Insights from Terminated ADCs: Glembatumumab Vedotin and Depatuxizumab Mafodotin

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Insights from Terminated ADCs: Glembatumumab Vedotin and Depatuxizumab Mafodotin

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Insights from Terminated ADCs: Glembatumumab Vedotin and Depatuxizumab Mafodotin

Over 260 antibody-drug conjugates (ADCs) have been studied in clinical trials for various cancer indications, with 92 of them terminated for reasons such as intolerable toxicity, insufficient efficacy, or commercial considerations.

In this analysis, we explore the data and reasons for termination of two ADCs: Glembatumumab Vedotin (CDX-011) and Depatuxizumab Mafodotin (ABT-414).

Figure 1. Brief overview of ADCs that have terminated clinical studies (classified by payload and clinical progress)

Glembatumumab Vedotin (CDX-011)

Developed by Celldex Therapeutics from 2006 to 2018, CDX-011 aimed to treat non-metastatic melanoma protein B (GPNMB)-expressing cancers. Despite promising preclinical data, the Phase III trial was discontinued on April 18, 2018, as CDX-011 failed to demonstrate superior efficacy over Xeloda® in metastatic triple-negative breast cancer (high GPNMB expression).

Preclinical Studies

CDX-011, a fully humanized IgG2 monoclonal antibody, showed effective and specific inhibition of GPNMB+ melanoma cells when conjugated with monomethyl auristatin E (MMAE). In mouse xenograft models, CDX-011 demonstrated dose-dependent tumor growth inhibition, with some tumors completely regressing.

Clinical Trials and Termination

Initiated in June 2006, CDX-011 progressed through Phase I, II, and III trials. However, the Phase III results did not meet the primary endpoint for metastatic triple-negative breast cancer. Common Grade ≥3 adverse events included severe rash, and the termination of the CDX-011 development plan led to a 20% workforce reduction at Celldex. Subsequent ADC development (CDX-014) targeting TIM-1 was also canceled.

Depatuxizumab Mafodotin (ABT-414)

Developed by Abbvie from 2013 to 2019, ABT-414 targeted the epidermal growth factor receptor (EGFR) and focused on treating glioblastomas.

Preclinical Studies

ABT-414, composed of ABT-806 and MMAF, demonstrated low normal tissue binding and potent cytotoxicity against EGFR-expressing tumor cell lines in preclinical studies. In xenograft models, ABT-414 showed significant tumor growth inhibition and regression, particularly in models expressing wild-type or mutated EGFR.

Clinical Trials and Termination

Despite promising preclinical results, ABT-414 faced challenges in clinical trials. Although granted orphan drug designation for glioblastoma treatment, a Phase III trial (UNITE) combining ABT-414 with radiochemotherapy was terminated in 2019 due to lack of survival benefit. Notably, ABT-414 exhibited some ocular toxicity.

Conclusion

While both ADCs showed promise in preclinical studies, the translation to clinical success proved challenging.

Lessons from these terminations highlight the complexity of ADC development, emphasizing the importance of rigorous clinical evaluation and the need for a deeper understanding of factors influencing efficacy and toxicity.

Insights from Terminated ADCs: Glembatumumab Vedotin and Depatuxizumab Mafodotin

References:

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(source:internet, reference only)

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