Over the past decade, the first-generation tyrosine kinase inhibitor (TKI) crizotinib has dominated the area of treating anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC).

Recently, however, next-generation AKL inhibitors have emerged as strong competitors against crizotinib, with remarkable therapeutic effects.

Roche’s Alecensa (ingredient: alectinib), in particular, has demonstrated solid survival data among ALK inhibitors to become the first-line treatment for ALK-positive NSCLC.

At the virtual meeting of the American Society of Clinical Oncology (ASCO) last weekend, the company released the five-year survival rate of Alecensa-treated patients in the ALEX study.

Korea Biomedical Review has met with Professor Cho Byung-chul of the Oncology Department of Severance Hospital to learn what the results of the ALEX study meant. He also serves as the head of the Yonsei Cancer Center’s Lung Cancer Center.

Question: Can you introduce Alecensa?

Answer: Alecensa proved its efficacy and safety in the global, randomized, phase-3 ALEX study, which compared its effect with that of crizotinib, the existing first-generation ALK inhibitor.

In February 2017, Alecensa met the primary endpoint of progression-free survival (PFS). At the time, the Alecensa treatment group rarely experienced tumor progression and did not reach the median of PFS, versus the crizotinib group’s 10.9 months. The hazard ratio (HR) at the time was 0.47. This meant that using Alecensa instead of crizotinib could reduce the absolute risk of disease progression by 53 percent.

Q: How should we interpret the five-year data of the ALEX study recently announced at ASCO?

A: Alecensa met PFS, the primary endpoint in the ALEX study, but people wondered if using another ALK inhibitor in the follow-up treatment, just like physicians do so when treating EGFR-muted lung cancer, could make patients’ overall survival similar anyway. However, the results of Alecensa released at the ASCO meeting were better than expected.

There are so many treatments mainly developed for lung cancer. The key topic in the latest ASCO was how we should use these drugs. The discussions were about whether to use less potent drugs first and then use more potent drugs later when drug resistance develops, or whether to use more potent drugs first.

In ALK-positive lung cancer, Alecensa demonstrated data that ended this discussion. The five-year overall survival (OS) was 62.5 percent in the Alecensa treatment group, while that of the crizotinib was 45.5 percent. The gap was over 15 percentage points. The hazard ratio was 0.67, meaning that Alecensa reduced the risk of death by 33 percent. The difference between the two drugs was significantly notable.

Q: Is there a group of particular patients for whom the Alecensa treatment is more beneficial?

A: Among ALK-positive NSCLC patients, there are differences in gender, age, and brain metastasis. Therefore, the researchers analyzed subgroups with clinically significant characteristics. Alecensa provided survival benefits over crizotinib in all subgroups. It showed a marked effect on patients with central nervous system (CNS) metastasis, that is, patients with brain metastasis from the beginning.

Two characteristics are emphasized when comparing the next-generation ALK inhibitor and crizotinib. The first is selectivity, a feature that works specifically for cancer cells. This is involved with side effects, especially related to long-term toxicity. The second is the CNS effect, which is the blood-brain barrier permeability. There is an essential factor that determines the characteristics of each carcinoma. In ALK-positive lung cancer, brain metastasis occurs often. About 40 percent of ALK-positive lung cancer patients have brain metastasis at the time of diagnosis. The brain is the most common site of metastasis in ALK-positive lung cancer patients after crizotinib treatment. About 70 percent of crizotinib-treated patients have brain metastasis.

Some patients develop metastasis not only in the brain but also in the meninges that surround the brain. The membrane surrounding the brain contains spinal fluid to protect the brain. When the lung cancer spreads in the meninges, the prognosis is very poor, with an average life span of two to three months. Because cancer cells continue to float along the meninges, it is difficult to treat, and a topical treatment alone does not work well. Patients with brain metastases are unable to walk and unable to control their urine and stool, showing symptoms of dementia. Many of them stay on bed and face death. Therefore, it is crucial to prevent brain metastasis, including meningeal metastasis. In this respect, Alecensa not only provides clinical benefit but have a significant impact on the patient’s quality of life.

Q: What about the tolerability and safety of Alecensa and crizotinib?

A: In terms of toxicity, both Alecensa and crizotinib superior tolerability compared to conventional chemotherapy. The two drugs barely cause nausea, vomiting, and a low white blood cell count that are common adverse reactions to chemotherapy.

Crizotinib, however, can cause digestive system disorders and blurred vision. Patients who took this medication can see split images or have a blurred outside view. When driving at night, it might not be easy to recognize an object if a car comes on the opposite side with the headlight on.

In contrast, Alecensa showed superior outcomes in terms of liver toxicity, digestive system disorders, and eye toxicity.

Q: But in Korea, there is no ALK inhibitor to be used after Alecensa treatment. What do you think about this?

A: This is a question that is difficult to answer easily. There are other things to consider, even if we have solid data. In some cases, it may be beneficial to use next-generation ALK inhibitor such as Alecensa after crizotinib. However, there is no way to determine which patients are more likely to benefit from long-term survival when receiving this treatment.

If a patient with ALK-positive NSCLC comes to the hospital today and asks which ALK inhibitor to choose, I have no other option but Alecensa. This is because I don’t know what will happen to this patient three years later. It is right to use more effective drugs based on the latest data. If we treat 100 patients, using Alecensa would save 62.5 percent of them five years later, and if we choose crizotinib, only 45.5 percent will survive.

Q: How will you predict how ALK-positive NSCLC treatment will change?

A: When crizotinib was used as the first-line treatment, the median overall survival was 57 months. About half of patients who used an ALK inhibitor after crizotinib had median survival at five years. If we assume that 100 percent of patients receive a follow-up treatment with a next-generation ALK inhibitor like Alecensa, this result will be better. Besides, as a result of the five-year follow-up of the ALEX study, Alecensa used as the primary treatment did not reach the median of overall survival. If we can use loratinib, we will be able to expect 10-year survival.