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Phase 2 study of osimertinib in combination with platinum and pemetrexed in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer: The OPAL Study
Correspondence to: Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka-city, Saitama 350-1298, Japan.
This trial evaluated first-line concurrent osimertinib and cytotoxic chemotherapy.
•
The combination of osimertinib and cytotoxic chemotherapy was found to be tolerable.
•
The objective response rate was 90.9% (95% confidence interval, 84.0–97.8).
•
The median PFS was 31.0 months (95% CI, 26.8 months–not reached).
Abstract
Background
This multicenter phase 2 trial evaluated the safety and efficacy of osimertinib and platinum-based chemotherapy (OPP) in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer (NSCLC).
Patients and methods
Patients received osimertinib 80 mg once daily (QD), with either cisplatin 75 mg/m2 (arm A) or carboplatin (area under the curve [AUC] = 5; arm B), plus pemetrexed 500 mg/m2 for four cycles and maintenance therapy of osimertinib 80 mg QD with pemetrexed 500 mg/m2 every 3 weeks. The primary end-points were safety and objective response rate (ORR), and the secondary end-points were complete response rate (CRR), disease control rate (DCR), and progression-free survival (PFS).
Results
In total, 67 patients (34 in arm A and 33 in arm B) were enrolled between July 2019 and February 2020. At the data cutoff (28th February 2022), 35 (52.2%) patients had discontinued the protocol treatment, including 10 (14.9%) due to adverse events. No treatment-related deaths occurred. In the full analysis set, the ORR, CRR, and DCR were 90.9% (95% confidence interval [CI], 84.0–97.8), 3.0% (0.0–7.2), and 97.0% (92.8–100.0), respectively. Based on updated survival data (data cutoff on August 31, 2022, median follow-up time: 33.4 months), the median PFS was 31.0 months (95% CI, 26.8 months–not reached) and median overall survival was not reached.
Conclusions
This is the first study to show that OPP has excellent efficacy with acceptable toxicity in previously untreated EGFR-mutated advanced non-squamous NSCLC patients.
The development of non-small cell lung cancer (NSCLC) therapies that specifically target driver mutations, such as epidermal growth factor receptor (EGFR)-sensitising mutations, has markedly changed the standard of care for patients with advanced NSCLC. Following the initial success of first- and second-generation EGFR–tyrosine kinase inhibitors (TKIs) [
Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial.
Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG–0802): a multicentre, open-label, randomised, phase 3 study.
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.
Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX–Lung 6): an open-label, randomised phase 3 trial.
], the third-generation EGFR–TKI, osimertinib, was developed. In the phase 3 FLAURA trial, osimertinib showed significantly improved progression-free survival (PFS) and overall survival (OS) compared with first-generation EGFR–TKIs in patients with previously untreated EGFR-mutated advanced NSCLC and has therefore become a standard first-line treatment [
A platinum agent, such as cisplatin or carboplatin, combined with pemetrexed (PEM) is the standard treatment regimen for advanced non-squamous NSCLC and is frequently used as the backbone chemotherapy of combination therapies [
Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial.
]. The results of our NEJ009 study demonstrated that gefitinib plus carboplatin and PEM (GCP) achieved significantly better PFS and longer OS than gefitinib monotherapy [
]. The combination of osimertinib and platinum-based chemotherapy is therefore expected to exhibit greater efficacy than osimertinib monotherapy. Our previous study named TAKUMI trial proved that this combination of osimertinib plus carboplatin and PEM (OCP) in the second-line setting was generally feasible [
Osimertinib versus osimertinib plus chemotherapy for non-small cell lung cancer with EGFR (T790M)-associated resistance to initial EGFR inhibitor treatment: an open-label, randomised phase 2 clinical trial.
Based on these data, this phase 2 trial aimed to evaluate the safety and efficacy of osimertinib plus cisplatin/carboplatin and PEM in patients with previously untreated EGFR-mutated advanced non-squamous NSCLC.
2. Materials and methods
2.1 Patients
The details of the OPAL study protocol have been published previously [
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).
]. This phase 2 clinical trial enrolled patients with treatment-naïve EGFR-mutated advanced non-squamous NSCLC. Inclusion criteria were no previous history of chemotherapy or EGFR-TKI treatment, clinical stage IIIb, IIIc, IVa, IVb (UICC 8th edition) or relapsed non-squamous NSCLC with sensitising EGFR mutations (exon 19 deletion or exon 21 L858R), age 20–75 years, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1, measurable disease by the Response Evaluation Criteria in Solid Tumours (RECIST) ver1.1, and adequate organ function. The exclusion criteria were serious concomitant systemic disorders, interstitial pneumonia, QTc ≥ 470 ms obtained from resting electrocardiography (ECG) or any clinically important resting ECG abnormalities, another primary malignancy, symptomatic brain metastases, and pregnancy. This study was approved by the Clinical Research Review Board of Saitama Medical University and conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all patients. The study protocol was registered in the Japan Registry of Clinical Trials (jRCTs031180226).
2.2 Study design
A total of 66 patients, with 33 in arm A (cisplatin cohort) and 33 in arm B (carboplatin cohort), were to be enrolled at the discretion of each investigator until the planned number of patients for each arm was met (Supplementary Fig. 1). Patients received osimertinib 80 mg once daily (QD), with either cisplatin 75 mg/m2 (arm A) or carboplatin (area under the curve [AUC] = 5, arm B), and PEM 500 mg/m2 every 3 weeks (Q3W) for four cycles. Both groups received maintenance therapy of osimertinib 80 mg QD and PEM 500 mg/m2 Q3W until disease progression or discontinuation. The dose was reduced by one level in the event of grade 4 neutropenia, ≥3 grade febrile neutropenia, thrombocytopenia, delayed recovery of bone marrow function lasting>5 weeks, or ≥ grade 3 non-haematologic toxicity. For grade 3 thrombocytopenia with a bleeding event, the dose was reduced by two levels (Supplementary Table 1). The primary end-points were safety and objective response rate (ORR), and the secondary end-points were complete response rate (CRR), disease control rate (DCR), and PFS in the total population. Tumour assessments were performed until disease progression and evaluated by central review.
2.3 Statistical analysis
Both arms were combined for safety and efficacy analyses. Separate exploratory analyses of arms A and B were also performed. If no events were observed in 60 patients, there is 95% confidence that the true event rate would be<6%. Furthermore, the precision of estimating ORR was within±14% in the 60 patients. For example, ORR, 80%; Clopper–Pearson 95% confidence interval (CI), 67.7–89.2 (Supplementary Table 2). Therefore, considering a 10% dropout rate, the target sample size was set to 66 patients. The full analysis set (FAS) included all patients who received at least one protocol treatment. The per-protocol set (PPS) included patients from the FAS for whom primary end-point measurements were available, except those who did not meet the inclusion and exclusion criteria or received concomitant drugs or therapies. The safety analysis population (SP) included all patients who received the protocol treatment at least once (Supplementary Fig. 2).
For the safety analysis, the frequency of the worst grade for each reported adverse event (AE) during all courses was recorded according to the Common Terminology Criteria for Adverse Events version 5.0. For the efficacy analysis, we obtained point estimates of ORR, CRR, and DCR using the RECIST version 1.1 and the 95% CIs using the Clopper–Pearson method. PFS and OS were estimated using the Kaplan–Meier method.
3. Results
3.1 Patient characteristics
In total, 67 patients (34 in arm A and 33 in arm B) were enrolled between July 2019 and February 2020. One patient with adenosquamous histology was excluded from the efficacy analysis (Supplementary Fig. 2). The baseline patient characteristics are shown in Table 1. In the SP, the median age was 67 years (range, 26–75 years), 64.2% were female, 31.3% smoked, 31.3% had an ECOG PS of 1, 98.5% had adenocarcinoma histology, 32.8% had central nervous system metastasis, and 52.2% had an L858R mutation.
Table 1Patient characteristics.
Characteristic
Cisplatin cohort (arm A), No. (%)
Carboplatin cohort (arm B), No. (%)
Total, No. (%)
No. of patients
34
33
67
Sex
Male
12 (35.3)
12 (36.4)
24 (35.8)
Female
22 (64.7)
21 (63.6)
43 (64.2)
Age, years
Median
65.5
70
67
Range
42–74
26–75
26–75
Smoking status
Never
24 (70.6)
22 (66.7)
46 (68.7)
Former or current
10 (29.4)
11 (33.3)
21 (31.3)
ECOG PS score
0
24 (70.6)
22 (66.7)
46 (68.7)
1
10 (29.4)
11 (33.3)
21 (31.3)
Histology
Adenocarcinoma
33 (97.1)
33 (100)
66 (98.5)
Other
1 (2.9)
0 (0)
1 (1.5)
Stage
IVa
13 (38.2)
14 (42.4)
27 (40.3)
IVb
17 (50.0)
15 (45.5)
32 (47.8)
Recurrence
4 (11.8)
4 (12.1)
8 (11.9)
CNS metastasis
Yes
12 (35.3)
10 (30.3)
22 (32.8)
No
22 (64.7)
23 (69.7)
45 (67.2)
EGFR mutation type
Ex19del
15 (44.1)
16 (48.5)
31 (46.3)
L858R
19 (55.9)
16 (48.5)
35 (52.2)
Both
0 (0)
1 (3.0)
1 (1.5)
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; CNS, central nervous system; EGFR, epidermal growth factor receptor
The data cutoff for response and safety was 28th February 2022, and the updated data cutoff for PFS and OS was 31st August 2022, resulting in a median follow-up time of 33.4 months (range, 30.2–37.7). In the FAS (n = 66), the ORR was 90.9% (95% CI, 84.0–97.8), with 60/66 evaluable patients achieving complete response (CR) or partial response (PR). The CRR and DCR were 3.0% (95% CI, 0.0–7.2) and 97.0% (95% CI, 92.8–100.0) (Table 2). Waterfall plots were drawn for arm A, B, and the total population (Fig. 1). All patients exhibited tumour shrinkage and two patients in arm B achieved CR. At the updated data cutoff, the median PFS was 31.0 months (95% CI, 26.8–NR), and the 12- and 24-month PFS rates were 90.4% (95% CI, 79.8–95.6) and 71.8% (95% CI, 58.6–81.4) (Fig. 2A). The median OS was NR (95% CI, NR–NR), and the 12- and 24-month survival rates were 96.9% (95% CI, 88.3–99.2) and 92.3% (95% CI, 82.5–96.7) (Fig. 2B).
Fig. 2Kaplan–Meier survival curves. (A) Progression-free survival curves (PFS) in the total population. (B) Overall survival (OS) curves in the total population. (C) PFS curves in arms A and B. (D) OS in arms A and B.
Separate efficacy analysis revealed a median PFS of 29.5 months (95% CI, 18.2–NR), and 12- and 24-month PFS rates of 86.9% (95% CI, 68.6–94.9) and 60.1% (95% CI, 40.6–75.1) in arm A. In arm B, the median PFS was NR (95% CI, 27.2 months–NR), and the 12- and 24-month PFS rates were 93.7% (95% CI, 77.2–98.4) and 83.6% (95% CI, 64.8–92.8) (Fig. 2C). In arm A, the median OS was NR (95% CI, NR–NR), and the 12- and 24-month survival rates were 96.9% (95% CI, 79.8–99.6) and 87.5% (95% CI, 70.0–95.1). In arm B, the median OS was NR (95% CI, NR–NR), and the 12- and 24-month survival rates were 97.0% (95% CI, 80.4–99.6) and 97.0% (95% CI, 80.4–99.6) (Fig. 2D).
In addition, post-hoc analysis of tumour response, PFS, and OS data based on mutation subtype was performed (Fig. 3 and Supplementary Table 3). Overall, for patients with exon 19 deletions (n = 30), the ORR, median PFS, and median OS were 96.7% (95% CI, 90.2–100.0), 30.6 months (95% CI, 24.5–NR), and NR (95% CI, NR–NR). In contrast, for patients with exon 21 L858R (n = 35), the ORR, median PFS, and median OS were 85.7% (95% CI, 74.1–97.3), 33.4 months (95% CI, 18.9–NR), and NR (95% CI, NR–NR) (Fig. 3, Fig. 3). In arm A, for patients with exon 19 deletions (n = 14), the ORR, median PFS, and median OS were 100% (95% CI, 100.0–100.0), 29.5 months (95% CI, 15.4–NR), and NR (95% CI, 31.3 months–NR), whereas for patients with exon 21 L858R (n = 19), the ORR, median PFS, and median OS were 84.2% (95% CI, 67.8–100.0), 30.5 months (95% CI, 13.9–NR), and NR (95% CI, NR–NR) (Fig. 3, Fig. 3). In arm B, for patients with exon 19 deletions (n = 16), the ORR, median PFS, and median OS were 93.8% (95% CI, 81.9–100.0), 30.6 months (95% CI, 24.5–NR), and NR (95% CI, NR–NR), whereas for patients with exon 21 L858R (n = 16), the ORR, median PFS, and median OS were 87.5% (95% CI, 71.3–100.0), NR (95% CI, 17.2 months–NR), and NR (95% CI, NR–NR) (Fig. 3, Fig. 3). There was also no difference in treatment efficacy (ORR, PFS, OS) based on the presence or absence of brain metastases at baseline (Appendix A, Appendix A). Of the 28 patients with confirmed PD, brain metastases represented the initial site of progression in only three patients.
Fig. 3Progression-free survival (PFS) and overall survival (OS) based on mutation subtype. (A) PFS of patients in the total population. (B) OS of patients in the total population. (C) PFS curves in arm A. (D) OS curves in arm A. (E) PFS curves in arm B. (D) OS curves in arm B.
At the data cutoff (28th February 2022), 35 (52.2%) patients in the SP (20 [58.8%] in arm A and 15 [45.5%] in arm B) had discontinued the protocol treatment, including 10 (14.9%) (6 [17.6%] in arm A and 4 [12.1%] in arm B) due to AEs. Grade 3/4 treatment-emergent AEs were observed in 60 patients (89.6%). The occurrence of neutropenia, anaemia, and thrombocytopenia was greater in arm B (Table 3). While prolonged QTc as AEs were mostly asymptomatic, one patient in arm B presented to the emergency department with dizziness on day 14 of the second course of induction therapy and was found to have grade 4 prolonged QTc with grade 3 hypokalemia, leading to discontinuation of the protocol treatment. Prolonged QTc ≥grade 3 occurred in 4 (11.8%) and 4 (12.1%) patients in arms A and B, whereas hypokalemia ≥grade 3 occurred in 3 (8.8%) and 3 (9.1%) patients in arms A and B. Grade 2 pneumonitis was reported in two patients (5.9%) in arm A, whereas grade 1 pneumonitis was reported in one patient (3.0%) in arm B. No treatment-related deaths were reported.
The status of treatment delivery in the FAS is shown in Appendix A, Appendix A. At the data cutoff (28 February 2022), 14 (42.4%) patients in arm A and 18 (54.5%) in arm B had continued the protocol treatment. The median duration of osimertinib treatment was 23.4 months (range, 0.1–31.2) in arm A and 25.5 months (range, 0.7–30.7) in arm B. The median cycles of cisplatin or carboplatin were 4 (range, 1–4) in both arms, whereas those of pemetrexed were 12 (range, 1–45) in arm A and 12 (range, 1–36) in arm B. The dose reduction status of each study drug at the initial 6 cycles and the 12th, 18th, 24th, and 30th cycles are shown in Supplementary Table 6.
4. Discussion
To the best of our knowledge, this is the first prospective study to evaluate the safety and efficacy of a third-generation EGFR–TKI plus platinum doublet chemotherapy in patients with previously untreated EGFR-mutated advanced non-squamous NSCLC. And the OPAL regimen gave the patients entered the highest response rate and the longest PFS among the previously reported articles (Supplementary Table 7) [
Effect of osimertinib and bevacizumab on progression-free survival for patients with metastatic EGFR-mutant lung cancers: a phase 1/2 single-group open-label trial.
Randomized phase 2 study of osimertinib plus bevacizumab versus osimertinib for untreated patients with nonsquamous NSCLC harboring EGFR mutations: WJOG9717L Study.
Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial.
Bevacizumab plus erlotinib versus erlotinib alone in Japanese patients with advanced, metastatic, EGFR-mutant non-small-cell lung cancer (NEJ026): overall survival analysis of an open-label, randomised, multicentre, phase 3 trial.
Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial.
Mechanisms of resistance against third-generation EGFR–TKIs differ from those of first- or second-generation EGFR–TKIs, being more heterogeneous and complex [
]. Therefore, it is important to develop first-line combination therapies that prevent or delay the emergence of such complex resistance mechanisms. There are two major strategies: the combination of EGFR–TKI and angiogenesis inhibitors, and the combination of EGFR–TKI and chemotherapy [
Third generation EGFR inhibitor osimertinib combined with pemetrexed or cisplatin exerts long-lasting anti-tumor effect in EGFR-mutated pre-clinical models of NSCLC.
Altered regulation of HIF-1α in naïve- and drug-resistant EGFR-mutant NSCLC: implications for a vascular endothelial growth factor-dependent phenotype.
To date, two phase 2 trials (Yu’s study and WJOG9717L) have investigated third-generation EGFR–TKI combinations of osimertinib and an angiogenesis inhibitor [
Effect of osimertinib and bevacizumab on progression-free survival for patients with metastatic EGFR-mutant lung cancers: a phase 1/2 single-group open-label trial.
Randomized phase 2 study of osimertinib plus bevacizumab versus osimertinib for untreated patients with nonsquamous NSCLC harboring EGFR mutations: WJOG9717L Study.
]. Combination therapy with first-generation EGFR–TKIs have been investigated in two phase 3 trials, which compared erlotinib plus an angiogenesis inhibitor (bevacizumab, ramucirumab) with erlotinib monotherapy (NEJ026, RELAY); and two phase 3 trials, which compared gefitinib plus platinum-based chemotherapy with gefitinib monotherapy (Noronha, NEJ009) [
Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial.
Bevacizumab plus erlotinib versus erlotinib alone in Japanese patients with advanced, metastatic, EGFR-mutant non-small-cell lung cancer (NEJ026): overall survival analysis of an open-label, randomised, multicentre, phase 3 trial.
Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial.
]. In addition to osimertinib monotherapy, these first-generation EGFR–TKI combination therapies are regarded as the preferable standard-of-care first-line treatment for EGFR–mutated advanced NSCLC. The 90.9% ORR and the 31.0-month median PFS in this OPAL study were superior to those of previous studies. As shown in the results of the Japanese subset of the FLAURA trial (median PFS 19.1 months) and the osimertinib monotherapy arm of the WJOG9717L trial (median PFS 20.2 months), EGFR–TKI may be more effective in Japanese patients than in other ethnic groups [
Randomized phase 2 study of osimertinib plus bevacizumab versus osimertinib for untreated patients with nonsquamous NSCLC harboring EGFR mutations: WJOG9717L Study.
]. However, the PFS of the OPAL study is approximately one year longer than the median PFS of osimertinib alone in these studies. In addition, although post-hoc analysis of the small sample size was performed, there was no difference in PFS between exon19 deletions and L858R and no difference in treatment effect was observed regardless of the presence or absence of brain metastases prior to treatment. Although the results of this OPAL study are still immature, the 92.3% 2 year-OS rate is more promising than the 74% of that in the FLAURA trial. The randomised phase 2 TAKUMI trial, which compared OCP to osimertinib as second-line treatment, did not show an improvement in PFS using OCP [
Osimertinib versus osimertinib plus chemotherapy for non-small cell lung cancer with EGFR (T790M)-associated resistance to initial EGFR inhibitor treatment: an open-label, randomised phase 2 clinical trial.
], possibly due to the difficulty of overcoming diverse resistance mechanisms. Collectively, these results and those of the preclinical and clinical studies mentioned above suggest that combining chemotherapy with osimertinib as first-line therapy is more effective than a combination of angiogenesis inhibitors for eradicating heterogeneous tumours.
This OPAL study showed that most of the adverse events of combined chemotherapy and EGFR–TKI were manageable. As reported in the TAKUMI trial, bone marrow suppression was a significant toxic side-effect, especially in the carboplatin group. Furthermore, in contrast to the TAKUMI trial, prolonged QTc was more common, but most cases were low-grade and asymptomatic. One reason for this is that the OPAL study required an ECG at each course. In addition, electrolyte abnormalities were likely to occur with concomitant chemotherapy, especially with induction therapy using a triple-drug combination. However, as the median number of cycles of platinum and pemetrexed administration in this study was 4 and 12, with appropriate dose reduction, this combination therapy could be safely administered for an extended period.
This study had a few limitations. First, this is a phase 2 trial with a small number of patients belonging to a single ethnic group. Second, although the response and prognosis of patients with EGFR-mutated NSCLC have been reported to be affected by the presence of concomitant mutations, precise molecular data were unavailable. Furthermore, although investigating resistance mechanisms through paired liquid biopsies prior to treatment and at the time of resistance would provide valuable insight, we were unable to perform such investigations in this study. Third, despite the promising 31.0-month median PFS, the minimum follow-up period of 2.5 years is too short for survival conclusions.
In conclusion, the results of the current OPAL study confirm the safety and efficacy of osimertinib plus platinum-based chemotherapy in patients with previously untreated EGFR-mutated advanced non-squamous NSCLC. Along with the ongoing global phase 3 study, which compares osimertinib monotherapy to osimertinib combined with platinum plus pemetrexed as first-line treatment for EGFR-mutated advanced non-squamous NSCLC (FLAURA2 study, ClinicalTrials.gov identifier no. NCT04035486), we believe that the results of the current OPAL study will impact future first-line treatment strategies for EGFR-mutated advanced non-squamous NSCLC.
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Saito reports no conflicts of interest.
Dr. Sugawara reports personal fees from AstraZeneca, Chugai Pharma, Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Nippon Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Eli Lilly and Company, Novartis, Kyowa Kirin, Yakult Honsha, Takeda, Nippon Kayaku, Merck, Amgen, AbbVie, Otsuka, Thermo Fisher Scientific, and TOWA PHARMACEUTICAL.
Dr. Ko reports grants from MSD and AstraZeneca, and personal fees from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Pfizer, AstraZeneca, Ono Pharmaceutical, Daiichi Sankyo, Takeda, and MSD.
Dr. Azuma reports personal fees from AstraZeneca, MSD, Bristol Myers Squibb, Ono Pharmaceutical and Chugai Pharmaceutical.
Dr. Morita reports no conflicts of interest.
Dr. Maemondo reports grants from Boehringer Ingelheim, and personal fees from AstraZeneca, Chugai, Boehringer Ingelheim, and Pfizer.
Dr. Oizumi reports grants from AstraZeneca, and personal fees from AstraZeneca and Eli Lilly.
Dr. Takahashi reports personal fees from AstraZeneca and Eli Lilly, and participation on a Data Safety Monitoring Board or Advisory Board of AstraZeneca and Eli Lilly.
Dr. Kagamu reports consultant fees from ImmuniT Research Inc., grants from Boehringer Ingelheim, Chugai, Eli Lilly, Ono Pharmaceutical, and Taiho Pharmaceutical, and personal fees from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Ono Pharmaceutical, Taiho Pharmaceutical.
Dr. Tsubata reports grants from Ono Pharmaceutical Co., Ltd. and Pfizer Health Research Foundation, and personal fees from Daiichi Sankyo Co. Ltd., AstraZeneca K.K., and Chugai Pharmaceutical Co. Ltd.
Dr. Seike reports grants from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, MSD K.K, Nippon Boehringer Ingelheim, and personal fees from AstraZeneca, MSD K.K, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Novartis, Takeda Pharmaceutical, Kyowa Hakko Kirin, Nippon Kayaku, Daiichi-Sankyo Company.
Dr. Kikuchi reports personal fees from Viatris, Astellas Pharma, Insmed, Boehringer Ingelheim, Terumo, Eli Lilly, AstraZeneca, Daiichi Sankyo, KYORIN Pharmaceutical, Novartis, MERCK, Bristol-Myers, NIPRO, Eisai, Ono Pharmaceutical, Chugai Pharma, GlaxoSmithKline, Sumitomo Dainippon Pharma, and Kyowa Kirin, and fees for Participation on a Data Safety Monitoring Board or Advisory Board from Janssen Pharmaceutical, and receipt of equipment, materials, drugs, medical writing, gifts or other services from Nobelpharma.
Dr. Okamoto reports grants from Boehringer Ingelheim, for the duration of the study, grants and personal fees from AstraZeneca, grants and personal fees from Taiho Pharmaceutical, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Ono Pharmaceutical, grants and personal fees from MSD Oncology, grants and personal fees from Eli Lilly, grants from Astellas Pharma, grants and personal fees from Bristol-Myers Squibb, grants from Novartis, grants and personal fees from Chugai Pharma, personal fees from Pfizer, grants from AbbVie.
Dr. Morita reports grants from Eisai Co., Ltd., and personal fees from AstraZeneca K.K., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co. Ltd., Eisai Co., Ltd, Eli Lilly Japan K.K., MSD K.K., Nippon Boehringer Ingelheim Co. Ltd., Ono Pharmaceutical Co. Ltd., Pfizer Japan Inc., and Taiho Pharmaceutical Co. Ltd.
Dr. Asahina reports grants from AstraZeneca, and personal fees from AstraZeneca, Eli Lilly, Chugai Pharma, Kyowa Kirin, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical.
Dr. Tanaka reports consultant fees from Daiichi-Sankyo, AstraZeneca, Eli Lilly, Takeda, Janssen, grants from Chugai, Ono Pharmaceutical, Boehringer Ingelheim, and personal fees from AstraZeneca, Chugai, Ono Pharmaceutical, Bristol-Myers, Eli Lilly, Daiichi Sankyo, Takeda, Novartis, and Pfizer.
Dr. Sugio reports no conflicts of interest.
Dr. Kobayashi reports personal fees from AstraZeneca, Eli Lilly, Chugai Pharma, Kyowa Kirin, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical.
Acknowledgements
The authors thank all the patients and their families for supporting this study. We also thank all the investigators for supporting this study: Efficacy Evaluation Committee Members: Hirohisa Yoshizawa, Akinobu Yoshimura, and Yuichi Takiguchi; Safety Evaluation Committee Member: Yasuo Saijo; Study secretary: Hiromi Odagiri; Study personnel: Yasutaka Kawai, Ryoichi Honda, Takuro Sakagami, Yuka Fujita, Tatsuro Fukuhara, Toshiyuki Harada, Noriyuki Ebi, Koichi Hagiwara, Tetsuya Kojima, Yasuo Shimizu, Shoichi Kuyama, Satoshi Watanabe, Taishi Harada, Kazuhiro Usui, Kouji Inoue, Tatsuro Okamoto, Noriaki Sukoh, Masaaki Okajima, Yoichiro Hamamoto, Yasunari Miyazaki, Yoko Shibata, Kageaki Taima, Akira Kisohara, Tetsuya Okano, Hiroshi Watanabe, Kei Takamura, Sumito Inoue, and Masato Shingyoji.
Funding
This work was supported by the North-East Japan Study Group (NEJSG) and Lung Oncology Group in Kyushu (LOGiK). The grant is supported by AstraZeneca.
Trial registration no.: jRCTs031180226.
Previous presentation
The results of this study have been presented in part at ASCO 2022.
Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial.
Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG–0802): a multicentre, open-label, randomised, phase 3 study.
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.
Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX–Lung 6): an open-label, randomised phase 3 trial.
Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial.
Osimertinib versus osimertinib plus chemotherapy for non-small cell lung cancer with EGFR (T790M)-associated resistance to initial EGFR inhibitor treatment: an open-label, randomised phase 2 clinical trial.
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).
Effect of osimertinib and bevacizumab on progression-free survival for patients with metastatic EGFR-mutant lung cancers: a phase 1/2 single-group open-label trial.
Randomized phase 2 study of osimertinib plus bevacizumab versus osimertinib for untreated patients with nonsquamous NSCLC harboring EGFR mutations: WJOG9717L Study.
Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial.
Bevacizumab plus erlotinib versus erlotinib alone in Japanese patients with advanced, metastatic, EGFR-mutant non-small-cell lung cancer (NEJ026): overall survival analysis of an open-label, randomised, multicentre, phase 3 trial.
Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial.
Third generation EGFR inhibitor osimertinib combined with pemetrexed or cisplatin exerts long-lasting anti-tumor effect in EGFR-mutated pre-clinical models of NSCLC.
Altered regulation of HIF-1α in naïve- and drug-resistant EGFR-mutant NSCLC: implications for a vascular endothelial growth factor-dependent phenotype.
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