Enfortumab vedotin and pembrolizumab show important benefits for urothelial carcinoma patients

Enfortumab vedotin and pembrolizumab show important benefits for urothelial carcinoma patients

Urothelium is the term for the mucosal membrane that lines the urinary tract. This includes the renal pelvis, ureter, urinary bladder and the upper part of the urethra. In most cases, urothelial carcinomas grow in the bladder (bladder carcinoma).

As of April 2022, enfortumab vedotin has been approved for the treatment of previously treated adults with locally advanced or metastatic urothelial carcinoma. Since September 2024, enfortumab vedotin in combination with pembrolizumab has also been approved for the first-line treatment of unresectable or metastatic urothelial carcinoma. The German Institute for Quality and Efficiency in Healthcare (IQWIG) has now conducted a performance assessment to examine whether the drug combination offers additional benefit for these patients compared to the current standard treatment.

According to this assessment, the combination of enfortumab vedotin and pembrolizumab promises benefits in terms of overall survival, particularly for patients with urothelial carcinoma for whom treatment with the platinum component cisplatin is not suitable. IQWIG sees an indication of additional benefit for this patient group. This is the first time that the Institute has awarded the highest degree, ie “Major”, label in this therapeutic indication.

There is also an additional benefit for patients eligible for cisplatin-based therapy. However, this is not quantifiable.

Study results can be interpreted despite uncertainty

The manufacturer submitted data from an ongoing study including patients with unresectable or metastatic urothelial carcinoma eligible for platinum-based chemotherapy. They were randomly assigned in a 1:1 ratio to treatment with enfortumab vedotin plus pembrolizumab or cisplatin plus gemcitabine (when cisplatin-based therapy was possible) or carboplatin plus gemcitabine (when cisplatin-based therapy was not possible).

According to the study design, regular maintenance treatment with avelumab was not planned in the comparator arm for patients who were progression-free after chemotherapy. However, maintenance therapy with avelumab is part of standard treatment.

However, the situation is not trivial: the study used for the assessment began in March 2020 at a time when avelumab had not yet been approved for maintenance therapy in this therapeutic indication. Approval was only granted shortly after the study began - in June 2020 for the USA and January 2021 for Europe. The manufacturer responded to this development and adapted its study design so that it did not add avelumab as part of the study medication, but explicitly included the option of maintenance therapy with local availability in the comparison arm. For the evaluation, the manufacturer additionally conducted so-called sensitivity analyzes for the overall survival outcome, which adequately addressed the lack of use of avelumab in some of the patients in the comparison arm. This allows interpretation of study results for early evaluation of enfortumab vedotin plus pembrolizumab.

Clear survival advantage

The advantage of treatment with enfortumab vedotin in combination with pembrolizumab is particularly clear with regard to overall survival: in patients with urothelial carcinoma for whom cisplatin-based therapy is not suitable, there is a clear advantage, including in all sensitivity analyzes presented by the manufacturer. This means that this major benefit would have existed even if avelumab had been available at the start of the study. In addition, there are advantages for individual outcomes of morbidity and health-related quality of life, as well as advantages and disadvantages, but also disadvantaged side effects.

For the first time, we have conferred significant benefit on a drug combination in this therapeutic indication. The main factor is the survival benefit for bladder cancer patients for whom cisplatin-based therapy is not an option. “

Katrin Nink, head of the oncology department (solid tumors) in the drug evaluation department of IQWIG

The G-BA decides on the extent of the additional benefit

The dossier assessment is part of the early performance assessment in accordance with the Act on the Reform of the Market for Medical Products (AMNOG), which was supervised by the G-BA. After publication of the dossier assessment, the G-BA carries out a comment process and makes a final decision on the extent of the additional benefit.

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