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The antibody-drug conjugate (ADC) enfortumab vedotin significantly improved overall survival (OS) in patients with advanced, previously treated bladder cancer, a large showed.

Median OS improved from about 9 months with standard chemotherapy to almost 13 months with enfortumab vedotin-ejfv (Padcev). Median progression-free survival also improved significantly with the ADC, from 3.71 to 5.55 months.

The incidence of treatment-related adverse events (TRAEs) was similar between treatment groups, including grade ≥3 TRAEs, reported Thomas Powles, MD, of Barts Cancer Center and Queen Mary University in London, during the virtual Genitourinary Cancers Symposium (GuCS). The results were published simultaneously in the .

"Enfortumab vedotin is the first drug beyond chemotherapy and immune therapy to show a significant survival advantage in previously treated advanced urothelial cancer," said Powles. "This is a big step in the right direction for patients with advanced urothelial cancer, where treatment options remain quite limited."

Following first-line platinum-based chemotherapy and anti-PD-1 treatment in second line, patients with locally advanced or metastatic urothelial cancer have few proven treatment options. Though many patients receive additional chemotherapy, advanced urothelial cancer is associated with intrinsic and acquired resistance.

The monoclonal antibody enfortumab targets the cell-adhesion molecule nectin-4, which is highly expressed in urothelial carcinoma and may contribute to growth and proliferation, Powles noted. After binding nectin-4, the ADC releases the microtubule disruptor auristatin E to induce .

Powles reported primary results from the , involving patients with locally advanced/metastatic urothelial carcinoma previously treated with cisplatin-based chemotherapy and a PD-1/L1 inhibitor. Investigators in 19 countries randomized 608 patients to single-agent enfortumab or to investigator's choice of chemotherapy (docetaxel, paclitaxel, or vinflunine). Treatment continued until disease progression or unacceptable toxicity, and the primary endpoint was OS.

The study population had a median age of 68, and men accounted for three-fourths of the patients. More than half of the patients were former smokers and another 10% were current tobacco users. Baseline clinical characteristics were comparable between groups, including Bellmunt risk score, primary disease site, presence of visceral involvement, and liver metastasis.

After a median follow-up of 11.1 months, the primary analysis showed a 30% reduction in the survival hazard with enfortumab (95% CI 0.56-0.89, P=0.001). The hazard for disease progression or death was reduced by 38% (95% CI 0.51-0.75, P<0.001). Subgroup analyses showed a consistent benefit with enfortumab versus chemotherapy.

TRAEs occurred in 94% of the enfortumab arm and 92% of the chemotherapy arm. Half the patients in each group had grade ≥3 TRAEs.

Additional support for enfortumab in previously treated advanced urothelial carcinoma came from an updated analysis of the phase II, single-arm, open-label EV-201 trial. As previously reported, the trial involved older patients (median age 75) with locally advanced or metastatic urothelial carcinoma ineligible for cisplatin-based chemotherapy and progression during or after treatment with a PD-1/L1 inhibitor. The primary endpoint was objective response.

Updated results showed an overall response rate of 52% in 89 evaluable patients, including complete responses in 20%. Median PFS and OS were 5.8 and 14.7 months, reported Arjun Vasant Balar, MD, of the Perlmutter Cancer Center at NYU Langone Health in New York City. The most common TRAEs were alopecia (51%), peripheral sensory neuropathy (47%), and fatigue (34%).

TRAEs of interest included rash (61% overall, 17% grade ≥3), peripheral neuropathy (54%, 8%), and hyperglycemia (10%, 6%). Four treatment-related deaths occurred, all involving patients older than 75 and with multiple comorbidities.

"The activity demonstrated in EV-201 builds upon the overall survival benefit that we just heard about in EV-301," said Balar, whose presentation followed Powles's. "Overall, what we observe is that enfortumab vedotin is active in advanced urothelial cancer across a spectrum of the disease. This data supports potentially a new standard of care in this population with a high unmet medical need."

Invited discussant Arlene Siefker-Radtke, MD, of the University of Texas MD Anderson Cancer Center in Houston, proclaimed that "enfortumab vedotin is here to stay," noting the drug received FDA approval in 2019.

"I've been impressed not only by the activity in visceral and liver metastases, but also by the impact in those with bone metastases, as this appears very helpful in controlling bone pain in many patients," she said. "The early evidence in the post-immunotherapy, platinum-ineligible group suggests this treatment can help patients with an unmet need due to their inability to receive platinum-based therapy.

"While it's currently approved in the third-line setting, we're all eagerly awaiting the outcomes of the frontline studies of enfortumab vedotin combined with pembrolizumab [Keytruda], which showed such promising objective response rates, as has been presented at earlier meetings."