
==== Front
Int J Clin Oncol
Int J Clin Oncol
International Journal of Clinical Oncology
1341-9625
1437-7772
Springer Nature Singapore Singapore

39190099
2588
10.1007/s10147-024-02588-y
Original Article
A phase 2 study of mobocertinib as first-line treatment in Japanese patients with non-small cell lung cancer harboring EGFR exon 20 insertion mutations
Yoh Kiyotaka 1
Azuma Koichi 2
Hayashi Hidetoshi 3
Nishio Makoto 4
Chikamori Kenichi 5
Ichihara Eiki 6
Watanabe Yasutaka 7
Asato Takayuki 8
Kitagawa Tadayuki 9
Fram Robert J. 10
http://orcid.org/0000-0002-6137-073X
Ohe Yuichiro yohe@ncc.go.jp

11
1 https://ror.org/03rm3gk43 grid.497282.2 Department of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa-Shi, Chiba, 277-8577 Japan
2 https://ror.org/057xtrt18 grid.410781.b 0000 0001 0706 0776 Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, 67, Asahi-Machi, Kurume, Fukuoka 830-0011 Japan
3 https://ror.org/05kt9ap64 grid.258622.9 0000 0004 1936 9967 Faculty of Medicine, Department of Medical Oncology, Kindai University, 377-2 Ōnohigashi,, Ōsakasayama-Shi, Ōsaka-Fu 589-0014 Japan
4 https://ror.org/00bv64a69 grid.410807.a 0000 0001 0037 4131 Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto, Tokyo 135-8550 Japan
5 https://ror.org/01v8mb410 grid.415694.b 0000 0004 0596 3519 Department of Medical Oncology, National Hospital Organization Yamaguchi-Ube Medical Center, 685 Higashi Kiwa, Ube, Yamaguchi 755-0241 Japan
6 https://ror.org/019tepx80 grid.412342.2 0000 0004 0631 9477 Center for Clinical Oncology, Okayama University Hospital, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558 Japan
7 https://ror.org/03a4d7t12 grid.416695.9 0000 0000 8855 274X Department of Thoracic Oncology, Saitama Cancer Center, 780 Komuro, Inamachi, Kitaadachi-Gun, Saitama, 362-0806 Japan
8 grid.419841.1 0000 0001 0673 6017 Oncology Clinical Research Department, Oncology Therapeutic Area Unit for Japan and Asia, Takeda Pharmaceutical Company Limited, 1-1, Doshomachi 4-Chome, Chuo-Ku, Osaka, 540-8645 Japan
9 grid.419841.1 0000 0001 0673 6017 Biostatistics, Japan Development Center, Takeda Pharmaceutical Company Limited, 1-1, Doshomachi 4-Chome, Chuo-Ku, Osaka, 540-8645 Japan
10 grid.419849.9 0000 0004 0447 7762 Takeda Development Center Americas, Inc, 40 Landsdowne Street, Cambridge, MA 02139 USA
11 https://ror.org/03rm3gk43 grid.497282.2 Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-Ku, Tokyo 104-0045 Japan
27 8 2024
27 8 2024
2024
29 10 14611474
24 4 2024
15 7 2024
© Takeda Pharmaceutical Company Limited 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Background

Mobocertinib is a novel, synthetic, orally administered tyrosine kinase inhibitor that inhibits many activated forms of epidermal growth factor receptor (EGFR), including those containing exon 20 insertion (ex20ins) mutations. This study aimed to assess the efficacy of mobocertinib in Japanese patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR ex20ins mutations.

Methods

This was a phase 2, open-label study. Patients with NSCLC harboring EGFR ex20ins mutations who had not had previous systemic treatment received mobocertinib 160 mg once daily. The primary endpoint was the confirmed objective response rate. A planned interim analysis was completed for the first 14 patients with a centrally confirmed EGFR ex20ins mutation, with enrollment stopped if the number of patients with an objective response was five or fewer.

Results

In total, 33 patients were enrolled into the study (63.6% women; median age: 66 years). At the interim analysis, the objective response rate evaluated by a central independent review committee was 28.6% (4/14, 90% confidence interval: 10.4–54.0); therefore, enrollment was stopped for futility. In the full analysis set, the objective response rate was 18.2% (6/33, 95% confidence interval: 7.0–35.5); of the six responders, one patient (3.0%) had a complete response and five patients (15.2%) had partial responses. The most common treatment-related adverse events were diarrhea, paronychia, stomatitis, and nausea.

Conclusion

Although study enrollment was terminated early owing to futility, our results showed modest activity of mobocertinib in Japanese patients with NSCLC with EGFR ex20ins mutations with no additional safety concerns.

Supplementary Information

The online version contains supplementary material available at 10.1007/s10147-024-02588-y.

Keywords

EGFR exon 20 insertion mutations
Mobocertinib
NSCLC
Tyrosine kinase inhibitor
Takeda Pharmaceutical Company Limitedissue-copyright-statement© Japan Society of Clinical Oncology 2024
==== Body
pmcIntroduction

Specific genetic lesions that drive the proliferation of cancer cells, such as those resulting in activation of certain tyrosine kinases, render many cancers highly sensitive to therapeutic agents that inhibit the affected kinase. These include activating mutations in the epidermal growth factor receptor gene (EGFR) which, according to a 2016 systematic review and meta-analysis, are found in around one-third of patients with non-small cell lung cancer (NSCLC) globally [1]. However, prevalence does vary geographically, with high mutation rates reported in Asian populations [1–3]. There are multiple classes of activating EGFR mutations, which vary widely in their degree of sensitivity to available tyrosine kinase inhibitors (TKIs). Given that inhibition of wild-type EGFR in normal tissues is associated with dose-limiting toxicities, substantial clinical benefit in NSCLC has been associated with TKIs that inhibit specific, activated variants of EGFR more potently than they inhibit wild-type EGFR [4].

The most common activating mutations in EGFR are in-frame deletions in exon 19 and a L858R substitution in exon 21, which together account for about 90% of all EGFR activating mutations [5–7]. The remaining 10–15% of de novo EGFR mutations comprise a cluster of in-frame insertions in exon 20 found in approximately 2% of all cases of NSCLC [1, 5, 8], as well as other rarer EGFR ‘uncommon’ point mutations [6]. Patients with NSCLC with EGFR exon 20 insertions exhibit similar clinical characteristics (e.g., age, smoking status, lung cancer subtype) to patients carrying common EGFR mutations [5, 9]. However, unlike mutations in exons 19 or 21, almost all EGFR exon 20 insertions confer in vitro and primary clinical resistance to the TKIs erlotinib, gefitinib, and afatinib [10–12]. Patients with exon 20 insertions are therefore more likely to benefit from novel targeted TKI therapies that selectively inhibit these particular EGFR mutations [4].

Although five TKIs targeting EGFR mutations (afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib) are approved in Japan, none are recommended in the Japan Lung Cancer Society clinical practice guidelines for the treatment of patients with EGFR exon 20 insertion mutations [13]. Mobocertinib is a novel, synthetic, orally administered TKI developed to address the limitations of these existing therapies. In clinical studies, mobocertinib has been shown to strongly inhibit many activated forms of EGFR, including those containing exon 20 activating insertions, uncommon activating mutations, or common activating mutations (exon 19 deletions and L858R) with or without the T790M resistance mutation [14]. A US phase 1/2 study of mobocertinib in platinum-pretreated patients with NSCLC with EGFR exon 20 insertion mutations determined that the maximum tolerated dose was 160 mg once daily (QD) [15]. A subsequent phase 1 study in Japan confirmed that this dose was also tolerable in a Japanese patient population [16]. Results from the Japanese study indicated that mobocertinib had a manageable safety profile in patients with NSCLC and provided pharmacokinetic data to support 160 mg QD as the recommended dose for phase 2 clinical studies in Japanese patients.

Here, we report the results of a phase 2 study designed to evaluate the efficacy of mobocertinib 160 mg QD in Japanese patients with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations and who have not previously received systemic treatment for locally advanced or metastatic disease.

Patients and methods

Study design

This was a phase 2, open-label, uncontrolled trial conducted at 17 sites in Japan with patients recruited between February 4, 2019 and March 10, 2021 (ClinicalTrials.gov: NCT03807778). The trial design included a 2–3-week screening period, a treatment period with a planned estimated average of 10–12 cycles (each cycle lasting 28 days), and a follow-up period. Mobocertinib 160 mg QD was self-administered until patients experienced progressive disease (PD) requiring an alternate therapy (in the opinion of the investigator), intolerable toxicity, or another discontinuation criterion.

The study protocol and associated documentation were reviewed by institutional review boards at each site. The study was carried out in compliance with the Declaration of Helsinki, the International Council for Harmonisation Good Clinical Practice guidelines, and all applicable local regulations. All patients provided written informed consent before enrollment.

Patients

Eligible patients were 20 years of age or older with histologically or cytologically confirmed locally advanced, recurrent, or metastatic (stage IV) NSCLC, measurable disease by RECIST v1.1, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1, a minimum life expectancy of at least 3 months, and adequate renal, hepatic, and bone marrow function. Patients could not have received prior systemic treatment for locally advanced or metastatic disease and had to have a locally documented EGFR in-frame exon 20 insertion mutation (either alone or in combination with other EGFR mutations [excluding exon 19 deletions or L858R] or human epidermal growth factor receptor 2 mutations). All patients had to have adequate tumor tissue available for central laboratory confirmation of EGFR exon 20 insertion mutation, which was confirmed using the Oncomine Dx Target Test. Key exclusion criteria were diagnosis of a primary malignancy other than NSCLC; spinal cord compression or leptomeningeal disease; significant, uncontrolled, or active cardiovascular disease; radiotherapy in the 14 days before the first dose of mobocertinib; or known active brain metastases. Patients were also excluded if they had received a moderate or strong cytochrome P450 3A inhibitor or inducer in the 10 days before the first dose of mobocertinib.

Study assessments

Disease assessment at screening included imaging of the chest, abdomen, pelvis, and brain using appropriate radiologic procedures (computed tomography scans or magnetic resonance imaging with contrast). Disease assessment was then performed at 8-week intervals (on Day 28 [± 7 days] of every even-numbered cycle) through cycle 14, and every three cycles thereafter until PD. Partial response (PR) and complete response (CR) were confirmed by a repeat tumor imaging assessment at least 4 weeks after the date the response was first documented.

Health-related quality of life (HRQoL) was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires, including lung cancer-specific module 13 (QLQ-LC13) v.3.0 [17]. Raw scores were converted into scale scores ranging from 0 to 100; for the functional scales and the global health status scale, higher scores represent better HRQoL, whereas for the symptom scales lower scores represent better HRQoL.

Treatment-emergent adverse events (hereafter referred to as AEs unless otherwise specified) were collected from study drug initiation to 30 days after study drug discontinuation or before the initiation of new anticancer therapy (whichever came first) and coded according to Medical Dictionary for Regulatory Activities (MedDRA) version 23.0. Severity grades were defined by the Common Terminology Criteria for Adverse Events version 5.0.

Study endpoints

The primary endpoint was the confirmed objective response rate (ORR; the proportion of patients who were confirmed to have achieved CR or PR), as assessed by the independent review committee (IRC) per RECIST v1.1. Confirmed responses were responses that persisted on repeat imaging for at least 4 weeks after initial response. Secondary endpoints included: confirmed ORR, as assessed by the investigator; duration of response (DOR), as assessed by the IRC and the investigator; disease control rate (DCR; the percentage of patients with best response of CR, PR, or stable disease [SD] of 42 days or longer) as assessed by the IRC and the investigator per RESIST v1.1; progression-free survival (PFS) as assessed by the IRC and the investigator; overall survival (OS); and patient-reported outcomes including the EORTC QLQ-LC13. Patients who discontinued study treatment in the absence of PD continued to have post-treatment PFS and OS follow-up assessments. Safety endpoints included AEs, laboratory values, vital signs, and physical examination findings.

Statistical methods

A sample size of 26 patients with centrally confirmed EGFR exon 20 insertion mutations was chosen based on an expected true ORR of 60% in the treatment-naive population and an ORR threshold response rate of 35%. This would give over 80% power to rule out an uninteresting rate of 35% in this population, with a 1-sided α of 0.05. The expected true ORR was based on the results of a preliminary efficacy analysis of mobocertinib, which demonstrated an ORR of approximately 60% in patients with unresectable advanced or recurrent NSCLC harboring EGFR exon 20 insertion mutations who had received prior chemotherapy. Also taking into consideration the general health status of chemotherapy-naïve patients, the expected response rate was therefore set at 60%. In chemotherapy-naïve patients with unresectable advanced or recurrent NSCLC positive for EGFR mutations, first-line treatment with platinum-based chemotherapy has been reported to have response rates ranging from 14.9 to 47.3% [18–25]; therefore the threshold ORR was set at 35% for our study.

The full analysis set (FAS) and safety population both included all patients who received at least one dose of mobocertinib. The centrally confirmed population (CCP) was defined as the first 26 patients with confirmed EGFR exon 20 insertion mutation by central test who received at least one dose of mobocertinib. An interim analysis for both futility and efficacy was planned based on the primary endpoint after the first 14 centrally confirmed patients had the opportunity to complete the ‘cycle 7, Day 1’ disease assessment. If the number of patients with a confirmed objective response was five or fewer, enrollment would be stopped for futility. If the number of patients with a confirmed objective response was nine or more, mobocertinib would be considered efficacious in this population.

For the primary analysis, a point estimate and 90% 2-sided exact confidence interval (CI) were calculated for the IRC-assessed confirmed ORR. For secondary analysis of the primary endpoint, the IRC-assessed confirmed ORR and 95% 2-sided exact CI were calculated using the CCP and the FAS. Secondary endpoints were also assessed in both the CCP and the FAS. For time-to-event endpoints, the Kaplan–Meier method was used; PFS, OS, and DOR were computed at 12 and 24 months.

Results

Patients

In total, 38 patients were screened and 33 enrolled into the study (Fig. 1). The median age was 66 years, 63.6% (21/33) of patients were women, 48.5% (16/33) had stage IVA disease at screening, and 63.6% (21/33) of patients had an ECOG PS of 0 (Table 1). There were 23 (69.7%) patients who had their EGFR exon 20 insertion mutation confirmed by central test; those whose mutation could not be confirmed centrally had either defective tumor tissue samples or insufficient quantities of DNA for testing.Fig. 1 Patient disposition. EGFR epidermal growth factor receptor

Table 1 Patient baseline characteristics (safety population)

	Mobocertinib 160 mg QD (N = 33)	
Age, years		
 Median	66.0	
 Minimum, maximum	39, 84	
Age category, years, n (%)		
  < 50	4 (12.1)	
 50– < 65	12 (36.4)	
 65– < 75	11 (33.3)	
  ≥ 75	6 (18.2)	
Sex, n (%)		
 Male	12 (36.4)	
 Female	21 (63.6)	
NSCLC stage at screening, n (%)		
 IVA	16 (48.5)	
 IVB	15 (45.5)	
 Othera	2 (6.1)	
Time since initial diagnosis, months		
 Median	1.90	
 Minimum, maximum	0.5, 166.0	
ECOG PS, n (%)		
 0	21 (63.6)	
 1	12 (36.4)	
CNS involvement at screening, n (%)		
 Yes	16 (48.5)	
 No	17 (51.5)	
Histopathological classification of NSCLC, n (%)		
 Adenocarcinoma	33 (100.0)	
Smoking history, n (%)		
 Never	17 (51.5)	
 Former	16 (48.5)	
EGFR exon 20 insertion mutation		
 Detected by local test, n (%)	33 (100.0)	
 Confirmed by central test, n (%)	23 (69.7)	
aIncludes postoperative recurrence and postoperative relapse

CNS central nervous system, ECOG Eastern Cooperative Oncology Group, EGFR epidermal growth factor receptor gene, NSCLC non-small cell lung cancer, PS performance status, QD once daily

All 33 patients received at least one dose of study drug. Here, data are presented as of November 8, 2021, at which point 11 patients were still receiving treatment. Overall, the median (range) duration of study drug exposure was 8.3 (0.4–18.0) months. The median (range) dose intensity was 114.8 (52–160) mg/day and the median (range) relative dose intensity was 71.7% (33–100). In total, eight patients (24.2%) experienced significant protocol deviations, which were most frequently related to concomitant medications (4 patients [12.1%]). None of the protocol deviations were considered to have had an impact on the efficacy or safety conclusions of the study.

Interim analysis

At the interim analysis (data cut-off: February 24, 2021), the IRC-assessed confirmed ORR for the first 14 patients in the CCP (primary endpoint) was 28.6% (4/14, 90% CI 10.4–54.0), and all four responders had PR as the best overall response. Because the number of patients with a confirmed objective response was five or fewer, enrollment was stopped for futility and the interim analysis became the primary analysis. Enrollment had not been suspended during the evaluation of the first 14 patients in the CCP, resulting in 33 patients being included in the FAS.

Efficacy outcomes

A summary of key final efficacy results as assessed by the IRC and the investigator for the FAS and the CCP is shown in Table 2. The IRC-assessed confirmed ORR in the FAS was 18.2% (6/33, 95% CI 7.0–35.5); of the six responders, one patient (3.0%) had CR and five patients (15.2%) had PR as best overall response (Table 3). The IRC-assessed confirmed ORR in the CCP was 13.0% (3/23, 95% CI 2.8–33.6); all three responders had PR as best overall response. One patient who was evaluated to have PR at the interim analysis had their response changed to SD at secondary analysis following a change in IRC reviewer. The investigator-assessed confirmed ORR in the FAS was 39.4% (13/33, 95% CI 22.9–57.9) and all responders had PR as best overall response (Table 3). In the CCP, this was 43.5% (10/23, 95% CI 23.2–65.5) and all 10 responders had PR as best overall response. Figure 2 shows the best percent change in target lesion as assessed by the IRC (panel a) and the investigator (panel b) for both the FAS and the CCP. Table 2 Summary of key efficacy results

Endpoint	Assessor	FAS (N = 33)	CCPa (N = 23)	
Responders, n/N	Point estimate (95% CI)	Responders,
n/N	Point estimate (95% CI)	
ORR	IRC	6/33	18.2% (7.0–35.5)	3/23	13.0% (2.8–33.6)	
Investigator	13/33	39.4% (22.9–57.9)	10/23	43.5% (23.2–65.5)	
DORb	IRC	–	7.4 months (3.7–NE)	–	7.4 months (7.3–NE)	
Investigator	–	7.4 months (3.6–NE)	–	6.6 months (1.8–NE)	
DCR	IRC	28/33	84.8% (68.1–94.9)	19/23	82.6% (61.2–95.0)	
Investigator	28/33	84.8% (68.1–94.9)	21/23	91.3% (72.0–98.9)	
PFSb	IRC	–	9.2 months (6.7–NE)	–	9.3 months (7.4–NE)	
Investigator	–	7.4 months (4.6–NE)	–	9.2 months (6.2–NE)	
aPatients whose tumor specimen had been retrospectively confirmed to have an EGFR exon 20 insertion mutation by an analytically validated central test

bData show median values

CCP centrally confirmed population, CI confidence interval, DCR disease control rate, DOR duration of response, FAS full analysis set, IRC independent review committee, NE not evaluable, ORR objective response rate, PFS progression-free survival

Table 3 Confirmed ORR (IRC- and investigator-assessed) (FAS)

Measure	Mobocertinib 160 mg QD (N = 33)	
IRC	Investigator	
Confirmed ORR (CR + PR), n (%)	6 (18.2)	13 (39.4)	
95% CIa	7.0–35.5	22.9–57.9	
Best overall response, n (%)			
CR	1 (3.0)	0 (0.0)	
PR	5 (15.2)	13 (39.4)	
SD	22 (66.7)	15 (45.5)	
Non-CR/non-PD	3 (9.1)	0 (0.0)	
PD	0 (0.0)	4 (12.1)	
NE	2 (6.1)	1 (3.0)	
aData show the exact Clopper–Pearson CI of the percentage

CI confidence interval, CR complete response, FAS full analysis set, IRC independent review committee, NE not evaluable, ORR objective response rate, PD progressive disease, PR partial response, QD once daily, SD stable disease

Fig. 2 Best percent change in target lesion as assessed by a the IRCa and b the investigatorb (FAS). aOf the 33 patients in FAS, five patients were excluded from the waterfall plot (three patients had no measurable target lesions by IRC assessment; two patients had no proper imaging assessment during study treatment). bOf the 33 patients in FAS, two patients were excluded from the waterfall plot (had no proper imaging assessment during study treatment). CR complete response, FAS full analysis set, IRC independent review committee, PD progressive disease, PR partial response, SD stable disease

The median DOR in the FAS was 7.4 months (95% CI 3.7–not evaluable [NE]) as assessed by the IRC and 7.4 months (95% CI 3.6–NE) as assessed by the investigator (Table 2). The DCR in the FAS was 84.8% (95% CI 68.1–94.9) as assessed by the IRC and 84.8% (95% CI 68.1–94.9) as assessed by the investigator (Table 2).

The median PFS in the FAS was 9.2 months (95% CI 6.7–NE) as assessed by the IRC and 7.4 months (95% CI 4.6–NE) as assessed by the investigator (Table 2). Kaplan–Meier estimates of PFS rates in the FAS at 6 and 12 months were 78.3% and 38.8%, respectively, as assessed by the IRC, and 64.5% and 36.3%, respectively, as assessed by the investigator (Fig. 3). Kaplan–Meier plots of OS in the FAS are presented in Fig. 4. The Kaplan–Meier estimated OS rates at 6 and 12 months were 93.9% and 80.3%, respectively. In total, eight patients (24.2%) died during the study and the median OS follow-up (12.1 months) was not reached.Fig. 3 PFS as assessed by a the IRC and b the investigator (FAS). FAS full analysis set, IRC independent review committee, PFS progression-free survival

Fig. 4 Overall survival (FAS). FAS full analysis set, OS overall survival

Swimlane plots of the IRC-assessed response profiles by patient in the FAS are shown in Fig. 5. In the FAS, 11 patients were still on study treatment at data cut-off, for whom the IRC-assessed best overall responses were CR (1 patient), PR (2 patients), and SD (8 patients).Fig. 5 Swimlane plot of IRC-assessed response profile by patient (FAS). Patients included in the CCP are shown by a filled circle; patients not included in the CCP are shown by an unfilled circle. CCP centrally confirmed population, CR complete response, FAS full analysis set, IRC independent review committee, PD progressive disease, PR partial response, SD stable disease

For the EORTC QLQ-LC13, there was no change from baseline in scores for dyspnea, coughing, hemoptysis, dysphagia, peripheral neuropathy, alopecia, pain in chest, pain in arm or shoulder, and pain (other parts) throughout the study. The mean (standard deviation) subscale score in sore mouth at baseline was 5.0 (12.0), which increased to 35.4 (30.6) at cycle 2. By cycle 6, the mean (standard deviation) score had improved to 17.2 (19.4), and this improvement was maintained throughout the remainder of the study.

Safety outcomess

An overview of AEs is provided in Supplementary Table S1. All patients had at least one AE and at least one treatment-related AE. The most common AEs were gastrointestinal disorders and skin and subcutaneous tissue disorders (Supplementary Table S2). AEs of grade 3 or higher were observed in 21 (63.6%) patients; the most frequently reported AE of grade 3 or higher was diarrhea (n = 7). The most common treatment-related AEs were diarrhea (n = 33), paronychia (n = 21), stomatitis (n = 20), and nausea (n = 19).

Overall, 81.8% (27/33) of patients had an AE leading to dose modification, 60.6% (20/33) had an AE leading to dose reduction, and 15.2% (5/33) discontinued treatment owing to an AE. Serious AEs (SAEs) were reported for 11 patients (33.3%). The most common SAE was decreased appetite (n = 3); all other SAEs were each reported in one patient. AEs resulting in death were reported in two patients (6.1%; cardiac failure and NSCLC); neither death was considered to be related to the study drug.

Discussion

This phase 2 study was designed to evaluate the efficacy of mobocertinib 160 mg QD in Japanese patients with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations and who had not previously received systemic treatment for locally advanced or metastatic disease. Results from the interim analysis showed that the IRC-assessed confirmed ORR in the first 14 centrally confirmed patients was 28.6% (4/14), which met the predefined criteria for futility and enrollment was terminated early.

Treating patients with NSCLC harboring EGFR exon 20 insertion mutations has been challenging owing to the limited efficacy of approved TKIs targeting EGFR mutations. The first- and second-generation EGFR TKIs only achieved response rates of approximately 10%, with an estimated median PFS of 1–3 months [26]. According to results from LC-SCRUM-Asia, a large-scale clinico-genomic database, Japanese patients with NSCLC harboring EGFR exon 20 insertion mutations treated with classical TKIs in the second-to-fourth line settings after platinum-based chemotherapy reported an ORR of 8% (95% CI 1.7–2.2) with a median PFS of 2.2 months (95% CI 1.6–3.7) [27]. In a phase 1/2 study that evaluated the third-generation EGFR TKI osimertinib (80 mg/day), none of the 12 enrolled patients with NSCLC harboring EGFR exon 20 insertion mutations experienced an objective response [28]. Seven (58.3%) and five (41.7%) patients had stable disease and disease progression, respectively, and the median PFS was 3.8 months.

To address these unmet medical needs, mobocertinib was developed to specifically target EGFR exon 20 insertion mutations. The antitumor activity of mobocertinib was demonstrated in an international phase 1/2 study that enrolled platinum-pretreated patients with NSCLC harboring EGFR exon 20 insertion mutations; the ORR was 28% (95% CI 20–37) and the IRC-assessed median PFS was 7.3 months (95% CI 5.5–9.2) [29]. Based on these results, mobocertinib was granted accelerated approval in the USA in September 2021 [30]. Subsequently, an international, phase 3, open-label study (EXCLAIM-2) compared first-line mobocertinib treatment to platinum-based chemotherapy in patients with locally advanced/metastatic NSCLC positive for EGFR exon 20 insertion mutations [31]. That study was terminated early owing to futility following the results of an interim analysis, in which the blinded IRC-assessed median PFS was similar for mobocertinib and platinum-based chemotherapy (9.6 months for both treatment arms).

The selection of ORR as the primary endpoint for our study was based on its utility as a marker of clinical improvement and discussions with Japanese regulatory authorities. Our results are comparable to those from the international mobocertinib studies [29, 31], though caution is warranted when comparing different studies. In our study, the IRC-assessed confirmed ORR was 18.2% (95% CI 7.0–35.5) and the median PFS was 9.2 months (95% CI 6.7–NE). Of note, our investigator-assessed confirmed ORR was 39.4%. The cause of this discrepancy was not clear. However, inconsistencies between assessments of ORR by investigators at local sites and assessments from blinded independent central review in uncontrolled oncology trials are not uncommon and have been reported elsewhere [32, 33].

Considering the available body of evidence, mobocertinib has demonstrated clinical activity in NSCLC harboring EGFR exon 20 insertion mutations, where efficacy has been historically low with other EGFR TKIs, albeit in different treatment line settings. The targeted efficacy of mobocertinib is also supported by data from a pre-clinical study, in which mobocertinib more potently inhibited the viability of multiple EGFR exon 20 insertion-driven cell lines than other TKIs and demonstrated in vivo antitumor efficacy in patient-derived xenograft animal models [14].

Regarding the tolerability profile of mobocertinib, high rates of dose reduction (60.6%) and dose interruption (81.8%) were observed in our study. However, the reported AEs were consistent with known AEs associated with other EGFR TKIs, and no new safety signals were observed [34]. Diarrhea is commonly observed with other EGFR TKIs, including afatinib, dacomitinib, and osimertinib [35–37], and this was the case with our study as well. The incidence of grade 3 or higher treatment-related diarrhea was 21.2% in our study which was similar to a previous phase 1/2 study [29].

Mobocertinib targets diverse EGFR exon 20 insertion mutations with selectivity over EGFR wild-type mutations [14]. However, skin-related AEs caused by off-targeting of EGFR wild-type mutations cannot be completely avoided. The types and severity of skin-related AEs observed with mobocertinib are consistent with those reported with other EGFR TKIs, with a low frequency of severe events [38].

Limitations of our study include the small sample size and that enrollment was terminated early owing to futility. In addition, relatively high rates of dose reduction and dose interruption, and a reduced relative dose intensity may have influenced the low ORR observed in our study. The study could have benefited from more experienced management of AEs to reduce the impact of these dose modifications. In the EXCLAIM-2 study, the frequency of AEs leading to dose interruption and dose reduction of mobocertinib was lower than in our study, likely reflecting the prophylactic management of AEs [31]. Finally, as EGFR exon 20 insertion mutations are highly heterogeneous, with more than 100 known variants [39], it is possible that some subtypes or specific variants may have conferred resistance to mobocertinib.

In conclusion, although our study was terminated early owing to futility, our results showed modest clinical activity of mobocertinib in Japanese patients with NSCLC harboring EGFR exon 20 insertion mutations and did not raise any additional safety concerns. Lastly, development of mobocertinib has now been terminated and market authorization has been voluntarily withdrawn (as of October 2023) from all relevant countries based on the results of the phase 3 EXCLAIM-2 study (NCT04129502).

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (PDF 174 KB)

Acknowledgements

The authors thank the patients and investigators at each study site for their contribution to this study. The authors also thank ICON plc, Osaka, Japan for clinical site monitoring, and LC-SCRUM-Asia, National Cancer Center Hospital East, Chiba, Japan, who actively contributed to patient enrollment. Medical writing support was provided by Emily Manktelow PhD from Oxford PharmaGenesis Melbourne and funded by Takeda Pharmaceutical Company Limited in accordance with Good Publication Practice (GPP 2022) guidelines (https://www.ismpp.org/gpp-2022).

Author contributions

TA and TK were responsible for the study conception and design. KY, KA, HH, MN, KC, EI, YW, TK, and YO were responsible for data acquisition. TA, TK, and RF were responsible for data analysis and all authors were responsible for data interpretation. All authors took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This study was sponsored by Takeda Pharmaceutical Company Limited.

Data availability

The data sets, including the redacted study protocol, redacted statistical analysis plan, and individual participant data supporting the results reported in this article, will be made available within three months from initial request to researchers who provide a methodologically sound proposal. The data will be provided after de-identification, in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization.

Declarations

Conflict of interest

KY has received honoraria or lecture fees from AbbVie, Amgen Inc., AstraZeneca plc, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo, Janssen Pharmaceuticals, Kyowa Kirin Co., Ltd, Lilly, Merck Serono, Novartis, Ono Pharmaceutical Co., Ltd, Otsuka Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd, and Takeda Pharmaceutical Co., Ltd; has received grants from AbbVie, Amgen Inc., AstraZeneca plc, Boehringer Ingelheim, Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo, Eli Lilly, MSD, Pfizer, Taiho Pharmaceutical Co., Ltd, and Takeda Pharmaceutical Co., Ltd. KA has received honoraria from AstraZeneca plc, Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd, MSD, Nippon Kayaku Co., Ltd, and Ono Pharmaceutical Co., Ltd. HH has received honoraria from Amgen Inc., AstraZeneca K.K, Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd, Daiichi-Sankyo K.K., Eli Lilly Japan K.K., Ono Pharmaceutical Co., Ltd, and Pfizer Japan Inc; has received fees for promotional materials from Guardant Health Japan Corp.; has received research funding from A2 Healthcare Corporation, AbbVie Inc., Amgen Inc., Astellas Pharma Inc., AstraZeneca K.K., Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd, CMIC Holdings Co., Ltd, Covance Japan Inc., Daiichi Sankyo Co., Ltd, Eisai Co., Ltd, EPS Corporation, GlaxoSmithKline K.K., IQVIA Services Japan K.K., Japan Clinical Research Operations, Janssen Pharmaceutical K.K., MSD K.K., Nippon Boehringer Ingelheim Co., Ltd, Novartis Pharma K.K., Pfizer R&D Japan G.K., PRA Health Sciences Inc., Sanofi K.K., Syneos Health clinical K.K., Taiho Pharmaceutical Co., Ltd, Takeda Pharmaceutical Co., Ltd, and West Japan Oncology Group; has received scholarship donations from Chugai Pharmaceutical Co., Ltd, Eisai Co., Ltd, Ono Pharmaceutical Co., Ltd, and Takeda Pharmaceutical Co., Ltd. MN has received honoraria or lecture fees from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo, Eli Lilly, Janssen, MSD, Nippon Kayaku, Novartis, Ono Pharmaceutical Co., Ltd, Pfizer, Taiho Pharmaceutical Co. Ltd, and Takeda Pharmaceutical Co., Ltd. KC has received honoraria from AstraZeneca, Chugai Co., Ltd, Eli Lilly, MSD, and Taiho Pharmaceutical Co., Ltd. EI has received honoraria from Eli Lilly; has received research funding from Janssen Pharmaceuticals, MSD, Ono Pharmaceutical Co., Ltd, and Takeda Pharmaceutical Co., Ltd. YW reports no conflicts of interest. TA and TK are employees and stock owners of Takeda Pharmaceutical Co., Ltd. RF is an employee and stock owner of Takeda Development Center Americas, Inc. YO has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo, Eisai Co. Ltd, Eli Lilly, Kyowa Hakko Kirin Co., Ltd, MSD, Nippon Kayaku, Ono Pharmaceutical Co., Ltd, Pfizer, and Taiho Pharmaceutical Co., Ltd; has received research funding from AstraZeneca, Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo, Eli Lilly, Janssen, Kissei Pharmaceutical, Kyowa Hakko Kirrin Co., Ltd, LOXO Oncology, Novartis, Pfizer, Sumitomo Pharma Co., Ltd, Taiho Pharmaceutical Co., Ltd, and Takeda Pharmaceutical Co., Ltd.

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References

1. Zhang Y-L Yuan J-Q Wang K-F Fu X-H Han X-R Threapleton D Yang Z-Y Mao C Tang J-L The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis Oncotarget 2016 7 48 78985 78993 10.18632/oncotarget.12587 27738317
Zhang Y-L, Yuan J-Q, Wang K-F et al (2016) The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget 7(48):78985–7899327738317
2. Yatabe Y Kerr KM Utomo A Rajadurai P Tran VK Du X Chou TY Enriquez ML Lee GK Iqbal J Shuangshoti S Chung JH Hagiwara K Liang Z Normanno N Park K Toyooka S Tsai CM Waring P Zhang L McCormack R Ratcliffe M Itoh Y Sugeno M Mok T EGFR mutation testing practices within the Asia Pacific region: results of a multicenter diagnostic survey J Thorac Oncol 2015 10 3 438 445 10.1097/JTO.0000000000000422 25376513
Yatabe Y, Kerr KM, Utomo A et al (2015) EGFR mutation testing practices within the Asia Pacific region: results of a multicenter diagnostic survey. J Thorac Oncol 10(3):438–445. 10.1097/JTO.000000000000042225376513
3. John T Taylor A Wang H Eichinger C Freeman C Ahn M-J Uncommon EGFR mutations in non-small-cell lung cancer: a systematic literature review of prevalence and clinical outcomes Cancer Epidemiol 2022 76 102080 10.1016/j.canep.2021.102080 34922050
John T, Taylor A, Wang H et al (2022) Uncommon EGFR mutations in non-small-cell lung cancer: a systematic literature review of prevalence and clinical outcomes. Cancer Epidemiol 76:102080. 10.1016/j.canep.2021.10208034922050
4. Vyse S Huang PH Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer Signal Transduct Target Ther 2019 4 5 10.1038/s41392-019-0038-9 30854234
Vyse S, Huang PH (2019) Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Signal Transduct Target Ther 4:5. 10.1038/s41392-019-0038-930854234
5. Arcila ME Nafa K Chaft JE Rekhtman N Lau C Reva BA Zakowski MF Kris MG Ladanyi M EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics Mol Cancer Ther 2013 12 2 220 229 10.1158/1535-7163.MCT-12-0620 23371856
Arcila ME, Nafa K, Chaft JE et al (2013) EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther 12(2):220–229. 10.1158/1535-7163.MCT-12-062023371856
6. Mitsudomi T Yatabe Y Epidermal growth factor receptor in relation to tumor development: EGFR gene and cancer FEBS J 2010 277 2 301 308 10.1111/j.1742-4658.2009.07448.x 19922469
Mitsudomi T, Yatabe Y (2010) Epidermal growth factor receptor in relation to tumor development: EGFR gene and cancer. FEBS J 277(2):301–308. 10.1111/j.1742-4658.2009.07448.x19922469
7. Murray S Dahabreh IJ Linardou H Manoloukos M Bafaloukos D Kosmidis P Somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor and tyrosine kinase inhibitor response to TKIs in non-small cell lung cancer: an analytical database J Thorac Oncol 2008 3 8 832 839 10.1097/JTO.0b013e31818071f3 18670300
Murray S, Dahabreh IJ, Linardou H et al (2008) Somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor and tyrosine kinase inhibitor response to TKIs in non-small cell lung cancer: an analytical database. J Thorac Oncol 3(8):832–839. 10.1097/JTO.0b013e31818071f318670300
8. Oxnard GR Lo PC Nishino M Dahlberg SE Lindeman NI Butaney M Jackman DM Johnson BE Janne PA Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions J Thorac Oncol 2013 8 2 179 184 10.1097/JTO.0b013e3182779d18 23328547
Oxnard GR, Lo PC, Nishino M et al (2013) Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol 8(2):179–184. 10.1097/JTO.0b013e3182779d1823328547
9. Yasuda H Kobayashi S Costa DB EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications Lancet Oncol 2012 13 1 e23 e31 10.1016/s1470-2045(11)70129-2 21764376
Yasuda H, Kobayashi S, Costa DB (2012) EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet Oncol 13(1):e23–e31. 10.1016/s1470-2045(11)70129-221764376
10. Yang JC Sequist LV Geater SL Tsai CM Mok TS Schuler M Yamamoto N Yu CJ Ou SH Zhou C Massey D Zazulina V Wu YL Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6 Lancet Oncol 2015 16 7 830 838 10.1016/S1470-2045(15)00026-1 26051236
Yang JC, Sequist LV, Geater SL et al (2015) Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol 16(7):830–838. 10.1016/S1470-2045(15)00026-126051236
11. Naidoo J Sima CS Rodriguez K Busby N Nafa K Ladanyi M Riely GJ Kris MG Arcila ME Yu HA Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: clinical outcomes and response to erlotinib Cancer 2015 121 18 3212 3220 10.1002/cncr.29493 26096453
Naidoo J, Sima CS, Rodriguez K et al (2015) Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: clinical outcomes and response to erlotinib. Cancer 121(18):3212–3220. 10.1002/cncr.2949326096453
12. Wu JY Wu SG Yang CH Gow CH Chang YL Yu CJ Shih JY Yang PC Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response Clin Cancer Res 2008 14 15 4877 4882 10.1158/1078-0432.CCR-07-5123 18676761
Wu JY, Wu SG, Yang CH et al (2008) Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response. Clin Cancer Res 14(15):4877–4882. 10.1158/1078-0432.CCR-07-512318676761
13. Japan Lung Cancer Society (2023) Lung Cancer Treatment Guidelines 2023 Edition - Stage IV Non-Small Cell Lung Cancer.
14. Gonzalvez F Vincent S Baker TE Gould AE Li S Wardwell SD Nadworny S Ning Y Zhang S Huang WS Hu Y Li F Greenfield MT Zech SG Das B Narasimhan NI Clackson T Dalgarno D Shakespeare WC Fitzgerald M Chouitar J Griffin RJ Liu S Wong KK Zhu X Rivera VM Mobocertinib (TAK-788): A targeted inhibitor of EGFR exon 20 insertion mutants in non-small cell lung cancer Cancer Discov 2021 11 7 1672 1687 10.1158/2159-8290.Cd-20-1683 33632773
Gonzalvez F, Vincent S, Baker TE et al (2021) Mobocertinib (TAK-788): A targeted inhibitor of EGFR exon 20 insertion mutants in non-small cell lung cancer. Cancer Discov 11(7):1672–1687. 10.1158/2159-8290.Cd-20-168333632773
15. Riely GJ Neal JW Camidge DR Spira AI Piotrowska Z Costa DB Tsao AS Patel JD Gadgeel SM Bazhenova L Zhu VW West HL Mekhail T Gentzler RD Nguyen D Vincent S Zhang S Lin J Bunn V Jin S Li S Jänne PA Activity and safety of mobocertinib (TAK-788) in previously treated non-small cell lung cancer with EGFR exon 20 insertion mutations from a phase I/II trial Cancer Discov 2021 11 7 1688 1699 10.1158/2159-8290.Cd-20-1598 33632775
Riely GJ, Neal JW, Camidge DR et al (2021) Activity and safety of mobocertinib (TAK-788) in previously treated non-small cell lung cancer with EGFR exon 20 insertion mutations from a phase I/II trial. Cancer Discov 11(7):1688–1699. 10.1158/2159-8290.Cd-20-159833632775
16. Hida T Nishino M Yoh K Asato T Kitagawa T A phase I dose-escalation study of mobocertinib (TAK-788), an oral tyrosine kinase inhibitor (TKI), in Japanese NSCLC patients (Poster 1246P presented at ESMO Congress, 16 Sep 2021, Paris (virtual) Ann Oncol 2021 32 S949 S1039
Hida T, Nishino M, Yoh K et al (2021) A phase I dose-escalation study of mobocertinib (TAK-788), an oral tyrosine kinase inhibitor (TKI), in Japanese NSCLC patients (Poster 1246P presented at ESMO Congress, 16 Sep 2021, Paris (virtual). Ann Oncol 32:S949–S1039
17. Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M (1994) The EORTC QLQ-LC13: a modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in lung cancer clinical trials. EORTC Study Group on Quality of Life. Eur J Cancer 30a (5):635–642. 10.1016/0959-8049(94)90535-5
18. Rosell R Carcereny E Gervais R Vergnenegre A Massuti B Felip E Palmero R Garcia-Gomez R Pallares C Sanchez JM Porta R Cobo M Garrido P Longo F Moran T Insa A De Marinis F Corre R Bover I Illiano A Dansin E de Castro J Milella M Reguart N Altavilla G Jimenez U Provencio M Moreno MA Terrasa J Muñoz-Langa J Valdivia J Isla D Domine M Molinier O Mazieres J Baize N Garcia-Campelo R Robinet G Rodriguez-Abreu D Lopez-Vivanco G Gebbia V Ferrera-Delgado L Bombaron P Bernabe R Bearz A Artal A Cortesi E Rolfo C Sanchez-Ronco M Drozdowskyj A Queralt C de Aguirre I Ramirez JL Sanchez JJ Molina MA Taron M Paz-Ares L 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 Lancet Oncol 2012 13 3 239 246 10.1016/s1470-2045(11)70393-x 22285168
Rosell R, Carcereny E, Gervais R et al (2012) 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. Lancet Oncol 13(3):239–246. 10.1016/s1470-2045(11)70393-x22285168
19. Wu YL Zhou C Liam CK Wu G Liu X Zhong Z Lu S Cheng Y Han B Chen L Huang C Qin S Zhu Y Pan H Liang H Li E Jiang G How SH Fernando MCL Zhang Y Xia F Zuo Y First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study Ann Oncol 2015 26 9 1883 1889 10.1093/annonc/mdv270 26105600
Wu YL, Zhou C, Liam CK et al (2015) First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol 26(9):1883–1889. 10.1093/annonc/mdv27026105600
20. Zhou C Wu YL Chen G Feng J Liu XQ Wang C Zhang S Wang J Zhou S Ren S Lu S Zhang L Hu C Hu C Luo Y Chen L Ye M Huang J Zhi X Zhang Y Xiu Q Ma J Zhang L You C 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 Lancet Oncol 2011 12 8 735 742 10.1016/S1470-2045(11)70184-X 21783417
Zhou C, Wu YL, Chen G et al (2011) 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. Lancet Oncol 12(8):735–742. 10.1016/S1470-2045(11)70184-X21783417
21. Mok TS Wu YL Thongprasert S Yang CH Chu DT Saijo N Sunpaweravong P Han B Margono B Ichinose Y Nishiwaki Y Ohe Y Yang JJ Chewaskulyong B Jiang H Duffield EL Watkins CL Armour AA Fukuoka M Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma N Engl J Med 2009 361 10 947 957 10.1056/NEJMoa0810699 19692680
Mok TS, Wu YL, Thongprasert S et al (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361(10):947–957. 10.1056/NEJMoa081069919692680
22. Mitsudomi T Morita S Yatabe Y Negoro S Okamoto I Tsurutani J Seto T Satouchi M Tada H Hirashima T Asami K Katakami N Takada M Yoshioka H Shibata K Kudoh S Shimizu E Saito H Toyooka S Nakagawa K Fukuoka M West Japan Oncology G 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 Lancet Oncol 2010 11 2 121 128 10.1016/S1470-2045(09)70364-X 20022809
Mitsudomi T, Morita S, Yatabe Y et al (2010) 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. Lancet Oncol 11(2):121–128. 10.1016/S1470-2045(09)70364-X20022809
23. Maemondo M Inoue A Kobayashi K Sugawara S Oizumi S Isobe H Gemma A Harada M Yoshizawa H Kinoshita I Fujita Y Okinaga S Hirano H Yoshimori K Harada T Ogura T Ando M Miyazawa H Tanaka T Saijo Y Hagiwara K Morita S Nukiwa T North-East Japan Study G Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR N Engl J Med 2010 362 25 2380 2388 10.1056/NEJMoa0909530 20573926
Maemondo M, Inoue A, Kobayashi K et al (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362(25):2380–2388. 10.1056/NEJMoa090953020573926
24. Sequist LV Yang JC Yamamoto N O’Byrne K Hirsh V Mok T Geater SL Orlov S Tsai CM Boyer M Su WC Bennouna J Kato T Gorbunova V Lee KH Shah R Massey D Zazulina V Shahidi M Schuler M Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations J Clin Oncol 2013 31 27 3327 3334 10.1200/JCO.2012.44.2806 23816960
Sequist LV, Yang JC, Yamamoto N et al (2013) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 31(27):3327–3334. 10.1200/JCO.2012.44.280623816960
25. Wu YL Zhou C Hu CP Feng J Lu S Huang Y Li W Hou M Shi JH Lee KY Xu CR Massey D Kim M Shi Y Geater SL 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 Lancet Oncol 2014 15 2 213 222 10.1016/S1470-2045(13)70604-1 24439929
Wu YL, Zhou C, Hu CP et al (2014) 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. Lancet Oncol 15(2):213–222. 10.1016/S1470-2045(13)70604-124439929
26. O’Kane GM Bradbury PA Feld R Leighl NB Liu G Pisters KM Kamel-Reid S Tsao MS Shepherd FA Uncommon EGFR mutations in advanced non-small cell lung cancer Lung Cancer 2017 109 137 144 10.1016/j.lungcan.2017.04.016 28577943
O’Kane GM, Bradbury PA, Feld R et al (2017) Uncommon EGFR mutations in advanced non-small cell lung cancer. Lung Cancer 109:137–144. 10.1016/j.lungcan.2017.04.01628577943
27. Okahisa M Udagawa H Matsumoto S Kato T Yokouchi H Furuya N Kanemaru R Toyozawa R Nishiyama A Ohashi K Miyamoto S Nishino K Nakamura A Iwama E Niho S Oi H Sakai T Shibata Y Izumi H Sugiyama E Nosaki K Umemura S Zenke Y Yoh K Kah Mun Low G Zhuo J Goto K Clinical outcomes in patients with non-small cell lung cancer harboring EGFR Exon20 in-frame insertions in the near-loop and far-loop: Results from LC-SCRUM-Asia Lung Cancer 2024 191 107798 10.1016/j.lungcan.2024.107798 38669727
Okahisa M, Udagawa H, Matsumoto S et al (2024) Clinical outcomes in patients with non-small cell lung cancer harboring EGFR Exon20 in-frame insertions in the near-loop and far-loop: Results from LC-SCRUM-Asia. Lung Cancer 191:107798. 10.1016/j.lungcan.2024.10779838669727
28. Yasuda H Ichihara E Sakakibara-Konishi J Zenke Y Takeuchi S Morise M Hotta K Sato M Matsumoto S Tanimoto A Matsuzawa R Kiura K Takashima Y Yano S Koyama J Fukushima T Hamamoto J Terai H Ikemura S Takemura R Goto K Soejima K A phase I/II study of osimertinib in EGFR exon 20 insertion mutation-positive non-small cell lung cancer Lung Cancer 2021 162 140 146 10.1016/j.lungcan.2021.10.006 34808485
Yasuda H, Ichihara E, Sakakibara-Konishi J et al (2021) A phase I/II study of osimertinib in EGFR exon 20 insertion mutation-positive non-small cell lung cancer. Lung Cancer 162:140–146. 10.1016/j.lungcan.2021.10.00634808485
29. Zhou C Ramalingam SS Kim TM Kim SW Yang JC Riely GJ Mekhail T Nguyen D Garcia Campelo MR Felip E Vincent S Jin S Griffin C Bunn V Lin J Lin HM Mehta M Jänne PA Treatment outcomes and safety of mobocertinib in platinum-pretreated patients with EGFR Exon 20 insertion-positive metastatic non-small cell lung cancer: a phase 1/2 open-label nonrandomized clinical trial JAMA Oncol 2021 7 12 e214761 10.1001/jamaoncol.2021.4761 34647988
Zhou C, Ramalingam SS, Kim TM et al (2021) Treatment outcomes and safety of mobocertinib in platinum-pretreated patients with EGFR Exon 20 insertion-positive metastatic non-small cell lung cancer: a phase 1/2 open-label nonrandomized clinical trial. JAMA Oncol 7(12):e214761. 10.1001/jamaoncol.2021.476134647988
30. Markham A Mobocertinib: first approval Drugs 2021 81 17 2069 2074 10.1007/s40265-021-01632-9 34716908
Markham A (2021) Mobocertinib: first approval. Drugs 81(17):2069–2074. 10.1007/s40265-021-01632-934716908
31. Jänne PA Wang BC Cho BC Zhao J Li J Hochmair MJ Peters S Besse B Kato T Wu YL Nguyen D Lin J Lin J Vranceanu F Lin M Fram RJ Mok TSK 507O EXCLAIM-2: Phase III trial of first-line (1L) mobocertinib versus platinum-based chemotherapy in patients (pts) with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins)+ locally advanced/metastatic NSCLC Ann Oncol 2023 34 S1663 S1664 10.1016/j.annonc.2023.10.586
Jänne PA, Wang BC, Cho BC et al (2023) 507O EXCLAIM-2: Phase III trial of first-line (1L) mobocertinib versus platinum-based chemotherapy in patients (pts) with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins)+ locally advanced/metastatic NSCLC. Ann Oncol 34:S1663–S1664. 10.1016/j.annonc.2023.10.586
32. Dello Russo C Cappoli N Pilunni D Navarra P Local investigators significantly overestimate overall response rates compared to blinded independent central reviews in phase 2 oncology trials J Clin Pharmacol 2021 61 6 810 819 10.1002/jcph.1790 33244770
Dello Russo C, Cappoli N, Pilunni D et al (2021) Local investigators significantly overestimate overall response rates compared to blinded independent central reviews in phase 2 oncology trials. J Clin Pharmacol 61(6):810–819. 10.1002/jcph.179033244770
33. Dello Russo C Navarra P Local investigators significantly overestimate overall response rates compared to blinded independent central reviews in uncontrolled oncology trials: a comprehensive review of the literature Front Pharmacol 2022 13 858354 10.3389/fphar.2022.858354 35652050
Dello Russo C, Navarra P (2022) Local investigators significantly overestimate overall response rates compared to blinded independent central reviews in uncontrolled oncology trials: a comprehensive review of the literature. Front Pharmacol 13:858354. 10.3389/fphar.2022.85835435652050
34. Yang JC Zhou C Jänne PA Ramalingam SS Kim TM Riely GJ Spira AI Piotrowska Z Mekhail T Garcia Campelo MR Felip E Bazhenova L Jin S Kaur M Diderichsen PM Gupta N Bunn V Lin J Eric NC Mehta M Nguyen D Characterization and management of adverse events observed with mobocertinib (TAK-788) treatment for EGFR exon 20 insertion-positive non-small cell lung cancer Expert Rev Anticancer Ther 2023 23 1 95 106 10.1080/14737140.2023.2157815 36537204
Yang JC, Zhou C, Jänne PA et al (2023) Characterization and management of adverse events observed with mobocertinib (TAK-788) treatment for EGFR exon 20 insertion-positive non-small cell lung cancer. Expert Rev Anticancer Ther 23(1):95–106. 10.1080/14737140.2023.215781536537204
35. Park K Tan EH O’Byrne K Zhang L Boyer M Mok T Hirsh V Yang JC Lee KH Lu S Shi Y Kim SW Laskin J Kim DW Arvis CD Kolbeck K Laurie SA Tsai CM Shahidi M Kim M Massey D Zazulina V Paz-Ares L Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial Lancet Oncol 2016 17 5 577 589 10.1016/S1470-2045(16)30033-X 27083334
Park K, Tan EH, O’Byrne K et al (2016) Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol 17(5):577–589. 10.1016/S1470-2045(16)30033-X27083334
36. Wu YL Cheng Y Zhou X Lee KH Nakagawa K Niho S Tsuji F Linke R Rosell R Corral J Migliorino MR Pluzanski A Sbar EI Wang T White JL Nadanaciva S Sandin R Mok TS Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial Lancet Oncol 2017 18 11 1454 1466 10.1016/S1470-2045(17)30608-3 28958502
Wu YL, Cheng Y, Zhou X et al (2017) Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol 18(11):1454–1466. 10.1016/S1470-2045(17)30608-328958502
37. Khozin S Weinstock C Blumenthal GM Cheng J He K Zhuang L Zhao H Charlab R Fan I Keegan P Pazdur R Osimertinib for the treatment of metastatic EGFR T790M mutation-positive non-small cell lung cancer Clin Cancer Res 2017 23 9 2131 2135 10.1158/1078-0432.CCR-16-1773 27923840
Khozin S, Weinstock C, Blumenthal GM et al (2017) Osimertinib for the treatment of metastatic EGFR T790M mutation-positive non-small cell lung cancer. Clin Cancer Res 23(9):2131–2135. 10.1158/1078-0432.CCR-16-177327923840
38. Hirsh V Managing treatment-related adverse events associated with egfr tyrosine kinase inhibitors in advanced non-small-cell lung cancer Curr Oncol 2011 18 3 126 138 10.3747/co.v18i3.877 21655159
Hirsh V (2011) Managing treatment-related adverse events associated with egfr tyrosine kinase inhibitors in advanced non-small-cell lung cancer. Curr Oncol 18(3):126–138. 10.3747/co.v18i3.87721655159
39. Zwierenga F van Veggel B van den Berg A Groen HJM Zhang L Groves MR Kok K Smit EF Hiltermann TJN de Langen AJ van der Wekken AJ A comprehensive overview of the heterogeneity of EGFR exon 20 variants in NSCLC and (pre)clinical activity to currently available treatments Cancer Treat Rev 2023 120 102628 10.1016/j.ctrv.2023.102628 37797348
Zwierenga F, van Veggel B, van den Berg A et al (2023) A comprehensive overview of the heterogeneity of EGFR exon 20 variants in NSCLC and (pre)clinical activity to currently available treatments. Cancer Treat Rev 120:102628. 10.1016/j.ctrv.2023.10262837797348
