Varlitinib and Paclitaxel for EGFR/HER2 Co-expressing Advanced Gastric Cancer: A Multicenter Phase Ib/II Study (K-MASTER-13)

Dong-Hoe Koo; Minkyu Jung; Yeul Hong Kim; Hei-Cheul Jeung; Dae Young Zang; Woo Kyun Bae; Hyunki Kim; Hyo Song Kim; Choong-kun Lee; Woo Sun Kwon; Hyun Cheol Chung; Sun Young Rha

doi:10.4143/crt.2023.1324

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Original Article Gastrointestinal cancer Varlitinib and Paclitaxel for EGFR/HER2 Co-expressing Advanced Gastric Cancer: A Multicenter Phase Ib/II Study (K-MASTER-13): Dong-Hoe Koo¹, Minkyu Jung², Yeul Hong Kim³, Hei-Cheul Jeung⁴, Dae Young Zang⁵, Woo Kyun Bae⁶, Hyunki Kim⁷, Hyo Song Kim², Choong-kun Lee², Woo Sun Kwon⁸, Hyun Cheol Chung², Sun Young Rha^2,8,9,; Cancer Research and Treatment : Official Journal of Korean Cancer Association 2024;56(4):1136-1145.
DOI: https://doi.org/10.4143/crt.2023.1324
Published online: April 29, 2024

¹Divison of Hematology/Oncology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

²Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea

³Division of Medical Oncology/Hematology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea

⁴Division of Medical Oncology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea

⁵Division of Hematology-Oncology, Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang, Korea

⁶Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea

⁷Department of Pathology, Yonsei University College of Medicine, Seoul, Korea

⁸Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea

⁹Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea

Correspondence: Sun Young Rha, Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, 50 Yonsei‑ro, Seodaemun‑gu, Seoul 03722, Korea
Tel: 82-2-2228-8053 Fax: 82-2-362-5592 E-mail: rha7655@yuhs.ac

*Dong-Hoe Koo and Minkyu Jung contributed equally to this work.

• Received: December 17, 2023 • Accepted: April 26, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract
Introduction
Materials and Methods
Results
Discussion
Electronic Supplementary Material
NOTES
REFERENCES

Abstract

Purpose
Varlitinib is a pan-human epidermal growth factor receptor (HER) inhibitor targeting epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and HER4. We present a phase Ib/II study of a combination of varlitinib and weekly paclitaxel as a second-line treatment for patients with EGFR/HER2 co-expressing advanced gastric cancer (AGC).
Materials and Methods
Patients whose tumors with EGFR and HER2 overexpression by immunohistochemistry (≥ 1+) were enrolled. Varlitinib and paclitaxel were investigated every 4 weeks. After determining the recommended phase II dose (RP2D) in phase Ib, a phase II study was conducted to evaluate the antitumor activity.
Results
RP2D was treated with a combination of varlitinib (300 mg twice daily) and paclitaxel. Among 27 patients treated with RP2D, the median progression-free survival and overall survival (OS) were 3.3 months (95% confidence interval [CI], 1.7 to 4.9) and 7.9 months (95% CI, 5.0 to 10.8), respectively, with a median follow-up of 15.7 months. Among 16 patients with measurable disease, the objective response rate (ORR) and disease control rate were 31% and 88%, respectively. Patients with strong HER2 expression (n=8) had a higher ORR and longer OS, whereas those with strong EGFR expression (n=3) had poorer outcomes. The most common adverse events (AEs) of any grade were neutropenia (52%), diarrhea (27%), aspartate aminotransferase/alanine transaminase elevation (22%), and nausea (19%). No treatment-related deaths or unexpected AEs resulting from treatment cessation were observed in patients with RP2D.
Conclusion
A combination of varlitinib and paclitaxel displayed manageable toxicity and modest antitumor activity in patients with EGFR/HER2 co-expressing AGC who progressed after first-line chemotherapy.
Key words: Chemotherapy, Stomach neoplasms, Epidermal growth factor receptor, HER2, Varlitinib

Introduction

Gastric cancer is the fifth most common cancer and the fourth leading cause of cancer mortality worldwide [1]. Systemic chemotherapy is the primary treatment for most patients with metastatic or recurrent advanced gastric cancer (AGC) [2,3]. Human epidermal growth factor receptor 2 (HER2) is part of a family of receptors associated with tumor cell proliferation, apoptosis, adhesion, migration, and differentiation [4]. Trastuzumab, an anti-HER2–targeted agent, has immensely improved the survival outcomes. Moreover, a combination of trastuzumab and a doublet of fluoropyrimidine and platinum has become the standard of care in patients with metastatic or unresectable HER2-positive AGC [2,5]. However, most patients eventually develop resistance to trastuzumab-based chemotherapy, and further therapeutic strategies are required [6,7].

Because the HER family members synergistically interact with the same or other HER subfamily members, HER2 activation results in increased epidermal growth factor receptor (EGFR or HER1) signaling, suggesting that the dual inhibition of HER2 and EGFR could overcome resistance to trastuzumab [8]. Therefore, pan-HER inhibitors are considered more potent than those inhibiting only one or two HER subfamily receptors. Several pan-HER inhibitors, such as lapatinib [9,10], dacomitinib [11], and afatinib [12] have been investigated for their antitumor activity in AGC patients; however, their efficacy has not been promising.

Varlitinib is a reversible small molecule pan-HER inhibitor targeting EGFR, HER2, and HER4 [13]. In addition, varlitinib effectively inhibits heterodimers with HER3, which lacks a kinase domain [14]. Preclinically, varlitinib inhibited multiple proliferation and anti-apoptosis pathways, including AKT, phosphoinositide 3-kinase, and survivin pathways, in a gastric cancer xenograft model [15,16]. Furthermore, early clinical studies suggested varlitinib as a potent inhibitor of signal transduction in EGFR and HER2 co-expressing AGC, with promising antitumor activity in combination with paclitaxel with/without carboplatin for several solid tumors [17-19]. Based on the previous data, we explored the clinical efficacy of a combination of varlitinib and paclitaxel in patients with EGFR/HER2 co-expressing AGC as a second-line treatment.

We determined the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of varlitinib when combined with paclitaxel (phase Ib part), and assessed the antitumor efficacy and safety of this combination in previously treated patients with EGFR/HER2 co-expressing AGC (phase II part).

Materials and Methods

1. Patients

This prospective phase Ib/II study was conducted at six centers in the Republic of Korea. Patients were included if patients aged ≥ 19 years; histopathologically confirmed unresectable, recurrent, or metastatic gastric adenocarcinoma (including adenocarcinoma of the esophagogastric junction); both EGFR and HER2 immunohistochemistry (IHC) expression ≥ 1+, or EGFR amplification/mutation on next-generation sequencing (NGS) and HER2 IHC ≥ 1+; the presence of one or more evaluable or measurable lesions by Response Evaluation Criteria in Solid Tumors (RECIST, ver. 1.1); after failure of the first-line chemotherapy, including fluoropyrimidine and/or platinum-based chemotherapy, irrespective of trastuzumab exposure; and adequate bone marrow and hepatic functions with good performance (Eastern Cooperative Oncology Group Performance Status [ECOG PS], 0-1). The key exclusion criteria were a history of other malignancies, interstitial lung disease, uncontrolled cardiac dysfunction, previous exposure to taxanes, and symptomatic central nervous system metastasis.

2. Study design

This study comprised two phases: phase Ib and phase II. Phase Ib was designed to determine the safety, tolerability, MTD, and RP2D of varlitinib administered daily in combination with weekly paclitaxel (80 mg/m²; days 1, 8, and 15) during the first cycle, based on the traditional 3+3 design, with a starting dose (dose level 1) and a reduced dose (dose level –1). Dose level 1 was varlitinib 300 mg twice daily with weekly paclitaxel; dose level –1 was varlitinib 300 mg bid for 4 days per week (4 days on, 3 days off, intermittent dose). Administration of study drugs at dose level 1 was planned for three patients until the first dose-limiting toxicity (DLT) was observed for 4 weeks. If DLT was not observed, phase II was conducted at dose level 1. If one or more DLTs were observed in three patients, the cohort was expanded to six. MTD was defined as the highest dose at which fewer than two of the six patients experienced DLT. If two or more DLTs were observed in six patients at dose level 1, the cohort was de-escalated to a lower level (dose level –1). Phase II study evaluated the safety and tolerability of varlitinib and paclitaxel combination therapy in RP2D and investigated its antitumor activity. Oral varlitinib was administered based on the RP2D, and paclitaxel was administered weekly at 80 mg/m² via intravenous infusion for 3 weeks every 4 weeks. It was discontinued in the event of disease progression, toxicity above an acceptable level, patient refusal, withdrawal of consent, or death.

3. Safety analyses and efficacy

Adverse events (AEs) were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, ver. 4.03). DLTs were defined as grade ≥ 3 non-hematologic toxicities (except for alopecia); grade ≥ 3 diarrhea, nausea, and vomiting, despite maximal dosage of anti-diarrhea and/or anti-emetic medication (as applicable); and grade 4 neutropenia sustained for ≥ 7 days, grade 3-4 neutropenia with fever or infection, grade 4 thrombocytopenia and grade 3 thrombocytopenia sustained for ≥ 7 days, or with accompanying bleeding, or requiring transfusion for 28 days. All patients who received at least one dose of varlitinib were included in the safety analysis. Tumor response was evaluated by conducting chest and abdomen/pelvis computed tomography or magnetic resonance imaging every 6 weeks from the start of the study to the 24th week, after which the frequency was reduced to once every 12 weeks until disease progression using the RECIST ver. 1.1, according to the investigator’s assessment.

4. Circulating tumor DNA assay for monitoring response to therapy

The circulating tumor DNA (ctDNA) was extracted from the patient’s plasma (10 mL) at two time points (before treatment and at the first response evaluation or end of the treatment). The DNA NGS library and solution-based target enrichment were performed at IMBdx, Inc. (Seoul, Korea), using AlphaLiquid100 as previously described [20]. The targeted gene panel of 118 cancer-related genes was used to detect the four classes of variations (single-nucleotide variants, indels, fusions, and copy number variations) in 118 cancer-related genes. The captured DNA libraries were sequenced using the Illumina NovaSeq 6000 platform (Illumina, San Diego, CA) in the 2×150 bp paired-end mode.

5. Statistical analysis

The primary objective of phase Ib was to determine the MTD of varlitinib in combination with paclitaxel. The primary objective of the phase II trial was to study progression-free survival (PFS) with varlitinib combined with paclitaxel. PFS was defined as the period from enrollment to the day on which (1) radiological or clinical progression was evident, (2) subsequent treatment was indicated, or (3) the patient died. Secondary objectives were to assess the safety, tolerability, objective response rate (ORR), disease control rate (DCR), and overall survival (OS). For phase II, the sample size was calculated according to statistical assumptions and checked using the null hypothesis (PFS of 2.9 months in the single paclitaxel group) and alternative hypothesis (PFS of 4.4 months in the paclitaxel and ramucirumab combination group) based on the RAINBOW study [21]. Therefore, the sample size was determined to be 50 subjects with a two-sided significance level of 10% at a power of 70%. Considering a dropout rate of 10%, the total number of subjects in phases Ib/II was 55.

Results

1. Patients’ characteristics

From January 2020 to December 2021, 31 patients were enrolled from six centers in the Republic of Korea. Although 22 patients were enrolled during the phase II study, this study was terminated early owing to the supply constraints of varlitinib following the sponsor’s decision to stop further development. Baseline characteristics of the study population are summarized in Table 1. The median age was 64 years (range, 34 to 83 years), and 18 patients (67%) were males. The first-line treatment regimens consisted of the following: fluoropyrimidine and/or platinum-based chemotherapy (17 patients), fluoropyrimidine/platinum with trastuzumab (6 patients), and fluoropyrimidine/platinum with pembrolizumab (4 patients). There were no statistical differences in best response and PFS according to the first-line treatment regimens (S1 Table).

2. Determination of RP2D

Although nine patients were enrolled at the dose 1 level of varlitinib 300 mg twice daily in the phase Ib study, three patients were excluded because of protocol violations (withdrawal, emergency surgery, and non-adherence to the study drug). Among the six patients, one of the first three experienced DLT of grade 4 aspartate aminotransferase/alanine aminotransferase elevation and hyperbilirubinemia in the first cycle. Three additional patients were enrolled, and there were no DLT at a dose level of 1. Therefore, RP2D was decided to be varlitinib 300 mg twice daily combined with weekly paclitaxel (80 mg/m² on days 1, 8, and 15) every 4 weeks.

3. Efficacy and survival outcomes

Among the 27 patients, including 22 patients treated with RP2D and five patients from the phase Ib study (one patient who experienced DLT grade 4 was not evaluated) for efficacy evaluation, the median follow-up duration was 15.7 months (95% confidence interval [CI], 11.3 to 20.1). The median PFS and OS were 3.3 months (95% CI, 1.7 to 4.9) and 7.9 months (95% CI, 5.0 to 10.8), respectively (Fig. 1A). Among the 16 patients with measurable disease who were administered RP2D, tumor shrinkage was observed in 11 patients (69%); therefore, confirmed objective response and disease control were observed in five patients (ORR, 31%; 95% CI, 9 to 54) and 14 patients (DCR, 88%; 95% CI, 71 to 100), respectively (Fig. 2).

Based on EGFR and HER2 expression, the patients were divided into three subgroups as follows: (1) low expression (EGFR 1+ and HER2 1+), (2) strong EGFR expression (EGFR 3+ and any HER2; EGFR 2+ and HER2 2+), and (3) strong HER2 expression (HER2 3+ and any EGFR; HER2 2+ and EGFR 1+) (S2 Table). Patients with strong HER2 expression (n=8) had higher ORR and longer OS than those in the other groups (Fig. 1B). In contrast, patients with strong EGFR (n=3) had poor outcomes for ORR, PFS, and OS. The low-expression group (n=16) comprised the largest number of patients and showed similar efficacy to the strong HER2 group (Table 2, Fig. 2C and D). Therefore, we could not establish a relationship between EGFR and HER2 expression and treatment efficacy.

4. Toxicity and safety

The safety analysis set consisted of six patients in phase Ib, as described in Table 3. Grade 3 or higher neutropenia was observed in three patients (50.0%). One of the first three patients experiencing grade 4 showed increased aspartate aminotransferase (AST)/alanine transaminase (ALT)/bilirubin at dose level 1 and recovered after 3 weeks. Among the 27 patients, the most common AEs were neutropenia (51.8%; 22.2% of grade 3/4), AST/ALT elevation (22.2%; 11.1% of grade 3/4), diarrhea (27.3%), and nausea (18.5%). No treatment-related deaths or unexpected AEs resulting from treatment cessation were observed in patients with RP2D.

5. Genomic alteration landscape in ctDNA analysis

A total of 25 samples from 15 patients were analyzed, and 26 mutations and seven gene amplifications were detected (Fig. 3). Among the 15 patients included in the baseline analysis, genetic alterations were detected in 11 patients (73.3%), with a median of five mutations per patient (range, 1 to 11). The most common baseline somatic alteration was TP53 (n=7, 63.6%), followed by ERBB2 amplification (n=4, 36.4%). Among the four patients with HER2 3+ expression and genetic alterations detected in ctDNA, three (75.0%) had ERBB2 amplification. However, there was no EGFR amplification in the two patients with strong EGFR expression, and genetic alterations were detected in the ctDNA. No differences were observed in the survival outcomes according to the detection of genetic alterations at baseline in terms of PFS (log-rank test, p=0.581) (Fig. 1C) and OS (p=0.391). However, six patients whose genetic alteration in the ctDNA were decreased or cleared after chemotherapy among 10 patients who were checked for follow-up ctDNA analysis had a trend toward better survival in terms of PFS (median, 5.5 months [95% CI, 1.5 to 2.6] vs. 1.4 months [95% CI, 1.2 to 1.5]; p=0.132) and OS (median, 7.9 months [95% CI, 2.6 to 13.2] vs. 5.8 months [1.3 to 10.4]; p=0.449) compared to that of the other nine patients.

Discussion

In this prospective, multicenter, open-label phase Ib/II study, a combination of 300 mg of varlitinib twice daily and paclitaxel displayed manageable toxicity and moderate efficacy in previously treated patients with EGFR/HER2 co-expressing AGC.

In a previous phase I study [18], the RP2D of varlitinib was determined at a dose of 300 mg twice daily (4 days on, 3 days off). The varlitinib study was performed mostly in patients with breast cancer treated with paclitaxel with or without trastuzumab. Although we selected 300 mg twice every day with weekly paclitaxel as RP2D, treatment-related AEs were slightly decreased, such as grade 3-4 neutropenia (20% vs. 40%), anemia (4% vs. 5%), and febrile neutropenia (7% vs. 11%), compared to the previous phase I study. Grade 3-4 non-hematologic toxicities, including diarrhea (0% vs. 5%), asthenia (0% vs. 11%), and mucositis (0% vs. 5%), decreased, except for hyperbilirubinemia/elevated AST (11% vs. 5%). However, these findings should be interpreted with caution not only due to differences in varlitinib dose but also to differences in patient groups and duration of treatment (median, 3.0 months; range, 0.1 to 17.1) in the phase Ib study [18].

The ORR, median PFS, and OS were 31%, 3.3, and 7.6 months, respectively. Compared to the paclitaxel alone group (ORR, 16%; PFS, 2.9 months; and OS, 7.4 months) in the RAINBOW trial [21], these results suggest that varlitinib as a pan-HER inhibitor, combined with chemotherapy, could be more potent for the second-line setting than chemotherapy alone. However, these results were based on a limited number of patients and additional studies are required to evaluate the efficacy of this combination therapy.

The ctDNA analysis performed in a subgroup of AGC patients whose tumors co-expressed EGFR and HER2 revealed 26 gene mutations and seven gene amplifications. An association was also observed between HER2 expression and ERBB2 amplification. Furthermore, a few patients whose ctDNA mutations decreased or were cleared after treatment reported a longer PFS. In addition, our findings suggested that gastric cancer has a high level of genetic diversity, and ctDNA dynamics using longitudinally obtained blood samples could predict response or resistance during treatment [22,23].

Because pretreatment biopsy was not mandatory, patients were enrolled based on EGFR and HER2 expression at initial diagnosis. Furthermore, it remains unclear whether IHC expression is an appropriate target biomarker for varlitinib. In addition, statistically planned patients could not be enrolled because of limited drug support.

In conclusion, a combination of varlitinib and paclitaxel displayed manageable toxicity and antitumor activity in patients with EGFR/HER2 co-expressing AGC who progressed after first-line chemotherapy. Further clinical studies are required to confirm the efficacy of dual inhibitors of EGFR/HER2 combined with paclitaxel in patients with EGFR/HER2-positive gastric cancer with a large sample size.

Electronic Supplementary Material

Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).

crt-2023-1324_S1_Table.pdf

crt-2023-1324_S2_Table.pdf

NOTES

Ethical Statement

This study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice Guidelines. The Institutional Review Board of each participating center approved this study (KCT0003583; NCT05400915). All patients provided written informed consent before enrollment.

Author Contributions

Conceived and designed the analysis: Koo DH, Jung M, Kim YH, Jeung HC, Zang DY, Bae WK, Kim H, Kim HS, Lee CK, Kwon WS, Chung HC, Rha SY.

Collected the data: Koo DH, Jung M, Kim YH, Jeung HC, Zang DY, Bae WK, Kim H, Kim HS, Lee CK, Kwon WS, Chung HC, Rha SY.

Contributed data or analysis tools: Koo DH, Jung M, Kim YH, Jeung HC, Zang DY, Bae WK, Kim H, Kim HS, Lee CK, Kwon WS, Chung HC, Rha SY.

Performed the analysis: Koo DH, Jung M, Rha SY.

Wrote the paper: Koo DH, Jung M, Rha SY.

Conflicts of Interest

Minkyu Jung; Employment: Ensol Biosciences; Stock and Other Ownership Interests: Ensol Biosciences; Honoraria: Lilly, Celltrion.

Yeul Hong Kim; Employment: Yuhan Corporation.

Hyun Cheol Chung; Employment: MDBiolab; Consulting or Advisory Role: Taiho Pharmaceutical, Celltrion, MSD, Lilly, Quintiles, Bristol Myers Squibb, Merck Serono, Gloria Biosciences, Amgen, Zymeworks, Beigene, Y-Biologics, Seagen; Speakers’ Bureau: Merck Serono, Lilly, Foundation Medicine; Research Funding: Lilly (Inst), GlaxoSmithKline (Inst), MSD (Inst), Merck Serono (Inst), Bristol Myers Squibb (Inst), Taiho Pharmaceutical (Inst), Amgen (Inst), Beigene (Inst), Incyte (Inst), Zymeworks (Inst).

Sun Young Rha; Consulting or Advisory Role: MSD Oncology, Daiichi Sankyo, Eisai, LG Chem, Eutilex, Astellas Pharma, Indivumed, AstraZeneca, Ono Pharmaceutical, Amgen; Speakers’ Bureau: Lilly, Eisai, MSD Oncology, BMS/Ono, Amgen, Daiichi, Sankyo/UCB Japan, AstraZeneca; Research Funding: MSD Oncology, Bristol Myers Squibb, Eisai, Roche/Genentech, Aslan Pharmaceuticals, Sillajen, Bayer, Daichii Sankyo, Lilly, AstraZeneca, BeiGene, Zymeworks, Astellas Pharma, Indivumed, Amgen (Inst). Other authors declare no conflict of interest.

Acknowledgements

Varlitinib was provided by ASLAN Pharmaceuticals Pte. Ltd. (Singapore) through a research collaboration. This study was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health and Welfare (HA15C0005) and the Ministry of Health and Welfare (HI17C2206), Republic of Korea.

Fig. 1.

Progression-free survival and overall survival in all patients (A). Progression-free survival and overall survival according to the epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) expression (B). Progression-free survival according to the circulating tumor DNA (ctDNA) analysis (C). CI, confidence interval.

Fig. 2.

Waterfall plot of the best percentage change in target lesion size from baseline for individual patients with measurable disease (A). Swimmer plot showing patients’ treatment duration and response (B). Waterfall plot (C) and Swimmer plot (D) according to the epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) expression. CR, complete response; F/U, follow-up; PD, disease progression; PR, partial response; SD, stable disease.

Fig. 3.

Genomic alteration landscape in circulating tumor DNA analysis according to the progression-free survival (PFS), overall survival (OS), and epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) immunohistochemical expression (n=15). IHC, immunohistochemistry; PD, disease progression.

Table 1.

Baseline characteristics

Characteristic	Phase Ib	Phase II	Total
No. of patients	6 (21.4)	22 (78.6)	28 (100)
Age (yr), median (range)	45 (34-77)	64 (41-83)	64 (34-83)
Sex
Male	4 (66.7)	15 (68.2)	19 (67.9)
Female	2 (33.3)	7 (31.8)	9 (32.1)
ECOG PS
0	3 (50.0)	12 (54.5)	15 (53.6)
1	3 (50.0)	10 (45.5)	13 (46.4)
Histology
WD/MD	3 (50.0)	12 (54.5)	15 (53.6)
PD/SRCC	3 (50.0)	10 (45.5)	13 (46.4)
Status
Recurrent	4 (66.7)	4 (18.2)	8 (28.6)
Initial metastatic	2 (33.3)	18 (81.8)	20 (71.4)
Measurable disease
Yes	5 (83.3)	16 (72.7)	21 (75.0)
EGFR IHC
1+	4 (66.6)	18 (81.8)	22 (78.6)
2+	1 (16.2)	4 (18.2)	5 (17.9)
3+	1 (16.2)	0	1 (3.5)
HER2 IHC
1+	2 (33.3)	16 (72.7)	18 (64.6)
2+/ISH–	4 (66.7)	1 (4.6)	5 (17.9)
3+	0	5 (22.7)	5 (17.9)
First-line treatment
FP-based therapy	5 (66.6)	13 (59.1)	18 (63.0)
FP+Tmab	0	6 (27.3)	6 (22.2)
FP+Pmab	1 (16.7)	3 (13.6)	4 (14.8)

Values are presented as number (%) unless otherwise indicated. ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; FP, fluoropyrimidine and/or platinum; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ISH, in situ hybridization; MD, moderately differentiated; PD, poorly differentiated; Pmab, pembrolizumab; PS, performance status; SRCC, signet ring cell carcinoma; Tmab, trastuzumab; WD, well differentiated.

Table 2.

Clinical efficacy of varlitinib combined with paclitaxel in phase Ib/II patients

Clinical efficacy	Both low (n=16)	Strong EGFR (n=3)	Strong HER2 (n=8)	Total (n=27)	p-value
Best response
PR	4 (25.0)	-	2 (25.0)	6 (22.2)	0.614
SD	5 (31.3)	2 (66.7)	5 (62.5)	12 (44.4)
PD	5 (31.3)	1 (33.3)	1 (12.5)	7 (25.9)
NA	2 (12.4)	-	-	2 (7.5)
ORR	4 (28.6)	-	2 (25.0)	6 (24.0)	0.466
DCR	9 (64.3)	2 (66.7)	7 (87.5)	18 (72.0)	0.334
PFS (mo), median (95% CI)	3.2 (0.2-6.2)	2.1 (NA)	3.1 (0.6-12.6)	3.3 (1.7-4.9)	0.362
OS (mo), median (95% CI)	7.9 (6.1-9.7)	5.8 (5.4-6.2)	10.9 (2.9-19.0)	7.9 (5.0-10.8)	0.764

Values are presented as number (%) unless otherwise indicated. CI, confidence interval; DCR, disease control rate; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; NA, not available; ORR, objective response rate; OS, overall survival; PD, disease progression; PFS, progression-free survival; PR, partial response; SD, stable disease.

Table 3.

Adverse events related to varlitinib combined with paclitaxel

	Toxicity grade
	Phase Ib (n=6^a))			Phase II (n=22)			Total (n=27)
	1-2	3	4	1-2	3	4	All	3-4
Hematologic adverse events
Neutropenia	0	2 (33.3)	1 (16.7)	3 (13.6)	3 (13.6)	5 (22.7)	14 (51.8)	6 (22.2)
Thrombocytopenia	0	0	0	0	0	0	0	0
Anemia	0	0	0	2 (13.6)	1 (4.5)	0	3 (11.1)	1 (3.7)
Febrile neutropenia	0	0	0	0	1 (4.5)	1 (4.5)	2 (7.4)	2 (7.4)
Hyperbilirubinemia	0	0	1 (16.7)	1 (4.5)	1 (4.5)	0	3 (11.1)	2 (11.1)
ALT increased	0	0	1 (16.7)	4 (18.2)	1 (4.5)	0	6 (22.2)	2 (7.4)
AST increased	0	0	1 (16.7)	3 (13.6)	1 (4.5)	1 (4.5)	6 (22.2)	3 (11.1)
Hyperkalemia	0	0	0	0	1 (4.5)	0	1 (3.7)	1 (3.7)
Hypokalemia	0	0	0	0	1 (4.5)	0	1 (3.7)	1 (3.7)
Hypophosphatemia	0	0	0	2 (9.1)	0	0	2 (7.4)	0
Hypothyroidism	0	0	0	0	1 (4.5)	0	1 (3.7)	1 (3.7)
Hyperglycemia	0	0	0	1 (4.5)	0	0	1 (3.7)	0
Creatinine elevation	0	0	0	1 (4.5)	0	0	1 (3.7)	0
Non-hematologic adverse events
Peripheral neuropathy	1 (16.7)	0	0	3 (13.6)	0	0	4 (14.8)	0
Rash	0	1 (16.7)	0	2 (9.1)	0	0	3 (11.1)	1 (3.7)
Acneiform eruption	0	0	0	1 (4.5)	0	0	1 (3.7)	0
Folliculitis	0	0	0	1 (4.5)	0	0	1 (3.7)	0
Pruritis	0	0	0	2 (9.1)	0	0	2 (7.4)	0
Anorexia	0	0	0	0	1 (4.5)	0	1 (3.7)	1 (3.7)
Nausea	0	0	0	4 (18.2)	1 (4.5)	0	5 (18.5)	1 (3.7)
Vomiting	1 (16.7)	0	0	2 (9.1)	0	0	3 (11.1)	0
Diarrhea	0	0	0	6 (27.3)	0	0	6 (27.3)	0
Constipation	0	0	0	1 (4.5)	0	0	1 (3.7)	0
Mucositis	0	0	0	4 (18.2)	0	0	4 (14.8)	0
Infection	2 (33.3)	0	0	0	0	0	2 (7.4)	0
Asthenia	0	0	0	1 (4.5)	0	0	1 (3.7)	0
Myalgia	0	0	0	2 (9.1)	0	0	2 (7.4)	0

Values are presented as number (%).

^a) One patient was excluded from further treatment and analysis owing to dose-limiting toxicity (liver enzyme elevation G4).

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Varlitinib and Paclitaxel for EGFR/HER2 Co-expressing Advanced Gastric Cancer: A Multicenter Phase Ib/II Study (K-MASTER-13)

Cancer Res Treat. 2024;56(4):1136-1145. Published online April 29, 2024

DOI: https://doi.org/10.4143/crt.2023.1324

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Varlitinib and Paclitaxel for EGFR/HER2 Co-expressing Advanced Gastric Cancer: A Multicenter Phase Ib/II Study (K-MASTER-13)

Fig. 1. Progression-free survival and overall survival in all patients (A). Progression-free survival and overall survival according to the epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) expression (B). Progression-free survival according to the circulating tumor DNA (ctDNA) analysis (C). CI, confidence interval.

Fig. 2. Waterfall plot of the best percentage change in target lesion size from baseline for individual patients with measurable disease (A). Swimmer plot showing patients’ treatment duration and response (B). Waterfall plot (C) and Swimmer plot (D) according to the epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) expression. CR, complete response; F/U, follow-up; PD, disease progression; PR, partial response; SD, stable disease.

Fig. 3. Genomic alteration landscape in circulating tumor DNA analysis according to the progression-free survival (PFS), overall survival (OS), and epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) immunohistochemical expression (n=15). IHC, immunohistochemistry; PD, disease progression.

Fig. 1.

Fig. 2.

Fig. 3.

Varlitinib and Paclitaxel for EGFR/HER2 Co-expressing Advanced Gastric Cancer: A Multicenter Phase Ib/II Study (K-MASTER-13)

Characteristic	Phase Ib	Phase II	Total
No. of patients	6 (21.4)	22 (78.6)	28 (100)
Age (yr), median (range)	45 (34-77)	64 (41-83)	64 (34-83)
Sex
Male	4 (66.7)	15 (68.2)	19 (67.9)
Female	2 (33.3)	7 (31.8)	9 (32.1)
ECOG PS
0	3 (50.0)	12 (54.5)	15 (53.6)
1	3 (50.0)	10 (45.5)	13 (46.4)
Histology
WD/MD	3 (50.0)	12 (54.5)	15 (53.6)
PD/SRCC	3 (50.0)	10 (45.5)	13 (46.4)
Status
Recurrent	4 (66.7)	4 (18.2)	8 (28.6)
Initial metastatic	2 (33.3)	18 (81.8)	20 (71.4)
Measurable disease
Yes	5 (83.3)	16 (72.7)	21 (75.0)
EGFR IHC
1+	4 (66.6)	18 (81.8)	22 (78.6)
2+	1 (16.2)	4 (18.2)	5 (17.9)
3+	1 (16.2)	0	1 (3.5)
HER2 IHC
1+	2 (33.3)	16 (72.7)	18 (64.6)
2+/ISH–	4 (66.7)	1 (4.6)	5 (17.9)
3+	0	5 (22.7)	5 (17.9)
First-line treatment
FP-based therapy	5 (66.6)	13 (59.1)	18 (63.0)
FP+Tmab	0	6 (27.3)	6 (22.2)
FP+Pmab	1 (16.7)	3 (13.6)	4 (14.8)

Clinical efficacy	Both low (n=16)	Strong EGFR (n=3)	Strong HER2 (n=8)	Total (n=27)	p-value
Best response
PR	4 (25.0)	-	2 (25.0)	6 (22.2)	0.614
SD	5 (31.3)	2 (66.7)	5 (62.5)	12 (44.4)
PD	5 (31.3)	1 (33.3)	1 (12.5)	7 (25.9)
NA	2 (12.4)	-	-	2 (7.5)
ORR	4 (28.6)	-	2 (25.0)	6 (24.0)	0.466
DCR	9 (64.3)	2 (66.7)	7 (87.5)	18 (72.0)	0.334
PFS (mo), median (95% CI)	3.2 (0.2-6.2)	2.1 (NA)	3.1 (0.6-12.6)	3.3 (1.7-4.9)	0.362
OS (mo), median (95% CI)	7.9 (6.1-9.7)	5.8 (5.4-6.2)	10.9 (2.9-19.0)	7.9 (5.0-10.8)	0.764

	Toxicity grade
	Phase Ib (n=6^a))			Phase II (n=22)			Total (n=27)
	1-2	3	4	1-2	3	4	All	3-4
Hematologic adverse events
Neutropenia	0	2 (33.3)	1 (16.7)	3 (13.6)	3 (13.6)	5 (22.7)	14 (51.8)	6 (22.2)
Thrombocytopenia	0	0	0	0	0	0	0	0
Anemia	0	0	0	2 (13.6)	1 (4.5)	0	3 (11.1)	1 (3.7)
Febrile neutropenia	0	0	0	0	1 (4.5)	1 (4.5)	2 (7.4)	2 (7.4)
Hyperbilirubinemia	0	0	1 (16.7)	1 (4.5)	1 (4.5)	0	3 (11.1)	2 (11.1)
ALT increased	0	0	1 (16.7)	4 (18.2)	1 (4.5)	0	6 (22.2)	2 (7.4)
AST increased	0	0	1 (16.7)	3 (13.6)	1 (4.5)	1 (4.5)	6 (22.2)	3 (11.1)
Hyperkalemia	0	0	0	0	1 (4.5)	0	1 (3.7)	1 (3.7)
Hypokalemia	0	0	0	0	1 (4.5)	0	1 (3.7)	1 (3.7)
Hypophosphatemia	0	0	0	2 (9.1)	0	0	2 (7.4)	0
Hypothyroidism	0	0	0	0	1 (4.5)	0	1 (3.7)	1 (3.7)
Hyperglycemia	0	0	0	1 (4.5)	0	0	1 (3.7)	0
Creatinine elevation	0	0	0	1 (4.5)	0	0	1 (3.7)	0
Non-hematologic adverse events
Peripheral neuropathy	1 (16.7)	0	0	3 (13.6)	0	0	4 (14.8)	0
Rash	0	1 (16.7)	0	2 (9.1)	0	0	3 (11.1)	1 (3.7)
Acneiform eruption	0	0	0	1 (4.5)	0	0	1 (3.7)	0
Folliculitis	0	0	0	1 (4.5)	0	0	1 (3.7)	0
Pruritis	0	0	0	2 (9.1)	0	0	2 (7.4)	0
Anorexia	0	0	0	0	1 (4.5)	0	1 (3.7)	1 (3.7)
Nausea	0	0	0	4 (18.2)	1 (4.5)	0	5 (18.5)	1 (3.7)
Vomiting	1 (16.7)	0	0	2 (9.1)	0	0	3 (11.1)	0
Diarrhea	0	0	0	6 (27.3)	0	0	6 (27.3)	0
Constipation	0	0	0	1 (4.5)	0	0	1 (3.7)	0
Mucositis	0	0	0	4 (18.2)	0	0	4 (14.8)	0
Infection	2 (33.3)	0	0	0	0	0	2 (7.4)	0
Asthenia	0	0	0	1 (4.5)	0	0	1 (3.7)	0
Myalgia	0	0	0	2 (9.1)	0	0	2 (7.4)	0

Table 1. Baseline characteristics

Values are presented as number (%) unless otherwise indicated. ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; FP, fluoropyrimidine and/or platinum; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ISH, in situ hybridization; MD, moderately differentiated; PD, poorly differentiated; Pmab, pembrolizumab; PS, performance status; SRCC, signet ring cell carcinoma; Tmab, trastuzumab; WD, well differentiated.

Table 2. Clinical efficacy of varlitinib combined with paclitaxel in phase Ib/II patients

Table 3. Adverse events related to varlitinib combined with paclitaxel

Values are presented as number (%).

One patient was excluded from further treatment and analysis owing to dose-limiting toxicity (liver enzyme elevation G4).