In HER2-positive breast cancer, overexpression of HER2 is associated with tumorigenesis and invasion. Trastuzumab has long been the “standard” treatment for HER2-positive breast cancer.
On July 17, 2017, the U.S. Food and Drug Administration (FDA) approved a new anti-HER2-targeted drug, lenatinib. When patients with HER2-positive breast cancer have completed 1 year of adjuvant trastuzumab therapy after surgery, lenatinib may be used to further reduce the risk of breast cancer recurrence by continuing extended anti-HER2 adjuvant therapy.
Lenatinib is the first targeted agent approved by the FDA that can be used for intensive anti-HER2 therapy in breast cancer. How much survival benefit can trastuzumab sequential lenatinib extension provide to patients in the early stages? This article will provide an in-depth description.
How does lenatinib work?
In HER2-positive breast cancer, overexpressed HER2 plays a role in signaling and promoting tumor cell proliferation. Trastuzumab has been the “standard” treatment for HER2-positive breast cancer, but about 15% of postoperative breast cancer patients treated with standard adjuvant chemotherapy and trastuzumab still experience recurrence and ultimately death.
Lenatinib also targets the HER2 target, but in a different way than trastuzumab. Trastuzumab interferes with tumor cell growth by “occupying” HER2. Lenatinib is a pan-tyrosine kinase inhibitor (TKI) that blocks the HER2 signaling pathway by inhibiting the active region on HER2, that is, by “disrupting” HER2 to interfere with tumor growth. 
Lenatinib not only targets HER2 with high selectivity, but also inhibits multiple members of the HER family that contribute to tumor growth (including HER1, HER2, and HER4), theoretically making it a stronger inhibitor of tumor growth signaling pathways.
ExteNET study: optional lenatinib to extend adjuvant anti-HER2 therapy
The ExteNET study is a large phase III clinical trial of 2840 patients with breast cancer. These patients enrolled were all HER2-positive and had completed standard trastuzumab therapy. The follow-up regimen was lenatinib or placebo for 1 year.
At 2 years of follow-up, lenatinib-treated patients had slightly higher invasive disease-free survival than the placebo group (93.9% and 91.6%, respectively), but diarrhea was more common, with a 40% incidence of grade 3 diarrhea.
In the 2017 update of the 5-year follow-up, patients treated with lenatinib had an invasive disease-free survival rate of 90.2%, up from 87.7% in the placebo group, and survival was 1.3 months longer. Diarrhea remains the most common complication of lenatinib treatment.
Lenatinib received marketing approval from the FDA based on the results of the ExteNET study. Despite the high incidence of diarrhea, the FDA was “lenient” and did not require a black box warning, but rather stated that loperamide hydrochloride is required to prevent severe diarrhea from the first dose of the drug until the end of the first 2 cycles of dosing; patients with grade 4 or higher diarrhea or grade 2 diarrhea at the lowest dose require treatment. Treatment is required.
However, some have questioned the role of lenatinib. Based on the numbers alone, lenatinib has shown limited improvement in patient survival, with less than 3% improvement in survival, but a high incidence of diarrhea. Caution is needed when choosing this drug for treatment.
Exploration: more applications in breast cancer are being explored
In the meantime, attempts to expand the use of lenatinib for additional breast cancer indications have not stopped. In addition to adjuvant therapy for early-stage breast cancer, researchers are exploring its use in areas such as treatment of metastatic breast cancer and, to date, have had “modest success” in controlling brain metastases.
The brain is a common site of metastasis in advanced breast cancer, and many drugs cannot reach the brain because of the blood-brain barrier, which is one of the reasons why brain metastases are so difficult to treat.
One study showed that in the first-line treatment of HER2-positive locally recurrent or metastatic breast cancer, lenatinib + paclitaxel was nearly as effective as trastuzumab + paclitaxel, with patient survival of about 13 months.
However, lenatinib combined with paclitaxel appears to be more effective in controlling brain metastases, with patients experiencing delayed central nervous system metastases. For patients with brain metastases, the risk of recurrence was reduced by 52% after treatment (from 17.3% to 8.3%).
And in another study of HER2-positive breast cancer with brain metastases, treatment with lenatinib + capecitabine, patients had an objective remission rate of only 8% and a median progression-free survival of only 1.9 months, which is not a satisfactory outcome.
Notably, the most common adverse effect of lenatinib is diarrhea, which can occur in up to 96% of some patients. It can usually be controlled with antidiarrheal medications and dose reduction.
What is the future of lenatinib in China?
Lenatinib is not currently available in China. However, in January 2018, it was reported that the domestic company received the sole license to authorize lenatinib in Greater China, which could potentially speed up the entry of lenatinib into China.
Summary
For patients with HER2-positive breast cancer, lenatinib can be used to intensify the effects of anti-HER2 therapy 1 year after completing standard trastuzumab adjuvant therapy after surgery, with the aim of reducing the risk of tumor recurrence.
There was benefit in lenatinib-treated patients in the ExteNET study, but diarrhea was common. If lenatinib treatment is attempted clinically, additional antidiarrheal medications or dose reductions are needed to avoid the appearance of severe diarrhea.
Lenatinib, a tyrosine kinase inhibitor, can play a role in anti-HER2 therapy for breast cancer and may have therapeutic potential in controlling brain metastases. However, the available evidence is not yet robust and further studies are needed.