Enfortumab vedotin combined with pembrolizumab is a treatment for adult patients diagnosed with urothelial carcinoma, a cancer that begins in the cells lining the bladder. This therapy is for cancer that is locally advanced, meaning it has grown into nearby tissues, or metastatic, where it has spread to distant parts of the body. The treatment combines two different medications: an antibody-drug conjugate and an immune checkpoint inhibitor. This dual-drug regimen provides a platinum-free alternative for newly diagnosed patients, regardless of their eligibility for cisplatin, a common chemotherapy.
The Two-Pronged Treatment Approach
The first drug, enfortumab vedotin, is an antibody-drug conjugate (ADC) engineered to function like a guided delivery system. Its antibody component finds and attaches to a protein called Nectin-4, which is frequently found on the surface of urothelial cancer cells. Once attached, the ADC is absorbed into the cancer cell, where it releases a powerful cell-killing agent called monomethyl auristatin E (MMAE). This targeted delivery concentrates the toxin inside tumor cells, leading to their destruction while minimizing exposure to healthy cells.
The second drug, pembrolizumab, works by engaging the body’s own immune system and is a type of immunotherapy called an immune checkpoint inhibitor. Cancer cells can produce proteins that act as a “stop signal” to immune cells called T-cells, preventing them from attacking the tumor. Pembrolizumab blocks this interaction, essentially “releasing the brakes” on the T-cells, which allows the immune system to better recognize and destroy cancer cells.
The combination of these drugs creates a synergistic effect. As enfortumab vedotin kills cancer cells, it causes the release of tumor-specific material. The T-cells, activated by pembrolizumab, can then identify this material, creating a more robust anti-cancer response than either drug could achieve on its own.
Clinical Trial Outcomes
The approval of this combination was based on the EV-302 clinical trial, which compared the therapy against platinum-based chemotherapy. The study evaluated the combination as a first-line treatment for patients with advanced disease. The trial measured two primary endpoints: overall survival and progression-free survival.
Overall survival refers to the length of time patients lived after starting treatment, while progression-free survival measures how long they lived before their cancer worsened. The findings from the EV-302 trial showed that patients who received the enfortumab vedotin and pembrolizumab combination experienced a substantial improvement in both metrics compared to those who received chemotherapy.
The median overall survival for patients on the combination therapy was 31.5 months, nearly double the 16.1 months in the chemotherapy group. A similar benefit was seen in progression-free survival, with a median of 12.5 months for the combination compared to 6.3 months for chemotherapy. These results established the combination as a new standard of care for this disease.
Common Side Effects and Management
While effective, this combination is associated with a range of side effects. The most frequently reported issues include skin rash, which can vary in severity, and peripheral neuropathy. Peripheral neuropathy manifests as numbness, tingling, or pain in the hands and feet. Patients also often experience fatigue and changes in their sense of taste.
The treatment can also cause hyperglycemia, or high blood sugar, which requires careful monitoring. The pembrolizumab component carries its own set of potential side effects known as immune-mediated adverse reactions. These occur when the activated immune system mistakenly attacks healthy tissues, which can affect organs like the lungs, colon, and endocrine glands.
Patients must maintain open communication with their oncology team and report any new or worsening symptoms immediately. Management strategies may involve adjusting the dose, pausing treatment, or administering other medications to counteract the side effects, such as steroids for a rash. For more severe immune-related events, treatment may be stopped entirely.
Patient Eligibility and Treatment Process
This combination therapy is approved for adult patients with urothelial carcinoma that is either locally advanced or has metastasized. A significant aspect of its approval is its availability to patients regardless of whether they are eligible for cisplatin-based chemotherapy. This factor previously limited treatment options for many individuals.
The administration of both drugs is done in a clinical setting, such as a hospital or infusion center, and both are delivered intravenously. The treatment follows a specific schedule organized into 21-day cycles. Within this 3-week cycle, patients receive infusions of both drugs on Day 1 and Day 8.
This schedule is repeated, and patients continue on the therapy based on its effectiveness and how well they tolerate it. The regimen may continue for up to two years if the patient is benefiting from it and side effects are manageable.