The addition of the first-in-class chimeric monoclonal antibody zolbetuximab to frontline epirubicin, oxaliplatin, and capecitabine chemotherapy resulted in prolonged progression-free survival and overall survival compared with EOX alone in patients with advanced Claudin 18.2-positive gastric and gastroesophageal junction adenocarcinoma, according to the primary results of the phase 2 FAST trial.
The addition of the first-in-class chimeric monoclonal antibody zolbetuximab (IMAB362) to frontline epirubicin, oxaliplatin, and capecitabine (EOX) chemotherapy resulted in prolonged progression-free survival (PFS) and overall survival (OS) compared with EOX alone in patients with advanced Claudin 18.2 (CLDN18.2)-positive gastric and gastroesophageal junction (GEJ) adenocarcinoma, according to the primary results of the phase 2 FAST trial that were published in Annals of Oncology.1
In the overall patient population, the median PFS was 7.5 months with zolbetuximab plus EOX (n = 77) vs 5.3 months with EOX alone (n = 84; HR, 0.44; 95% CI, 0.29-0.67; P < .0005). In patients with 70% or more CLDN18.2-positive tumor cells, the median PFS was 9.0 months (n = 57) vs 5.7 months (n = 59), respectively (HR, 0.38; 95% CI, 0.23-0.62; P < .0005). In patients with 40% to 69% of CLDN18.2-positive tumor cells, the median PFS was 4.3 months (n = 20) vs 4.1 months (n = 20), respectively (HR, 0.71; 95% CI, 0.32-1.57; P = .497).
In the overall patient population, the median OS was 13.0 months with zolbetuximab plus EOX compared with 8.3 months with EOX alone (HR, 0.55; 95% CI, 0.39-0.77; P < .0005). In patients with 70% or more CLDN18.2-positive tumor cells, the median OS was 16.5 months vs 8.9 months, respectively (HR, 0.50; 95% CI, 0.33-0.74; P < .0005). In patients with 40% to 69% of CLDN18.2-positive tumor cells, the median OS was 8.3 months vs 7.4 months, respectively (HR, 0.78; 95% CI, 0.40-1.49; P = .401).
“This randomized phase II trial showed a favorable benefit/risk ratio for zolbetuximab [plus] EOX compared with EOX in a large biomarker-enriched population of patients with advanced gastro-oesophageal cancers, with clinically meaningful prolongation of PFS and OS. These data provide compelling evidence for the role of CLDN18.2 as a potential therapeutic target,” lead study author Uğur Şahin, MD, co-founder and chief executive officer of BioNTech, and co-authors wrote in the study publication.
Gastric, GEJ, and oesophageal adenocarcinomas are aggressive cancers that confer a high mortality rate. Currently, chemotherapy remains the standard of care. However, more novel targeted options have expanded the treatment armamentarium for certain patients. Despite these advances, 2-year survival rates remain low.
CLDN18.2 is present in tight junctions of gastric mucosal cells in healthy tissue. Epitopes of CLDN18.2, which are mostly inaccessible to intravenous antibodies, can become exposed to targeted monoclonal antibody–binding during malignant cell transformation.
As such, zolbetuximab, a CLDN18.2-directed chimeric monoclonal immunoglobulin G1 antibody that mediates tumor cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, could confer significant activity in patients with CLDN18.2-positive gastrointestinal malignancies.
Notably, zolbetuximab demonstrated potential synergistic efficacy with chemotherapy in preclinical studies. Single-agent zolbetuximab also demonstrated anticancer effects in patients with CLDN18.2-positive advanced gastric/GEJ cancer in the phase 2a MONO study (NCT01197885).2
The 21-day cycles of EOX consisted of 50 mg/m2 of intravenous (IV) epirubicin and 130 mg/m2 of IV oxaliplatin on day 1 plus 625 mg/m2 of oral capecitabine twice daily for a maximum of 8 cycles. Zolbetuximab was administered at a loading dose of 800 mg/m2 on day 1 of cycle 1 before EOX followed by 600 mg/m2 on day 1 of subsequent cycles.
Patients were able to continue on single-agent zolbetuximab every 3 weeks as maintenance therapy following EOX until disease progression, withdrawn consent, or unacceptable toxicity.
Of the 730 patients screened for eligibility, 478 were ineligible for treatment because of non-assessable CLDN18.2 (n = 44), CLDN18.2 negativity (n = 352), or other criteria not fulfilled (n = 82). Of the 252 patients randomized to treatment, 6 did not go on to receive treatment.
Notably, a third exploratory arm was added to the study 15 months following the start of enrollment; patients in this arm received 1000 mg/m2 of zolbetuximab plus EOX (n = 85).
Overall, 52 patients in the EOX alone arm discontinued treatment within the first 8 cycles of treatment, and 0 continued on zolbetuximab monotherapy. In the lower-dose zolbetuximab arm, 42 patients discontinued treatment within the first 8 cycles of treatment, and 32 (41.6%) patients continued zolbetuximab monotherapy. In the higher-dose zolbetuximab arm, 45 patients discontinued treatment within the first 8 cycles of treatment, and 27 (31.8%) patients continued zolbetuximab monotherapy.
Dose adjustments with EOX were allowed, antiemetic prophylaxis was recommended during the first 3 days of each cycle, and patients received a proton-pump inhibitor for mucosal protection.
Baseline characteristics in the zolbetuximab plus EOX arms and EOX alone arm were generally well balanced, wrote Şahin and co-authors. Most patients had moderate-to-strong (≥70%) CLDN18.2 expression.
Additional results from the higher-dose zolbetuximab cohort demonstrated a median PFS of 7.1 months with the addition of zolbetuximab vs 5.3 months with EOX alone (HR, 0.58; 95% CI, 0.39-0.85; P = .0114). In patients with 70% or more CLDN18.2-positive tumor cells, the median PFS was 6.3 months (n = 67) vs 5.7 months, respectively (HR, 0.68; 95% CI, 0.44-1.05; P = .1285).
In the higher-dose zolbetuximab cohort, the median OS was 9.6 months compared with 8.3 months with EOX alone (HR, 0.75; 95% CI, 0.55-1.04; P = .1292). In patients with 70% or more CLDN18.2-positive tumor cells, the median OS was 9.4 months vs 8.9 months, respectively (HR, 0.82; 95% CI, 0.57-1.18; P = .390).
“Zolbetuximab 1000 mg/m2 plus EOX demonstrated statistically significant improvements in PFS over EOX in the overall population, but not in patients with CLDN18.2 expression in 70% [or more] of cancer cells; no significant improvement in OS was observed in either population,” wrote Şahin and co-authors.
The objective response rate (ORR) per independent review was 39% with zolbetuximab plus EOX vs 25% with EOX alone. Per investigator assessment, the ORR was 37.7% vs 26.2%, respectively. The disease control rates were 83.1% vs 76.2%, respectively, per independent review, and 83.1% vs 81%, respectively, per investigator assessment.
Regarding safety, any-grade adverse effects (AEs) were observed in 96.1% of patients with zolbetuximab plus EOX vs 100% of patients with EOX. Of these, 70.1% vs 64.3% were grade 3 or higher AEs, respectively.
The most common any-grade AEs reported in either arm included nausea, vomiting, neutropenia, and anemia. Notably, the incidence of vomiting was lower in patients who received zolbetuximab and underwent a total or partial gastrectomy (n = 8 of 21) vs those who did not undergo a gastrectomy (n = 44 of 56).
Findings from a patient-reported outcome (PRO) analysis of the FAST trial demonstrated that the addition of zolbetuximab to EOX maintained good quality of life and low symptom burden for longer compared with EOX alone.3
In the patient population evaluable for PRO data (n = 143), time-to-deterioration for most scores favored the combination regimen vs EOX alone. The scores favoring the addition of zolbetuximab were statistically significant with regard to global health status (P = .008).
The phase 3 SPOTLIGHT trial (NCT03504397) has been initiated and will compare frontline zolbetuximab plus modified FOLFOX6 (mFOLFOX6) with placebo plus mFOLFOX6 in patients with unresectable or metastatic CLDN18.2-positive, HER2-negative gastric/GEJ cancer.4 Additionally, the phase 3 GLOW trial (NCT03653507) is comparing frontline zolbetuximab plus capecitabine/oxaliplatin (CAPOX) vs placebo plus CAPOX in the same patient population.5