Phase 1 trial of zolbetuximab in Japanese patients with CLDN18.2+ gastric or gastroesophageal junction adenocarcinoma

Abstract

Zolbetuximab is a chimeric monoclonal antibody that targets claudin‐18.2, a candidate biomarker in patients with advanced gastric/gastroesophageal cancer. This nonrandomized phase 1 study (NCT03528629) enrolled previously treated Japanese patients with claudin‐18.2–positive locally advanced/metastatic gastric/gastroesophageal cancer in two parts: Safety (Arms A and B, n = 3 each) and Expansion (n = 12). Patients received intravenous zolbetuximab 800 mg/m² on cycle 1, day 1 followed by 600 mg/m² every 3 weeks (Q3W; Safety Part Arm A and Expansion) or 1000 mg/m² Q3W (Safety Part Arm B). For the Safety Part, the primary endpoint was safety (i.e., dose‐limiting toxicities [DLTs]) and a secondary endpoint was objective response rate (ORR) by investigator. For the Expansion Part, the primary endpoint was ORR by investigator and secondary endpoints included ORR by central review and safety. Additional secondary endpoints for both the Safety and Expansion Parts were disease control rate (DCR), overall survival (OS), progression‐free survival (PFS), duration of response, pharmacokinetics, and immunogenicity. In 18 patients, no DLTs (Safety Part) or drug‐related treatment‐emergent adverse events (TEAEs) grade ≥3 were observed. Most TEAEs were gastrointestinal. In 17 patients with measurable lesions, best overall response was stable disease (64.7%) or progressive disease (35.3%). The DCR was 64.7% (95% confidence interval 38.3–85.8). In Arm A and Expansion combined (n = 15), median OS was 4.4 months (2.6–11.4) and median PFS was 2.6 months (0.9–2.8). In Arm B (n = 3), median OS was 6.4 months (2.9–6.8) and median PFS was 1.7 months (1.2–2.1). Zolbetuximab exhibited no new safety signals with limited single‐agent activity in Japanese patients.

Here we show for the first time that zolbetuximab treatment does not lead to any new safety signals specifically in Japanese patients with advanced G/GEJ cancer; most (94.4%) patients experienced zolbetuximab‐related gastrointestinal adverse events, which were not severe (grade 1–2) and did not lead to study discontinuation or death. Zolbetuximab monotherapy exhibited limited anticancer efficacy in this study. The promising efficacy profile of zolbetuximab when combined with chemotherapy observed in phase 2 trials and the tolerable safety profile observed in this study suggest that zolbetuximab in combination with chemotherapy may be a suitable treatment specifically for Japanese patients with advanced G/GEJ cancer.

Abbreviations

1L

first‐line

2L

second‐line

3L

third‐line

AE

adverse event

AUC_tau

area under the serum concentration‐time curve from the time of dosing to the start of the next dosing interval

BOR

best overall response

BSA

body surface area

CI

confidence interval

CLDN18.2

claudin‐18 splice variant 2

C _max

maximum serum concentration

CR

complete response

DCR

disease control rate

DLT

dose‐limiting toxicity

DOR

duration of response

G/GEJ

gastric or gastroesophageal junction

GC

gastric cancer

HR

hazard ratio

IHC

immunohistochemistry

IRR

infusion‐related reaction

NE

not evaluable

ORR

objective response rate

OS

overall survival

PD

progressive disease

PFS

progression‐free survival

PK

pharmacokinetic

PR

partial response

Q3W

every 3 weeks

RECIST v1.1

Response Evaluation Criteria in Solid Tumors version 1.1

SD

stable disease

TEAE

treatment‐emergent adverse event

t _max

time to C _max

1. INTRODUCTION

The standard first‐line (1L) treatment for patients with metastatic gastric or gastroesophageal junction (G/GEJ) cancer is combination therapy with platinum‐ and fluoropyrimidine‐based agents, with the addition of trastuzumab for patients with human epidermal growth factor receptor 2‐positive tumors. ¹ Recently, nivolumab plus chemotherapy as 1L treatment was shown to improve overall survival (OS) compared with chemotherapy in patients with G/GEJ cancer, with enriched survival benefit in patients with a high programmed death‐ligand 1 combined positive score, and has become standard treatment in some countries, including Japan. ² , ³ In the second‐line (2L) setting, treatment with taxanes plus the vascular endothelial growth factor receptor 2 inhibitor ramucirumab is recommended. ¹ Irinotecan, trifluridine/tipiracil, or nivolumab for patients who previously failed on ≥2 chemotherapy regimens are preferred treatments in third‐line (3L) or later settings. ¹ , ⁴ , ⁵ Although there have been recent advances in treatment strategies for patients with G/GEJ cancer, survival rates remain low and rapid recurrence or progression of disease is likely. ⁶ , ⁷

Claudin‐18 splice variant 2 (CLDN18.2) is a candidate biomarker in treating patients with advanced G/GEJ cancer. CLDN18.2 is a tight junction protein that is critical for normal epithelial tissue function. ⁸ In normal cells, CLDN18.2 is concentrated within the tight junctions of gastric epithelial cells and may be less accessible to intravenously‐delivered antibodies. ⁸ , ⁹ , ¹⁰ During malignant cell transformation, cell polarity is disturbed and CLDN18.2 may be exposed at the surface of gastric mucosa cells, which could render it more accessible to targeted therapies. ⁹ , ¹⁰ , ¹¹ In European patients with advanced G/GEJ cancer, moderate‐to‐high CLDN18.2 expression was observed in ≥40% of tumor cells in 49% of patients based on immunohistochemistry (IHC). ¹² In Japanese patients with gastric cancer (GC), CLDN18.2 expression in any tumor cell was observed in 87% of primary tumors and 80% of metastases, and moderate‐to‐high CLDN18.2 expression was observed in ≥40% of tumor cells in 52% of primary tumors and 45% of metastases based on IHC. ¹³ Together, this evidence suggests that CLDN18.2 is a candidate biomarker for targeted anticancer therapy in patients with G/GEJ cancer.

Zolbetuximab is an engineered chimeric monoclonal antibody that targets CLDN18.2 and mediates the cell death of CLDN18.2‐positive (CLDN18.2+) G/GEJ cancer cells via antibody‐dependent cellular cytotoxicity and complement‐dependent cytotoxicity. ⁹ , ¹⁰ , ¹⁴ In previous global phase 1 and 2 studies, zolbetuximab monotherapy had a manageable safety profile and showed efficacy in patients with advanced, previously treated, CLDN18.2+ G/GEJ cancer. ¹⁰ , ¹⁵ In the phase 2a MONO study (NCT01197885), of the 10 patients who achieved clinical benefit (partial response [PR] or stable disease [SD]), nine (90%) had moderate‐to‐high CLDN18.2 expression in ≥70% of tumor cells based on IHC. ¹⁵ The phase 2b FAST study (NCT01630083) in patients with advanced G/GEJ cancer demonstrated that 1L zolbetuximab in combination with chemotherapy increased progression‐free survival (PFS) and OS versus chemotherapy alone; the magnitude of PFS and OS improvement was greater in patients with moderate‐to‐high CLDN18.2 expression in ≥70% of tumor cells based on IHC (PFS hazard ratio [HR] 0.38, OS HR 0.50) versus the overall population (PFS HR 0.44, OS HR 0.55). ¹² The study detailed in this article investigated for the first time the safety, tolerability, and efficacy of zolbetuximab monotherapy in Japanese patients with CLDN18.2+, previously treated, locally advanced or metastatic G/GEJ cancer.

2. MATERIALS AND METHODS

2.1. Study design

This was an open‐label, nonrandomized, phase 1 study conducted at a single site in Japan.

The study consisted of two parts: a Safety Part, which was further divided into Arms A and B, and an Expansion Part. The enrollment of Safety Part Arm A occurred first. Once safety and tolerability were confirmed, the enrollment of Safety Part Arm B and the Expansion Part occurred.

2.2. Patients

Adult (≥20 years of age) Japanese patients with histologically confirmed locally advanced or metastatic G/GEJ cancer, for whom no standard‐of‐care treatment existed or who were ineligible to receive available standard of care based on investigator's assessment, were eligible to participate in the study. Patients with any CLDN18.2 membrane‐staining intensity, defined as ≥1+ intensity in any tumor cell based on central IHC testing, were eligible for enrollment in the Safety Part. Only patients with high CLDN18.2 membrane‐staining intensity, defined as ≥2+ intensity in ≥75% of tumor cells based on central IHC testing, were eligible for enrollment in the Expansion Part. Study treatment was discontinued if the patient experienced radiological progressive disease (PD) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as assessed by the investigator, clinical progression as assessed by the investigator, developed unacceptable toxicity, received other anticancer treatments, or if zolbetuximab treatment was delayed >28 days from scheduled treatment.

2.3. Treatments

In Safety Part Arm A, patients received intravenous zolbetuximab at a loading dose of 800 mg/m² body surface area (BSA) on cycle 1, day 1, followed by zolbetuximab 600 mg/m² BSA once every 3 weeks (800/600 mg/m² Q3W). A gradual increase of infusion rate was recommended at cycle 1, day 1. For subsequent doses, the infusion rate was increased or reduced based on patient tolerability and investigator clinical judgment. Contingent on a favorable safety profile in Safety Part Arm A, the same dosing scheme was used in the Expansion Part. In Safety Part Arm B, patients received intravenous zolbetuximab at a dose of 1000 mg/m² BSA Q3W. Treatment continued until the discontinuation criteria were met.

2.4. Safety assessments

The primary endpoints of the Safety Part were the safety and tolerability of zolbetuximab. Safety was a secondary endpoint of the Expansion Part. In Safety Part Arm A, patients were observed for 2 h following the first zolbetixumab infusion and for 1 h following subsequent zolbetuximab infusions if no adverse events (AEs) were experienced. Dose‐limiting toxicities (DLTs) were assessed from cycle 1, day 1 to cycle 2, day 1.

2.5. Efficacy, pharmacokinetic, and immunogenicity assessments

The primary endpoint of the Expansion Part and a secondary endpoint of the Safety Part was objective response rate (ORR, defined as complete response [CR] + PR) as assessed by the investigator. ORR as assessed by independent central review was a secondary endpoint of the Expansion Part. Secondary endpoints for both the Safety and Expansion Parts also included PFS, OS, disease control rate (DCR, defined as the proportion of patients with the best overall response [BOR] of CR, PR, or SD ≥4 weeks), duration of response (DOR), pharmacokinetic (PK) profile, and immunogenicity (assessment of antidrug antibodies) of zolbetuximab. Tumor responses were evaluated by imaging at screening, every 6 (±1) weeks for the first 8 treatment cycles, and then every 12 (±2) weeks thereafter. Responses were assessed per RECIST v1.1. PK evaluations (AUC_tau, area under the serum concentration‐time curve from the time of dosing to the start of the next dosing interval; C _max, maximum serum concentration; t _max, time to C _max) were conducted on days 1, 2, 4, 8, and 15 of cycles 1 and 3, on day 1 of cycles 4 and 5, and then every 4 weeks thereafter.

2.6. Statistical methods

ORR and DCR were reported with exact 95% confidence intervals (CIs). PFS, OS, and DOR were estimated using the Kaplan–Meier method with 95% CIs. Safety and PK data were summarized descriptively.

3. RESULTS

3.1. Patient disposition

Between June 8, 2018 and June 9, 2020, 71 patients were screened (Figure 1); 58/71 (81.7%) had tumors with CLDN18.2 expression in tumor cells at any intensity and, of those, 25/71 (35.2%) had tumors with ≥2+ CLDN18.2 intensity in ≥75% of tumor cells. Of the 71 screened patients, 18 met eligibility criteria and were assigned to the Safety (Arm A, n = 3; Arm B, n = 3) or Expansion (n = 12) Parts of the study. Study exclusions (n = 53) were due to ineligible tumor CLDN18.2 expression (n = 44), failing to meet other study inclusion criteria (n = 2), declining to participate in the study (n = 2), or other reasons (n = 5). All 18 enrolled patients were included in data analysis (Figure 1). Baseline demographics and characteristics are summarized in Tables 1 and S1.

FIGURE 1.

Patient disposition.

TABLE 1.

Demographics and baseline characteristics

Parameter	Category/statistic	Safety Part Arm A Zolbetuximab 800/600 mg/m2 (n = 3)	Safety Part Arm B Zolbetuximab 1000 mg/m2 (n = 3)	Expansion Part Zolbetuximab 800/600 mg/m2 (n = 12)	Zolbetuximab 800/600 mg/m2 (n = 15)	Total (N = 18)
Sex, n (%)	Male	2 (66.7)	0	5 (41.7)	7 (46.7)	7 (38.9)
	Female	1 (33.3)	3 (100.0)	7 (58.3)	8 (53.3)	11 (61.1)
Race, n (%)	Japanese	3 (100.0)	3 (100.0)	12 (100.0)	15 (100.0)	18 (100.0)
Age, years	Median	59.0	64.0	62.5	59.0	61.5
	Min–max	49–65	49–65	46–82	46–82	46–82
BSA, m2	Median	1.53	1.50	1.56	1.56	1.54
	Min–max	1.50–1.70	1.40–1.63	1.19–1.88	1.19–1.88	1.19–1.88
CLDN18.2 expression category 1 a , n (%)	Any positive	3 (100.0)	3 (100.0)	12 (100.0)	15 (100.0)	18 (100.0)
CLDN18.2 expression category 2 b , n (%)	Negative	0	1 (33.3)	0	0	1 (5.6)
	Below intermediate	0	1 (33.3)	0	0	1 (5.6)
	Intermediate	0	0	0	0	0
	High	3 (100.0)	1 (33.3)	12 (100.0)	15 (100.0)	16 (88.9)
Primary tumor type, n (%)	Gastric	3 (100.0)	3 (100.0)	10 (83.3)	13 (86.7)	16 (88.9)
	GEJ	0	0	2 (16.7)	2 (13.3)	2 (11.1)
ECOG performance status, n (%)	0	1 (33.3)	1 (33.3)	8 (66.7)	9 (60.0)	10 (55.6)
	1	2 (66.7)	2 (66.7)	4 (33.3)	6 (40.0)	8 (44.4)
Previous lines of therapy, n	Median	5	4	3	3	4
	Min–max	4–8	2–5	2–5	2–8	2–8
Prior gastrectomy, n (%)		2 (66.7)	0	0	2 (13.3)	2 (11.1)

Abbreviations: BSA, body surface area; CLDN, claudin; ECOG, Eastern Cooperative Oncology Group; GEJ, gastroesophageal junction; max, maximum; min, minimum; SAF, safety analysis set.

^a CLDN18.2 expression was tested at prescreening and classified by negative (no intensity), any positive (>0% of any intensity [≥1+]), or unknown.

^b CLDN18.2 expression was tested at prescreening and classified by negative (membrane 2+ plus membrane 3+ = 0), below intermediate (membrane 2+ plus membrane 3+ <50%), intermediate (membrane 2+ plus membrane 3+ ≥ 50% and < 75%), high (membrane 2+ plus membrane 3+ ≥75%), or unknown.

3.2. Exposure

The median duration of zolbetuximab treatment was 75 days (range 45–226) in Safety Part Arm A, 23 days (23–49) in Safety Part Arm B, and 44 days (1–315) in the Expansion Part. Dose delays occurred in 4 (22.2%) patients. No dose changes or premature discontinuations of infusions were reported.

3.3. Safety and tolerability

No DLTs were observed. Treatment‐emergent AEs (TEAEs) are summarized in Table S2. No patients in the study experienced TEAEs of grade >3 severity. No TEAEs led to study discontinuation or death (Table S2). TEAEs were similar across the zolbetuximab 800/600 mg/m² and 1000 mg/m² cohorts (Table S2). The most common TEAEs experienced by patients were grade 1–2 severity gastrointestinal disorders (94.4%), including nausea (61.1%), upper abdominal pain (44.4%), and vomiting (38.9%). None of the TEAEs were considered serious and all were considered to be zolbetuximab‐related (Table 2). Grade 3 severity TEAEs were anemia (5.6%), blood creatinine increase (11.1%), and hypoalbuminemia (5.6%), which were assessed as not related to zolbetuximab (Table 2).

TABLE 2.

Zolbetuximab‐related treatment‐emergent adverse events ^a

Adverse events, n (%)	Safety Part Arm A Zolbetuximab 800/600 mg/m2 (n = 3)	Safety Part Arm B Zolbetuximab 1000 mg/m2 (n = 3)	Expansion Part Zolbetuximab 800/600 mg/m2 (n = 12)	Zolbetuximab 800/600 mg/m2 tot (n = 15)	Total (N = 18)
Overall	3 (100.0)	3 (100.0)	11 (91.7)	14 (93.3)	17 (94.4)
Gastrointestinal disorders	3 (100.0)	3 (100.0)	11 (91.7)	14 (93.3)	17 (94.4)
Nausea	2 (66.7)	2 (66.7)	7 (58.3)	9 (60.0)	11 (61.1)
Abdominal pain upper	3 (100.0)	0	5 (41.7)	8 (53.3)	8 (44.4)
Vomiting	2 (66.7)	1 (33.3)	4 (33.3)	6 (40.0)	7 (38.9)
Abdominal discomfort	0	1 (33.3)	1 (8.3)	1 (6.7)	2 (11.1)
Abdominal pain	0	2 (66.7)	1 (8.3)	1 (6.7)	3 (16.7)
Constipation	0	0	1 (8.3)	1 (6.7)	1 (5.6)
General disorders and administration‐site conditions	1 (33.3)	1 (33.3)	1 (8.3)	2 (13.3)	3 (16.7)
Malaise	0	1 (33.3)	1 (8.3)	1 (6.7)	2 (11.1)
Pyrexia	1 (33.3)	0	0	1 (6.7)	1 (5.6)
Investigations	0	0	1 (8.3)	1 (6.7)	1 (5.6)
Blood pressure decreased	0	0	1 (8.3)	1 (6.7)	1 (5.6)
Metabolism and nutrition disorders	1 (33.3)	3 (100.0)	6 (50.0)	7 (46.7)	10 (55.6)
Decreased appetite	1 (33.3)	3 (100.0)	6 (50.0)	7 (46.7)	10 (55.6)
Skin and subcutaneous tissue disorders	1 (33.3)	0	0	1 (6.7)	1 (5.6)
Rash	1 (33.3)	0	0	1 (6.7)	1 (5.6)
Vascular disorders	1 (33.3)	0	0	1 (6.7)	1 (5.6)
Hypertension	1 (33.3)	0	0	1 (6.7)	1 (5.6)

^a Infusion‐related reactions are included in treatment‐related adverse events.

Additional AEs of special interest included infusion‐related reactions (IRRs; 94.4%) and noninfusion‐related hypersensitivity reactions (5.6%), anemia (5.6%), and neutropenia (0%). IRRs were identified based on TEAEs flagged by investigator as IRRs per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Most TEAEs were considered as symptoms related to IRRs. The most common IRR events by preferred terms (present in ≥2 patients) were nausea (56.6%), upper abdominal pain (44.4%), vomiting (38.9%), abdominal pain (16.7%), and abdominal discomfort (11.1%). The severity of IRRs was grade 1–2. Reducing the initial infusion rate may be associated with lower severity of gastrointestinal toxicity events and better patient tolerability. In response to IRRs, zolbetuximab infusion times were lengthened in subsequent cycles as follows: the original infusion rate was calculated for a planned infusion over 2 h. In the lengthened infusion times, the infusion rate was reduced to one‐fourth of the original rate for the first 30 min, to one‐half of the original rate for the next 30 min, and then increased to the original infusion rate as tolerated (Figure S2).

3.4. Antitumor activity

Per investigator, in 17 patients with measurable lesions, the BOR was SD (64.7%) or PD (35.3%). The DCR was 64.7% (95% CI 38.3–85.8) (Table 3). Per central independent review, in 7 patients with measurable lesions in the Expansion Part, the BOR was SD (42.9%), PD (42.9%), or not evaluable (NE; 14.3%). The DCR was 42.9% (95% CI 9.9–81.6) (Table 3). Two patients had SD >6 months (Figure S1). Per investigator, across 17 patients with measurable lesions, 7 patients experienced some degree of reduction in tumor size (Figure 2). Per central independent review, among 7 patients with measurable lesions in the Expansion Part, 4 patients experienced a reduction in tumor size within SD (Figure 3). All patients ultimately discontinued treatment due to PD (Figure S1). Following study discontinuation, subsequent anticancer therapies were administered to 12 (66.7%) patients.

TABLE 3.

Overall response in patients with measurable lesions by investigator or central independent review

	Assessed by investigator					Assessed by central independent review
Parameter	Safety Part Arm A Zolbetuximab 800/600 mg/m2 (n = 2)	Safety Part Arm B Zolbetuximab 1000 mg/m2 (n = 3)	Expansion Part Zolbetuximab 800/600 mg/m2 (n = 12)	Zolbetuximab 800/600 mg/m2 (n = 14)	Total (n = 17)	Expansion Part Zolbetuximab 800/600 mg/m2 (n = 7)
BOR, n (%) a
CR	0	0	0	0	0	0
PR b	0	0	0	0	0	0
SD	2 (100.0)	2 (66.7)	7 (58.3)	9 (64.3)	11 (64.7)	3 (42.9)
PD	0	1 (33.3)	5 (41.7)	5 (35.7)	6 (35.3)	3 (42.9)
NE	0	0	0	0	0	1 (14.3)
ORR, n (%)	0	0	0	0	0	0
95% CI (%) c	(0.0–84.2)	(0.0–70.8)	(0.0–26.5)	(0.0–23.2)	(0.0–19.5)	(0.0–41.0)
DCR, n (%) d	2 (100.0)	2 (66.7)	7 (58.3)	9 (64.3)	11 (64.7)	3 (42.9)
95% CI (%) c	(15.8–100.0)	(9.4–99.2)	(27.7–84.8)	(35.1–87.2)	(38.3–85.8)	(9.9–81.6)

Abbreviations: BOR, best overall response; CI, confidence interval; CR, complete response; DCR, disease control rate; NE, not evaluable; ORR, objective response rate; PD, progressive disease; PR, partial response; RECIST v1.1, response evaluation criteria in solid tumors version 1.1; SD, stable disease.

^a The definition of BOR followed RECIST v1.1. CR/PR had to be confirmed by two scans ≥4 weeks apart. When SD was believed to be the BOR, the assessment had to be ≥35 days from the first zolbetuximab infusion date.

^b PR included target lesions, nontarget lesions, and new lesions.

^c Using the exact method based on binomial distribution (Clopper–Pearson).

^d DCR was defined as the proportion of patients who had a BOR of CR, PR, or SD of ≥4 weeks.

FIGURE 2.

Best percentage change in tumor size, by investigator. Each bar represents an individual patient. Measurable lesions were only present in 17/18 patients. “Best change from baseline” represents the change in the sum of tumor diameters for target lesions. BOR, best overall response; BSA, body surface area; max, maximum; min, minimum; PD, progressive disease; PR, partial response; SD, stable disease; STD, standard deviation. ^aBOR was SD.

FIGURE 3.

Best percentage change in tumor size in the Expansion Part, by central independent review. Each bar represents an individual patient. Measurable lesions were only present in 7/12 patients. “Best change from baseline” represents the change in the sum of tumor diameters for target lesions. BOR, best overall response; BSA, body surface area; max, maximum; min, minimum; PD, progressive disease; PR, partial response; SD, stable disease; STD, standard deviation. ^aBOR was SD.

The median PFS was 2.6 months (95% CI 0.9–2.8) in Safety Part Arm A and the Expansion Part combined (zolbetuximab 800/600 mg/m²), and 1.7 months (1.2–2.1) in Safety Part Arm B (zolbetuximab 1000 mg/m²) (Table 4). The median OS was 4.4 months (95% CI 2.6–11.4) in Safety Part Arm A and the Expansion Part combined and 6.4 months (2.9–6.8) in Safety Part Arm B (Table 4).

TABLE 4.

Summary of progression‐free and overall survival outcomes

Parameter	Safety Part Arm A + Expansion Part Zolbetuximab 800/600 mg/m2 (n = 15)	Safety Part Arm B Zolbetuximab 1000 mg/m2 (n = 3)
PFS events, n (%)	14 (93.3)	3 (100.0)
Duration of PFS (months) a
Median (95% CI)	2.6 (0.9–2.8)	1.7 (1.2–2.1)
Range	0.10–11.07	1.18–2.10
Duration of OS (months) a
Median (95% CI)	4.4 (2.6–11.4)	6.4 (2.9–6.8)
Range	1.77–13.96	2.89–6.83
Follow‐up time (months) b
Median (95% CI)	NE (2.5–NE)	NE (NE–NE)

PFS was defined as the time from start of zolbetuximab treatment until death from any cause or radiographic disease progression per RECIST v1.1, whichever occurred first. For patients with none of these events, PFS was censored based on the rules defined in the statistical analysis plan.

Abbreviations: CI, confidence interval; NE, not estimable; OS, overall survival; PFS, progression‐free survival; RECIST v1.1, response evaluation criteria in solid tumors version 1.1.

^a Based on Kaplan–Meier estimate.

^b Based on reverse Kaplan–Meier estimate.

3.5. Pharmacokinetic profile

The PK profile of zolbetuximab was assessed in samples from all 18 patients in the study after the first (cycle 1, day 1) and third (cycle 3, day 1) infusions, if available. The exposure (C _max and AUC_tau) of zolbetuximab was generally greater in Safety Part Arm B (1000 mg/m²) than in Safety Part Arm A and the Expansion Part (800/600 mg/m²), either independently or combined (Table S3 and Figure 4).

FIGURE 4.

Pharmacokinetics of zolbetuximab. Mean zolbetuximab serum levels over time in patients following the first infusion (cycle 1, solid line) or third infusion (cycle 3, dotted line) presented on a semilogarithmic scale for (A) the total zolbetuximab 800/600 mg/m² cohort (Safety Part Arm A + Expansion Part) and (B) the zolbetuximab 1000 mg/m² cohort (Safety Part Arm B). Standard deviation was not calculated since ≥50% of values were below the LLOQ or the number of observations was ≤2 at a given time point. LLOQ, lower limit of quantification.

3.6. Immunogenicity profile

No patients developed antidrug antibodies to zolbetuximab following treatment.

4. DISCUSSION

In accordance with the Japanese Pharmaceuticals and Medical Devices Agency guidelines, regardless of prior phase 1 or 2 studies conducted in Western populations, phase 1 studies in Japanese patients are required before allowing enrollment in global phase 3 studies. This phase 1 study evaluated the safety, tolerability, and efficacy of zolbetuximab monotherapy in a Japanese population of patients with CLDN18.2+ locally advanced or metastatic G/GEJ cancer who had previously received multiple lines of therapy.

Zolbetuximab monotherapy at doses of 600–1000 mg/m² was well tolerated. No DLTs were observed. Nearly all (94.4%) patients experienced grade 1–2 zolbetuximab‐related TEAEs that were gastrointestinal in nature and related symptoms to IRRs. No TEAEs led to study discontinuation or death. This is consistent with the safety data observed in phase 1 and 2 trials of zolbetuximab as a monotherapy or in combination with chemotherapy. ¹⁰ , ¹² , ¹⁵ In this study, 2/15 patients had undergone prior gastrectomy, limiting the ability to compare the incidence and severity of AEs in patients with or without primary tumors. The 13/15 patients who had not undergone prior gastrectomy experienced gastrointestinal TEAEs related to IRRs. In the phase 2b FAST study, patients who had not undergone prior gastrectomy were more likely to experience gastrointestinal TEAEs, suggesting that the stomach‐specific toxicity of zolbetuximab resulting from expression of CLDN18.2 in normal gastric tissue could underlie these events. ¹²

The multiple lines of previous treatment received by patients before enrollment in this study posed a notable clinical challenge. Durable antitumor efficacy in patients with heavily pretreated, advanced disease is often limited. ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ Furthermore, these patients frequently present with a high symptom burden and medical comorbidities that introduce challenges in achieving antitumor efficacy while managing patient quality of life. ²¹ Traditional chemotherapy treatments have focused on disease control and palliation of symptoms. ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ In this study, the efficacy response to targeted zolbetuximab monotherapy was limited: 2 patients had SD lasting >6 months. Limited single‐agent activity was also observed in other phase 1 and 2 studies of zolbetuximab monotherapy in previously treated patients with G/GEJ cancer. ¹⁰ , ¹⁵ The addition of chemotherapy may increase the antitumor efficacy of zolbetuximab: in the phase 2b FAST study, the combination of 1L zolbetuximab and chemotherapy was shown to provide prolonged PFS and OS compared with chemotherapy alone in patients with CLDN18.2+ advanced G/GEJ cancer. ¹² While CLDN18.2 expression was not evaluated in paired primary and metastatic samples from each patient in this study, previous data suggest that CLDN18.2 expression is maintained in metastases with similar expression observed in pair‐matched primary GC tumors versus lymph‐node metastases in Japanese patients with GC. ¹³ The prior data suggest that this is likely not a major contribution to the limited efficacy observed in this study.

The PK profile of zolbetuximab in this study (mean C _max 391–805 μg/ml in patients receiving 600–1000 mg/m² zolbetuximab) was similar to that observed in phase 1 (mean C _max 331–517 μg/ml in patients receiving 600–1000 mg/m² zolbetuximab) and phase 2a (mean C _max 355 μg/ml in patients receiving 600 mg/m² zolbetuximab) studies in European patients. ¹⁰ , ¹⁵ No antidrug antibodies were identified in patients following treatment with zolbetuximab in this study.

To our knowledge, this is the first study of zolbetuximab specifically for the treatment of Japanese patients with CLDN18.2+, previously treated, locally advanced, G/GEJ cancer who had disease progression on previous lines of therapy. This study did not identify any new safety signals related to zolbetuximab treatment in Japanese patients. The manageable toxicity profile of zolbetuximab in this study suggests this may be a suitable treatment to combine with other agents in this population. Ongoing studies include a phase 2 trial of zolbetuximab as monotherapy, or in combination with chemotherapy (with or without nivolumab), or in combination with pembrolizumab (NCT03505320, “ILUSTRO”), and two phase 3 trials of 1L zolbetuximab in combination with chemotherapy (NCT03504397, “SPOTLIGHT”; NCT03653507, “GLOW”) as treatment for patients with locally advanced or metastatic G/GEJ cancer and CLDN18.2 expression. ²² , ²³ , ²⁴

AUTHOR CONTRIBUTIONS

Substantial contribution to study design: K.S., A.H., Y.N., M.F., Y.U., J.R., and A.A. Acquisition of study data: K.S., Y.N., S.F., Y.U., J.R., and A.A. Analysis of study data: A.H. and M.F. Interpretation of study data: K.S., A.H., Y.N., S.F., M.F., Y.U., J.R., and A.A. Wrote or contributed to writing of the manuscript: K.S., A.H., Y.N., S.F., M.F., Y.U., J.R., and A.A.

FUNDING INFORMATION

This study was funded by Astellas Pharma Inc.

CONFLICT OF INTEREST

K.S. received payment or honoraria and consulting fees from Takeda Pharmaceuticals and Bristol Myers Squibb. K.S. received consulting fees from Eli Lilly and Company, Pfizer Inc., Novartis, AbbVie, GlaxoSmithKline, Boehringer Ingelheim, and Janssen Pharmaceuticals. K.S. received grants or contracts from Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Medi Science, and Eisai Co., Ltd. K.S. received grants or contracts and consulting fees from Daiichi Sankyo, Ono Pharmaceutical, Taiho Pharmaceutical, Merck & Co., and Amgen. A.K. received grants or contracts from Merck & Co., Bayer, Sumitomo Dainippon Pharma, and AstraZeneca. A.K. received payment or honoraria from Caiichi Sankyo, Eli Lilly and Company, Ono Pharmaceutical, Taiho Pharmaceutical, Bristol Meyers Squibb, and EMD Serono. A.H. received consulting fees from Ono Pharmaceutical, AbbVie, Kissei, Nippon Shinyaku Co., Ltd., and Kyowa Hakko Kirin Co., Ltd. A.H. has participated on data safety monitoring or advisory boards and received consulting fees and payment or honoraria from Chugai Pharmaceutical Co., Ltd. A.H. has participated on data safety monitoring or advisory boards and received consulting fees from Astellas Pharma Inc. and Novartis. Y.N., S.F., and M.F. are employees of Astellas Pharma Inc. J.R. was an employee of Astellas Pharm Inc. at the time the study was conducted. Y.U. and A.A. are employees, shareholders, and stockholders of Astellas Pharma Inc.

ETHICS STATEMENT

Approval of the research protocol by an institutional review board: The protocol was submitted to an IRB/IEC by the investigator, reviewed, and approved before the study was initiated. This study was conducted in accordance with the protocol and consensus ethical principles derived from international guidelines, including the following: the Declaration of Helsinki and the Council for International Organizations of Medical Sciences International Ethical Guidelines, applicable ICH GCP guidelines, and applicable laws and regulations.

Informed consent: Patients provided written informed consent prior to the study.

Registry and the registration no. of the study/trial: The trial was registered at www.clinicaltrials.gov: NCT03528629.

Animal studies: N/A.

Supporting information

Table S1.

Table S2.

Table S3.

Figure S1.

Figure S2.

Figures Caption

Shitara K, Kawazoe A, Hirakawa A, et al. Phase 1 trial of zolbetuximab in Japanese patients with CLDN18.2+ gastric or gastroesophageal junction adenocarcinoma. Cancer Sci. 2023;114:1606‐1615. doi: 10.1111/cas.15684