Added benefit of crizotinib is not proven

The drug crizotinib (trade name: Xalkori) has been available in Germany since October 2012 for patients with non-small-cell lung cancer (bronchial carcinoma) who have a high activity of anaplastic lymphoma kinase (ALK) and have already received another treatment. 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) has now examined the added benefit of this drug.

For patients who can continue to be treated with chemotherapy, one study provides hints of an added benefit regarding quality of life, but also of greater harm in the form of sometimes serious side effects. The manufacturer's dossier does not contain data on patients who are no longer eligible for chemotherapy due to their poor general condition. Overall, the added benefit is regarded as not proven.

Drug aims to inhibit the enzyme and thus tumour growth

Some patients with non-small-cell bronchial carcinoma have an abnormal enzyme in the tumour tissue, called anaplastic lymphoma kinase (ALK): they are ALK-positive. ALK can contribute to uncontrolled tumour growth. Crizotinib is supposed to inhibit this enzyme, among other things, and thus stop further tumour growth.

Comparison with chemotherapy and best supportive care

The Federal Joint Committee (G-BA) distinguishes between two situations in its specifications for the appropriate comparator therapy: For patients who are eligible for (further) chemotherapy (the "chemotherapy population”) crizotinib is to be compared with a chemotherapy (cytostatics: docetaxel or pemetrexed).

For patients who are no longer eligible for chemotherapy due to their poorer general condition, a therapy known as "best supportive care” (BSC) is considered to be the appropriate comparator therapy. This means the best possible supportive therapy, optimized for the individual patient, for alleviation of symptoms and improvement in the quality of life.

Study results with great uncertainty

Regarding the chemotherapy population, IQWiG could draw on the partial results of an approval study (PROFILE 1007) submitted in the dossier. These are subject to great uncertainty, however: On the one hand, almost two thirds (62%) of the study participants changed from the control group to the crizotinib group (cross-over). On the other, neither patients nor treating staff were blinded. Finally, the manufacturer only presented the data of a few selected outcomes.

Possible advantages regarding quality of life

In the approval study, health-related quality of life was assessed using a disease-specific instrument (EORTC QLQ-C30). According to this, the results were better in the crizotinib group in 5 out of 6 subscales. But the differences between the groups were so small in 3 of the subscales that they are not regarded as relevant. In view of the uncertainty of results described, IQWiG derives a hint of an added benefit here. Its extent is rated as minor. Regarding the outcome "overall survival”, the data do not show any statistically significant differences between the crizotinib and the chemotherapy group.

Higher risk of side effects with crizotinib

The total number of side effects in the crizotinib group was the same as in the chemotherapy group, and there were no differences in the discontinuations of treatment due to side effects, either. However, certain non-serious side effects such as impaired vision and gastrointestinal problems were more common with crizotinib. The risk of serious side effects was also higher with crizotinib than with chemotherapy.

IQWiG therefore derives a hint of greater harm. Its extent is considerable for non-serious side effects, and cannot be quantified for serious side effects.

Balancing positive and negative effects

On the basis of the information currently available, it cannot be conclusively assessed whether the positive effects (better quality of life) outweigh the negative ones (more frequent side effects. At any rate, an added benefit of crizotinib compared with chemotherapy is not proven.

The same applies to the second therapy situation, the comparison with BSC, as the manufacturer did not submit any study regarding the BSC population.

G-BA decides on the extent of added benefit

The dossier assessment is part of the overall procedure for early benefit assessments supervised by theG-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 crizotinib.

The G-BA website contains both general English-language information on benefit assessments pursuant to §35a Social Code Book V and specific German-language information on the assessment of crizotinib.

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 this information is available, please send an e-mail to info@iqwig.de.