Atezolizumab, pembrolizumab, nivolumab in urothelial carcinoma: Studies of direct comparison are useful

Four dossier assessments involving comparisons between immunotherapies and chemotherapies for the same therapeutic indication in 2017 / comparison of the immunotherapies among each other missing

After nivolumab and pembrolizumab, the German Institute for Quality and Efficiency in Health Care (IQWiG) assessed atezolizumab, and thus a third monoclonal antibody for the treatment of urothelial carcinomas in late 2017. In two early benefit assessments of this drug, the Institute achieved inconsistent results. Due to a lack of suitable data, an added benefit of atezolizumab versus the comparator therapy is not proven for first-line treatment of adult patients with locally advanced or metastatic urothelial carcinoma for whom cisplatin-based chemotherapy is not an option. However, as second-line treatment, i.e. after pretreatment with platinum-based chemotherapy, there is a hint of a considerable added benefit. The two other dossier assessments also produced mixed results.

Mixed results

At present, none of the three drugs can be considered as first-line treatment instead of a chemotherapy: An added benefit is not proven for pembrolizumab versus the comparator therapy, and nivolumab is not approved for application as first-line treatment. This looks better for the use as second-line treatment, i.e. following chemotherapeutic pretreatment: There is a hint of a considerable added benefit of atezolizumab and an indication of a considerable added benefit of pembrolizumab. However, an added benefit of nivolumab as second-line treatment is not proven since suitable study data are lacking.

Inconsistent data situation

The broad range of the results can largely be ascribed to the inconsistent data situation. For three of the total of five research questions, the drug manufacturers did not cite studies in which their drugs were directly contrasted with a comparator therapy. Instead, they submitted data from individual study arms some of which were incomplete. However, for two research questions there is one randomized controlled trial each demonstrating that the advantages of the new drugs outweigh their disadvantages compared with chemotherapies. The studies or study arms cited in the dossiers also differ considerably with regard to the patient numbers and further details.

Head-to-head studies would be desirable

“The procedure of the early benefit assessment does unfortunately not allow a comparison of new drugs against each other”, says Jürgen Windeler, Director of IQWiG. “Such measure appears to be almost indispensable in the case of urothelial carcinoma: We now have three drugs for the same therapeutic indication, but are unable to reasonably relate the assessment results to each other. For instance, physicians should not be forced to compare several assessments on their own to decide on the immunotherapy best suited for their patients“.

Since such constellations become more frequent with every passing year following the introduction of the early benefit assessment, the procedure should now be modified to enable the Federal Joint Committee (G-BA) and therewith also IQWiG to explicitly refer to benefit assessments already conducted before. “Such studies should be funded by public means if manufacturers still refrain from implementing the direct comparisons required to ensure good health care”, demands Jürgen Windeler.

Editorial note from 15 January 2018:

In the above text, “‘It is indeed curious that we were able to assess two second-line treatments as positive, but useful first-line data are lacking for both of the drugs’, says Jürgen Windeler, Director of IQWiG. ‘Moreover, the procedure of the early benefit assessment does unfortunately not allow a comparison of new drugs against each other’, he adds” has been modified to “ ‘The procedure of the early benefit assessment does unfortunately not allow a comparison of new drugs against each other’, says Jürgen Windeler, Director of IQWiG.”

G-BA decides on the extent of added benefit

The dossier assessments are 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 their publication, the G-BA conducts a commenting procedure and makes a final decision on the extent of the added benefit.

More English-language information will be available soon (extracts of the dossier assessments as well as easily understandable information on If you would like to be informed when these documents are available, please send an e-mail to

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