On September 1, 2017, the U.S. Food and Drug Administration (FDA) reapproved an antibody-drug-coupled targeted agent, gituzumab (trade name: Macrota, manufactured by Pfizer Inc. Pfizer Inc.) for an indication. The drug is administered intravenously for the treatment of newly diagnosed CD33-positive adults with acute myeloid leukemia (AML) and patients older than 2 years with relapsed refractory AML.
The route to market for gituzumab has been a “rocky one,” as it received accelerated FDA approval back in May 2000 for monotherapy in older CD33-positive AML patients who relapsed after initial therapy. However, validation clinical trials showed that nitrozumab did not improve survival and was associated with serious side effects and an increased risk of early death. in 2010, Pfizer voluntarily withdrew the drug from the market. This reapproval also means that gituzumab is back on the US market.
It is important to note that the indications for this approval are all different than they were in 2000 – for primary CD33-positive acute myeloid leukemia, this approval is for nitrozumab in combination with induction chemotherapy, or conditional monotherapy, and low-dose therapy.
What is CD33-positive acute myeloid leukemia?
Acute myeloid leukemia is a rapidly progressive cancer in which a large number of abnormal white blood cells appear in the patient’s blood and bone marrow. Acute myeloid leukemia is the most common form of acute leukemia in adults, accounting for about 80% of all acute leukemia cases. Current treatments have shown extremely limited improvement in survival for patients with acute myeloid leukemia, with only 25% of patients with acute myeloid leukemia surviving longer than 5 years.
CD33 is a member of the immunoglobulin superfamily, consisting of 364 amino acid residues. CD33 myeloid differentiation antigen is detected in 90% of physicians’ patients, and more importantly, it is not expressed on the surface of hematopoietic stem cells.
These are the most important factors in the development of tumor therapy.
What is nitrozumab?
Nituzumab is a monoclonal antibody that targets CD33 coupled to the cytotoxic kachimycin. When nituzumab is injected into the body intravenously, it binds to the CD33 antigen. CD33 then absorbs the kachimycin from nitrozumab into the lysosomes in the cells and then releases the kachimycin inside the leukemia cells, causing breaks in single- and double-stranded DNA, blocking the growth of the cancer cells and causing their death.
Evidence of efficacy: 7.8 months longer event-free survival
The approval of nitrozumab as an induction therapy was based primarily on a clinical trial (ALFA-0701). In the trial, patients with newly diagnosed acute myeloid leukemia were randomized to receive either an induction chemotherapy regimen or nituzumab + induction chemotherapy (ruxolithromycin combined with cytarabine). The results found that nitrozumab combined with induction chemotherapy increased the median event-free survival by 7.8 months (17.3 months vs. 9.5 months). Event-free survival time was defined as the time between the start of randomization grouping and the time when the patient could not tolerate induction chemotherapy, or the disease recurred, or died.
The study also found no increase in treatment-related deaths after adding nitrozumab to induction chemotherapy.
The other indication for this prompt approval – monotherapy with nitumumab under certain conditions – was based primarily on the results of two small clinical trials.
In the first trial, 237 patients over the age of 75 (61 to 75 years) who refused intensive induction chemotherapy were randomly assigned to receive either gituzumab or best supportive care (including palliative chemotherapy). The mean overall survival time was longer with gituzumab treatment (4.9 months vs 3.6 months).
In another study, 57 patients who had a first relapse and were first treated with toltuzumab followed by consolidation chemotherapy with cytarabine achieved complete remission in 26% of patients, with a mean relapse-free survival of 11.6 months.
Black box warning: need to be alert for serious and fatal liver injury
Common adverse reactions to nitrozumab mainly include fever, nausea, infection, vomiting, bleeding, thrombocytopenia, mouth ulcers and stomatitis, constipation, rash, headache, and neutropenia.
It is important to note that the instructions for nitrozumab include a black box warning that the drug, either alone or in combination with induction chemotherapy, may cause lethal liver injury, including severe or fatal hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS). VOD or SOS refers to occlusion of small hepatic veins due to endovasculitis and fibrosis. The main manifestations are dilated hepatic blood sinuses, hepatosplenomegaly, ascites, and portal hypertension.
In addition to liver injury, other rare but serious side effects of gituzumab include allergic reaction to the infusion, bleeding, and fetal toxicity.
How do I use nitrozumab?
According to the approved product insert, the recommended use and dosage of nitrozumab is as follows:
- Oral dosing of 650 mg acetaminophen along with 50 mg phenazopyridine and 1 mg/kg of prednisone or equivalent glucocorticoid replacement is required half an hour prior to nitrozumab infusion.
- For the new indication, the recommended use of nitrozumab is 1 induction cycle and 2 consolidation cycles. In the induction cycle, the recommended dose is 3 mg/m (up to a maximum of 4.5 mg in one bottle), and nituzumab should not be used again in the second induction cycle for patients who require a second induction. In the consolidation cycle, only the first day is recommended, and the recommended dose is 3 mg/m (up to a vial of 4.5 mg).
- Women who are pregnant or breastfeeding should not take nitumumumab because it may cause harm to a developing fetus or newborn.
- Liver function should be monitored frequently during treatment.
The tortuous route to market for nitrozumab suggests that not everyone will benefit from treatment with this drug. Current evidence suggests that patients with acute myeloid leukemia at low risk of relapse benefit most from treatment with nituzumab, whereas patients at high risk of relapse have extremely limited benefit. This may be due to the fact that nitrozumab is inherently toxic and requires time to respond to the drug before it can be effective, and patients at high risk of relapse have limited time to respond to the drug, so the efficacy is poor. However, it is not completely clear which patients are most likely to benefit from nitrozumab.
In addition, reapproval has benefited from lower dosing, but nitrozumab still has more serious side effects. Therefore, for patients most at risk for side effects, more attention needs to be paid to adjusting treatment doses, planning treatment appropriately, and avoiding toxicity of therapy.
Nituzumab (Mylota) has not yet been approved in China, and the approved nitrozumab is Tyson, manufactured by Biotec, which is mainly used for the treatment of nasopharyngeal carcinoma.