Long-term follow-up results from the GLORY study: phase II study of gumarontinib in East Asian patients with MET exon 14 skipping mutated non-small cell lung cancer

Introduction

Lung cancer has become the disease with the highest mortality rate globally. In 2022, there were nearly 2.5 million new cases, accounting for 12.5% of all cancer cases, and it is estimated to cause around 1.8 million deaths each year, making up 18.7% of all cancer-related fatalities (1). Approximately 60% of lung cancer cases harbor oncogenic driver mutations, and target therapy remains the basis for non-small cell lung cancer (NSCLC) (2). With the advent of advanced gene-testing platforms and the swift progress of specific molecular-targeted therapies, an increasing number of patients with potentially positive oncogenic driver mutations can individually benefit from these treatments (3).

MET exon 14 skipping mutation (METex14) skipping mutation is recognized as an independent driver, occurring in approximately 3% to 4% of lung adenocarcinomas (4-6) with the incidence of ~1.3% in the Chinese population (7). Patients with METex14 skipping mutated NSCLC were predominantly female, older, and enriched in sarcomatoid and adenosquamous histologies (5,8-12). Multiple studies have confirmed that traditional treatment methods have limited efficacy in NSCLC patients harboring METex14 skipping mutations. Previous data have shown that the median overall survival (OS) of such patients receiving first-line chemotherapy is only 6.7 months, with a suboptimal overall therapeutic effect (13). Furthermore, immunotherapy has also failed to bring significant benefits to this population. For patients with locally advanced or metastatic NSCLC harboring METex14 skipping mutations who receive first-line immunotherapy, the objective response rate (ORR) is only 17–35.7%, and the median progression-free survival (PFS) is merely 1.9–4.9 months (14,15). Subsequently, the approval and market launch of numerous highly selective mesenchymal epithelial transition factor (MET)-tyrosine kinase inhibitors (TKIs) have together ushered in a new era in the treatment of NSCLC with METex14 skipping mutations.

Gumarontinib is a potent, highly selective, ATP competitive, reversible type Ib inhibitor of c-met, having significantly in vivo or in vitro activity in various types of MET activation (16). The clinical efficacy and safety of gumarontinib were assessed in the GLORY study (17), which was an open-label, multi-countries phase Ib/II study in patients with METex14 skipping mutated locally advanced or metastatic NSCLC (stage IIIb, IIIc or IV).

In this article, we report the updated clinical efficacy and safety data from GLORY study after 18 months of additional follow-up. We present this article in accordance with the TREND reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-638/rc).

Methods

Study design and population

This was a single-arm, open-label, multicenter, phase II study (NCT04270591) to evaluate the ORR of gumarontinib in East Asian patients with locally advanced or metastatic METex14 skipping mutation-positive NSCLC. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics board of the leading site, Shanghai Chest Hospital (No. LS1910) and informed consent was obtained from all individual participants. The other institutions were also informed and approved the study. Full details regarding the GLORY study have been published previously at eClinicalMedicine and available with the full text of protocol is available at https://cdn.amegroups.cn/static/public/tlcr-2025-638-1.pdf (17). To be brief, patients with locally advanced or metastatic NSCLC (stage IIIb, IIIc or IV) harboring METex14 skipping mutation that have been pre-screened by local or sponsor-designated central laboratory, who are not eligible for chemotherapy or refuse chemotherapy after well-informed or have failed one or two prior lines of systemic therapies and have not had prior MET inhibitor for the advanced NSCLC and meet the inclusion/exclusion criteria in the protocol will be enrolled.

Procedures

Gumarontinib was administered orally at the starting dose of 300 mg once daily continuously in 21-day treatment cycles. Treatment would be continued until disease progression as determined by the investigators and confirmed by the blinded independent review committee (BIRC); the emergence of intolerable toxicity; per investigator or patient decision; were lost to follow up or death. Treatment beyond disease progression was allowed only when there was convincing evidence of clinical benefit.

Tumor assessments were carried out by both BIRC and investigators in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, where at baseline and every 6 weeks during the first 8 treatment cycles, and every 9 weeks thereafter or as clinically required until treatment discontinuation.

Safety was monitored at baseline, at subsequent visit or as clinically indicated by the judgement of investigators.

Study endpoints

The primary endpoint was the ORR assessed by a BIRC. The secondary endpoints were to evaluate the ORR assessed by the investigators and other endpoints: disease control rate (DCR), duration of response (DOR), time to response (TTR), PFS, OS and safety graded by the National Cancer Institute’s Common Terminology for Adverse Events (CTCAE), version 5.0.

Statistical analysis

The statistical analysis plan was the same as that which was described for the prior analysis of this study (17). Full analysis set (FAS) will include all patients who received at least one dose of gumarontinib. Efficacy was analyzed in the efficacy analysis set (EAS), which included all patients with METex14 skipping mutated NSCLC confirmed by the sponsor-designated central laboratory who received gumarontinib 300 mg once daily and had a valid baseline tumor assessment. For the ORR, DOR, PFS, DCR and OS, 95% confidence interval (CI) were calculated using the Clopper-Pearson method.

All statistical analyses will be performed using SAS 9.4 (SAS Institute, Cary, NC, USA) or above version. The statistical analysis plan (SAP) is available at supplementary appendix, where additional details regarding the study endpoints and methods are described.

Results

Patients disposition

From August 2, 2019 to April 28, 2021, overall, 148 subjects completed screening at 42 sites (31 sites in China, and 11 sites in Japan), of which 64 screen failed (Figure 1). As of the primary analysis on April 28, 2022 (the data cut-off date), a total of 84 patients (46 treatment-naïve and 38 pre-treated patients) with METex14 skipping mutation locally advanced or metastatic NSCLC were enrolled and treated at gumarontinib 300 mg QD. Seventy-nine patients (44 treatment-naïve patients and 35 pre-treated patients) were included in the EAS, and five patients were excluded due to the absence of central laboratory confirmed METex14 mutation status. As of October 28, 2023 for this analysis, all 84 patients had discontinued from the treatment. The primary reason for treatment discontinuation was disease progression (46/84, 54.8%).

Figure 1 The study flowchart and patient disposition. ICF, informed consent form.

Baseline characteristics

Baseline characteristics for patients in the FAS are shown in Table 1. The median age of the patients was 68.5 years. Seventy-four patients (88.1%) were Chinese and 10 patients (11.9%) were Japanese. Specifically, 42.9% of the patients were aged 65 years or older but less than 75 years old. In terms of gender distribution, 57.1% were males and 42.9% were females. The Eastern Cooperative Oncology Group (ECOG) performance status of the majority of patients (95.2%) was 1. More than half of the patients (46/84, 54.8%) had never smoked. Adenocarcinoma was the most prevalent pathological subtype, observed in 63 patients (75.0%). Additionally, 14 patients (16.7%) had brain metastases at baseline.

Efficacy

Among patients with locally advanced or metastatic METex14 skipping mutated NSCLC, the primary endpoint of ORR as determined by the BIRC was 65.8% (95% CI: 54.3% to 76.1%) for overall patients and the ORR for the treatment-naïve and pre-treated populations were 70.5% (95% CI: 54.8% to 83.2%) and 60.0% (95% CI: 42.1% to 76.1%), respectively (Table 2). Besides, ORR was comparable as per baseline characteristics and consistent trend was observed across subgroups (Figure 2).

Figure 2 ORR of BIRC assessment of gumarontinib according to baseline characteristics (efficacy analysis set). The CIs are calculated using Clopper-Pearson exact method for binomial proportions. BIRC, blinded independent review committee; CI, confidence interval; NA, not applicable; ORR, objective response rate.

The maximum reduction in tumor diameter relative to the baseline reached 90.5% (Figure 3), and the longest treatment duration was 187.4 weeks (Figure 4). As assessed by BIRC, the median DOR was 8.3 (95% CI: 6.2 to 18.3) months overall, with the treatment-naïve population achieving a median DOR of 10.5 (95% CI: 6.2 to 20.9) months and the pre-treated population showing a median DOR of 8.2 (95% CI: 5.1 to 18.7) months (Table 2). The median PFS assessed by BIRC was 7.7 (95% CI: 7.6 to 9.7) months, and the median PFS of treatment-naïve and pre-treated populations was 9.7 (95% CI: 7.6 to 21.9) and 7.6 (95% CI: 4.1 to 9.6) months, respectively (Figure 5, Table 2). The DCR was 83.5% (95% CI: 73.5% to 90.9%) with a median TTR of 1.4 months (Table 2). The investigators’ assessment of the efficacy results was generally consistent with that of the BIRC, with no significant changes observed compared to the primary analysis (Figure 6, Table 2). After a median follow-up period of 35 months, the median OS was 19.4 (95% CI: 12.1 to 30.1) months. Significantly, the treatment-naïve population had a median OS of 25.4 [95% CI: 11.7 to not evaluable (NE)] months. Meanwhile, the pre-treated population’s median OS was 16.3 (95% CI: 8.7 to NE) months (Figure 7, Table 2).

Figure 3 Best change in target lesion from baseline assessed by BIRC (efficacy analysis set). Waterfall plot of the best change in target lesions (the largest percentage reduction or smallest percentage increase in the absence of a reduction) in the volume of the target lesion from baseline and best response. BIRC, blinded independent review committee; PD, progressive disease; PR, partial response; SD, stable disease.

Figure 4 Swimmer plot for individual subject efficacy evaluation results by BIRC (efficacy analysis set). Treatment duration is the time from treatment initiation until treatment termination. BIRC, blinded independent review committee.

Figure 5 KM plot for progression-free survival by treatment status at baseline (BIRC determined) (efficacy analysis set). B: overall population. B*a: pre-treated. B*b: treatment naive. The triangle, circle and square in the picture mean censor. BIRC, blinded independent review committee; KM, Kaplan-Meier.

Figure 6 KM plot for progression-free survival by treatment status at baseline (investigator assessed) (efficacy analysis set). B: overall population. B*a: pre-treated. B*b: treatment naive. The triangle, circle and square in the picture mean censor. KM, Kaplan-Meier.

Figure 7 KM plot for overall survival by treatment status at baseline (efficacy analysis set). B: overall population. B*a: pre-treated. B*b: treatment naive. The triangle, circle and square in the picture mean censor. KM, Kaplan-Meier.

Safety

Overall, 82 (97.6%) patients who received gumarontinib experienced at least one treatment-related adverse event (TRAE), while 45 (53.6%) patients had experienced ≥ grade 3 TRAEs (Table 3). Oedema was the most common TRAE (67/84, 79.8%), with 18 (21.4%) experiencing grade 3 or higher oedema. Other commonly reported (≥20%) TRAEs of any grade were hypoalbuminemia (32/84, 38.1%), decreased appetite (27/84, 32.1%), headache (27/84, 32.1%), nausea (24/84, 28.6%), blood bilirubin increased (23/84, 27.4%), alanine aminotransferase (ALT) increased (22/84, 26.2%), vomiting (21/84, 25.0%), aspartate aminotransferase (AST) increased (18/84, 21.4%), and were mostly lower grades. Additionally, 30 (35.7%) patients experienced dose interruption, 31 (36.9%) required dose reduction, and 7 (8.3%) were withdrawn from treatment due to TRAEs, with oedema being the most common cause. Eight (9.5%) patients died due to causes other than disease progression during the treatment, of which 3 (3.6%) patients with unknown causes were considered as drug-related (17) (Table 4).

Discussion

In this extended-over of Asian patients with locally advanced or metastatic METex14 skipping mutated NSCLC in GLORY study, with a median follow-up of 35 months, gumarontinib exhibited sustained and robust antitumor effects, overall and across subgroups, along with tolerable toxicity, which can offer significant benefits that can be converted to long-term survival benefits regardless of the previous treatment setting. The efficacy demonstrated clinical significance among treatment-naive patients (n=44, with an ORR of 70.5%) as well as among those who had received prior treatment (n=35, with an ORR of 60.0%). Particularly, clinical efficacy was durable in patients receiving gumarontinib as first-line therapy with the median OS of 25.4 months and the median DOR was 10.5 months. The outcomes in this expanded Asian patient population, which had a longer follow-up period, verified the earlier findings and provided additional support for the approval and utilization of gumarontinib in clinical practice. Additionally, other MET TKIs, like capmatinib, tepotinib have been approved in both China and Japan for the treatment of locally advanced or metastatic METex14 skipping mutated NSCLC. The final results of the GEOMETRY mono-1 study reported that the ORR was 68%, with median DOR of 16.6 months and median OS of 21.4 months in treatment naïve patients (18). The phase II GEOMETRY-C study on capmatinib reported its efficacy in Chinese adult patients with ORR 53.3% (8/15) and the investigator-assessed ORR was 60% (9/15) (19). Similarly, in the VISION study of Asian subgroup analysis, 56.6% of ORR was reported with 25.5 months of median OS in overall Asian patients detected in liquid or tissue biopsy (20). Notably, gumarontinib has been approved by the Ministry of Health, Labour and Welfare (MHLW) of Japan in 2024 for adult patients with locally advanced or metastatic METex14 skipping mutated NSCLC. Concurrently, gumarontinib along with capmatinib and tepotinib, has been recommended by The Japan Lung Cancer Society in treatment guidelines for adults with locally advanced or metastatic METex14 skipping mutated NSCLC (21).

No unexpected new safety issues were identified in this long-term follow-up. The most commonly (≥20%) reported TRAEs of any grade included oedema, hypoalbuminemia, decreased appetite, headache, nausea, blood bilirubin increased, ALT increased, vomiting and AST increased. The adverse event (AE) of gumarontinib is similar to those of other TKI agents, however, the safety profile is heterogeneous across patient populations and trial background. Oedema remains one of the most common TRAEs in all MET inhibitors’ studies (22-25). It occurs in 79.8% of cases with gumarontinib, and the incidence is comparable to that in cases with other products in the same class, which perhaps can be attributed to the attenuation of hepatocyte growth factor-mediated signaling in the vascular endothelium (26,27). For other TRAEs, such as nausea, increased ALT, increased AST, increased blood creatinine, hypoalbuminemia, and decreased appetite, overlapping occurrences have been observed across various studies. However, attention should be paid to the fact that cross-trial safety comparisons must be drawn with caution.

The long-term follow-up data from the GLORY study provide further evidence supporting the efficacy and safety of gumarontinib in East Asian patients NSCLC with METex14 skipping. Consistent with the pivotal phase II findings, the updated results confirm that gumarontinib yields a substantial ORR, with durable responses across both treatment-naïve and pre-treated populations. Notably, the median overall survival of 19.4 months, with longer survival observed in treatment-naïve patients, adds to the growing body of evidence that targeted inhibition of METex14 skipping mutations can translate into meaningful long-term clinical benefit for this patient population, which historically has limited treatment options and has poor prognosis with conventional chemotherapy or immunotherapy.

In terms of safety, the profile remains consistent with previous reports, with edema and hypoalbuminemia as the most common treatment-related adverse events. The relatively low rate of permanent discontinuation due to adverse events suggests that the safety profile of gumarontinib is generally manageable in clinical practice, supporting its feasibility for long-term administration.

These findings reinforce the role of gumarontinib as a valuable therapeutic option for East Asian patients of NSCLC with METex14 skipping, particularly in settings where frontline or subsequent-line targeted therapy is indicated.

Conclusions

Overall, gumarontinib continued to show substantial anti-tumor activity regardless of the treatment setting, supported by the durability of the observed responses and prolonged survival in patients with METex14 skipping mutated locally advanced or metastatic NSCLC. Gumarontinib 300 mg QD showed promising efficacy and acceptable toxicities, with a rapid onset of action, substantial and durable response, which can be converted into a long-term survival benefit. The reported adverse events were well-tolerated and could be managed by dose interruption and/or reduction, which were usually reversible.

Acknowledgments

We acknowledge all patients and their families, the investigators, research nurses, study coordinators, and operation staff who participated in this trial.

The key results of this article have been published in the ESMO-Asia 2024 in Singapore as a poster titled “Efficacy and safety outcomes of SCC244 in NSCLC patients harboring MET exon 14 skipping (METex14) mutations: long-term follow-up from the Phase II GLORY study” (Poster ID: #651P).

Footnote

Reporting Checklist: The authors have completed the TREND reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-638/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-638/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-638/prf

Funding: This study was supported by Haihe Biopharma Co., Ltd. in part by grants from the National Science and Technology Major Project of China for “Clinical Research of Gumarontinib, a highly selective MET inhibitor” (No. 2018ZX09711002-011-003) to S.L.; the National Natural Science Foundation of China (Nos. 82030045 and 82172633); Shanghai Municipal Science & Technology Commission Research Project (No. 19411950500); Shanghai Shenkang Action Plan (No. 16CR3005A) and Shanghai Chest Hospital Project of Collaborative Innovation (No. YJXT20190105).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-638/coif). S.L. reports grants from Haihe Biopharma Co., Ltd., outside the submitted work. K.G. reports grants and personal fees from Amgen Inc., grants and personal fees from Amgen K.K., personal fees from Amoy Diagnosties Co., Ltd., grants from Amgen Astellas BioPharma K.K., grants and personal fees from AstraZeneca K.K., personal fees from Bayer U.S., grants from Bayer Yakuhin, Ltd., grants from Boehringer Ingelheim Japan, Inc., grants and personal fees from Bristol-Myers Squibb K.K., grants from Blueprint Medicines Corporation, grants and personal fees from Chugai Pharmaceutical Co., Ltd., grants and personal fees from Daiichi Sankyo Co., Ltd., grants and personal fees from Eisai Co., Ltd., grants and personal fees from Eli Lilly Japan K.K., personal fees from Guardant Health Inc., grants from Ignyta, Inc., grants and personal fees from Janssen Pharmaceutical K.K., grants from Kissei Pharmaceutical Co., Ltd., grants from Kyowa Kirin Co., Ltd., personal fees from Life Technologies Japan Ltd., grants from Loxo Oncology, Inc., grants from Medical & Biological Laboratories Co., Ltd., personal fees from Medpace Japan K.K., grants and personal fees from Merck Biopharma Co., Ltd., grants from Merus N.V., grants and personal fees from MSD K.K., grants from NEC Corporation, grants and personal fees from Novartis Pharma K.K., grants and personal fees from Ono Pharmaceutical Co., Ltd., grants from Pfizer Japan Inc., grants from Sumitomo Dainippon Pharma Co., Ltd., grants from Spectrum Pharmaceuticals, Inc., grants from Sysmex Corporation, grants and personal fees from Taiho Pharmaceutical Co., Ltd., grants and personal fees from Takeda Pharmaceutical Co., Ltd., grants from Turning Point Therapeutics, Inc., outside the submitted work. K.N. reports grants from ONO pharmaceutical Co., Ltd., grants and personal fees from MSD, grants from Taiho Pharmaceutical Co., Ltd., grants from AbbVie, grants from Daiichi Sankyo Company, Limited, grants from Amgen, grants from Eisai Co., Ltd., grants from Sanofi K.K., grants from Janssen Pharmaceutical K.K., grants from Novartis Pharmaceuticals, grants from Pfizer, grants from Eli Lilly Japan, grants and personal fees from Merck Biopharma Co., Ltd., grants and personal fees from Takeda Pharmaceutical Co., Ltd., grants and personal fees from Chugai pharmaceutical, grants from Merus, grants and personal fees from AstraZeneca, personal fees from Nippon Boehringer Ingelheim, personal fees from Roche Diagnostics, personal fees from Bristol Myers Squibb, personal fees from Nippon Kayaku, outside the submitted work. Y. Yoneshima reports grants from Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited., and from Eisai Co., Ltd., outside the submitted work. F.L., W.D. and Y.W. are employed by Haihe Biopharma Co., Ltd. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics board of the leading site, Shanghai Chest Hospital (No. LS1910) and informed consent was obtained from all individual participants. The other institutions were also informed and approved the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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