PHASE II STUDIES

Osimertinib for patients with poor performance status and EGFR

T790M mutation-positive advanced non-small cell lung cancer:

a phase II clinical trial

Kazuhisa Nakashima

1,2

& Yuichi Ozawa

& Haruko Daga

& Hisao Imai

& Motohiro Tamiya

& Takaaki Tokito

Takahisa Kawamura

& Hiroaki Akamatsu

& Yuko Tsuboguchi

& Toshiaki Takahashi

& Nobuyuki Yamamoto

Keita Mori

& Haruyasu Murakami

Received: 26 March 2020 /Accepted: 29 April 2020

Springer Science+Business Media, LLC, part of Springer Nature 2020

Summary

Osimertinib is a molecularly targeted agent used to treat non-small cell lung cancer (NSCLC) patients with an epidermal growth

factor receptor (EGFR) T790M mutation. However, its efficacy and safety profile when patients have poor performance status

(PS) is unknown. Therefore, we conducted an open-label, multi-center, single-arm phase II study to evaluate its efficacy and

safety in EGFR T790M mutation-positive NSCLC patients with Eastern Cooperative Oncology Group PS scores of between 2

and 4. Patients received 80 mg of osimertinib once daily. Our primary endpoint was progression-free survival. Eighteen patients

were enrolled between June 2017 and November 2018. The median age was 77 years (range: 55–85 years). Ten, six, and two

patients had PS scores of 2, 3, and 4, respectively. All patients had adenocarcinoma with common EGFR mutations and had been

treated with first- or second-generation EGFR- tyrosine kinase inhibitors previously. The overall median progression-free

survival was 7.0 months (90% confidence interval: 5.5–8.9 months). The overall response rate and median overall survival were

53% and 12.7 months, respectively. Moreover, improved PS scores were observed in 72% of the patients. Although the incidence

of grade 3 adverse events was low, with no grade 4 or 5 events observed, three patients required treatment cessation due to the

development of interstitial lung disease. Osimertinib therapy could be beneficial for EGFR T790M mutation-positive advanced

NSCLC patients with poor PS. This trial was registered with the Japan Registry of Clinical Trials on March 12, 2019 (trial no.

jRCT1041180081).

Keywords EGFR T790M mutation-positive

Non-small-cell lung cancer

Osimertinib

Poor performance status

Introduction

Lung cancer is the most common type of cancer worldwide,

with approximately 85% of diagnosed lung cancers being

non-small cell lung can cer (NSCLC). About 70% of

NSCLC patients are diagnosed at advanced stages, and the

disease is a common cause of cancer-related mortality [1, 2].

Epidermal growth factor receptor (EGFR) gene mutations

are detected in roughly 30% of East Asian NSCLCs patients

[3, 4]. First- and second-generation EGFR tyrosine kinase

* Kazuhisa Nakashima

kazuhin@med.shimane-u.ac.jp

Division of Thoracic Oncology, Shizuoka Cancer Center,

Shizuoka, Japan

Department of Internal Medicine, Division of Medical Oncology &

Respiratory Medicine, Shimane University Faculty of Medicine, 89-1

Enya-cho, Izumo, Shimane, Japan

Internal Medicine III, Wakayama Medical University,

Wakayama, Japan

Department of Medical Oncology, Osaka City General Hospital,

Osaka, Japan

Division of Respiratory Medicine, Gunma Prefectural Cancer Center,

Ota, Gunma, Japan

Department of Thoracic Oncology, Osaka International Cancer

Institute, Osaka, Japan

Department of Medicine, Division of Respirology, Neurology, and

Rheumatology, Kurume University School of Medicine,

Fukuoka, Japan

Clinical Research Center, Shizuoka Cancer Center, Shizuoka, Japan

Investigational New Drugs

https://doi.org/10.1007/s10637-020-00943-0

inhibitors (TKIs) have yielded promising response rates in

EGFR-mutant NSCLC patients. However, most patients ex-

perience disease progression within 9–13 months after EGFR-

TKIs treatment [5–10]. In about 60% of patients, an additional

EGFR mutation, T790M, is detected at the time of disease

progression. [11]. Osimertinib is a third-generation EGFR-

TKI reported t o be effective against NSCLC with EGFR

T790M mutation [12, 13]. Therefore, osimertinib monothera-

py is the standard treatment for EGFR T790M-positive

NSCLC patients with a good performance status (PS).

In our previous retrospective study, osimertinib therapy

yielded favorable outcomes and safety profile, even in

EGFR T790M mutation-positive advanced NSCLC patients

with poor PS [14]. However, the efficacy and safety of

osimertinib in patients with poor PS required further investi-

gation. Therefore, we conducted an open-label, multi-center,

single-arm phase II study to evaluate the efficacy of

osimertinib in EGFR T790M muta tion- po sitive advanced

NSCLC patients with Eastern Cooperative Oncology Group

(ECOG) PS scores of between 2 and 4.

Patients and methods

Patient selection

The eligibility criteria were as follows: 1) age of 20 years or

older, 2) histologically or cytologically confirmed advanced

(Stage IIIB, IV, postoperative recurrence, or recurrence after

radiotherapy) NSCLC, 3) ECOG PS 2–4 (PS was assessed by

more than two doctors), 4) treatment with first- or second-

generation EGFR-TKIs, 5) positive EGFR-T790M mutation

detection, 6) the presence of evaluable lesions, and 7) ade-

quate organ function.

The exclusion criteria were 1) treatment with third-

generation EGFR-TKIs, 2) diagnosis of interstitial pneumonia,

3) corrected QT interval (QTc) >470 msec obtained from an

electrocardiogram, 4) presence of uncontrolled pleural effusion,

ascites or pericardial effusion, 5) reception of palliative thoracic

radiotherapy, 6) administration of immune checkpoint inhibi-

tors in the latest treatment line, 7) the presence of a severe

complication, and 8) pregnancy or breastfeeding status.

All patients provided written informed consent.

Osimertinib treatment

Enrolled patients received a single dose of 80 mg osimertinib

daily. Treatment continued until disease progression or the

development of severe side effects. Treatment efficacy was

assessed using the Response Evaluation Criteria in Solid

Tumors (RECIST), version 1.1. Adverse events were evaluat-

ed using the Common Terminology Criteria for Adverse

Events (CTCAE), version 4.0.

Statistical analysis

The primary endpoint was progression-free survival (PFS).

PFS was defined as the interval between the date of enrollment

and the date of the first observation of disease progression or

death. Several studies reported the efficacy of carboplatin plus

paclitaxel therapy for patients with NSCLC and PS 2 [15–18].

The median PFS was appro ximately 3 months for the

carboplatin plus paclitaxel therapy for Japanese patients with

NSCLC and PS 2 [18]. In our previous study, the median PFS

was 8.2 months for osimertinib therapy for patients with

NSCLC and poor PS [14]. Therefore, the PFS threshold of

3.0 months and an expected PFS of 8.2 months was set for

the present study. To reach 5% (one-sided) significance and

80% statistical power, a minimum sample size of 17 patients

was calculated to be required, based on the statistical model

described by Brookmeyer and Crowley [19]. Assuming a 10%

exclusion rate, the planned sample size was 18 patients.

The second ary endpoints were overall response rate

(ORR), PS improvement rate, overall survival (OS), and ad-

verse events. ORR was defined as the proportion of patients in

whom the best response was a partial or complete response

among patients with target lesions. PS improvement rate was

defined as the proportion of patients whose best PS during the

study-treatment was improved from baseline. OS was defined

as the interval between the date of enrollment and that of

death. PFS and OS were estimated using the Kaplan–Meier

method. Subgroup analysis based on PS and local existence

(central nervous system metastasis, carcinomatous pleural ef-

fusion, or bone metastasis) was performed.

Results

Patient characteristics

Eighteen patients, including 4 men and 14 women, were en-

rolled in this study from June 2017 to November 2018. The

patient characteristics are listed in Table 1. The median age

was 77 (range: 55–85) years. Ten, six, and two patients had PS

scores of 2, 3, and 4, respectively. All patients had been treat-

ed with first- or second-generation EGFR-TKIs and harbored

common EGFR mutations (either exon 19 deletion or exon 21

L858R point mutation). T790M was detected in the tumor

samples of 7 patients, and the blood samples of 11 patients.

Overall efficacy

Response to treatment was evaluated in 17 patients because

one patient did not have target lesions. A waterfall plot for the

percentage change in target-lesion size is shown in Fig. 1.

Zero, nine, five, and three patients showed complete response,

partial response, stable disease state, and progressive disease

Invest New Drugs

state, respectively. The ORR was 53% (95% confidence inter-

val: 31–74%) and the disease control rate was 82% (95%

confidence interval: 59–94%). The median time to response

(n = 9) was 1.5 months, and the median duration of response

was 6.7 months.

The patients had a median PFS duration of 7.0 months

(90% confidence interval: 5.5–8.9 months, and 95%

confidence interval: 5.5–11.0 months) (Fig. 2). The median

PFS of patients with central nervous system metastasis, carci-

nomatous pleural effusion, and bone me tastasis were

6.5 months, 5.3 months, and 7.8 months, respectively. The

median follow-up period for OS was 8.7 months; patients

had a median OS of 12.7 months (95% confidence interval:

7.3–NA months) (Fig. 3).

The overall changes in the PS scores during treatment are

shown in Fig. 4. The PS score improved in 13 out of 18

patients (72%), while 8 patients (44%) showed an improve-

ment to a score of 1. The results of the subgroup analysis of

performance status scores are shown in Table 2.Patientswith

PS scores of 3–4 had a lower ORR and disease control rate, as

well as shorter PFS and OS than patients with PS scores of 2.

Efficacy in patients with PS score of 4

Our study included two patients with a PS score of 4. The first

patient was a 78-year-old woman who had an adenocarcinoma

with a deletion in EGFR exon 19. She had a poor PS, owing to

bone metastasis-related pain. EGFR T790M mutation was de-

tected in the blood sample. Although she showed only a 3%

shrinkage of the primary lesions after osimertinib administra-

tion, the pain was alleviated and the PS score improved to 1,

which was the best PS score during treatment. She had a PFS

of 8.1 months.

The s econd patient was a 71-year-old man, who was

diagnosed with adenocarcinoma harboring an EGFR

L858Rmutationinexon21.Thepatientalsohadbrain

metastasis and carcinomatous meningitis. EGFR T790M

mutation was detected in the blood sample. Despi te

osimertinib administration, the meningitis symptoms and

PS score did not improve. Osimertinib administration was

discontinued on day 25 due to his central nervous system

Table 1 Patient characteristics

N =18

Age Median (range) 77 (55–85)

Sex Male

Female

ECOG performance status score 2

CNS metastasis Positive

Negative

Carcinomatous pleural effusion Positive

Negative

Bone metastasis Positive

Negative

Histology Adenocarcinoma 18

Previous EGFR-TKI therapy Gefitinib

Erlotinib

Afatinib

Number of previous anticancer

regimens for advanced disease

Median

Range

1–6

Type of EGFR mutation Exon 19 deletion

Exon 21 L858R

EGFR T790M mutation Blood samples

Tumor samples

CNS central nervous system, EGFR epidermal growth factor receptor,

ECOG Eastern Cooperative Oncology Group, TKI tyrosine kinase

inhibitor

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

Best percentage change in target-lesion size (%)

Baseline performance status score

2 (n = 9)

3(n=6)

4(n=2)

Overall response rate: 53%

95% conﬁdence interval: 31-74%

Fig. 1 Waterfall plots for the best

percentage change in target-lesion

size

Invest New Drugs

metastasis progression; he died on day 42 of treatment

initiation.

Safety

The adverse events experienced by patients during osimertinib

treatment are listed in Table 3. Although anemia, rash, and

anorexia were frequently reported, the incidence of grade 3

adverse events was low, and no grade 4 or 5 events were

observed. In 7 patients, osimertinib treatment was interrupted

once because of adverse events. Four of these patients re-

quired a dose reduction to 40 mg once daily because of grade

2 anorexia, grade 2 rash, or grade 3 rash.

Three patients that experienced interstitial l ung disease

(ILD) withdrew from osimertinib treatment. These pa-

tients were all women, and they were aged 71, 79, and

80 years old. Two of them had a PS score of 2, while one

had a PS score of 3. The time of ILD incidence was

0.9 months, 6.5 months, and 7.5 months, respectively.

All three patients recovered from ILD after treatment with

steroids.

Post-study treatment

By the cut-off date of osimertinib treatment, 16 out of 18

patients had experienced disease progression. Five of t hem

continued receiving osimertinib, while two patients re-

ceived post-study treatment with cytotoxic chemotherapy.

Discussion

In our phase II clinical trial, osimertinib therapy demonstrated

favorable efficacy and safety outcomes in patients with EGFR

100

0 5 10 15 20

PFS probability (%)

Months

Median PFS: 7.0 months

90% conﬁdence interval: 5.5–8.9 months

95% conﬁdence interval: 5.5–11.0 months

Fig. 2 Kaplan-Meier curve for

progression-free survival (PFS)

100

0 5 10 15 20 25

OS probability (%)

Months

Median OS: 12.7 months

95% conﬁdence interval: 7.3–NA months

Fig. 3 Kaplan-Meier curve for

overall survival (OS)

Invest New Drugs

T790M mutation-positive advanced NSCLC that have a poor

PS. The median PFS of 7.0 months met the primary endpoint;

the lower limit of the 90% confidence interval for the PFS was

5.5 months. The ORR was 53%, and the median OS was

12.7 months. Moreover, the median PFS of patients with cen-

tral nervous system metastasis, carcinomatous pleural effu-

sion, and bone metastasis were 6.5 months, 5.3 months, and

7.8 months, respectively. The treatment achieved an effect to

some extent, regardless of local existence. The improvements

in PS observed in our study were also promising.

Our study included ten patients with a PS score of 2 and

eight with PS scores of 3–4. In patients with PS score of 2, the

overall response rate was 67%, the media n PFS was

7.7 months, and the median OS was 22.0 months. In patients

with PS scores of 3–4, the overall response rate was 38%, the

median PFS was 5.5 months, and the median OS was

6.6 months. These outcomes are not as good as those observed

in previous studies, which reported ORRs of 61–71% and

median PFS durations of 9.6–10.1 months in patients with

good PS scores [12, 13]. Osimertinib therapy might be less

effective in patients with poor PS, especially in those with PS

PS before

the treatment

Best PS during

the treatment

Performance Status

Fig. 4 Change in the performance status (PS) of each patient during

treatment

Table 2 Subgroup analysis of

performance status (PS) score

All PS 2 PS 3/4

(n =18) (n =10) (n =8)

Tumor response*

Partial response 9 6 3

Stable disease 5 2 3

Progressive disease 3 1 2

Overall response rate 53% 67% 38%

Disease control rate 82% 89% 75%

PS score improvement 72% 60% 88%

PS score improvement to score of 1 44% 60% 25%

Median progression-free survival 7.0 months 7.7 months 5.5 months

Median overall survival 12.7 months 22.0 months 6.6 months

*Tumor response was evaluated in 17 patients because one patient had no target lesions

Table 3 Adverse events graded according to the common toxicity

criteria for adverse events (CTCAE)

All Grade 1 Grade 2 Grade 3 Grade 4

Hematologic AEs

Anemia 10 6 4 0 0

Thrombocytopenia 8 7 1 0 0

Leucopenia 4 0 4 0 0

Neutropenia 4 1 1 2 0

Nonhematologic AEs

Rash 10 7 2 1 0

Anorexia 10 3 4 3 0

Paronychia 9540–

Fatigue 9 5 2 2 –

Dryskin 8800–

Creatinine elevation 6 5 1 0 0

Diarrhea 55000

Pruritus 5 4 1 0 –

Constipation 4 3 1 0 0

Interstitial lung disease 3 0 2 1 0

AE Adverse event

Invest New Drugs

scores of 3–4. Nevertheless, osimertinib treatment for patients

with poor PS could still be beneficial and clinically meaning-

ful, considering that cytotoxic chemotherapy provides limited

benefits in NSCLC patients with a PS score of 2, and that

currently, the only option for patients with PS scores of 3–4

is best supportive care.

The safety profile of osimertinib in our patients was also

favorable. However, three patients (17%) experienced ILD.

Although their ILD was successfully managed with appropri-

ate treatment and no grade 4 or 5 events were observed, ILD is

a severe adverse event associated with EGFR-TKI use [20].

The frequency of occurrence of ILD is reportedly higher in

patients treated with osimertinib than in those treated with

other EGFR-TKIs or cytotoxic chemotherapy [13, 21]. In pa-

tients with poor PS, osimertinib-induced ILD may be more

prevalent; therefore, the use of osimertinib in such patients

requires careful observation.

Our study had several limitations. First, the cohort size

was very small (18 patients). Moreover, our present study

included only two patients with a PS score of 4 , while our

previous retrospective study included no patients with a

PS score of 4 [14]. Therefore, the potential clinical benefit

of osimertinib for patients with PS score of 4 remains

unclear. Second, the evaluation of PS was very difficult.

PS w as ass ess ed by more tha n two docto rs in our st udy .

However, bias arising from the investigator’s subjectivity

can not be excluded completely. Furthermore, despite

osimertinib being the first-line treatment for patients with

EGFR T790M mutation-positive advanced NSCLC [21],

our study excluded treatment-naive patients. Therefore,

the efficacy and safety of osimertinib as a first-line treat-

ment for patients with poor PS remain unknown.

However, osimertinib might not be the best option as a

first-line treatment for NSCLC patients with poor PS who

can receive other EGFR-TKIs. In our study, the frequency

of occurrence of ILD was high, although all three patients

recovered from ILD. Poor PS may increase the risk for

osimertinib-related ILD. Inoue et al. r eported the efficacy

and safety of gefitinib for EGFR-TKI-naive patients with

poor PS [22]. In their study, the ORR was 66%, the me-

dian PFS was 6.5 months, the PS improvement rate was

66%, and the incidence of ILD was 3.3%. Gefitinib might

be a better choice compared to osimertinib for EGFR-

TKI-naive patients with poor PS. Although the ILD risk

is high, osimertinib therapy could be a promising ap-

proach for patients harboring EGFR T790M mutations

had received other EGFR-TKIs, as the treatment options

for these patients are limited. In fact, only two patients

could receive post-study treatment other than osimertinib

after disease progression.

The treatment of advanced NSCLC has progressed re-

markably in the last years; however, the development of

therapies for patients with poor PS is not making the

required progress. Further studies are needed to establish

the most clinically beneficial approach to treating NSCLC

patients with poor PS.

Conclusions

Osimertinib therapy exhibited promising efficacy and safety

profiles in patients harboring EGFR T790M mutation-positive

advanced NSCLC who had a poor PS, and it could be a prom-

ising treatment option for such patients.

Authors’ contributions Kazuhisa Nakashima (Corresponding Author):

creating the study protocol, recruitment of patients, and writing the man-

uscript; Yuichi Ozawa: recruitment of patients and reviewing the manu-

script; Haruko Daga: recruitment of patients and reviewing the manu-

script; Hisao Imai: recruitment of patients and reviewing the manuscript;

Motohiro Tamiya: recruitment of patients and reviewing the manuscript;

Takaaki Tokito: recruitment of patients and reviewing the manuscript;

Takahisa Kawamura: recruitment of patients and reviewing the manu-

script; Hiroaki Akamatsu: recruitment of patients and reviewing the man-

uscript; Yuko Tsuboguchi: recruitment of patients and reviewing the

manuscript; Toshiaki Takahashi: recruitment of patients and reviewing

the manuscript; Nobuyuki Yamamoto: recruitment of patients and

reviewing the manuscript; Keita Mori (Primary biostatistician of the

study): creating the study protocol, statistical analysis, and reviewing

the manuscript; Haruyasu Murakami: creating the study protocol, recruit-

ment of patients, and writing the manuscript.

Funding information This research did not receive any specific grant

from funding agencies in the public, commercial, or not-for-profit sectors

Compliance with ethical standards

Conflict of interest Kazuhisa Nakashima declares that he has no conflict

of interest. Yuichi Ozawa had received personal fees from AstraZeneca,

Boehringer Ingelheim, and Chugai Pharma. Haruko Daga had received

personal fees from Boehringer Ingelheim, Chugai Pharma, and Ono

Pharmaceutical, and grants from Astella, Pfizer, and Taiho

Pharmaceutical. Hisao Imai declares that he has no conflict of interest.

Motohiro Tamiya had received personal fees from Asahi Kasei

Pharmaceutical, AstraZeneca, Chugai Pharma, Eli Lilly, MSD, and

Taiho Pharmaceutical, and personal fees and grants from Boehringer

Ingelheim, Bristol-Myers Squibb, and Ono Pharmaceutical. Takaaki

Tokito had received personal fees from AstraZeneca, Boehringer

Ingelheim, and Chugai Pharma. Takahisa Kawamura declares that he

has no conflict of interest. Hiroaki Akamatsu had received personal fees

from AstraZeneca, Boehringer Ingelheim, Chugai Pharma, and Pfizer.

Yuko Tsuboguchi declares that he has no conflict of interest. Toshiaki

Takahashi had received personal fees from Boehringer Ingelheim and

Roche Diagnostics K.K., grants from Ja pan Agency for Medical

Research and Development, and personal fees and grants from

AstraZeneca, Chugai Pharma, Eli Lilly, MSD, Ono Pharmaceutical, and

Pfizer. Nobuyuki Yamamoto had received personal fees fro m

AstraZeneca, and personal fees and grants from Boehringer Ingelheim

and Chugai Pharma. Keita Mori declares that he has no conflict of inter-

est. Haruyasu Murakami had received personal fees from Bristol-Myers

Squibb, Ono Pharmaceutical, and MSD, grants from Abbvie, Daiichi

Sankyo, and IQvia, and personal fees and grants from AstraZeneca,

Chugai Pharma, Eli Lilly, Taiho Pharmaceutical, and Takeda.

Invest New Drugs

Ethics approval All procedures performed in studies involving human

participants were in accordance with the ethical standards of the institu-

tional review board and the 1964 Helsinki declaration and its later amend-

ments or with comparable ethical standards. This trial was registered with

the Japan Registry of Clinical Trials on March 12, 2019 (trial no.

jRCT1041180081).

Informed consent Informed consent was obtained from all individual

participants included in the study.

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