Potent Last-Resort Drug Lorlatinib Launched in Hong Kong for Non-Small Cell Lung Cancer Treatment

By Xiao Bing

Lorlatinib (brand name: Alunbrig), a third-generation ALK inhibitor, is currently marketed in Hong Kong, China. It has been approved for the treatment of patients with ALK-positive advanced non-small cell lung cancer (NSCLC) who have progressed on crizotinib or at least one other ALK inhibitor. This not only brings hope to patients with resistance to ALK inhibitors but also represents significant good news for patients with ROS1-positive lung cancer.

Lorlatinib, developed and manufactured by Pfizer, offers the advantage of remaining effective even after patients have developed resistance to multiple other ALK inhibitors, earning it the reputation as a potent "last-resort" medication. Furthermore, due to its high blood-brain barrier permeability, it demonstrates superior efficacy in non-small cell lung cancer (NSCLC) with central nervous system metastases. It is indicated for the treatment of advanced ALK-positive and ROS1-positive NSCLC. Lorlatinib was approved for marketing in Japan on September 12, 2018; received formal approval from the U.S. Food and Drug Administration (FDA) in November 2018; and was approved by the European Medicines Agency (EMA) in March 2019. Its recent approval in Hong Kong, China, is indeed cause for celebration!

The approval of lorlatinib was based on the results of a Phase I/II clinical trial (B7461001). This was a non-randomized, dose-escalation, multi-cohort, multicenter Phase II clinical study. In this trial, 215 patients with ALK-positive non-small cell lung cancer (NSCLC) who had previously received treatment with ≥1 ALK inhibitor were enrolled; 69% of the patients had a history of brain metastases. The overall objective response rate (ORR) was 48% (95% CI: 42%, 55%), the median duration of response (DoR) was 12.5 months (95% CI: 8.4–23.7), and the intracranial response rate was 60% (95% CI: 49%, 70%). Regarding safety, the most common adverse reactions (≥20%) were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea. The most common serious adverse reactions were pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), altered mental status (1.4%), and respiratory failure (1.4%).

As a next-generation ALK inhibitor, the advantage of lorlatinib lies in its potential efficacy even after patients have developed resistance to multiple other ALK inhibitors, thereby significantly prolonging patient survival!

Lorlatinib for the Treatment of ROS1-Positive Advanced NSCLC

In an open-label, single-arm phase I/II clinical trial conducted from January 22, 2014, to October 2, 2016, 69 patients with histologically confirmed ROS1-positive advanced non-small cell lung cancer (NSCLC), with or without central nervous system (CNS) metastases, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, were enrolled. Patients received oral lorlatinib at a dose of 100 mg once daily in 21-day cycles until disease progression, unacceptable toxicity, withdrawal from the study, or death. The primary endpoints were overall and intracranial tumor response.

Among the patients, 21 (30%) had not previously received TKI therapy (Group A), 40 (58%) had previously received only one TKI, crizotinib (Group B), and the remaining 8 (12%) had previously received either a non-crizotinib ROS1 TKI or two or more ROS1 TKIs (Group C). The median follow-up time was 21 months. Objective responses were achieved in 13 patients (62%) in Group A and 14 patients (35%) in Group B. Intracranial responses were observed in 7 of 11 patients (64%) in Group A and 12 of 24 patients (50%) in Group B. The most common grade 3–4 treatment-related adverse events were hypertriglyceridemia (13/69, 19%) and hypercholesterolemia (10/69, 14%). Five patients experienced severe treatment-related adverse events. There were no treatment-related deaths.

Lorlatinib demonstrated clinical activity in patients with ROS1-positive advanced non-small cell lung cancer (NSCLC), including those with central nervous system (CNS) metastases and those previously treated with crizotinib.

In summary, regardless of the number of prior TKI targeted therapies or chemotherapy regimens used, lorlatinib consistently serves as the ultimate salvage therapy for ALK/ROS1 resistance, demonstrating robust intracranial control across all lines of treatment!

The launch of lorlatinib in Hong Kong has significantly increased the access of lung cancer patients to high-quality medications, and it is believed that mainland China will also see its approval in the near future.

Reference Source:

1.Alice T Shaw， et al.Lorlatinib in advanced ROS1-positive non-small-cell lung cancer：a multicentre， open-label， single-arm， phase 1-2 trial.The Lancet Oncology. October 25， 2019. https：//doi.org/10.1016/S1470-2045(19)30655-2;

2.https://www.onclive.com/web-exclusives/fda-approves-lorlatinib-for-alk-nsclc.

Original Title: Lung Cancer | Potent Last-Resort Drug Lorlatinib Commercially Launched in Hong Kong, China!