Novartis' Second-Generation ALK-TKI Ceritinib Nears Approval in China for First-Line Treatment of ALK+ NSCLC

By Cai Cai

Recently, the new indication for Novartis’ second-generation ALK inhibitor ceritinib capsules (Acceptance No.: JXHS1900008) has been updated to “Under Review,” with approval for market launch expected in the near future. Ceritinib was the first second-generation ALK inhibitor to enter the Chinese market, and this new indication is anticipated to be for the first-line treatment of ALK-positive non-small cell lung cancer (NSCLC).

(Source: NMPA)

The First Second-Generation ALK Inhibitor to Enter China

Ceritinib (trade name: Zykadia) is an orally administered, highly selective and potent small-molecule inhibitor of anaplastic lymphoma kinase (ALK). As a second-generation ALK inhibitor developed by Novartis, it was approved by the US FDA in 2014 and by the Chinese NMPA in June 2018. It is indicated for the treatment of patients with ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib, becoming the first second-generation ALK inhibitor marketed in China.

Crizotinib and ceritinib were both included in the National Reimbursement Drug List (NRDL) through national price negotiations in October 2018, with annual costs reduced to RMB 160,000–190,000 and RMB 217,000, respectively. When alectinib was first launched in China, it offered a patient assistance program providing “5+8 free doses in the first year and 4+9 free doses in the second year,” resulting in an annual cost of approximately RMB 230,000. Following its inclusion in the NRDL through national negotiations in 2019, the estimated annual cost was around RMB 200,000.

(Source: Pharmadigger)

The ASCEND-4 study of ceritinib facilitated its FDA approval for first-line treatment of ALK-positive NSCLC. This study compared the efficacy of first-line ceritinib versus chemotherapy, demonstrating a median PFS of 16.6 months with ceritinib compared to 8.1 months with chemotherapy (HR=0.55).

Overall Efficacy Comparison of Crizotinib, Alectinib, Ceritinib, and Brigatinib

(Source: Publicly available information)

The "Diamond Mutation" in ALK-Positive NSCLC

According to statistics from the National Cancer Center, there were 733,000 lung cancer patients in China in 2015, with an annual growth rate of 3%. Among them, there were 509,300 male patients and 224,000 female patients. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases in China. NSCLC is divided into three histological subtypes: lung adenocarcinoma, squamous cell lung cancer, and large cell carcinoma. Currently, the distribution of these three subtypes in China is changing annually; among all NSCLC subtypes, the proportion of squamous cell lung cancer is decreasing year by year, while the proportion of lung adenocarcinoma is increasing year by year. According to relevant literature from 2015, the proportions of the three subtypes among male patients in China were 36.68% (lung adenocarcinoma), 35.13% (squamous cell carcinoma), and 13.98% (large cell carcinoma), whereas among female patients, the proportions were 60.83% (lung adenocarcinoma), 14.77% (squamous cell carcinoma), and 9.26% (large cell carcinoma). The prevalence of ALK gene mutations among Chinese patients with lung adenocarcinoma and squamous cell lung cancer is approximately 6% and 2%, respectively. Based on this estimation, the number of new lung cancer patients with ALK mutations in China in 2020 was approximately 33,800.

Source: Target and Therapy

The overall mutation rate of ALK in NSCLC is only 3.3%-6.1%, which is more common in patients with lung adenocarcinoma. Due to the lower incidence of drug resistance, ALK inhibitors have shown good overall treatment outcomes for patients. Therefore, ALK is also referred to as the "diamond mutation" in NSCLC.

There are 5 ALK inhibitors marketed globally.

Currently, there are five ALK inhibitors approved for marketing worldwide, three of which are available in China: the first-generation ALK inhibitor crizotinib, and the second-generation ALK inhibitors ceritinib and alectinib.

Global R&D Progress of ALK Inhibitors

(Source: Wind Pharmaceutical Database; Note: The indications for both first-line and second-line therapies are ALK-positive NSCLC.)

The first-generation ALK inhibitor crizotinib has become the standard first-line treatment for ALK-positive non-small cell lung cancer (NSCLC). The second-generation ALK inhibitor alectinib, as a first-line therapy, significantly prolongs median progression-free survival (mPFS) compared with crizotinib. In the second-line setting, brigatinib demonstrates superior efficacy, with an mPFS of up to 16.7 months. The third-generation inhibitor lorlatinib was approved by the FDA in November 2018. Lorlatinib can inhibit tumor mutations that confer resistance to other ALK inhibitors and is capable of crossing the blood-brain barrier, showing favorable efficacy in recent clinical studies.

(Original Title: Approval | Novartis’ Second-Generation ALK-TKI “Ceritinib” for First-Line Treatment of ALK+ NSCLC Poised for Domestic Approval in China)