ALK-positive NSCLC adds new members to the front line. How to choose the first-line treatment of six ALK inhibitors?

Author: Cornflower This article is published by Yimaitong authorized by the author, please do not reprint without authorization
.

On July 13, the application for new indications of Ensatinib Hydrochloride Capsules has been accepted by the National Medical Products Administration (NMPA) of China
.

This time, the new indication for Ensatinib is: first-line treatment for patients with anaplastic lymphoma kinase (ALK) positive locally advanced or metastatic non-small cell lung cancer (NSCLC)
.

ALK fusion is an important treatment target for advanced NSCLC, known as the "diamond mutation", and the mutation rate in NSCLC patients is about 5-7%
.

Since the US Food and Drug Administration (FDA) approved the first-generation ALK-TKI (tyrosine kinase inhibitor) crizotinib, the second-generation ALK-TKI aletinib, ceritinib, brigatinib, and ensatinib And the three generations of ALK-TKI lorlatinib have successively enriched the sequential medication pattern, and the median overall survival (OS) of ALK-positive patients has been greatly extended
.

However, the question arises.
These six ALK inhibitors, except for Ensatinib, have been approved by the FDA for first-line treatment.
So, how to choose the first-line treatment for ALK+ NSCLC? 1.
Ensatinib The first-line indication of Ensatinib is based on the research data of phase III randomized controlled study eXalt3 [1]
.

A total of 290 ALK-positive non-small cell lung cancer patients were enrolled in the study.
Among the intent-to-treat (ITT) population, they were randomly assigned to the Ensatinib or Crizotinib treatment group
.

As of December 8, 2020, the median progression-free survival (PFS) of patients in the Ensatinib group was 31.
1 months, which was significantly longer than that of the crizotinib group of 12.
7 months (HR 0.
51, 95%CI 0.
35- 0.
72)
.

The overall objective response rate (ORR) of ensatinib was better than crizotinib, at 75% and 67%, respectively
.

The 2-year OS rate in the Ensatinib group was 78%, confirming the good overall survival trend of patients in the Ensatinib group
.

The results of the patient's quality of life follow-up report showed that the quality of life of patients in the Ensatinib treatment group was significantly improved compared with that of the crizotinib group
.

2.
Ceritinib In May 2020, NMPA officially approved Ceritinib as a single agent for patients with ALK-positive locally advanced or metastatic NSCLC
.

Since then, ceritinib has entered the first-line treatment of patients with ALK-positive locally advanced or metastatic NSCLC
.

The approval is based on the ASCEND-8 research of the ASCEND series [2]
.

The study included a total of 306 treated and newly-treated patients who were randomly given ceritinib 450 mg with meals, 600 mg with meals, and 750 mg on an empty stomach at a ratio of 1:1:1, until they were unable to tolerate them and the disease progressed and withdrew from the study
.

With a median follow-up of 37.
65 months, the results showed that the ORR and disease control rate (DCR) of all patients in the 450mg meal group and 750mg fasting group were evaluated by the blinded Independent Review Committee (BIRC) as a whole, with ORRs of 78.
1%.
(95% CI: 66.
9-86.
9) and 75.
7% (64.
3%-84.
9%), the DCR was 90.
4% (95% CI: 81.
2-96.
1) and 90.
5% (81.
5%-96.
1%), respectively
.

The median duration of response (DoR) in the 750 mg fasting group of ceritinib was 17.
9 months (95% CI: 12.
5-NE), and the DoR of the 450 mg meal group had not yet reached (95% CI: 14.
5-NE)
.

The results of the study showed that ceritinib 450 mg with meals has a better therapeutic effect, and in people with brain metastases at baseline, the ORR is as high as 75%, and the DCR is as high as 91.
7%
.

ORR and DCR for fasting treatment higher than 750 mg (52.
4% and 76.
2%)
.

3.
Aletinib Aletinib was approved in China for its first-line indication as early as 2018
.

The approval was based on the global multicenter, randomized, open-label Phase III ALEX study [3], which included a total of 303 ALK-positive NSCLC patients who were randomly assigned to the aletinib group or the crizotinib group at 1:1
.

The results showed that the investigator-assessed (INV) PFS in the aletinib group was 34.
8 months, which was significantly better than the 10.
9 months in the crizotinib group (HR=0.
43, P<0.
0001)
.

The results of the subgroup analysis showed that, regardless of whether the baseline was associated with central nervous system metastasis, aletinib showed the benefit of PFS
.

Although the final OS data is not yet mature, at the 5th year, the aletinib group showed a clinically significant improvement in OS (62.
5% vs 45.
5%)
.

4.
Brigatinib In May 2020, the FDA approved a new indication of brigatinib for the first-line treatment of ALK-positive advanced NSCLC patients
.

Approval is based on ALTA-1L research [4]
.

A total of 275 ALK-positive NSCLC patients were enrolled and randomly assigned to the brigatinib group and the crizotinib group according to 1:1
.

The results showed that the brigatinib group compared with the crizotinib group: the median PFS was 24 months vs.
11 months, and the risk of disease progression was reduced by 51% (HR=0.
49, P<0.
0001); the 2-year PFS rate was 48%, respectively vs 26%
.

In terms of ORR, the rates of brigatinib and crizotinib were 74% vs 62%, respectively, and brigatinib was better than crizotinib
.

5.
Lorlatinib In March 2021, the FDA approved lorlatinib for the first-line treatment of ALK-positive metastatic NSCLC patients
.

 The approval is based on the results of the Phase III CROWN clinical study [5]
.

The study included 296 patients with ALK-positive advanced NSCLC
.

Randomly receive lorlatinib or crizotinib at a ratio of 1:1
.

According to the BIRC assessment, compared with crizotinib, lorlatinib can significantly prolong the median PFS.
The two groups were not reached and 9.
3 months, respectively, and reduced the risk of disease progression or death by 72% (HR=0.
28, 95% CI, 0.
191-0.
413; P＜0.
001); the ORRs of the two groups were 76% and 58% (95% CI, 1.
35-3.
89)
.

It is worth mentioning that the intracranial ORR of the lorlatinib group was as high as 82%, far exceeding the 23% (95% CI, 1.
95-163.
23) of the crizotinib group
.

Among them, 71% (12 cases) of patients with measurable brain metastases at baseline used lorlatinib to achieve complete intracranial remission (CR), reflecting the amazing ability of lorlatinib to enter the brain
.

Three generations of ALK inhibitors have greatly enriched the medication options for ALK-positive NSCLC patients
.

On the whole, the second and third generations of ALK-TKI have become the general trend for first-line treatment.
In PFS, the above drugs are better than the first generation of crizotinib, but there is still a lack of head-to-head comparison between the second and third generations of ALK-TKI.
The first-line OS data of Ensatinib and lorlatinib need further follow-up
.

Need to consider many factors when selecting drugs, including duration of treatment, central nervous system activity, toxicity profiles and so on
.

In short, the competition on the stage of ALK inhibitors will be very fierce in the future.
Whether it is drug development or clinical treatment, it should be patient-centered
.

 Reference: 1.
2020 WCLC: eXalt3: Global Phase3, Open-Label, Randomized, Multicenter Study.
2.
BC Cho et al.
Efficacy and Safety of Ceritinib (450 mg/d or 600 mg/d) With Food Versus 750-mg/d Fasted in Patients With ALK Receptor Tyrosine Kinase (ALK)--Positive NSCLC: Primary Efficacy Results From the ASCEND-8 Study.
Journal of Thoracic Oncology.
14, 1255–1265 (2019) 3.
Camidge DR, Dziadziuszko R, Peters S, et al: Updated Efficacy and Safety Data and Impact of the EML4-ALK Fusion Variant on the Efficacy of Alectinib in Untreated ALK-positive Advanced Non-small-cell Lung Cancer in the Global Phase III ALEX Study.
J Thorac Oncol, 2019.
4.
Camidge DR, Kim HR, Ahn MJ, et al.
Brigatinib Versus Crizotinib in Advanced ALK Inhibitor-Naive ALK-Positive Non-Small Cell Lung Cancer: Second Interim Analysis of the Phase III ALTA-1L Trial [published online ahead of print,2020 Aug 11].
J Clin Oncol.
2020;JCO2000505.
doi:10.
1200/JCO.
20.
00505.
5.
Solomon B et al.
Lorlatinib vs Crizotinib in the First-line Treatment of Patients (pts) with Advanced ALK-Positive Non-Small Cell Lung Cancer (NSCLC): Results of the Phase 3 CROWN Study.
ESMO Virtual Congress 2020, LBA2.