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FDA approves Vyloy (zolbetuximab-clzb)

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On October 18, 2024, the US Food and Drug Administration (FDA) approved zolbetuximab-clzb (Vyloy, Astellas Pharma US, Inc.) for the first-line treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (G/GEJ) adenocarcinoma whose tumors are CLDN18.2 positive, as determined by an FDA-approved test. FDA also approved the VENTANA CLDN18 (43-14A) RxDx Assay (Ventana Medical Systems, Inc./Roche Diagnostics) as a companion diagnostic device to identify patients with gastric or GEJ adenocarcinoma who may be eligible for treatment with zolbetuximab.

The recommended zolbetuximab-clzb dosage with fluoropyrimidine- and platinum-containing chemotherapy is 800 mg/m2 intravenously (IV) as the first dose, with subsequent dosages of 600 mg/m2 IV every 3 weeks, or 400 mg/m2 IV every 2 weeks.

Zolbetuximab is a chimeric IgG1 antibody targeting Claudin 18.2 (CLDN18.2) originally developed by Ganymed Pharmaceuticals AG, which was acquired by Astellas. Japan’s Ministry of Health, Labour and Welfare approved VYLOY™ for patients with CLDN18.2-positive, unresectable, advanced or recurrent gastric cancer in March 2024 and zolbetuximab was subsequently approved for untreated CLDN18.2-positive, HER2-negative unresectable advanced G/GEJ adenocarcinoma in the United Kingdom and the European Union in August and September 2024, respectively.

The marketing approvals were based on data from the Phase 3 SPOTLIGHT (NCT03504397) and GLOW clinical trials (NCT03653507). Both were randomized (1:1), double-blind, multicenter trials that included patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic G/GEJ adenocarcinoma. The SPOTLIGHT trial included 565 patients randomized to receive either zolbetuximab (800 mg/m2 loading dose administered IV followed by 600 mg/m2 every 3 weeks) plus mFOLFOX6 chemotherapy (283 patients) or placebo plus mFOLFOX6 (282 patients). The GLOW study evaluated zolbetuximab plus capecitabine and oxaliplatin as first-line treatment in 507 patients.

In the SPOTLIGHT study, the median progression-free survival (PFS) was 10.6 months (95% CI: 8.9, 12.5) in the zolbetuximab-clzb/chemotherapy arm and 8.7 months (95% CI: 8.2, 10.3) in the placebo/chemotherapy arm (hazard ratio [HR] 0.751 [95% CI: 0.598, 0.942]; 1-sided p-value=0.0066). Median overall survival (OS) was 18.2 months (95% CI: 16.4, 22.9) and 15.5 months (95% CI: 13.5, 16.5), respectively, (HR 0.750 [95% CI: 0.601, 0.936]; 1-sided p-value=0.0053).

In the GLOW study, the median PFS was 8.2 months (95% CI: 7.5, 8.8) in the zolbetuximab-clzb/chemotherapy arm and 6.8 months (95% CI: 6.1, 8.1) in the placebo/chemotherapy arm (hazard ratio [HR] 0.687 [95% CI: 0.544, 0.866]; 1-sided p-value=0.0007). Median OS was 14.4 months (95% CI: 12.3, 16.5) and 12.2 months (95% CI: 10.3, 13.7), respectively (HR 0.771 [95% CI: 0.615, 0.965]; 1-sided p-value=0.0118).

Curious about what other antibody therapeutics are approved or in regulatory review? Our online table contains details for over 200 such antibodies! 

FDA approves HYMPAVZI™ (marstacimab-hncq)

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On October 11, 2024, Pfizer Inc. announced that the U.S. Food and Drug Administration approved HYMPAVZI™ (marstacimab-hncq) for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and pediatric patients 12 years of age and older with hemophilia A (congenital factor VIII deficiency) without factor VIII (FVIII) inhibitors, or hemophilia B (congenital factor IX deficiency) without factor IX (FIX) inhibitors. Marstacimab is an IgG1l monoclonal antibody targeting tissue factor pathway inhibitor, a single-chain polypeptide that can reversibly inhibit Factor Xa. The antibody’s Fc mutations (L234A, L235A, G237A) impair Fc effector functions.

HYMPAVZI  is the first hemophilia medicine approved in the U.S. to be administered via a pre-filled, auto-injector pen. The approval was based on results of the Phase 3 BASIS study (NCT03938792), which evaluated the efficacy and safety marstacimab in adult and teenage participants with severe hemophilia A or moderately severe to severe hemophilia B.  In the study, HYMPAVZI reduced the annualized bleeding rate (ABR) for treated bleeds by 35% and 92% after a 12-month active treatment period compared to routine prophylaxis and on-demand treatment, respectively, in patients with hemophilia A or B without inhibitors. The safety profile for HYMPAVZI was consistent with Phase 1/2 results.

In September 2024, the European Medicines Agency’s Committee for Medicinal Products for Human Use adopted a positive opinion for marstacimab for the routine prophylaxis of bleeding episodes in adults and adolescents 12 years and older with severe hemophilia A without FVIII inhibitors, or severe hemophilia B without FIX inhibitors. A decision by the European Commission is expected by the end of 2024.

Curious about what other antibody therapeutics are approved or in regulatory review? Our online table contains details for over 200 such antibodies! 

 

Ordspono™ (odronextamab) approved in the European Union

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On August 26, 2024, Regeneron announced that the European Commission approved Ordspono™ (odronextamab) to treat adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) or R/R diffuse large B-cell lymphoma (DLBCL), after two or more lines of systemic therapy. This marks the first regulatory approval of Ordspono in the world for these patients.

Odronextamab (REGN1979) is a hinge-stabilized, bispecific human IgG4k antibody targeting CD20 and CD3 with an Fc that was modified to reduce Fc receptor binding. The antibody was derived from Regeneron’s VelocImmune® technology and Veloci-Bi® platform and is being developed for the treatment of RR B-cell NHL. In 2020, Regeneron granted Zai Lab rights to develop and exclusively commercialize odronextamab in oncology in mainland China, Hong Kong, Taiwan, and Macau. Odronextamab received Fast Track designation from FDA and Orphan Drug designations by the FDA and EMA for the treatment of patients with FL and DLBCL, which are subtypes of NHL.

The approval in the European Union is based on results from the Phase 1 ELM-1 (NCT02290951)  and pivotal Phase 2 ELM-2 (NCT03888105) trials, which demonstrated robust, durable response rates in adults with R/R FL or R/R DLBCL

  • Results from ELM-1 (N=60) in R/R DLBCL patients who had progressed after CAR-T therapy, as assessed by an independent review committee (IRC) showed 48% objective response rate (ORR), with 32% achieving a complete response (CR). Among responders (n=29), the median duration of response (DoR) was 15 months (95% CI: 3 months to not estimable (NE)).
  • Results from ELM-2 (N=127) in R/R DLBCL patients who were CAR-T therapy naive, as assessed by an IRC showed 52% ORR, with 31% achieving a CR. Among complete responders the median DoR was 18 months (95% CI: 10 months to NE).
  • In R/R FL, results from ELM-2 (N=128) as assessed by an IRC showed an objective response rate (ORR) of 80%, with 73% achieving a CR. Among complete responders, the median DoR was 25 months (95% confidence interval [CI]: 20 months to NE).

Regeneron submitted biologics license applications (BLAs) for odronextamab for RR FL and DLBCL to FDA. In March 2024, Regeneron announced that the FDA issued complete response letters for the Biologics License Applications for odronextamab. The company noted that FDA’s only approvability issue is related to the enrollment status of the confirmatory trials.

FDA approves IMDELLTRA™ (tarlatamab-dlle) for extensive-stage small cell lung cancer

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On May 16, 2024, the U.S. Food and Drug Administration (FDA) granted an accelerated approval for IMDELLTRA™ (tarlatamab-dlle) for the treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) with disease progression on or after platinum-based chemotherapy. The approval was based on surrogate endpoints, including response rate and duration of response observed in clinical studies, and continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

IMDELLTRA is bispecific T cell engager (BiTE®, (scFv)2-scFc)) antibody that targets DLL3 on tumor cells and CD3 on the patient’s T cells and has mutations in the Fc (N297G; R292C, V302C) to extend the half-life of the molecules.

FDA’s accelerated approval of IMDELLTRA is based on results from the Phase 2 DeLLphi-301 clinical trial (NCT05060016) that evaluated IMDELLTRA in patients with SCLC who had failed two or more prior lines of treatment, and who had received the 10 mg every two weeks dosing (Q2W) regimen. As reported in the New England Journal of Medicine, results from the study found that IMDELLTRA at the 10 mg Q2W dose demonstrated an objective response rate of 40% and median progression-free survival of 4.9 months. treatment-related adverse events that caused patients discontinuation of tarlatamab treatment occurred in a low percentage (3%) of patients.

IMDELLTRA is currently being evaluated in two Phase 3 studies of SCLC. The Phase 3 DeLLphi-304 study (NCT05740566) is evaluating tarlatamab compared with standard of care in subjects with relapsed SCLC after platinum-based first-line chemotherapy. The Phase 3 DeLLphi-306 study (NCT06117774) is evaluating tarlatamab in subjects with limited-stage SCLC who have not progressed following concurrent chemoradiation therapy. A third Phase 3 study, DeLLphi-305 (NCT06211036), evaluating tarlatamab in combination with durvalumab vs durvalumab alone in subjects with ES-SCLC following platinum, etoposide and durvalumab was not yet recruiting patients as of the last update posted on May 10, 2024.

Details for all approved antibody therapeutics are found in our searchable online table.

TEVIMBRA (tislelizumab-jsgr) granted first FDA approval for esophageal squamous cell carcinoma

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On March 13, 2024, the U.S. Food and Drug Administration (FDA) approved TEVIMBRA (tislelizumab-jsgr) as monotherapy for the treatment of adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC) after prior systemic chemotherapy that did not include a PD-(L)1 inhibitor. TEVIMBRA, a humanized IgG4 antibody engineered with modifications that stabilize the hinge region and abrogate binding to Fc receptors, was approved as an orphan drug for this indication.

FDA’s approval is based on the Phase 3 RATIONALE 302 trial (NCT03430843), which met its primary endpoint in the intention-to-treat (ITT) population, with a median overall survival (OS) in the TEVIMBRA arm or 8.6 months (95% CI: 7.5, 10.4) compared to 6.3 months (95% CI: 5.3, 7.0) in the chemotherapy arm (p=0.0001; hazard ratio [HR]=0.70 [95% CI: 0.57, 0.85]). The results showed a statistically significant and clinically meaningful survival benefit for TEVIMBRA compared with chemotherapy and the safety profile of TEVIMBRA was favorable over chemotherapy.

In 2019, China’s National Medical Products Administration granted the first global approval of tislelizumab. In 2023, the product received approval by the European Commission for advanced or metastatic ESCC after prior chemotherapy, and it received a positive opinion by the Committee for Medicinal Products for Human Use of the European Medicines Agency in February 2024 as a treatment for non-small cell lung cancer across three indications.

Biologics license applications for tislelizumab as first-line treatment for patients with unresectable, recurrent, locally advanced, or metastatic ESCC and patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma are currently undergoing FDA review. The target action dates for these applications are in July and December 2024, respectively.

Details for all approved antibody therapeutics and those in regulatory review can be found in our searchable table.