Introduction

Brigatinib (trade name: Alunbrig) has been approved in Germany since November 2018 for the treatment of advanced non-small-cell lung cancer in adults. It can be used in patients who have certain mutated cancer cells that can lead to faster tumor growth. These patients should also have already had treatment with crizotinib.

Lung cancer is caused by the malignant growth of cells in the airways (bronchi). It is also referred to as a bronchogenic carcinoma. There are two main types of lung cancer:

  • Small-cell lung carcinoma (SCLC)
  • Non-small-cell lung cancer (NSCLC)

NSCLC is surgically removed. But sometimes the tumor has already become too large or the cancer has spread to other parts of the body (metastasis) through the blood or lymphatic system. It is then called advanced lung cancer.

Some people with non-small-cell lung cancer have an abnormal enzyme in the tumor tissue called anaplastic lymphoma kinase (ALK). The full name of the cancer is then ALK-positive non-small-cell lung cancer. The enzyme ALK can lead to uncontrolled growth of the tumor tissue.

Brigatinib is used to try to block the ALK enzyme, thereby inhibiting further tumor growth.

Application

Brigatinib is available in the form of tablets, in the doses 30 mg, 90 mg and 180 mg.

For the first seven days, the dose is 90 mg brigatinib. After that, it is increased to 180 mg brigatinib.

Other treatments

In patients with ALK-positive NSCLC who have not yet had treatment with an ALK inhibitor, other treatment options are alectinib or crizotinib.

In people with ALK-positive NSCLC who have already had treatment with crizotinib, treatment with ceritinib is an option.

Assessment

In 2019, the Institute for Quality and Efficiency in Health Care (IQWiG, Germany) looked into the advantages and disadvantages of brigatinib compared with the standard treatment (ceritinib) in people with ALK-positive non-small-cell lung cancer who have already had treatment with crizotinib. But the manufacturer didn’t provide any suitable data with which to do the assessment.

In 2020, IQWiG looked into the advantages and disadvantages of brigatinib compared to alectinib or crizotinib in people with ALK-positive non-small-cell lung cancer who have not yet had treatment with an ALK inhibitor.

For this purpose, the manufacturer provided an early analysis of an ongoing study with 275 participants: 138 people had treatment with brigatinib, and 138 had treatment with crizotinib.

What are the advantages of brigatinib?

Life expectancy: Here the study suggests that brigatinib has an advantage in people whose cancer has already spread to their brain (brain metastases): About 45 out of 100 people who had treatment with crizotinib died within an average (median) observation period of about 27 months, compared to about 24 out of 100 people who had treatment with brigatinib within the same period of time. There was no difference between the patients who did not have brain metastases.

Pain: The early results suggest that there is an advantage in women here: Pain worsened in about 66 out of 100 women who had treatment with crizotinib, and in about 51 out of 100 women who used brigatinib. There was no difference here for men.

Nausea and vomiting: The early results suggest that brigatinib has an advantage here: These problems got worse in about 70 out of 100 people who had treatment with crizotinib, compared with about 51 out of 100 people who received brigatinib.

Constipation: The early results suggest that brigatinib has an advantage here: Constipation got worse in about 64 out of 100 people who had treatment with crizotinib, compared with about 50 out of 100 people who used brigatinib.

Health-related quality of life: The early results suggest that brigatinib has an advantage over crizotinib regarding various aspects of quality of life:

  • Overall assessment of health and quality of life (global health): The patient's own assessment of their overall health got worse in about 53 out of 100 people who had treatment with crizotinib, compared with about 44 out of 100 people who received brigatinib.
  • Feeling irritable, down, worried or tense (emotional functioning): These kinds of feelings got worse in about 52 out of 100 people who had treatment with crizotinib, compared with about 37 out of 100 people who received brigatinib.
  • Limitations affecting everyday life, free time and work (role functioning): These kinds of limitations got worse in about 65 out of 100 women who had treatment with crizotinib, compared with about 49 out of 100 women who received brigatinib. There was no difference here in men.
  • Limitations affecting family life, outings with friends and other social activities (social functioning): Here too, there was a difference in women: These kinds of limitations got worse in about 63 out of 100 women who had treatment with crizotinib, compared with about 35 out of 100 women who received brigatinib. There was no difference here in men.

Side effects: The early results suggest that brigatinib has an advantage compared with crizotinib regarding various side effects:

  • Eye diseases: About 55 out of 100 people who had treatment with crizotinib developed an eye disease, compared with about 16 out of 100 people who used brigatinib.
  • Peripheral edema: About 45 out of 100 people who had treatment with crizotinib developed water retention in their arms or legs, compared with about 7 out of 100 people who received brigatinib.
  • Gastrointestinal diseases: About 88 out of 100 people who had treatment with crizotinib developed a gastrointestinal disease, compared with about 77 out of 100 people who used brigatinib.

What are the disadvantages of brigatinib?

There were disadvantages in terms of individual severe side effects:

  • Very high enzyme levels: The early results suggest that brigatinib has a disadvantage here compared with crizotinib: About 2 out of 100 people who had treatment with crizotinib had high levels of creatine kinase, compared to about 24 out of 100 people who received brigatinib.
  • Severe high blood pressure: The early results suggest that brigatinib has a disadvantage here, too: About 3 out of 100 people who had treatment with crizotinib had very high blood pressure, compared to about 12 out of 100 people who received brigatinib.

The early results suggest that brigatinib has a disadvantage in terms of mild skin diseases:

  • About 16 out of 100 people aged 65 years and over who had treatment with crizotinib developed a skin disease, compared to about 54 out of 100 people who received brigatinib. There was no difference in people aged 65 years and under.

No difference

Symptoms of the disease: There was no (relevant) difference in terms of diarrhea, sleep problems, shortness of breath, fatigue and loss of appetite.

Health-related quality of life: No difference was found regarding various aspects of quality of life:

  • Managing activities of daily living such as shopping or washing (physical functioning)
  • Concentration and memory (cognitive functioning)

Severe side effects: There was no overall difference in terms of severe side effects.

Treatment stopped due to side effects: There was no difference here either.

More information

This information summarizes the main results of reviews produced by the Institute for Quality and Efficiency in Health Care (IQWiG, Germany). The reviews were commissioned by the German Federal Joint Committee (G-BA) as part of the “early benefit assessment of medications.” On the basis of these reviews and the hearings received, the G-BA passed a resolution on the added benefit of brigatinib (Alunbrig) with and without previous treatment with an ALK inhibitor.