EMA Accepts Marketing Application for Zolbetuximab in CLDN18.2+ Gastric/GEJ Adenocarcinoma

The European Medicines Agency (EMA) has accepted a marketing authorization application (MAA) seeking the approval of zolbetuximab (IMAB362) for first-line treatment of patients with Claudin18.2 (CLDN18.2)-positive, HER2-negative, unresectable, locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.¹

The application is based on data from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials. If approved, zolbetuximab would be the first CLDN18.2-targeted therapy available in Europe for this patient population.

Data from SPOTLIGHT demonstrated that zolbetuximab plus mFOLFOX6 (levoleucovorin calcium, fluorouracil, and oxaliplatin) generated a statistically significant improvement in 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), zolbetuximab plus mFOLFOX6 elicited a median PFS of 10.61 months (95% CI, 8.90-12.48) compared with 8.67 months (95% CI, 8.21-10.28) for placebo/mFOLFOX6 (HR, 0.75; 95% CI, 0.60-0.94; P = .0066).^2,3

Furthermore, 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 produced a median OS of 18.23 months (95% CI, 16.43-22.90) vs 15.54 months (95% CI, 13.47-16.53) for mFOLFOX6 alone (HR, 0.75; 95% CI, 0.60-0.94; P = .0053).

Additionally, findings from GLOW showed that treatment with zolbetuximab plus CAPOX (capecitabine plus oxaliplatin) led to 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), zolbetuximab plus CAPOX produced a median PFS of 8.21 months (95% CI, 7.46-8.84) compared with 6.80 months (95% CI, 6.14-8.08) for placebo plus CAPOX (HR, 0.687; 95% CI, 0.544-0.866; P = .0007). Furthermore, those in the zolbetuximab arm achieved a median OS of 14.39 months (95% CI, 12.29-16.49) vs 12.16 months (95% CI, 10.28-13.67) for those in the placebo arm (HR, 0.771; 95% CI, 0.615-0.965; P = .0118).⁴

“Patients with gastric cancer in Europe face extremely low 5-year survival rates regardless of their disease stage, and innovative therapies that extend survival are needed,” Moitreyee Chatterjee-Kishore, PhD, MBA, senior vice president and head of Immuno-Oncology Development at Astellas, stated in a news release.¹ “The EMA’s acceptance of the zolbetuximab MAA continues a cascade of regulatory milestones for Astellas that are aimed at bringing a new option to patients with advanced gastric and GEJ cancer.”

On July 6, 2023, the FDA granted priority review to the biologics license application (BLA) for zolbetuximab for the first-line treatment of patients with unresectable, locally advanced or metastatic, HER2-negative, gastric or GEJ adenocarcinoma whose tumors are CLDN18.2 positive.⁵ The BLA was also supported by findings from SPOTLIGHT and GLOW.

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

The study randomly assigned patients in a 1:1 fashion to receive 800 mg/m² of zolbetuximab as a loading dose, followed by 600 mg/m² of zolbetuximab every 3 weeks, plus mFOLFOX6 every 2 weeks, or placebo plus mFOLFOX6, for four 42-day cycles. Zolbetuximab or placebo were then continued alone 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).

PFS by independent review committee assessment per RECIST v1.1 criteria was the primary end point. Secondary end points included OS, time to confirmed deterioration, objective response rate (ORR), duration of response (DOR), and safety/tolerability.

Additional findings from SPOTLIGHT 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.

Furthermore, the ORRs for the zolbetuximab and placebo groups were 48% (95% CI, 42%-54%) and 48% (95% CI, 42%-54%), respectively. 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.

Regarding toxicity, no new safety signals were reported in SPOTLIGHT. Grade 3 or higher treatment-emergent adverse effects (TEAEs) occurred in 87% of patients in the zolbetuximab group vs 78% of those in the placebo group. The most common grade 3 or higher AEs included nausea, vomiting, and decreased appetite. Two percent of patients in the zolbetuximab group and 1% of patients in the placebo group experienced treatment-related deaths.

GLOW was a global, multicenter, double-blind, randomized study that included previously untreated patients with CLDN18.2-positive, HER2-negative, unresectable, locally advanced or metastatic gastric or GEJ cancer. CLDN18.2 positivity was again defined as at least 75% of tumor cells with moderate-to-strong membranous CLDN18.2 staining. An ECOG performance status of 0 or 1 was also required.⁴

Patients were randomly assigned 1:1 to 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. Following 8 cycles of CAPOX, zolbetuximab or placebo could be continued alone 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 served as the primary end point, and secondary end points consisted of OS, ORR, DOR, safety, and patient-reported outcomes.

Additional data showed among patients who were evaluable for response, the zolbetuximab regimen (n = 195) generated an ORR of 53.8% (95% CI, 46.58%-60.99%) vs 48.8% (95% CI, 41.76%-55.84%) for the placebo regimen (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.

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

Additionally, 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. Notably, 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% and 2.8% of patients in the experimental arm and control arms, respectively.

References

1. European Medicines Agency accepts Astellas’ marketing authorization application for zolbetuximab. News release. Astellas. July 14, 2023. Accessed July 17, 2023. https://www.astellas.com/en/news/28146
2. Shitara K, Lordick F, Bang YJ, 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 YJ, 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 4):LBA292. doi:10.1200/JCO.2023.41.4_suppl.LBA292
4. Xu RH, 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
5. Astellas announces US FDA grants priority review for zolbetuximab biologics license application. News release. Astellas. July 6, 2023. Accessed July 17, 2023. https://www.astellas.com/en/system/files/news/2023-07/81743d9407/20230706_en_1.pdf