Urothelium is the term for the mucous membrane that lines the urinary tract. This includes the renal pelvis, ureter, urinary bladder and the upper part of the urethra. In the vast majority of cases, urothelial carcinomas grow in the bladder (bladder carcinoma).
Since April 2022, enfortumab vedotin has been approved for the treatment of pretreated 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 Health Care (IQWiG) has now examined in a benefit assessment whether the drug combination offers an added benefit for these patients in comparison with the present standard treatment.
According to this assessment, the combination of enfortumab vedotin and pembrolizumab promises benefits in terms of overall survival, particularly for those patients with urothelial carcinoma for whom treatment with the platinum component cisplatin is unsuitable. IQWiG sees a hint of major added benefit for this patient group. This is the first time that the Institute has awarded the label for the highest extent, i.e. "major", in this therapeutic indication.
There is also an added benefit for patients who are 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 who are eligible for platinum-containing chemotherapy. They were randomly assigned in a 1:1 ratio to treatment with enfortumab vedotin plus pembrolizumab or cisplatin plus gemcitabine (if cisplatin-based therapy was possible) or carboplatin plus gemcitabine (if cisplatin-based therapy was not possible).
According to the study design, no regular maintenance treatment with avelumab was planned in the comparator arm for patients who were progression-free following chemotherapy. However, maintenance therapy with avelumab is part of the standard treatment.
But the situation is not trivial: The study used for the assessment started 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 start of the study - in June 2020 for the USA and in January 2021 for Europe. The manufacturer reacted to this development and adapted its study design to the effect that, although it did not add avelumab as part of the study medication, it explicitly described the possibility of maintenance therapy with local availability in the comparator arm. For the assessment, the manufacturer additionally conducted so-called sensitivity analyses for the outcome of overall survival, which adequately address the lack of use of avelumab in some of the patients in the comparator arm. This enables the interpretation of the study results for the early benefit assessment of enfortumab vedotin plus pembrolizumab.
Clear survival advantage
The advantage of treatment with enfortumab vedotin in combination with pembrolizumab becomes particularly clear in terms of overall survival: For patients with urothelial carcinoma for whom cisplatin-based therapy is not suitable, there is a clear advantage, also in all sensitivity analyses presented by the manufacturer. This means that this great advantage would also exist if avelumab had already 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, but also disadvantages, for specific side effects.
"For the first time, we have awarded a major added benefit to a drug combination in this therapeutic indication," explains Katrin Nink, Head of the Oncology Division (solid tumours) in IQWiG's Drug Assessment Department. The main decisive factor is the survival advantage for bladder cancer patients for whom cisplatin-based therapy is not an option."
The G-BA decides on the extent of added benefit
The dossier assessment is part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the G-BA. After publication of the dossier assessment, the G-BA conducts a commenting procedure and makes a final decision on the extent of the added benefit.
