Pertuzumab: hint of major added benefit

Pertuzumab (trade name: Perjeta) has been approved in Germany since March 2013 as add-on therapy for certain patients with advanced HER2-positive breast cancer. In an early benefit assessment pursuant to the Act on the Reform of the Market for Medicinal Products (AMNOG), the German Institute for Quality and Efficiency in Health Care (IQWiG) examined whether this new drug offers an added benefit over the current standard therapy.

According to this, patients with visceral metastases have a survival advantage. Because of the uncertain data it is not possible to draw conclusions on potential harm in the form of side effects, however. IQWiG therefore does not consider there to be an indication, but only a hint of a major added benefit. In contrast, no added benefit can be derived from the dossier for patients with non-visceral metastases and for patients with locally recurrent breast cancer.

The G-BA distinguished between two therapeutic indications

Pertuzumab is an option as add-on therapy for patients with metastatic or locally recurrent unresectable HER2-positive breast cancer. In addition, the patients should not have received previous chemotherapy or anti-HER2 therapy for this disease.

The Federal Joint Committee (G-BA) distinguished between two patient groups and specified different appropriate comparator therapies for them: If HER2-positive breast cancer recurs in the breast area (local recurrence) and cannot be operated on, pertuzumab is to be compared with radiotherapy. If, in contrast, the breast cancer has formed metastases, pertuzumab is to be compared with a treatment with trastuzumab and a taxane (docetaxel, paclitaxel). Pertuzumab is to be administered in combination with the drugs trastuzumab and docetaxel.

No data on locally recurrent breast cancer

The results of a randomized controlled trial, the approval study (CLEOPATRA), were available for the assessment. Patients with locally recurrent breast cancer were also enrolled in this study, but the comparator therapy in the control arm of the study deviated from the G-BA's specification: instead of radiotherapy, the participants received drug therapy consisting of trastuzumab and docetaxel. Hence, due to a lack of data, an added benefit of pertuzumab is not proven for this subpopulation.

Survival advantage in patients with metastases in internal organs

The study showed an advantage regarding overall survival in patients with metastatic breast cancer. But this advantage depended on the location of the metastases: If they were visceral metastases, i.e. metastases in internal organs such as the lungs or the liver, considerably more women had died in the comparator group (44%) than in the pertuzumab group (30%) after 51 months of study duration. Here IQWiG derives an indication of a major added benefit. However, in non-visceral metastases, which had formed in other organs such as bones or lymph nodes, there was no difference between the treatment groups.

No data on morbidity and quality of life

The pharmaceutical company did not provide any or any evaluable data on the outcomes "health-related quality of life" and "morbidity", i.e. symptoms, complaints and complications, in its dossier.

Results on side effects were not informative

No conclusions can be drawn regarding the potential harm from pertuzumab. This is mainly due to the fact that the treatment and observation duration of the patients differed between the two treatment arms. The longer a treatment lasts, the more likely it becomes that side effects occur. However, the drug manufacturer did not consider this difference adequately in the analysis of the data. It also failed to examine whether the location of the metastases also influences the result on side effects.

Greater harm from pertuzumab can therefore not be excluded, and it is not possible to draw a conclusion on harm from pertuzumab due to the overall uncertain data.

"Hint" instead of "indication"

As the extent of the advantage regarding survival considerably exceeded the limit between "considerable" and "major", IQWiG does not assume that the potentially greater harm raises doubts about the added benefit as a whole. At the same time, it sees an increased uncertainty because the data on harm in the dossier were not analysed adequately. Overall, it downgraded the added benefit regarding its probability from an "indication" to a "hint" of a major added benefit.

For all remaining patient groups, i.e. patients with non-visceral metastases and locally recurrent breast cancer, an added benefit is not proven.

G-BA decides on the extent of added benefit

The dossier assessment is part of the overall procedure for early benefit assessments supervised by the G-BA. After publication of the manufacturer’s dossier and IQWiG’s assessment, the G-BA conducts a commenting procedure, which may provide further information and result in a change to the benefit assessment. The G-BA then decides on the extent of the added benefit, thus completing the early benefit assessment.

An overview of the results of IQWiG's benefit assessment is given by a German-language executive summary. In addition, the website www.gesundheitsinformation.de, published by IQWiG, provides easily understandable and brief German-language information on pertuzumab.

The G-BA website contains both general English-language information on benefit assessment pursuant to §35a Social Code Book V and specific German-language information on the assessment of pertuzumab. More English-language information will be available soon (Sections 2.1 to 2.6 of the dossier assessment as well as subsequently published health information on www.informedhealthonline.org). If you would like to be informed when these documents are available, please send an e-mail to info@iqwig.de.