Clinical trialPhase 3Stomach cancer

Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial

Nat Med · 2023507 patients

Shah MA, Shitara K, Ajani JA, et al. Nat Med. 2023. 29:2133-2141

Study type: Clinical trial
Study name: GLOW
Phase: Phase 3
Design: Global, randomised, double-blind, placebo-controlled trial (1:1 randomisation in blocks of two)
Sample size: 507 patients
Source: Nat Med · 2023
Trial registration: NCT03653507

In plain words

GLOW asked the same question as the SPOTLIGHT study with a different chemotherapy regimen (CAPOX, that is, capecitabine tablets with oxaliplatin infusions) and had a similar result: in patients with CLDN18.2-positive, HER2-negative tumours, adding zolbetuximab both delayed the growth of the disease and made life longer by about 2 months on average. Nausea and vomiting are the most common side effects of this drug.

Key results

8.21 vs 6.80 months

Median progression-free survival

HR 0.687 (95% CI 0.544–0.866); P=0.0007

14.39 vs 12.16 months

Median overall survival

HR 0.771 (95% CI 0.615–0.965); P=0.0118

72.8% vs 69.9%

Grade 3 or higher treatment-emergent adverse events

Zolbetuximab vs placebo

Drugs in this study:Capecitabine (Xeloda)Fluorouracil (5-FU)Ibrutinib (Imbruvica)Oxaliplatin (Eloxatin)Venetoclax (Venclexta)

Dose and schedule cards

Zolbetuximab + mFOLFOX6 or CAPOX (SPOTLIGHT and GLOW trials)

Advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, HER2-negative and CLDN18.2-positive (moderate to strong membranous CLDN18 staining in 75% or more of tumour cells); particularly with PD-L1 CPS below 1On the page “Stomach cancer” · Advanced or metastatic disease, first-line: HER2-negative

Drug	Dose	Route	Schedule
Zolbetuximab	First dose 800 mg/m²; then 600 mg/m² every 3 weeks or 400 mg/m² every 2 weeks	IV, before chemotherapy (not as a bolus)	Day 1
mFOLFOX6 (42-day cycle, up to 12 administrations)
Oxaliplatin	85 mg/m²	IV	Days 1, 15 and 29
Leucovorin	400 mg/m²	IV	Days 1, 15 and 29
Fluorouracil	400 mg/m² bolus, then 2400 mg/m² continuous infusion	IV	Days 1, 15 and 29
Or CAPOX (21-day cycle, up to 8 cycles)
Oxaliplatin	130 mg/m²	IV	Day 1
Capecitabine	1000 mg/m² twice daily	Oral	Days 1–14

Cycle length: mFOLFOX6 every 14 days (days 1, 15 and 29 of a 42-day cycle) or CAPOX every 21 days
Duration: Zolbetuximab until progression or unacceptable toxicity; after the oxaliplatin administrations are completed, the fluoropyrimidine (and leucovorin) may be continued at the physician’s discretion

Doses from the FDA label for zolbetuximab (description of SPOTLIGHT and GLOW). Before each infusion, premedication with a combination of antiemetics (such as an NK-1 and/or 5-HT3 antagonist) is required, and any existing nausea or vomiting must have improved to grade 1 or lower before the first infusion. Each infusion starts at a slow rate for the first 30 to 60 minutes (first dose 100, then 200 to 265 mg/m² per hour). Dose reduction is not recommended; adverse reactions are managed by slowing or interrupting the infusion, and the drug is permanently discontinued for a grade 4 reaction or anaphylaxis.

On the page “Stomach cancer” · Advanced or metastatic disease, first-line: HER2-negative

Fixed-duration ibrutinib + venetoclax (GLOW; FLAIR with MRD-guided duration)

Untreated CLLCycle length: Every 28 daysOn the page “Blood cancers (leukaemia, lymphoma and myeloma)” · Treatment regimens and dosing in leukaemias

Untreated CLL

Drug	Dose	Route	Schedule
Cycles 1–3
Ibrutinib	420 mg once daily	Oral	Continuous
Cycles 4–15
Ibrutinib + venetoclax	Ibrutinib 420 mg; venetoclax with a 5-week ramp-up to 400 mg once daily	Oral	Continuous

Cycle length: Every 28 days
Duration: 15 cycles in GLOW; in FLAIR, MRD-guided duration

On the page “Blood cancers (leukaemia, lymphoma and myeloma)” · Treatment regimens and dosing in leukaemias

Fixed-duration ibrutinib + venetoclax (GLOW; FLAIR with MRD-guided duration)

Untreated CLL; in GLOW, patients aged 65 years and older, or aged 18 to 64 years with a CIRS score above 6 or CrCl below 70 mL/min, ECOG ≤2On the page “Leukaemia” · Regimens and dosing in CLL: fixed-duration targeted therapy

Untreated CLL; in GLOW, patients aged 65 years and older, or aged 18 to 64 years with a CIRS score above 6 or CrCl below 70 mL/min, ECOG ≤2

Drug	Dose	Route	Schedule
Cycles 1–3 (lead-in)
Ibrutinib	420 mg once daily	Oral	Continuous
Cycles 4–15
Ibrutinib	420 mg once daily	Oral	Continuous
Venetoclax	5-week ramp-up to 400 mg once daily	Oral, with food	Continuous

Cycle length: Ibrutinib daily and continuously from cycle 1; venetoclax daily and continuously from cycle 4 (28-day cycles)
Duration: 15 cycles in GLOW; in FLAIR, treatment duration was determined by MRD

The doses are from the GLOW abstract; in FLAIR, treatment duration was guided by MRD monitoring, and the details are in the full text of the paper. This combination is not in the US FDA label.

On the page “Leukaemia” · Regimens and dosing in CLL: fixed-duration targeted therapy

CLDN18.2-positive adenocarcinoma: zolbetuximab + mFOLFOX6 or CAPOX (SPOTLIGHT and GLOW)

Advanced HER2-negative, CLDN18.2-positive adenocarcinoma (moderate to strong staining in 75% or more of tumour cells); FDA label in gastric and gastroesophageal junction tumours; particularly with PD-L1 below 1Each drug’s schedule in the tableOn the page “Oesophageal cancer” · Advanced or metastatic disease, first-line: adenocarcinoma

Drug	Dose	Route	Schedule
Zolbetuximab	First dose 800 mg/m²; then 600 mg/m² every 3 weeks or 400 mg/m² every 2 weeks	IV, before chemotherapy	First dose on Day 1; then every 3 weeks or every 2 weeks, depending on the dose
With one of two regimens
mFOLFOX6	Oxaliplatin 85, leucovorin 400, fluorouracil 400 bolus and 2400 mg/m² continuous infusion	IV	Every 2 weeks (up to 12 treatments)
CAPOX	Oxaliplatin 130 mg/m² on Day 1 (up to 8 cycles) + capecitabine 1000 mg/m² twice daily on Days 1–14	IV / oral	Every 3 weeks

Cycle schedule: mFOLFOX6 every 2 weeks or CAPOX every 3 weeks; zolbetuximab every 3 weeks (600 mg/m²) or every 2 weeks (400 mg/m²)
Duration: Zolbetuximab until progression or unacceptable toxicity

Doses from the zolbetuximab FDA label and the ASCO guideline. Premedication with a combination of antiemetics (an NK-1 and/or 5-HT3 receptor antagonist) is required before each infusion; the infusion is started at a slow rate, and dose reduction is not recommended.

On the page “Oesophageal cancer” · Advanced or metastatic disease, first-line: adenocarcinoma

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Zolbetuximab + CAPOX

Zolbetuximab IV (infusion over at least 2 hours): loading dose 800 mg/m² on day 1 of cycle 1, then 600 mg/m² every 3 weeks from day 22 until discontinuation criteria are met.

CAPOX in 21-day cycles: oxaliplatin 130 mg/m² IV (over 2 hours) on day 1, up to 8 doses; capecitabine 1000 mg/m² orally twice daily on days 1 to 14. After 8 doses of oxaliplatin, capecitabine could be continued at the investigator's discretion.

FDA label (Vyloy): premedicate before each infusion with an antiemetic combination (NK-1 and/or 5-HT3 receptor antagonist); on days when both are given, infuse zolbetuximab before chemotherapy; start the infusion at a slow rate for the first 30 to 60 minutes; dose reduction is not recommended. The label also allows a maintenance dose of 400 mg/m² every 2 weeks as an alternative to 600 mg/m² every 3 weeks.

2Placebo + CAPOX (control group)

Matching zolbetuximab placebo on the same schedule, with CAPOX at the same doses and schedule.

Source of the regimen details: ClinicalTrials.gov NCT03653507 (dose and schedule of zolbetuximab, oxaliplatin and capecitabine) and the FDA label for Vyloy (loading dose 800 and maintenance 600 mg/m² every 3 weeks); section 2 of the label (premedication, infusion rate)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with unresectable locally advanced or metastatic, CLDN18.2-positive, HER2-negative gastric or gastro-oesophageal junction adenocarcinoma who had not received first-line therapy.

Endpoints

Primary endpoint: progression-free survival (PFS).

Key secondary endpoint: overall survival (OS).

Safety and side effects

Grade 3 or higher treatment-emergent adverse events were similar in the two groups (72.8% with zolbetuximab versus 69.9% with placebo). According to the NCCN guideline, nausea and vomiting were the adverse events that occurred more than 10% more often with zolbetuximab than with placebo and were also among the most common grade 3 or higher adverse events; anaemia and neutropenia were other grade 3 or higher adverse events in GLOW.

Clinical significance and place in guidelines

Together with SPOTLIGHT, GLOW was the basis for the FDA approval of zolbetuximab (Vyloy) in October 2024, in combination with fluoropyrimidine-‎ and platinum-containing chemotherapy, for advanced HER2-negative, CLDN18.2-positive gastric and gastro-oesophageal junction adenocarcinoma. The NCCN guideline (version 2.2025) lists this combination as a preferred category 1 first-line option.

Limitations

The absolute gain in median overall survival is about 2.2 months (14.39 versus 12.16 months), and the objective response rate was similar in the two groups (42.5% versus 40.3% according to the NCCN guideline). The study included only CLDN18.2-positive patients and has no comparison with immunotherapy plus chemotherapy. It was funded by the manufacturer (Astellas).

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.