In the recent early benefit assessment of nivolumab, the G-BA not only accepted the submitted ITC, but this also resulted in a better additional benefit rating.
Acceptance of ITCs in Germany
It is very rare that the G-BA includes ITCs in their assessment. Generally, the G-BA considers ITCs as being more uncertain. The IQWiG methods set out strict rules for including ITCs in early benefit assessments. For example, the studies included in the ITC must be similar in relevant aspects, such as patient population, endpoints, and study design. These criteria are often not met, and the G-BA consequently rejects these ITCs.
Nivolumab early benefit assessments
Nivolumab is indicated as a supportive treatment after surgery (adjuvant treatment) for melanoma with lymph node involvement or metastases.
First assessment
The first assessment of nivolumab in this indication was completed in February 2019. The available evidence was not robust enough and the G-BA saw “a non-quantifiable additional benefit”. Thus, the resolution was restricted until 1 April 2021. This time restriction meant the G-BA would re-assess nivolumab after the expiry date and gives the manufacturer an opportunity to submit more meaningful studies.
Second assessment
The re-assessment of nivolumab started in April 2021 and was completed now. The ACT was:
- pembrolizumab (only for patients with tumor stage III after complete resection) or
- dabrafenib in combination with trametinib (only for patients with BRAF V600 mutation-positive melanoma with tumor stage III after complete resection) or
- “watchful waiting”.
Direct comparative studies of nivolumab against any of the ACT options are not available. Therefore, the manufacturer submitted an ITC, using the Bucher methodology. In the ITC, nivolumab was compared with placebo, which was considered to reflect watchful waiting, using ipilimumab as a bridge comparator.
The data for OS, patient-reported morbidity endpoints, or HRQL could not be evaluated. However, there were clear benefits for nivolumab in terms of recurrence rate and recurrence-free survival. These advantages were based on solid data from studies with a long observation period. On the other hand, there were more treatment discontinuations due to AEs with nivolumab. Despite the worse side effect profile, the G-BA decided to not reduce the overall additional benefit rating given the curative intent of the treatment and the importance of reducing recurrence rates.
Due to the nature of ITCs, there are per se relevant uncertainties. Therefore, the G-BA assigned only the certainty level “hint”.
Overall, the G-BA assigned a hint of considerable additional benefit.
The full G-BA re-assessment of nivolumab can be found here (in German only). The English translation is expected in September 2021.