Resistance mechanisms to antibody-drug conjugates

(UroToday.com) The 2024 IBCN Annual Meeting included a session on the current status and future developments in antibody-drug conjugates, including a presentation by Dr. Markus Eckstein discussing the mechanisms of resistance to antibody-drug conjugates.

Dr. Eckstein began his presentation by stating that antibody-drug conjugates target proteins regardless of protein function, but are dependent on the expression of the membranous target proteins. There are several possible mechanisms of resistance, including:

• Deficiency and limitation of target proteins
• Conventional – similar to chemotherapy resistance
• Redesign of the microenvironment

Lack and restriction of target proteins is a mechanism of action for sacituzumab-govitecan resistance in triple-negative breast cancer: high MGH18-TROP2 is associated with partial remission, while negative MGH20-TROP2 is associated with primary progressive disease. The following timeline shows a single case from Dr. Eckstein's molecular tumor board from the pre-enfortumab-vedotin era:
The absence or limitation of target proteins (e.g. nectin-4) has also been investigated in clinical studies, particularly in the EV-101 study.¹ In EV-101, there was strong nectin-4 IHC expression in >95% of patients with urothelial carcinoma with a median H-score of 290 and 95% of tumors with an H-score of >150:

In early 2024, Dr. Eckstein's group aimed to characterize associations of protein and gene expression of TACSTD2/TROP2 and NECTIN-4/NECTIN-4 with morphomolecular and clinicopathological features of advanced urothelial carcinoma.² TROP2/TACSTD2 and NECTIN-4/NECTIN-4 were highly expressed at the protein and transcript levels in advanced urothelial carcinoma, and their expression status did not correlate with patient survival. NECTIN-4/NECTIN-4 expression was higher in luminal tumors and reduced in advanced squamous cell carcinoma. In addition, NECTIN-4 was negative in 10.6% of samples, 18.4% of samples had low expression (H-score
Dr. Eckstein then spoke about the EV-302 study.³ particularly the relationship with nectin-4. Dr. Klumper and Dr. Eckstein have previously shown that membranous nectin-4 expression is frequently decreased during metastatic spread of urothelial carcinoma and is associated with resistance to enfortumab vedotin.⁴ In this analysis, they showed that absence or weak membranous nectin-4 expression (H-score 0-99) is associated with shorter progression-free survival under enfortumab vedotin:

At ESMO 2024, Dr. Tom Powles showed in the EV-302 cohort that there was a consistent objective response benefit with enfortumab vedotin + pembrolizumab in all Nectin 4-H score subgroups. In particular, in patients with an H score
Dr. Klumper and Eckstein recently investigated NECTIN4 Amplifications as a genomic biomarker to predict enfortumab vedotin response in metastatic urothelial carcinoma.⁵ This found that NECTIN4 The amplification represents a stable genomic alteration during metastatic progression and is associated with increased membranous nectin-4 protein expression:

A total of 96% of patients with NECTIN4 Amplifications showed objective responses to enfortumab vedotin compared to 32% in the non-amplified subgroup (p
However, nectin-4 amplification is not meaningful because it was not associated with overall survival in metastatic urothelial carcinoma not treated with enfortumab vedotin:

Regarding other targets of antibody-drug conjugates, Dr. Eckstein discussed trastuzumab deruxtecan, which targets HER2. Trastuzumab deruxtecan was studied in HER2-expressing tumors in the Destiny-PanTumor02 trial and demonstrated an objective response rate of 39% in patients with urothelial carcinoma, but up to 56.3% in IHC3+ patients. Disitamab vedotin is another experimental antibody-drug conjugate consisting of a fully humanized monoclonal antibody targeting HER2. At ESMO 2024, Dr. Matt Galsky reported on the preliminary efficacy and safety of disitamab vedotin with pembrolizumab in the RC48G001 cohort C trial. Disitamab vedotin confirmed the objective response with the best percent change in the sum of diameters from baseline tumors and confirmed the response in both the HER2-positive and HER2-low groups:
In conclusion, Dr. Eckstein pointed out that alterations in target proteins and payload resistance are a known mechanism of resistance to antibody-drug conjugates in other tumors (e.g., Hodgkin lymphoma), as well as to conventional chemotherapy and small molecules (e.g., TKIs).

Dr. Eckstein concluded his talk on the mechanisms of resistance to antibody-drug conjugates with the following take-home slide:
Regarding our future, especially beyond the enormous success of the EV-302, he concluded with a quote from Jacques Monod (June 17, 1976): “In science, complacency is death. Personal complacency is the death of the scientist. Collective complacency is the death of science. It is restlessness, anxiety, dissatisfaction and anguish that feed science.”