New Drug Combination Approved for Advanced Bladder Cancer in Italy

Although often overlooked, bladder cancer is the fourth most frequent cancer in Italy after age 50, with approximately 31,000 new cases diagnosed each year. In 75% of patients, the disease is identified at an early stage and confined to the superficial layers of the bladder wall, where surgical intervention is possible with good chances of recovery; five years after diagnosis, eight out of ten patients are still alive on average. However, a significant proportion of people are diagnosed with the neoplasm at a locally advanced stage, where the risk of metastatic evolution of the disease is very high.

It is for these patients that the Italian Medicines Agency (AIFA) has recently approved a new combination of medicines, enfortumab vedotin in association with pembrolizumab, for the first-line treatment of unresectable or metastatic urothelial carcinoma.

Symptoms Not to Be Ignored

Urothelial carcinoma, more commonly known as bladder cancer, is a malignant neoplasm originating in the urothelium, the mucosa lining the inside of the bladder. In about half of the cases, it is linked to tobacco use; cases are increasing, especially among women, who are increasingly smokers. “The main warning sign is the presence of blood in the urine, or hematuria – explains Patrizia Giannatempo, of Genitourinary Oncology, Fondazione IRCCS Istituto Nazionale Tumori in Milan –: it should be reported as soon as possible to your doctor and urologist for more specific examinations with a diagnostic purpose (although it can be an expression of various pathologies, even benign ones).” Time is precious: early diagnosis not only means that the chances of healing are greater, because the disease is still localized and has not metastasized, but also that it can be treated with less invasive therapies, with fewer side effects and a better quality of life. “Women are more likely to neglect hematuria, discovering the neoplasm at a more advanced stage, because blood loss is often attributed to urinary tract infections or interpreted as post-menopausal disorders,” continues the oncologist. “Persistent pain and burning should also not be neglected: it is better to talk to a doctor who can prescribe, if necessary, simple investigations such as a urine test or ultrasound.” If a neoplasm is suspected, the next step is cystoscopy, necessary to reach a certain diagnosis.

Therapies for Early Stages

The choice of the most appropriate treatment depends, first of all, on the histological type of the tumor, the stage and the spread of the disease. “The treatments currently available are surgery, chemotherapy, immunotherapy and radiotherapy – clarifies Roberto Iacovelli, Associate Professor of Medical Oncology at the Catholic University of Sacred Heart – Policlinico Universitario Gemelli IRCCS in Rome –. In cases where the neoplasm is localized inside the bladder and has not invaded the muscular layer, the tumor is removed during cystoscopy according to a procedure called TURB, followed by washes based on chemotherapeutic drugs or with BCG (Bacillus Calmette-Guerin) which aim to prevent or delay a possible recurrence.”

In cases where the tumor has invaded the muscular layer of the bladder, the situation is more complex. “The first step is a so-called neoadjuvant treatment (i.e., pre-operative), based on chemotherapy and immunotherapy, carried out to reduce the tumor and eliminate any tumor cells that may have already spread into the bloodstream – continues the expert –. This is followed by the actual surgical act, which unfortunately is demolitive and involves the removal of the organ (cystectomy), which may be followed by reconstruction. We also have a third situation in which patients with muscle-invasive disease and certain clinical characteristics may be eligible for so-called “trimodal” treatment, which includes TURB, chemotherapy and radiotherapy with the aim of preserving the bladder.”

When the Tumor is Advanced or Metastatic: The Standard Changes

In cases of bladder cancer in an advanced, unresectable or metastatic stage, the aim of treatment is to counteract the progression of the disease and allow for the longest possible survival. “And it is for this condition that we now also have in Italy the association between enfortumab vedotin (an antibody-drug conjugate) and pembrolizumab (an immune checkpoint inhibitor) in first line – says Iacovelli –. A therapeutic option that represents a great novelty because it has the possibility of changing the clinical history of these patients, a real revolution compared to the standard treatment based on platinum-containing chemotherapy followed by maintenance immunotherapy or second-line therapy and able to provide a response to the current need, considering that today few patients receive subsequent therapy lines to the first.”

The approval of reimbursement by AIFA came in light of the results of the Phase 3 EV-302 clinical trial (also known as KEYNOTE-A39), which evaluated the efficacy and safety of enfortumab vedotin in association with pembrolizumab in patients with locally advanced or metastatic urothelial carcinoma previously untreated: “It is the first regimen to be approved in Italy in the treatment of advanced urothelial carcinoma that has demonstrated superiority over platinum-containing chemotherapy (the current standard of care used for almost 40 years) – Giannatempo emphasizes. The results of the EV-302 study show that the association of the two drugs nearly doubled both median overall survival and progression-free survival and significantly increased the objective response rate (i.e., the number of patients who benefit from the treatment) compared to standard chemotherapy.”

The Cure Works for Long Periods (Even Two Years)

Enfortumab vedotin is an antibody-drug conjugate that delivers a chemotherapeutic agent inside tumor cells, starting from the binding between the antibody-drug conjugate and Nectin-4, a ubiquitous adhesion protein particularly expressed on the cells of many tumors, including urothelial cancer. Pembrolizumab, “awakens” the ability of the immune system to recognize the tumor cell. “Together, these drugs act on two different fronts and synergistically with the aim of destroying tumor cells – says Iacovelli. Having the availability of this therapeutic combination in an early stage of treatment means allowing these patients a longer survival than was possible until now with chemotherapy alone. The evidence obtained tells us that in about 30% of patients a complete disappearance of the disease can be obtained, albeit temporarily.”

“More recent data presented last summer show that over 74% of patients who had a benefit with complete response continue to be in response even 24 months later – Giannatempo concludes –. And the evidence demonstrates that, in those who initially have a complete response to the treatment, progression tends to occur after long intervals.”