CI, 0.64-1.00; P = .046).11 Based on these results, osimertinib is now a standard first-line treatment of patients with EGFR mutation-positive NSCLC.

One of the promising strategies to further improve patients’ prognosis using osimertinib is combination therapy with other agents. Moreover, given their different mechanisms of action, combination treatment with EGFR-TKIs and chemotherapy might further improve the outcomes. Combination cisplatin/carboplatin plus pemetrexed is the standard treatment regimen for advanced nonsquamous NSCLC and has been frequently used as the backbone of combination treatment.12, 13, 14

The NEJ009 study compared gefitinib monotherapy with gefitinib plus carboplatin plus pemetrexed in NSCLC patients with sensitive EGFR mutations. Gefitinib plus carboplatin plus pemetrexed demonstrated significantly better PFS compared with gefitinib monotherapy (median PFS, 20.9 vs. 11.9 months; HR, 0.49; 95% CI, 0.39-0.62; P < .001). Additional OS analysis revealed that the median survival time for the combination regimen was much longer than that for monotherapy (50.9 vs. 38.8 months; HR, 0.722; P = .021).14 As described, osimertinib resulted in significantly longer PFS compared with first-generation EGFR-TKIs. Therefore, the combination of osimertinib and chemotherapy might offer more effective treatment of previously untreated EGFR-mutated NSCLC.

The Lung Oncology Group in Kyushu and the North East Japan Study Group, major clinical trial groups in Japan, conducted a randomized phase II study to evaluate the efficacy and safety of second-line osimertinib plus carboplatin plus pemetrexed compared with osimertinib monotherapy for patients with disease progression during first-line EGFR-TKI therapy with EGFR T790M resistance mutations (TAKUMI trial; protocol no. jRCTs071180062). In the safety review of the first treatment course for the initial 24 patients, no critical safety concerns were reported for the combination arm.15

Based on these data, we have planned this phase II study to evaluate the safety and preliminary efficacy of osimertinib plus cisplatin/carboplatin plus pemetrexed therapy for patients with previously untreated EGFR-mutated NSCLC.

Section snippets

Study Design and Clinical Endpoints

This study, the OPAL study (trial registration no. NEJ032C/LOGIK1801), is designed as a phase II clinical trial. This study aims to investigate the safety and preliminary efficacy of osimertinib plus platinum-based chemotherapy for previously untreated patients with EGFR-mutated NSCLC. A total of 66 patients will be enrolled in arm A (cisplatin cohort; 33 patients) and arm B (carboplatin cohort; 33 patients) at the discretion of each investigator until the planned number of patients is met in

Discussion and Conclusions

To the best of our knowledge, this is the first study to explore the efficacy and safety of osimertinib, a third-generation EGFR-TKI, combined with platinum-based chemotherapy in NSCLC patients with EGFR-sensitizing mutations. Takeda et al16 reported that both PFS and OS were significantly longer for EGFR mutation–positive NSCLC patients treated with first-generation EGFR-TKIs who had achieved an objective response (complete or partial response) than in those who had experienced stable disease.

Disclosures

K.H. assumed an advisory role for ImmuniT Research Inc. K.T. received honoraria from Abbott Japan. H.A., Ke.T., M.M., I.O., S.O., H.K., K.T., T.I., and K.K. received honoraria from AstraZeneca. Ke.T. received honoraria from Abbvie. H.A., K.T., T.I., and K.K. received honoraria from Boehringer Ingelheim. H.K., K.T., and K.K. received honoraria from Bristol-Myers Squibb. H.A., Ke.T., H.K., K.T., and K.K. received honoraria from Chugai. K.T. received honoraria from Daiichi-Sankyo. K.T. received

CRediT authorship contribution statement

Hajime Asahina: Conceptualization, Methodology, Writing - original draft. Kentaro Tanaka: Writing - review & editing. Satoshi Morita: Methodology, Formal analysis, Writing - review & editing. Makoto Maemondo: Supervision, Writing - review & editing. Masahiro Seike: Supervision, Writing - review & editing. Isamu Okamoto: Supervision, Writing - review & editing. Satoshi Oizumi: Supervision, Writing - review & editing. Hiroshi Kagamu: Supervision, Writing - review & editing. Kazuhisa Takahashi:

Acknowledgments

The present study is funded by AstraZeneca (England). The authors would like to thank the late professor Yoshiki Ishii, MD, PhD, of Dokkyo Medical University for helping promote this collaborative clinical study. The authors are also grateful to the data managers and other support staff of the North East Japan Study Group and Lung Oncology Group in Kyushu. This study will be conducted with support from the North East Japan Study Group Data Center, Saitama, Japan.

References (16)

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