Clinical trialPhase 3Stomach cancer

Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial

Lancet · 2023565 patients (283 zolbetuximab + mFOLFOX6 and 282 placebo + mFOLFOX6)

Shitara K, Lordick F, Bang YJ, et al. Lancet. 2023. 401:1655-1668

Study type: Clinical trial
Study name: SPOTLIGHT
Phase: Phase 3
Design: Global, randomised, double-blind, placebo-controlled trial at 215 centres in 20 countries (1:1 randomisation)
Sample size: 565 patients (283 zolbetuximab + mFOLFOX6 and 282 placebo + mFOLFOX6)
Source: Lancet · 2023
Trial registration: NCT03504397

In plain words

According to the NCCN guideline, in about 24% to 38% of advanced cancers of the stomach and of the junction between the stomach and the oesophagus, the tumour cells carry a protein called claudin 18.2 (CLDN18.2) on their surface. Zolbetuximab is an antibody that sticks to this protein and helps the immune system destroy the cancer cells. In this study, adding zolbetuximab to FOLFOX chemotherapy in patients who were CLDN18.2-positive and HER2-negative lengthened both the time the disease was kept under control and survival. The most important side effect is nausea and vomiting, especially with the first infusions, which can be controlled with anti-sickness medicines and by slowing the infusion. Before using this drug, the tumour sample must first be tested for CLDN18.2.

Key results

10.61 vs 8.67 months

Median progression-free survival

HR 0.75 (95% CI 0.60 to 0.94); p=0.0066

HR 0.75

Overall survival

95% CI 0.60 to 0.94; p=0.0053

18.2 vs 15.5 months

Median overall survival (FDA label)

From the efficacy table of the FDA label for Vyloy

87% vs 78%

Grade 3 or higher adverse events

242 of 279 vs 216 of 278 patients

Drugs in this study:Capecitabine (Xeloda)Fluorouracil (5-FU)Oxaliplatin (Eloxatin)

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

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 + mFOLFOX6

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

mFOLFOX6 on days 1, 15 and 29 of each 42-day cycle, for up to 12 administrations (4 cycles): oxaliplatin 85 mg/m² and folinic acid 400 mg/m² (each as a 2-hour infusion), fluorouracil 400 mg/m² bolus, then 2400 mg/m² as a continuous infusion over 46 to 48 hours. After 12 administrations, continuation of fluorouracil and folinic acid at the investigator's discretion.

FDA label (Vyloy): before each infusion, premedication with an antiemetic combination (NK-1 and/or 5-HT3 antagonist); on shared days, zolbetuximab is given 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 + mFOLFOX6 (control group)

Placebo matching zolbetuximab on the same schedule, with mFOLFOX6 at the same doses and schedule.

Source of the regimen details: Abstract of the paper (Lancet 2023), ClinicalTrials.gov NCT03504397 (mFOLFOX6 doses and zolbetuximab schedule) and the FDA label for Vyloy (section 14); 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

Adults with untreated locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma, with a CLDN18.2-positive tumour (moderate to strong membranous CLDN18 staining in 75% or more of tumour cells) and HER2-negative, radiologically evaluable disease per RECIST 1.1, ECOG performance status 0 or 1 and adequate organ function.

Endpoints

Primary outcome: progression-free survival (PFS) by independent review committee in all randomised patients.

Secondary outcomes: including overall survival (OS), objective response and safety.

Safety and side effects

Treatment-emergent grade 3 or higher adverse events occurred in 87% of the zolbetuximab group and 78% of the placebo group. The most common grade 3 or higher events were nausea, vomiting and decreased appetite. Treatment-related deaths were reported in 5 patients (2%) in the zolbetuximab group and 4 patients (1%) in the placebo group. Nausea and vomiting are common, especially with the first infusions, and the FDA label recommends premedication with antiemetics before each infusion.

Clinical significance and place in guidelines

Based on SPOTLIGHT and GLOW, in October 2024 the FDA approved zolbetuximab (Vyloy) with fluoropyrimidine-‎ and platinum-containing chemotherapy for first-line treatment of locally advanced unresectable or metastatic HER2-negative, CLDN18.2-positive (by an FDA-approved test) gastric and gastro-oesophageal junction adenocarcinoma. The NCCN guideline (version 2.2025) lists fluoropyrimidine + oxaliplatin + zolbetuximab as a preferred category 1 first-line option for these patients and recommends CLDN18.2 testing at diagnosis of advanced disease.

Limitations

Only CLDN18.2-positive patients with a specific definition (75% or more of cells) were enrolled. The objective response rate was almost the same in the two groups (40.3% versus 39.7% per the FDA label), and severe gastrointestinal adverse events were more frequent. There was no direct comparison with immunotherapy plus chemotherapy, and this study has no data on combining zolbetuximab with PD-1 inhibitors.

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.