GU cancer

Antibody-drug conjugate a promising option in metastatic bladder cancer


Promising results have been obtained with the a combination of antibody-drug conjugate (ADC) and checkpoint inhibitor in the treatment of patients with locally advanced or metastatic urothelial cancer.

The use of enfortumab vedotin plus pembrolizumab resulted in high objective response rates with rapid responses compared to ADC monotherapy in a first-line cisplatin-ineligible population, according to researchers from Memorial Sloan Kettering Cancer Center, New York.

Enfortumab vedotin is a conjugate of a microtubule-disrupting agent monomethyl auristatin E, which is linked to an antibody targeting the nectin-4 protein on urothelial cancer cells.

The combination of ADC plus checkpoint inhibitor produced ORRs in nearly two thirds (64.5%) of patients, but at a cost of significant skin adverse effects, the results presented by Dr Jonathan Rosenberg at the ESMO 2022 meeting showed.

The phase 1/2 trial (EV-103/KEYNOTE-869 Cohort K) involved 149 previously untreated cisplatin-ineligible pts with locally advanced or metastatic urothelial cancer, who were  randomised 1:1 to enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab.

With a median follow up of 15 months, the confirmed ORR for EV + pembrolizumab was 64.5% with the median duration of response (DOR) not reached, whereas for EV monotherapy the confirmed ORR was 45.2% and median DOR was 13.2 months.

For the EV + pembrolizumab combination 10.5% of patients experienced a complete response (compared to 4.1% with monotherapy) and 53.9% of patients had a partial response (vs 41.1% with monotherapy).

The median time to ORR was 2.1 months in both groups.

Treatment related adverse events included skin reactions (67.1% vs 45.2%), peripheral neuropathy (60.5% vs 54.8%) and ocular disorders such as dry eye and blurred vision; (26.3% vs 28.8%).

“These data support ongoing investigations of first-line enfortumab vedotin and pembrolizumab in patients with locally advanced or metastatic urothelial cancer who have a high unmet need,” the study investigators concluded

Dr Rosenberg noted that the response rates seen with the EV and pembrolizumab treatment were much better than those for conventional chemotherapy treatments such as gemcitabine and carboplatin, “suggesting that perhaps in the future this may be a first line treatment option for patients with metastatic urothelial cancer who are ineligible for cisplatin.”

“While immunotherapy has gotten more attention in recent years, antibody-drug conjugates might end up making a bigger positive impact in treating bladder cancer, especially in combination with checkpoint inhibitors as shown in this trial,” he said.

He noted that EV plus pembrolizumab was considered for accelerated approval by the FDA for this indication, and there are more ADCs to come out of the pipeline, “[so] we’ll continue exploring ways to combine them with other drugs, such as checkpoint inhibitors, to make them even more effective.”

“Although bladder cancer cases are going down, the death rates haven’t changed significantly … having these new treatment options available brightens the outlook considerably for many bladder cancer patients,” he said.

The study was sponsored by Astellas, makers of enfortumab vedotin.

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