Journal Pre-proof

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

Ryota Saito, Shunichi Sugawara, Ryo Ko, Koichi

Azuma, Ryo Morita, Makoto Maemondo, Satoshi
Oizumi, Kazuhisa Takahashi, Hiroshi Kagamu,
Yukari Tsubata, Masahiro Seike, Toshiaki Kikuchi,
Isamu Okamoto, Morita Satoshi, Hajime Asahina,
Kentaro Tanaka, Kenji Sugio, Kunihiko Kobayashi

PII: S0959-8049(23)00115-6
DOI: https://doi.org/10.1016/j.ejca.2023.02.023
Reference: EJC12835

To appear in: European Journal of Cancer

Received date: 26 December 2022
Revised date: 20 February 2023
Accepted date: 22 February 2023
Please cite this article as: Ryota Saito, Shunichi Sugawara, Ryo Ko, Koichi
Azuma, Ryo Morita, Makoto Maemondo, Satoshi Oizumi, Kazuhisa Takahashi,
Hiroshi Kagamu, Yukari Tsubata, Masahiro Seike, Toshiaki Kikuchi, Isamu
Okamoto, Morita Satoshi, Hajime Asahina, Kentaro Tanaka, Kenji Sugio and
Kunihiko Kobayashi, 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,
European Journal of Cancer, (2022)
doi:https://doi.org/10.1016/j.ejca.2023.02.023
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 1

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

Ryota Saitoa, Shunichi Sugawarab, Ryo Koc, Koichi Azumad, Ryo Moritae,

Makoto Maemondof, Satoshi Oizumig, Kazuhisa Takahashic, Hiroshi Kagamuh,

f
Yukari Tsubatai, Masahiro Seikej, Toshiaki Kikuchik, Isamu Okamotol, Satoshi,

oo
Moritam, Hajime Asahinan, Kentaro Tanakal, Kenji Sugioo, and Kunihiko

pr
Kobayashih e-
a
Department of Respiratory Medicine, Tohoku University, Sendai, Japan
Pr

b
Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai, Japan
c
Department of Respiratory Medicine, Juntendo University Graduate School of
al

Medicine, Tokyo, Japan

n

d
Division of Respirology, Neurology, and Rheumatology, Department of Internal
ur

Medicine, Kurume University School of Medicine, Kurume, Japan

Jo

e
Department of Respiratory Medicine, Akita Kousei Medical Center, Akita,

Japan
f
Division of Pulmonary Medicine, Department of Internal Medicine, Iwate

Medical University School of Medicine, Yahaba, Japan

g
Department of Respiratory Medicine, National Hospital Organization Hokkaido

Cancer Center, Sapporo, Japan

h
Department of Respiratory Medicine, Saitama Medical University International

Medical Center, Hidaka, Japan

 2

I
Department of Internal Medicine, Division of Medical Oncology & Respiratory

Medicine, Shimane University Faculty of Medicine, Izumo, Japan

j
Department of Pulmonary Medicine and Oncology, Graduate School of

Medicine, Nippon Medical School, Tokyo, Japan

k
Department of Respiratory Medicine and Infectious Diseases, Graduate

School of Medical and Dental Sciences, Niigata University, Niigata, Japan

f
l
Department of Respiratory Medicine, Graduate School of Medical Sciences,

oo
Kyushu University, Fukuoka, Japan

pr
m
Department of Biomedical Statistics and Bioinformatics, Kyoto University

Graduate School of Medicine, Kyoto, Japan

e-
n
Department of Respiratory Medicine, Hokkaido University Graduate School of
Pr

Medicine, Sapporo, Japan

o
Department of Thoracic and Breast Surgery, Oita University Faculty of
al

Medicine, Oita, Japan

n

Corresponding author:
ur

Kunihiko Kobayashi
Jo

Department of Respiratory Medicine, Saitama Medical University International

Medical Center, 1397–1 Yamane, Hidaka–city, Saitama 350–1298, Japan

Phone: +81–42–984–4111

Fax: +81–42–984–4740

E–mail address: kobakuni@saitama–med.ac.jp

Funding

This work was supported by the North-East Japan Study Group (NEJSG) and
 3

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

f
at ASCO 2022.

oo
pr
Conflict of interest:

Dr. Saito reports no conflicts of interest.

e-
Dr. Sugawara reports personal fees from AstraZeneca, Chugai Pharma, Ono
Pr

Pharmaceutical, Bristol-Myers Squibb, MSD, Nippon Boehringer Ingelheim,

Pfizer, Taiho Pharmaceutical, Eli Lilly and Company, Novartis, Kyowa Kirin,
al

Yakult Honsha, Takeda, Nippon Kayaku, Merck, Amgen, AbbVie, Otsuka,

n

Thermo Fisher Scientific, and TOWA PHARMACEUTICAL.

ur

Dr. Ko reports grants from MSD and AstraZeneca, and personal fees from Taiho
Jo

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
 4

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

f
Pharmaceutical, and personal fees from AstraZeneca, Bristol-Myers Squibb,

oo
Chugai Pharmaceutical, Ono Pharmaceutical, Taiho Pharmaceutical.

pr
Dr. Tsubata reports grants from Ono Pharmaceutical Co., Ltd. and Pfizer Health

Research Foundation, and personal fees from Daiichi Sankyo Co. Ltd.,
e-
AstraZeneca K.K., and Chugai Pharmaceutical Co. Ltd.
Pr

Dr. Seike reports grants from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli

Lilly, MSD K.K, Nippon Boehringer Ingelheim, and personal fees from
al

AstraZeneca, MSD K.K, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly,

n

Ono Pharmaceutical, Bristol-Myers Squibb, Nippon Boehringer Ingelheim,

ur

Novartis, Takeda Pharmaceutical, Kyowa Hakko Kirin, Nippon Kayaku, Daiichi-

Jo

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

 5

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,

f
grants from Astellas Pharma, grants and personal fees from Bristol-Myers

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Squibb, grants from Novartis, grants and personal fees from Chugai Pharma,

pr
personal fees from Pfizer, grants from AbbVie.

Dr. Morita reports grants from Eisai Co., Ltd., and personal fees from
e-
AstraZeneca K.K., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co.
Pr

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
al

Pharmaceutical Co. Ltd.

n

Dr. Asahina reports grants from AstraZeneca, and personal fees from
ur

AstraZeneca, Eli Lilly, Chugai Pharma, Kyowa Kirin, MSD, Ono Pharmaceutical,
Jo

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.

 6

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

f
Patients received osimertinib 80 mg once daily (QD), with either cisplatin 75

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mg/m2 (arm A) or carboplatin (area under the curve [AUC] = 5; arm B), plus

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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 endpoints

e-
were safety and objective response rate (ORR), and the secondary endpoints
Pr

were complete response rate (CRR), disease control rate (DCR), and

progression-free survival (PFS).

al

Results
n

In total, 67 patients (34 in arm A and 33 in arm B) were enrolled between July
ur

2019 and February 2020. At the data cutoff (February 28, 2022), 35 (52.2%)
Jo

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.

Conclusion
 7

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.

Keywords:

non–small cell lung cancer, EGFR mutation, osimertinib, platinum-based

f
chemotherapy, pemetrexed

oo
1. Introduction

pr
The development of non-small cell lung cancer (NSCLC) therapies

that specifically target driver mutations, such as epidermal growth factor

e-
receptor (EGFR)-sensitizing mutations, has markedly changed the standard of
Pr

care for patients with advanced NSCLC. Following the initial success of first-

and second-generation EGFR–tyrosine kinase inhibitors (TKIs) [1-6], the third-

al

generation EGFR–TKI, osimertinib, was developed. In the phase 3 FLAURA

n

trial, osimertinib showed significantly improved progression-free survival (PFS)

ur

and overall survival (OS) compared with first-generation EGFR–TKIs in patients

Jo

with previously untreated EGFR-mutated advanced NSCLC and has therefore

become a standard first-line treatment [7,8].

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 [9-11]. The results of our NEJ009 study demonstrated

that gefitinib plus carboplatin and PEM (GCP) achieved significantly better PFS

and longer OS than gefitinib monotherapy [11,12]. The combination of

 8

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 [13].

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

f
previously untreated EGFR-mutated advanced non-squamous NSCLC.

oo
pr
2. Materials and methods

2.1. Patients
e-
The details of the OPAL study protocol have been published
Pr

previously [14]. This phase 2 clinical trial enrolled patients with treatment-naïve

EGFR-mutated advanced non-squamous NSCLC. Inclusion criteria were no

al

previous history of chemotherapy or EGFR-TKI treatment, clinical stage IIIb, IIIc,

n

IVa, IVb (UICC 8th edition) or relapsed non-squamous NSCLC with sensitizing
ur

EGFR mutations (exon 19 deletion or exon 21 L858R), age 20–75 years,

Jo

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

 9

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

f
B (carboplatin cohort), were to be enrolled at the discretion of each investigator

oo
until the planned number of patients for each arm was met (Supplementary

pr
Figure 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
e-
B), and PEM 500 mg/m2 every 3 weeks (Q3W) for four cycles. Both groups
Pr

received maintenance therapy of osimertinib 80 mg QD and PEM 500 mg/m2

Q3W until disease progression or discontinuation. The dose was reduced by

al

one level in the event of grade 4 neutropenia, ≥ 3 grade febrile neutropenia,

n

thrombocytopenia, delayed recovery of bone marrow function lasting > 5 weeks,

ur

or ≥ grade 3 non-hematologic toxicity. For grade 3 thrombocytopenia with a

Jo

bleeding event, the dose was reduced by two levels (Supplementary Table 1).

The primary endpoints were safety and objective response rate (ORR), and the

secondary endpoints were complete response rate (CRR), disease control rate

(DCR), and PFS in the total population. Tumor 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
 10

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

f
(FAS) included all patients who received at least one protocol treatment. The

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per-protocol set (PPS) included patients from the FAS for whom primary

pr
endpoint measurements were available, except those who did not meet the

inclusion and exclusion criteria or received concomitant drugs or therapies. The

e-
safety analysis population (SP) included all patients who received the protocol
Pr

treatment at least once (Supplementary Figure 2).

For the safety analysis, the frequency of the worst grade for each
al

reported adverse event (AE) during all courses was recorded according to the
n

Common Terminology Criteria for Adverse Events version 5.0. For the efficacy
ur

analysis, we obtained point estimates of ORR, CRR, and DCR using the
Jo

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 Figure 2).
 11

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.

3.2. Efficacy

The data cutoff for response and safety was February 28, 2022, and

f
the updated data cutoff for PFS and OS was August 31, 2022, resulting in a

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median follow-up time of 33.4 months (range, 30.2–37.7). In the FAS (n = 66),

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the ORR was 90.9% (95% CI, 84.0–97.8), with 60/66 evaluable patients

achieving CR or PR. The CRR and DCR were 3.0% (95% CI, 0.0–7.2) and
e-
97.0% (95% CI, 92.8–100.0) (Table 2). Waterfall plots were drawn for arm A, B,
Pr

and the total population (Figure 1). All patients exhibited tumor shrinkage and

two patients in arm B achieved CR. At the updated data cutoff, the median PFS
al

was 31.0 months (95% CI, 26.8–NR), and the 12- and 24-month PFS rates
n

were 90.4% (95% CI, 79.8–95.6) and 71.8% (95% CI, 58.6–81.4) (Figure 2A).
ur

The median OS was NR (95% CI, NR–NR), and the 12- and 24-month survival
Jo

rates were 96.9% (95% CI, 88.3–99.2) and 92.3% (95% CI, 82.5–96.7) (Figure

2B).

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) (Figure 2C). In arm

A, the median OS was NR (95% CI, NR–NR), and the 12- and 24-month
 12

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)

(Figure 2D).

In addition, post-hoc analysis of tumor response, PFS, and OS data

based on mutation subtype was performed (Figure 3 and Supplementary Table

f
3). Overall, for patients with exon 19 deletions (n = 30), the ORR, median PFS,

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and median OS were 96.7% (95% CI, 90.2–100.0), 30.6 months (95% CI, 24.5–

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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),
e-
33.4 months (95% CI, 18.9–NR), and NR (95% CI, NR–NR) (Figure 3A, 3B). In
Pr

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),
al

and NR (95% CI, 31.3 months–NR), whereas for patients with exon 21 L858R
n

(n = 19), the ORR, median PFS, and median OS were 84.2% (95% CI, 67.8–
ur

100.0), 30.5 months (95% CI, 13.9–NR), and NR (95% CI, NR–NR) (Figure 3C,
Jo

3D). 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) (Figure 3E,

3F). There was also no difference in treatment efficacy (ORR, PFS, OS) based

on the presence or absence of brain metastases at baseline (Supplementary

Table 4 and Supplementary Figure 3). Of the 28 patients with confirmed PD,
 13

brain metastases represented the initial site of progression in only three patients.

3.3. Safety

At the data cutoff (February 28, 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

f
to AEs. Grade 3/4 treatment-emergent AEs were observed in 60 patients

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(89.6%). The occurrence of neutropenia, anemia, and thrombocytopenia was

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greater in arm B (Table 3). While prolonged QTc as AEs were mostly

asymptomatic, one patient in arm B presented to the emergency department

e-
with dizziness on day 14 of the second course of induction therapy and was
Pr

found to have grade 4 prolonged QTc with grade 3 hypokalemia, leading to

discontinuation of the protocol treatment. Prolonged QTc ≥ grade 3 occurred in

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4 (11.8%) and 4 (12.1%) patients in arms A and B, whereas hypokalemia ≥

n

grade 3 occurred in 3 (8.8%) and 3 (9.1%) patients in arms A and B. Grade 2

ur

pneumonitis was reported in two patients (5.9%) in arm A, whereas grade 1

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pneumonitis was reported in one patient (3.0%) in arm B. No treatment-related

deaths were reported.

3.4. Treatment delivery

The status of treatment delivery in the FAS are shown in

Supplementary Figure 4 and Supplementary Table 5. At the data cutoff

(February 28, 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

 14

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.

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4. Discussion

pr
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

e-
doublet chemotherapy in patients with previously untreated EGFR-mutated
Pr

advanced non-squamous NSCLC. And the OPAL regimen gave the patients

entered the highest response rate and the longest PFS among the previously
al

reported articles (Supplementary table 7) [11,12, 15–20].

n

Mechanisms of resistance against third-generation EGFR–TKIs differ

ur

from those of first- or second-generation EGFR–TKIs, being more

Jo

heterogeneous and complex [21]. 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 [22–25].

To date, two phase 2 trials (Yu’s study and WJOG9717L) have

investigated third-generation EGFR–TKI combinations of osimertinib and an

angiogenesis inhibitor [15, 16]. Combination therapy with first-generation

 15

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) [17-20]. In addition to osimertinib

monotherapy, these first-generation EGFR-TKI combination therapies are

f
regarded as the preferable standard-of-care first-line treatment for EGFR–

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mutated advanced NSCLC. The 90.9% ORR and the 31.0-month median PFS

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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)
e-
and the osimertinib monotherapy arm of the WJOG9717L trial (median PFS
Pr

20.2 months), EGFR-TKI may be more effective in Japanese patients than in

other ethnic groups [16, 26]. However, the PFS of the OPAL study is
al

approximately one year longer than the median PFS of osmimertinib alone in
n

these studies. In addition, although post-hoc analysis of the small sample size
ur

was performed, there was no difference in PFS between exon19 deletions and
Jo

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 randomized phase 2

TAKUMI trial, which compared OCP to osimertinib as second-line treatment, did

not show an improvement in PFS using OCP [13], 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
 16

combining chemotherapy with osimertinib as first-line therapy is more effective

than a combination of angiogenesis inhibitors for eradicating heterogeneous

tumors.

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,

f
especially in the carboplatin group. Furthermore, in contrast to the TAKUMI trial,

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prolonged QTc was more common, but most cases were low-grade and

pr
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

e-
concomitant chemotherapy, especially with induction therapy using a triple-drug
Pr

combination. However, as the median number of cycles of platinum and

pemetrexed administration in this study was 4 and 12, with appropriate dose
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reduction, this combination therapy could be safely administered for an

n

extended period.
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This study had a few limitations. First, this is a phase 2 trial with a
Jo

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
 17

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-

f
line treatment for EGFR-mutated advanced non-squamous NSCLC (FLAURA2

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study, ClinicalTrials.gov identifier no. NCT04035486), we believe that the results

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of the current OPAL study will impact future first-line treatment strategies for

EGFR-mutated advanced non-squamous NSCLC.

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Acknowledgments

The authors thank all the patients and their families for supporting this study.
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We also thank all the investigators for supporting this study: Efficacy Evaluation
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Committee Members: Hirohisa Yoshizawa, Akinobu Yoshimura, and Yuichi

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Takiguchi; Safety Evaluation Committee Member: Yasuo Saijo; Study secretary:

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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.

 18

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23. La Monica S, Minari R, Cretella D, et al. Third generation EGFR inhibitor

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Cancer Res. 2019;38:222. https://doi.org/10.1186/s13046–019–1240–x

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24. Nilsson MB, Robichaux J, Herynk MH, et al. Altered regulation of HIF-1α in

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25. Moore S, Wheatley-Price P. EGFR combination therapy should become the

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new standard first-line treatment in advanced EGFR-mutant NSCLC. J

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26. Ohe Y, Imamura F, Nogami N, et al. Osimertinib versus standard-of-care

EGFR-TKI as first-line treatment for EGFRm advanced NSCLC: FLAURA

Japanese subset. Jpn J Clin Oncol. 2019;49:29–36.

https://doi:10.1093/jjco/hyy179.
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Figure captions

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Figure 1. Waterfall plots showing the response depth for Arm A, Arm B, and the
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total population.
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Figure 2. Kaplan–Meier survival curves. (A) Progression-free survival curves

(PFS) in the total population. (B) Overall survival (OS) curves in the total
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population. (C) PFS curves in arms A and B. (D) OS in arms A and B.

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Figure 3. Progression-free survival (PFS) and overall survival (OS) based on

mutation subtype. (A) PFS of patients in the total population. (B) OS of patients

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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.

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Table 1. Patient characteristics

Cisplatin cohort Carboplatin cohort

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Characteristic Total, No. (%)

(arm A), No. (%) (arm B), No. (%)
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No. of patients 34 33 67
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Sex
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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)

 26

Former or
10 (29.4) 11 (33.3) 21 (31.3)
current

ECOG PS score

0 24 (70.6) 22 (66.7) 46 (68.7)

1 10 (29.4) 11 (33.3) 21 (31.3)

Histology

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Adenocarcinoma 33 (97.1) 33 (100) 66 (98.5)

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Other 1 (2.9) 0 (0) 1 (1.5)

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Stage

IVa 13 (38.2) 14 (42.4) 27 (40.3)

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IVb 17 (50.0) 15 (45.5) 32 (47.8)
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Recurrence 4 (11.8) 4 (12.1) 8 (11.9)

CNS metastasis
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Yes 12 (35.3) 10 (30.3) 22 (32.8)

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No 22 (64.7) 23 (69.7) 45 (67.2)

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EGFR mutation
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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
 27

Table 2. Objective response

Carboplatin arm
Cisplatin arm (A) Total
(B)

No. % No. % No. %

Total no. of
33 100 33 100 66 100
patients

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CR 0 0.0 2 6.1 2 3.0

PR 30 90.9 28 84.8 58 87.9

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SD 3 9.1 1 3.0 4 6.1

PD 0 0.0 1 3.0 1 1.5

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NE 0 0.0 1 3.0 1 1.5
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ORR, %
90.9 (81.1–100) 90.9 (81.1–100) 90.9 (84.0–97.8)
(95%CI)
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CR rate, %
0 (0–0) 6.1 (0–14.2) 3.0 (0–7.2)
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(95%CI)
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DCR, %
100 (100–100) 93.9 (85.8–100) 97.0 (92.8–100)
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(95%CI)

Abbreviations: CR, complete response; PR, partial response; SD, stable

disease; PD, progressive disease; NE, not evaluable; ORR, objective response

rate; DCR, disease control rate

 28

Table 3. Adverse

events

Grade, No. (%)

Arm A (n = 34) Arm B (n = 33) Total (n = 67)

Most commonly
All All All
reported AEs and ≥3 ≥3 ≥3
grade grade grade

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selected AEs

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Neutrophil count 22 10 29 20 51 30

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decreased (64.7) (29.4) (87.9) (60.6) (76.1) (44.8)

32 32 10 64 15
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Anemia 5 (14.7)
(94.1) (97.0) (30.3) (95.5) (22.4)
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Platelet count 28 31 14 59 14
0 (0.0)
decreased (82.4) (93.9) (42.4) (88.1) (20.9)
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13 22
Fatigue 9 (26.5) 2 (5.9) 2 (6.1) 4 (6.0)
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(39.4) (32.8)
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18 12 30
Mucositis oral 1 (2.9) 0 (0.0) 1 (1.5)
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(52.9) (36.4) (44.8)

20 19 39
Anorexia 5 (14.7) 4 (12.1) 9 (13.4)
(58.8) (57.6) (58.2)

23 18 41
Nausea 0 (0.0) 2 (6.1) 2 (3.0)
(67.6) (54.5) (61.2)

12
Vomiting 6 (17.6) 1 (2.9) 6 (18.2) 1 (3.0) 2 (3.0)
(17.9)
 29

13 10 23
Constipation 0 (0.0) 1 (3.0) 1 (1.5)
(38.2) (30.3) (34.3)

17 15 32
Diarrhea 0 (0.0) 0 (0.0) 0 (0.0)
(50.0) (45.5) (47.8)

15 12 27
Rash acneiform 1 (2.9) 1 (3.0) 2 (3.0)
(44.1) (36.4) (40.3)

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15 23

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Dry skin 2 (5.9) 8 (24.2) 0 (0.0) 2 (3.0)
(44.1) (34.3)

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Pruritus 4 (11.8) 1 (2.9) 5 (15.2) 0 (0.0) 9 (13.4) 1 (1.5)

11 20
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Paronychia 9 (26.5) 2 (5.9) 0 (0.0) 2 (3.0)
(33.3) (29.9)
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Aspartate
28 28 56
aminotransferase 1 (2.9) 3 (9.1) 4 (6.0)
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(82.4) (84.8) (83.6)

increased
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Alanine
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23 22 45
aminotransferase 3 (8.8) 3 (9.1) 6 (9.0)
(67.6) (66.7) (67.2)
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increased

Creatinine 25 23 48
0 (0.0) 0 (0.0) 0 (0.0)
increased (73.5) (69.7) (71.6)

23 16 39
Hyponatremia 3 (8.8) 0 (0.0) 3 (4.5)
(67.6) (48.5) (58.2)

12 20
Hypokalemia 8 (23.5) 3 (8.8) 3 (9.1) 6 (9.0)
(36.4) (29.9)
 30

16 23
Hyperkalemia 0 (0.0) 7 (21.2) 0 (0.0) 0 (0.0)
(47.1) (34.3)

Electrocardiogram
12 15 27
QT-corrected interval 4 (11.8) 4 (12.1) 8 (11.9)
(35.3) (45.5) (40.3)
prolonged

Ejection fraction 16
9 (26.5) 2 (5.9) 7 (21.2) 3 (9.1) 5 (7.5)

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decreased (23.9)

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Pneumonitis 2 (5.9) 0 (0.0) 1 (3.0) 0 (0.0) 3 (4.5) 0 (0.0)

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Febrile neutropenia 0 (0.0) 0 (0.0) 2 (6.1) 2 (6.1) 2 (3.0) 2 (3.0)

Abbreviations: AE, adverse event

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List of Supplementary material

Supplementary Figure 1. Study design

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Supplementary Figure 2. Study population flowchart

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Supplementary Figure 3. Progression-free survival (PFS) and overall

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survival (OS) based on the presence or absence of brain metastasis at

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baseline

Supplementary Figure 4. The status of treatment delivery

Supplementary Table 1. Dose reduction level

Supplementary Table 2. Precision of estimating ORR

Supplementary Table 3. Objective response based on mutation subtype

Supplementary Table 4. Objective response, median PFS, and median OS

based on the presence or absence of brain metastasis at baseline

 31

Supplementary Table 5. Treatment delivery

Supplementary Table 6. Dose reduction status at each cycle

Supplementary Table 7. Previous trials that examined EGFR–TKIs with

either chemotherapy or anti-VEGF antibody combinations as first-line

treatment

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 32

CRediT Statement:

Kunihiko Kobayashi: Resources, Conceptualization, Investigation, Visualization,

Writing - review and editing.

Hajime Asahina: Resources, Conceptualization, Investigation, Writing.

Ryota Saito, Shunichi Sugawara, Ryo Ko, Koichi Azuma, Ryo Morita, Makoto

Maemondo, Satoshi Oizumi, Kazuhisa Takahashi, Hiroshi Kagamu, Yukari

f
Tsubata, Masahiro Seike, Toshiaki Kikuchi, Isamu Okamoto, Satoshi Morita,

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Kentaro Tanaka, and Kenji Sugio: Resources, Investigation, Writing - review

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and editing. e-
Declaration of Competing Interest
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☐ The authors declare that they have no known competing financial interests or
personal relationships that could have appeared to influence the work reported
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in this paper.
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☒The authors declare the following financial interests/personal relationships which may be
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considered as potential competing interests:

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 33

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,

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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.
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Dr. Maemondo reports grants from Boehringer Ingelheim, and personal fees from AstraZeneca, Chugai,
Boehringer Ingelheim, and Pfizer.
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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.
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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,
n

Bristol-Myers Squibb, Chugai Pharmaceutical, Ono Pharmaceutical, Taiho Pharmaceutical.

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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.
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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
 34

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,

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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.

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 35

Highlights

 •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,

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84.0–97.8).

 •The median PFS was 31.0 months (95% CI, 26.8 months–not reached).

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