Professor Chen Ping talked about the hard power of the three generations of ALK-TKI lorlatinib

*For medical professionals only

Lolatinib provides first-line treatment preference for patients with ALK+ advanced NSCLC
.

Anaplastic lymphoma kinase (ALK) mutation because of its low incidence and high efficiency of ALK-tyrosine kinase inhibitor (TKI) is called "diamond mutation", there are many clinically targeted drugs, and the recently marketed three generations of ALI-TKI lorlatinib has obvious advantages in first-line treatment efficacy, penetration of the blood-brain barrier, etc.
, while also taking into account safety
。 In order to learn more about the advantages of lorlatinib in ALK+ non-small cell lung cancer (NSCLC) patients, so as to better guide clinical practice medication, "Medical Tumor Channel" is honored to invite Professor Chen Ping of Yancheng First People's Hospital to share academic and personal insights
.

Innovative construction for exceptional results

ALK was first discovered in 1996 as a proto-oncogene for a subtype of anaplastic large cell lymphomas (ALCLs), and its fusion gene with nucleolar phosphoprotein (NPM) is the first discovered ALK fusion gene [1], which is formed
by translocation of the short arm of chromosome 2 containing the ALK locus and the long arm of chromosome 5 containing the NPM gene loci 。 In ALK fusion proteins, there is a specific kinase domain, the binding site of adenosine triphosphate (ATP), and binding of ALK fusion protein to ATP can lead to constitutive activation of ALK and its downstream signaling pathway, resulting in abnormal cell proliferation and differentiation [2].

Studies have shown that the growth and survival of tumor cells with ALK fusion gene depend on the continuous activation of ALK and its downstream signaling pathway [3], and blocking the binding of ALK fusion protein to ATP can lead to cell growth restriction and apoptosis
.
At present, the ALK-TKI that has been marketed are all ATP competitive TKIs, but there are differences with ALK kinase domain binding sites, and the first/second generation ALK-TKIs are acyclic compounds, while the third-generation ALK-TKIs such as lorlatinib innovatively introduce macrocyclic amide structure
.

Professor Chen Ping introduced: "The large ring structure is more compact, increasing the buried area, and can almost completely enter the pocket center of the ATP binding site, while other TKIs cannot fully enter the pocket due to the long chain [4].

The non-pocket portion is susceptible to pre-solvent mutations such as G1202R, forming pre-solvent residues and developing resistance to these drugs in direct contact with a variety of first/second generation ALK-TKIs [5], which can be avoided by the compact macrocyclic structure of the third generation ALK-TKI, thereby improving antitumor activity and blood-brain barrier penetration [4].

The recently marketed third-generation ALK-TKI lorlatinib has well verified its structural advantages
in the first-line treatment of ALK+ advanced NSCLC and the treatment of patients with brain metastases.
”

Figure 1.
ALK kinase domain ATP-binding pocket ALK-TKI

*A：TAE684； B: crizotinib ; C: ceritinib ; D: Alletinib; E: lorlatinib ; F: Burglitinib

First-line benefit, lorlatinib breakthrough extended median PFS to more than 3 years

Lolatinib's compact macrocyclic amide structure and smaller molecular weight increase anti-tumor activity, making lorlatinib show good efficacy in the first-line treatment of ALK+NSCLC patients, and fully demonstrated
in the CROWN study.
The CROWN study [6] is an international multicenter, randomized, phase III study to evaluate the efficacy and safety
of lorlatinib versus crizotinib in the first-line treatment of ALK+NSCLC patients.
A total of 296 patients with ALK+ advanced NSCLC who were newly treated were randomized to receive lorlatinib (n=149) and crizotinib (n=147) in
a 1:1 ratio.

Professor Chen Ping said: "The 2022 American Association for Cancer Research (AACR) Annual Meeting announced the latest results of the CROWN study, especially the widely watched 3-year progression-free survival (PFS) results
.
Data as of September 20, 2021, based on the primary endpoint PFS results assessed by the Blinded Independent Review Committee (BICR), the median follow-up time for PFS in the lorlatinib and crizotinib groups was 36.
7 and 29.
3 months, respectively, and lorlatinib continued to show excellent clinical efficacy:

• The median PFS in the lorlatinib and crizotinib groups was NR vs 9.
  3 months (95% CI: 0.
  184 to 0.
  388),
  respectively.
  

• The 3-year PFS rate in the lorlatinib group was 63.
  5%, far exceeding the 18.
  9%
  in the crizotinib group.
  

Although the current first-line median PFS results of lorlatinib in the CROWN study have not yet been reached, it has been breakthrough extended to more than 3 years, and the curve has not seen a downward trend, and it will continue to benefit
in the future.
In addition, in the CROWN study, after first-line treatment with lorlatinib, the risk of disease progression or death in patients with ALK+ advanced NSCLC was reduced by 73% compared with crizotinib (HR=0.
27), which means that patients can achieve greater benefit
.
Lolatinib may be preferred first-line therapy for patients with advanced NSCLC ALK+
.
”

Figure 2.
PFS results in the lorlatinib versus crizotinib group in the CROWN study

Strong penetration, lolatinib has outstanding brain protection ability

Brain is the most common distant metastatic site in lung cancer patients, which is difficult to treat and seriously affects the quality of life and survival prognosis
of patients.
Because most drugs cannot penetrate the blood-brain barrier, the treatment of patients with brain metastases is a major clinical difficulty
.
Professor Chen Ping pointed out that lorlatinib is easier to penetrate the blood-brain barrier
because of its small molecular weight and macrocyclic amide structure that can completely enter the pocket center.

In the CROWN study, for patients with baseline brain metastases, the 3-year PFS rate was 50.
3% in the lorlatinib group and no data in the crizotinib group; The objective response rate (ORR) was 83.
3% in the lorlatinib group and 23.
3% in the crizotinib group.
A whopping 72.
2 percent of patients achieved complete intracranial remission (CR) after first-line lolatinib therapy, compared with 7.
7 percent in the crizotinib group [6].

It is also worth noting that Professor Chen Ping emphasized that in the 3-year follow-up of 112 patients with baseline non-encephalebral metastasis, only 1 case had intracranial progression, and the 3-year intracranial progression rate was as high as 99.
1% [6].

This also means that lorlatinib is significantly effective in preventing or delaying brain metastases in patients without encephaly metastases at baseline
.

Professor Chen Ping concluded: "Lolatinib's overall tumor control ability in ALK+ advanced NSCLC patients is amazing, not only can effectively treat brain metastases, but also has intracranial protective effect
.
In addition, lorlatinib did not bring more adverse effects while effectively treating brain metastases, and no new safety signals appeared in the lorlatinib group during the long-term follow-up of the CROWN study, and the permanent discontinuation rate due to adverse events was only 7.
4%, lower than the 9.
9% of crizotinib [6], and the vast majority of patients continued to benefit
from it.
Lolatinib is expected to break the deadlock of brain metastasis while ensuring quality of life
.
”

It is expected that lorlatinib will be included in medical insurance as soon as possible to benefit more patients

Professor Chen Ping finally mentioned an equally critical issue: "The long survival of ALK+NSCLC patients also means that they have to bear a more lasting economic burden, and the treatment of tumors often affects the income source of patients in many ways, and economic issues are also one of the key factors affecting patients' choice of
drugs.
" At present, how to line up ALK-TKI 'three generations in the same household' in order to obtain the best treatment benefits has been the focus of clinical debate, one of the reasons is the cost of
drugs.
It is expected that lorlatinib will be included in medical insurance as soon as possible in the future, providing patients with more accessible and affordable priority options, and giving full play to the advantages of lorlatinib to bring tangible benefits
to the majority of lung cancer patients.
”