First trial showing safety of a combination of two antibody-drug conjugates

A new phase I trial, recently published on Annals of Oncology, shows for the first time in any tumor the safety of a combination of two antibody-drug conjugates  (ADCs),  sacituzumab govitecan (SG) plus enfortumab vedotin (EV), in patients with metastatic urothelial carcinoma.

ADCs have emerged as a key therapeutic approach following progression on platinum-containing chemotherapy and/or immunotherapy. SG and EV are standard monotherapies for metastatic urothelial carcinoma and have different targets and payloads: thus, researchers treated 23 patients who had progressed on platinum and/or immunotherapy with SG + EV administered on days 1 + 8 of a 21-day cycle until progression or unacceptable toxicity. Results showed that the maximum tolerated doses in combination was SG 10 mg/kg and EV 1.25 mg/kg days 1+8 every 21 days, with no new safety signals compared to monotherapy, and combination recommended phase II dose is SG 8 mg/kg + EV 1.25 mg/kg on days 1, 8 of every 21-day cycle. The objective response rate was 70% with three complete responses; with a median follow-up of 14 months, 9 of 23 patients have ongoing response including 6 responses lasting over 12 months. «To our knowledge this is the first trial to demonstrate the safety of combining two different ADCs in the treatment of any malignancy», authors say. «The non-overlapping toxicities of these two ADCs allowed for administration of effective combination doses in the present trial, and the overall toxicity in this study compares favorably to monotherapy. With over a dozen different ADCs currently approved by the US FDA and several more in development, the strategy of ADC combination studies as presented in our trial can represent a paradigm shift for various tumor types. Our data suggest that combining ADC therapies with differing payloads, targets, and toxicity profiles should be explored across malignancies».