enapotamab vedotin (HuMax-AXL-ADC)

EnaV had an acceptable safety profile; however, because the evaluation of antitumor activity did not show clinically meaningful responses, clinical development of EnaV was discontinued.

Preclinical studies highlight the efficacy of Axl inhibitors, such as bemcentinib, brigatinib, and enapotamab vedotin, in overcoming drug resistance and enhancing immune responses. Clinical trials combining Axl inhibitors with ICIs (e.g., pembrolizumab) show promise, particularly in STK11-mutant NSCLC, with manageable toxicity profiles. However, challenges persist in optimizing dosing, managing adverse events, and identifying predictive biomarkers. Ongoing research into combination strategies and biomarker-driven approaches aims to refine Axl-targeted therapies and improve outcomes for patients with advanced NSCLC.

Doxorubicin (doxo) remains the standard of care for patients with advanced soft tissue sarcoma (STS), even though response rates to doxo are only around 14% to 18%. One model was found negative for AXL on experimental passage and did not respond to EnaV. This study provides a preclinical rationale for the evaluation of AXL-targeting ADCs in the treatment of AXL-expressing sarcomas.

P1/2, N=306, Completed, Genmab | Active, not recruiting --> Completed | Trial primary completion date: Aug 2021 --> Nov 2021

Here we show that enapotamab vedotin (EnaV), an antibody-drug conjugate (ADC) targeting AXL, effectively targets tumors that display insensitivity to immunotherapy or tumor-specific T cells in several melanoma and lung cancer models...Combining EnaV with tumor-specific T cells proved superior to either treatment alone in models of melanoma and lung cancer and induced ICB benefit in models otherwise insensitive to anti-PD-1 treatment. Our findings indicate that targeting AXL-expressing, immunotherapy-resistant tumors with EnaV causes an immune-stimulating tumor microenvironment and enhances sensitivity to ICB, warranting further investigation of this treatment combination.