Lung cancer is a major type of cancer in the world, with the highest morbidity and mortality among all malignant tumors. ALK-positive non-small cell lung cancer (ALK+ NSCLC) is a relatively rare and dangerous subtype, with patients suffering from a high incidence rate of brain metastases. Statistics show that about 55% of ALK-positive advanced NSCLC patients will develop brain metastases during the treatment process, which is a serious challenge facing oncologists. In recent years, the application of targeted therapies has significantly prolonged the survival of patients. However, drug resistance, brain metastases, and other problems have become increasingly prominent in clinical practice.

Lorlatinib is a dual-target inhibitor of ALK and ROS1, approved for marketing by FDA in 2018. It can effectively combat various ALK-secondary resistance gene mutations, and has strong central nervous system permeability, maintaining high blood concentration in brain tissues.

About anaplastic lymphoma kinase (ALK)

ALK was first identified in a subtype of anaplastic large-cell lymphoma (ALCL), hence named anaplastic lymphoma kinase (ALK). Subsequently, multiple types of ALK gene rearrangements were identified in NSCLC, diffuse large B-cell lymphoma, and inflammatory myofibroblastic tumor (IMT) respectively, proving ALK to be a potent oncogenic driver.

Researchers developed a retroviral cDNA expression library to screen for novel oncogenes. They transfected a cDNA library derived from lung adenocarcinoma in a 62-year-old Japanese male smoker who had been prescreened negative for KRAS and EGFR mutations. Then they engineered transgenic mice to specifically express EML4-ALK in alveolar cells, resulting in the generation of numerous lung adenocarcinoma nodules. Treatment for these transgenic mice with an ALK inhibitor brought about a reduced tumor burden compared with untreated mice. And treatment with the same ALK inhibitor resulted in no EML4-ALK/3T3 cell infiltration in the lung and prolonged survival. This study strongly confirms that EML4-ALK is the only mutation driver in NSCLC and that inhibition of EML4-ALK activity in vivo leads to a decreased lung cancer burden.

FDA approved ALK inhibitors

So far, 6 ALK inhibitors have been approved by FDA, including Crizotinib (first-generation ALK drug), Ceritinib, Alectinib, Brigatinib, Ensartinib (second-generation), and Lorlatinib (third-generation).

1.Crizotinib

Crizotinib is the first ALK-positive small molecule inhibitor on the market, which targets ROS1 and MET in addition to ALK. Crizotinib in the first-line treatment of ALK-positive lung cancer can significantly prolong the PFS, improve the objective response rate, and improve the life quality of patients compared with chemotherapy. However, more than half of patients who have disease progression after Crizotinib treatment have intracranial progression.

2.Ceritinib

Ceritinib was approved by FDA in 2014, and its targets include ROS1, IGF-1R, etc. Ceritinib is the same as Crizotinib, which can be used as the first-line treatment for ALK-positive lung cancer with good effect. But Ceritinib has shown some side effects on brain metastases.

3.Alectinib

Alectinib was approved by FDA in 2015 as a highly potent breakthrough therapy, highly selective for ALK and several associated mutation sites. Alectinib has a good effect on patients with ALK-positive brain metastases, which is significantly better than Crizotinib. To date, Alectinib has been approved in 65 countries worldwide for first-line treatment of ALK-positive advanced NSCLC.

4.Brigatinib

Brigatinib is highly active against untreated ROS1 tumors and also inhibits EGFR, but it does not appear to be active against EGFR. For the activity against ALK-positive cells, Brigatinib was 10 times more active and selective than Crizotinib. On May 23, 2020, FDA approved Brigatinib as a first-line treatment for patients with metastatic NSCLC who are genetically ALK-positive.

5.Ensartinib

Ensartinib is featured with high efficiency, low toxicity, and outstanding effect on brain metastasis. It is a new type of potent, highly selective second-generation ALK inhibitor. Ensartinib can be used in the treatment of patients who have progressed after previous Crizotinib treatment and are unable to tolerate Crizotinib. Patients who are positive for ALK mutations with locally advanced or metastatic NSCLC can also be treated with Ensartinib. The survival time of such patients can be improved and prolonged.

6.Lorlatinib

On March 4, 2021, the FDA approved Pfizer's third-generation ALK inhibitor Lorlatinib for first-line treatment of ALK-positive NSCLC. The third-generation targeted drug overcomes all known ALK resistance mutations and can cross the blood-brain barrier. It can inhibit 9 mutations of Crizotinib resistance and has high efficacy against second-generation TKI resistance. Lorlatinib also has a strong blood-brain barrier permeability, which is particularly suitable for advanced NSCLC patients with other ALK resistance.

Challenges need to be addressed

Brain metastases are still the main causes of death and disability in ALK-positive advanced lung cancer patients, and lead to a significant decline in patients' life quality. Since the effect of previous therapies for brain metastasis control is limited, it is agreed with clinicians and researchers that this sticking point needs to be solved urgently.