Trifluridine / tipiracil (Lonsurf) for the treatment of metastatic colorectal cancer

The drug is available in tablet form in two different doses: 15 mg of trifluridine / 6 mg of tipiracil, and 20 mg of trifluridine / 8 mg of tipiracil. The dose is determined by the doctor, based on the patient's body surface area. A typical dose would be 35 mg of trifluridine per square meter of body surface area.

The drug is used in treatment cycles of 28 days each: During the first five days, it is taken twice per day. This is followed by a two-day break from use of the drug, which is then taken twice a day again for five days. After a total of 28 days the next treatment cycle begins.

Treatment is stopped if the cancer progresses or if serious side effects arise.

Best supportive care (BSC) is the standard treatment for metastatic colorectal cancer in patients for whom previous chemotherapy treatments (using the drugs fluoropyrimidine, oxaliplatin or irinotecan, as well as VEGF- or EGFR-targeted treatments) were not effective or not possible. BSC should be tailored to the patient's individual needs, relieve symptoms such as pain, and improve quality of life.

In 2020, the Institute for Quality and Efficiency in Health Care (IQWiG, Germany) last looked into the advantages and disadvantages of trifluridine / tipiracil in adults with metastatic colorectal cancer compared with the standard treatment BSC.

The manufacturer provided two suitable studies. One of the studies involved 800 people. 534 of them had treatment with trifluridine / tipiracil and BSC, while the other 266 were given BSC and a placebo. The other study provided usable data from a total of 94 people. 61 of these participants had treatment with trifluridine / tipiracil and BSC, while the other 33 were given BSC and a placebo. All of the participants had received at least two previous treatments.

The two studies only included patients for whom physical activity was either slightly affected or not at all affected by their illness. The manufacturer did not provide any studies on people who were no longer able to work or who required nursing care due to the cancer.

What are the advantages of the fixed-dose combination trifluridine / tipiracil?

Life expectancy: Initial results based on the larger of the two studies suggest that treatment with trifluridine / tipiracil has advantages for people who had had at least three previous treatments: About 95 out of 100 patients in the placebo group died, compared to 85 out of 100 in the trifluridine / tipiracil group. There was no difference here between people had had two previous treatments.

Mental health problems: Initial results based on the larger of the two studies suggest that adding treatment with trifluridine / tipiracil has an advantage regarding this side effect: About 16 out of 100 people who did not use trifluridine / tipiracil had anxiety or sleeping problems, for instance, compared to only 8 out of 100 who used trifluridine / tipiracil.

Severe high blood pressure: Initial results based on the larger of the two studies suggest that adding treatment with trifluridine / tipiracil has an advantage for this side effect: About 4 out of 100 people who did not use trifluridine / tipiracil had severe high blood pressure, compared to only about 1 out of 100 who used trifluridine / tipiracil.

Treatment stopped due to side effects: Initial results suggest that treatment with trifluridine / tipiracil has an advantage in people aged 65 and over: About 19 out of 100 people who did not use trifluridine / tipiracil stopped their treatment early, compared to only 7 out of 100 who used trifluridine / tipiracil. There was no difference here in people under the age of 65.

What are the disadvantages of trifluridine / tipiracil?

Severe side effects overall: Initial results suggest that adding treatment with trifluridine / tipiracil has a disadvantage here: About 53 out of 100 people who did not use trifluridine / tipiracil had severe side effects, compared to about 65 out of 100 who used trifluridine / tipiracil.

These severe side effects included severe damage to the bone marrow called myelosuppression or bone marrow suppression: The studies suggest that adding trifluridine / tipiracil to the treatment has a disadvantage here: About 10 out of 100 people who did not use trifluridine / tipiracil developed severe myelosuppression, compared to about 43 out of 100 who used trifluridine / tipiracil. Myelosuppression affects the production of blood cells in the bone marrow.

Common signs of severe myelosuppression include severe anemia and a major reduction of various immune system cells in the body:

• Anemia: Initial results suggest that treatment with trifluridine / tipiracil has a disadvantage here: About 2 out of 100 people aged 65 and over who did not use trifluridine / tipiracil developed anemia, compared to about 20 out of 100 who used trifluridine / tipiracil. There was no difference here in people under the age of 65.
• Leukopenia: Initial results suggest that treatment with trifluridine / tipiracil has a disadvantage here: In the larger of the two studies, about 3 out of 100 people who used trifluridine / tipiracil developed leukopenia, compared to zero people who did not use trifluridine / tipiracil. In leukopenia, the body does not have enough immune system cells in the bloodstream.
• Neutropenia: The studies suggest that treatment with trifluridine / tipiracil has a disadvantage here: In the studies, roughly 20 out of 100 people who used trifluridine / tipiracil developed neutropenia, compared to zero people who did not use trifluridine / tipiracil. In neutropenia, the body does not have enough neutrophils (a certain type of immune system cell).
• Febrile neutropenia: In febrile neutropenia, fever also occurs. Initial results suggest that there is also a disadvantage in terms of febrile neutropenia: In the larger study, about 4 out of 100 people who used trifluridine / tipiracil developed febrile neutropenia, compared to zero people who did not use trifluridine / tipiracil..

Side effects: The studies suggested that treatment with trifluridine / tipiracil also had a disadvantage regarding other side effects, such as gastrointestinal (stomach and bowel) problems: About 61 out of 100 people who did not use trifluridine / tipiracil had gastrointestinal problems, compared to about 77 out of 100 who used trifluridine / tipiracil.

These gastrointestinal problems include:

• Diarrhea: Initial results suggest that treatment with trifluridine / tipiracil has a disadvantage here: About 11 out of 100 people who did not use trifluridine / tipiracil had diarrhea, compared to about 25 out of 100 who used trifluridine / tipiracil.
• Nausea: Initial results suggest that treatment with trifluridine / tipiracil has a disadvantage here: About 20 out of 100 people who did not use trifluridine / tipiracil experienced nausea, compared to nearly twice as many (41 out of 100) who used trifluridine / tipiracil.
• Vomiting: Initial results suggest that treatment with trifluridine / tipiracil has a disadvantage regarding vomiting as well: About 16 out of 100 people who did not use trifluridine / tipiracil experienced vomiting, compared to about 27 out of 100 who used trifluridine / tipiracil..

What remains unanswered?

The manufacturer did not provide any suitable data on the following:

• Symptoms of the disease
• Health-related quality of life

This information summarizes the main results of several 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 the reviews and the hearings received, the G-BA passed a resolution on the added benefit of the fixed-dose combination trifluridine / tipiracil (Lonsurf).