FDA Grants Priority Review to Zolbetuximab for CLDN18.2+ Advanced Gastric/GEJ Adenocarcinoma

The FDA has granted a priority review to the biologics license application (BLA) seeking the approval of zolbetuximab (IMAB362) for the first-line treatment of patients with unresectable, locally advanced or metastatic, HER2-negative, gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are Claudin18.2 (CLDN18.2) positive.¹

The BLA is supported by data from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials. The regulatory agency has set a target action date of January 12, 2024, under the Prescription Drug User Fee Act. If approved, zolbetuximab would be the first CLDN18.2-targeted therapy available for this patient population.

Findings from SPOTLIGHT showed that zolbetuximab plus mFOLFOX6 (leucovorin calcium, fluorouracil, and oxaliplatin) significantly improved progression-free survival (PFS) and overall survival (OS) compared with placebo plus mFOLFOX6. At a median follow-up of 12.94 months for the zolbetuximab group (n = 283) and 12.65 months for the placebo group (n = 282), the median PFS was 10.61 months (95% CI, 8.90-12.48) with zolbetuximab/mFOLFOX6 vs 8.67 months (95% CI, 8.21-10.28) with placebo/mFOLFOX6 (HR, 0.75; 95% CI, 0.60-0.94; P = .0066).^2,3

Additionally, at a median follow-up of 22.14 months for the experimental arm and 20.93 months for the control arm, the addition of zolbetuximab to mFOLFOX6 resulted in a median OS of 18.23 months (95% CI, 16.43-22.90) compared with 15.54 months (95% CI, 13.47-16.53) with mFOLFOX6 alone (HR, 0.75; 95% CI, 0.60-0.94; P = .0053).

Data from GLOW demonstrated that the combination of zolbetuximab and CAPOX (capecitabine plus oxaliplatin) provided a statistically significant improvement in PFS and OS vs placebo plus CAPOX. At a median follow-up of 12.62 months for the zolbetuximab arm (n = 254) and 12.09 months for the placebo arm (n = 253), patients treated with zolbetuximab plus CAPOX achieved a median PFS of 8.21 months (95% CI, 7.46-8.84) vs 6.80 months (95% CI, 6.14-8.08) for those treated with placebo plus CAPOX (HR, 0.687; 95% CI, 0.544-0.866; P = .0007). The median OS was 14.39 months (95% CI, 12.29-16.49) in the experimental arm vs 12.16 months (95% CI, 10.28-13.67) in the control arm (HR, 0.771; 95% CI, 0.615-0.965; P = .0118).⁴

“Astellas is committed to bringing innovative therapies to patients with hard-to-treat cancers, including gastric cancer. While rare in the United States, gastric cancer can be deadly when diagnosed in the late stages,” Moitreyee Chatterjee-Kishore, PhD, MBA, senior vice president and head of Immuno-Oncology Development at Astellas, stated in a news release.1 “The FDA’s acceptance of the BLA filing and priority review designation for zolbetuximab confirms the urgent therapeutic need and brings us one step closer to delivering on this commitment to patients, families, and caregivers.”

The global, randomized, placebo-controlled, double-blind SPOTLIGHT trial enrolled patients at least 18 years of age with HER2-negative, previously untreated, unresectable, locally advanced or metastatic gastric or GEJ adenocarcinoma that was CLDN18.2 positive, defined as moderate-to-strong membranous CLDN18 staining on at least 75% of tumor cells. Patients were also required to have evaluable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function.²

Patients were randomly assigned 1:1 to receive zolbetuximab at 800 mg/m2 as a loading dose and then 600 mg/m2 every 3 weeks plus mFOLFOX6 every 2 weeks, or placebo plus mFOLFOX6, for four 42-day cycles. Patients then continued zolbetuximab or placebo in the absence of disease progression. Stratification factors included region (Asia vs non-Asia), number of organs with metastases (0 to 2 vs ≥3), and previous gastrectomy (yes vs no).

Independent review committee–assessed PFS per RECIST v1.1 criteria served as the trial’s primary end point. Secondary end points included OS, time to confirmed deterioration, objective response rate (ORR), duration of response (DOR), and safety/tolerability.

Additional data showed that the estimated 12- and 24-month PFS rates were zolbetuximab/mFOLFOX6 were 49% (95% CI, 42%-55%) and 24% (95% CI, 17%-32%), respectively; those rates were 35% (95% CI, 28%-42%) and 15% (95% CI, 9%-22%) for placebo/mFOLFOX6, respectively. The 12- and 24-month OS rates for the zolbetuximab arm were 68% (95% CI, 61%-73%) and 39% (95% CI, 32%-46%), respectively, compared with 60% (95% CI, 54%-66%) and 28% (95% CI, 22%-35%) for the placebo arm, respectively.

Moreover, the ORR was 48% (95% CI, 42%-54%) in the zolbetuximab group vs 48% (95% CI, 42%-54%) in the placebo group. The median DOR was 9.00 months (95% CI, 6.87-10.25) in the zolbetuximab arm vs 8.05 months (95% CI, 6.47-10.81) in the placebo arm.

No new safety signals were identified in SPOTLIGHT. Grade 3 or higher treatment-emergent adverse effects (TEAEs) were reported in 87% of patients in the zolbetuximab group compared with 78% of those in the placebo group. The most common grade 3 or higher AEs included nausea, vomiting, and decreased appetite. Treatment-related deaths occurred in 2% of patients in the zolbetuximab group vs 1% in the placebo group.

GLOW, the global, multicenter, double-blind, randomized study, enrolled previously untreated patients with CLDN18.2-positive/HER2-negative, unresectable, locally advanced or metastatic gastric or GEJ cancer. CLDN18.2 positivity was defined as at least 75% of tumor cells with moderate-to-strong membranous CLDN18.2 staining. Patients also need to have an ECOG performance status of 0 or 1.⁴

The trial randomly assigned patients 1:1 to receive 800 mg/m2 of zolbetuximab on day 1 of the first 21-day cycle, followed by 600 mg/m2 on day 1 of subsequent cycles, plus CAPOX, or placebo plus CAPOX. After 8 cycles of CAPOX, treatment with zolbetuximab or placebo could continue at investigator’s discretion, and treatment continued until progressive disease or discontinuation criteria were met. Stratification factors included region (Asia vs non-Asia), number of organs with metastases (0 to 2 vs ≥3), and prior gastrectomy (yes vs no).

PFS was the primary end point, and secondary end points included OS, ORR, DOR, safety, and patient-reported outcomes.

Additional data showed that patients in the zolbetuximab arm who were evaluable for response (n = 195) achieved an ORR of 53.8% (95% CI, 46.58%-60.99%) vs 48.8% (95% CI, 41.76%-55.84%) for evaluable patients in the placebo arm (n = 205). The median DOR was 6.28 months (95% CI, 5.39-8.28) and 6.18 months (95% CI, 4.53-6.41) for zolbetuximab/CAPOX and placebo/CAPOX, respectively.

Any-grade TEAEs occurred in 98.8% of patients in the zolbetuximab group compared with 98.0% in the placebo group. Rates of grade 3 or higher TEAEs were 72.8% and 69.9%, respectively. The most common any-grade TEAEs included nausea (zolbetuximab, 68.5%; placebo, 50.2%), vomiting (66.1%; 30.9%), and decreased appetite (41.3%; 33.7%).

Treatment-related AEs (TRAEs) led to discontinuation of any study drug in 21.7% of patients in the zolbetuximab arm and 15.7% of those in the placebo arm. Additionally, 7.1% of patients in the experimental arm discontinued zolbetuximab due to TRAEs, and 4.4% of patients in the control arm discontinued placebo due to TRAEs. TRAEs leading to death occurred in 2.4% of patients in the experimental arm vs 2.8% of those in the control arm.

References

1. Astellas announces US FDA grants priority review for zolbetuximab biologics license application. News release. Astellas. July 6, 2023. Accessed July 6, 2023. https://www.astellas.com/en/system/files/news/2023-07/81743d9407/20230706_en_1.pdf
2. Shitara K, Lordick F, Bang Y-J, et al. 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. 2023;401(10389):1655-1668. doi:10.1016/S0140-6736(23)00620-7
3. Shitara K, Lordick F, Bang Y-J, et al. Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) withclaudin-18.2+ (CLDN18.2+) / HER2− locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: primary results from phase 3 SPOTLIGHT study. J Clin Oncol. 2023;41(suppl 3):LBA292. doi:10.1200/JCO.2023.41.3_suppl.LBA292
4. Xu R, Shitara K, Ajani JA, et al. Zolbetuximab + CAPOX in 1L Claudin-18.2+ (CLDN18.2+)/HER2− locally advanced (LA) or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: primary phase 3 results from GLOW. J Clin Oncol. 2023;41(suppl 36):405736. doi:10.1200/JCO.2023.41.36_suppl.405736