First-line aletinib, followed by a drug that can be continued - Professor Zhou Chengzhi interprets the progress of 2022 WCLC ALK positive NSCLC diagnosis and treatment

For medical professionals only

First-line ALK-TKI resistance? There is medicine in the back line that can be renewed!

Non-small cell lung cancer (NSCLC) is a common type of lung cancer, accounting for 80% to 85% of all lung cancers, and has a poor prognosis and difficulty in early diagnosis[1].

Anaplastic lymphoma kinase (ALK) is a transmembrane receptor tyrosine kinase, belonging to the insulin receptor superfamily, ALK fusion mutation is also a new molecular target for the treatment of NSCLC, known as the "diamond mutation"

in NSCLC.

In China, the first/second/third generation of ALK-tyrosine kinase inhibitors (TKI) have been approved for marketing, constantly refreshing the efficacy and safety of drugs, bringing double benefits

to patients.

However, the diversification of drug options can also lead to questions such as: What are the differences in efficacy between different drugs? What kind of platoon layout can bring greater benefits? At the same time, with the improvement of the efficacy of ALK-TKI in patients with advanced NSCLC, treatment forward shift has become a more concerned issue for clinicians

.

Based on this, the "Medical Oncology Channel" specially invited Professor Zhou Chengzhi of the First Affiliated Hospital of Guangzhou Medical University to interpret

the highlights and diagnosis and treatment progress of ALK-positive NSCLC at the 2022 World Lung Cancer Congress (WCLC).

What is the first-line progress model of the second generation ALK-TKI? How to choose the back line?

The results of the analysis of the comprehensive efficacy and safety of aletinib sequential bugotinib in the ALTA-2 study and the J-ALTA study were reported at this conference^[2

].

The study included 133 patients (patients treated with aletinib or ceritinib in the ALTA-2 study, n = 86; patients after aletinib in the main cohort of the J-ALTA study, n = 47).

The median follow-up period for the overall population was 11.

1 months, with the majority of patients (57.
9%) receiving aletinib as the only prior treatment ALK-TKI
.
The results showed that the objective response rate (ORR) of patients with sequential bugotinib after treatment with aletinib was 30.
8% (95% CI: 23.1% to 39.4%), 40 patients achieved partial response (PR) and 1 patient achieved complete response (CR), and the median progression-free survival (PFS) assessed by a blinded independent review committee (BIRC) was 5.2 months (95%) :3.7-7.3) to provide more options
for follow-up treatment for patients with first-line treatment progression with aletinib.
"After taking aletinib sequentially bugotinib, the ORR can still reach more than 30 percent, and individual patients can also achieve the efficacy of CR, including PFS for more than 5 months, these data are unexpected
.
"
Professor Zhou Chengzhi said, "In the previous treatment, if you directly replace another second-generation ALK-TKI or other therapy after the second-generation ALK-TKI resistance, the effect may not be so obvious
.
"
Now after accurate drug resistance detection, we can find the specific situation of ALK kinase domain resistance mutations in different second-generation ALK-TKI, and select the appropriate second-generation ALK-TKI for sequential treatment accordingly, so as to play the role of this class of drugs as much as possible in the ALK pathway, so that patients can get the greatest benefit and delay the occurrence
of drug resistance.

"
In addition, to explore the mechanisms of drug resistance, a real-world study^[3] retrospectively analyzed patients who failed treatment with second-generation ALK-TKI, with investigators including patients with aletinib first-line treatment failure in cohort 1 (n=20) and cruzotinib sequentially enrolling patients with progression to second-generation ALK-TKI treatment cohort 2 (n=52).

Results showed that the proportion of patients with central nervous system (CNS) progression (15% vs 57.7%, p=0.001) and symptomatic CNS progression (5% vs 32.7%, p=0.016) in cohort 1 was much lower than that of first-line patients
receiving crizotinib.

The main resistance mechanism of the second generation ALK-TKI is resistance mutations in the ALK kinase domain (24/43, 55.8%), specifically G1202R (15/43, 34.9%)
.

In addition, MET amplification, BRAF fusion, BRAF V600E mutation, KRAS amplification, KRAS mutation and squamous cell carcinoma transformation may also be responsible for
drug resistance.

The ALK compound mutation that occurs after multiple ALK-TKI treatments is the main mechanism
of third-generation ALK-TKI loratinib resistance.
Some patients who had not undergone secondary biopsy after previous ALK-TKI therapy responded poorly to subsequent ALK-TKIs, and biopsies of such patients after multi-line therapy indicated that patients may have developed resistance during treatment with the initial ALK-TKI
.

Patients receiving first-line aletinib are less
likely to progress to THE CNS and symptomatic CNS than first-line cretinib therapy.

In the era of second-generation ALK-TKI, high priority should be given to secondary biopsy, which may facilitate the selection of clinical options and the evaluation
of subsequent treatment effects.
It is worth mentioning that in a study by ASCO (abs 6510) in 2020, after showing second-generation ALK-TKI resistance (multi-line), third-generation ALK-TKI loratinib treatment can be selected, suggesting that the "2+3" regimen can also bring benefits
to patients.

Choosing the right ALK-TKI, adverse reactions are also the focus

When selecting therapeutic drugs in clinical practice, in addition to the efficacy of the efficacy, the safety and tolerability of patients receiving treatment is also a major focus of clinicians
.
A study on the adverse effects of ALK-TKI in the real world was presented at the conference^[4], which collected data
on the diagnosis and treatment of respondents through a regular survey conducted by members of a registered charity.
Research analysis shows that:

• The first three adverse reactions to taking aletinib are sun sensitivity, fatigue and constipation;
• The first three adverse reactions to taking bugatinib are hypertension, diarrhea, and nausea;
• The top four adverse reactions to taking loratinib were neuropathy, mood swings, increased appetite, and weight gain
  .
  
  

"It can be seen that there are certain differences
in the adverse reactions of different ALK-TKI.

Adverse reactions such as aletinib are relatively easy to manage, while taking bugatinib and loratinib require more attention
to cardiovascular, gastrointestinal or nervous system.

Therefore, we should choose the treatment drug for patients in the clinic, such as women, elderly patients, or patients who already have poor gastrointestinal function, hypertension, and neurological problems, they should refer to their common adverse reactions to choose drugs
.

Professor Zhou Chengzhi said
.

The efficacy of ALK-TKI neoadjuvant therapy is beginning to appear, and it is expected to benefit more patients

ALK-TKI has benefited many patients with advanced NSCLC, but can early patients also benefit? The NAUTIKA1 study^[5] is an ongoing phase II study of targeted adjuvant/neoadjuvant therapy NSCLC that included phase II resectable NSCLC patients with ALK, ROS1, NTRK, BRAF V600E, RET positive, and PD-L1 positive phase II-III resectable NSCLC
.

The WCLC reports the initial efficacy and safety of aletinib as a neoadjuvant targeted therapy in ALK-positive NSCLC patients
.
As of 9 May 2022, a total of eight ALK-positive patients were included in the study, of which 5 had completed adjuvant adjuvant aletinib, had surgery to achieve R0 resection (R0 resection rate: 100%), and had no delays or serious surgical complications
.

In a preliminary analysis of the ALK-positive cohort of the NAUTIKA1 study, aletinib was well tolerated as a neoadjuvant therapy in patients with ALK-positive NSCLC
.

Suggests that aletinib has the feasibility
of neoadjuvant therapy in patients with ALK-positive NSCLC.
Professor Zhou Chengzhi introduced: "ALK-positive late NSCLC has good data out, we will consider whether these drugs can be used in the early, perioperative period
.

In addition to the above studies, an ARNEO study ^[6] explored the efficacy and safety
of aletinib in the treatment of patients with resectable locally advanced ALK-positive NSCLC.

Initially, the enrollment time is still relatively short, and the survival time of perioperative patients is relatively long, so the long-term benefit data in the study have not yet been released
.

But in the NAUTIKA1 study we have seen the feasibility of aletinib as a neoadjuvant therapy, as well as a good safety profile
.

Professor Zhou Chengzhi added: "
On the other hand, whether OS and disease-free survival (DFS) can be extended for surgical patients treated with aletinib is also a very important concern, but it is not yet possible to draw conclusions, and we look forward to the updating of follow-up data to bring benefits
to more patients.
"
”

brief summary

Professor Zhou Chengzhi said that ALK mutation, as a "diamond mutation", has brought long-term survival to ALK-positive advanced NSCLC patients, and in the future, it is hoped that ALK-TKI can also improve the tumor radical cure rate for early patients and increase their 5-year OS rate
.

In addition, while the efficacy of ALK-TKI is guaranteed, reducing the incidence of adverse reactions is also a key point, and the clinical treatment choice is based on the individualized situation of the patient, so as to achieve high efficiency and low toxicity, and bring greater benefits
to patients.

Expert Profile Professor Zhou Chengzhi

 

Director of the Clinical Diagnosis and Treatment Department of the National Respiratory Medicine Center of the First Affiliated Hospital of Guangzhou Medical University, Deputy Director of the Department of Respiratory and Critical Care of Guangzhou Institute of Respiratory Health, Director of the Department of
Oncology.

He took the lead in proposing the concept of "severe lung cancer" in the world, and led the publication of the first edition of the "International Consensus on Severe Lung Cancer"
.

The whole process management concept
of lung cancer is proposed, such as "co-treatment of cancer and lung", "PS score has reversibility and volatility", and "anti-tumor drug upgrading".

Academic Appointments:

Deputy Leader of the Lung Cancer Group of the Respiratory Branch of the Chinese Medical Association

Member of the Lung Cancer Working Group of the Respiratory Branch of the Chinese Medical Doctor Association

Secretary General of the China Respiratory Oncology Collaborative Group (CROC) and Vice Chairman of the Youth Committee

Vice Chairman of the Expert Committee of the China Lung Cancer Early Diagnosis and Early Treatment Capacity Improvement Project

Member of CSCO Youth Committee, Patient Education Committee and Geriatric Cancer Prevention and Treatment Committee

Chairman of the Critical Oncology Committee of the Guangdong Society of Thoracic Oncology

Chairman of Lung Cancer Branch of Guangdong Society for Precision Medicine Application

Deputy Leader of lung cancer group of Respiratory Disease Branch of Guangdong Medical Association

Vice Chairman of the Pulmonary Oncology Branch of Guangdong Medical Association

Vice Chairman of the Oncology Branch of Guangdong Medical Doctor Association

Vice Chairman of lung cancer branch and real-world research branch of Guangdong Clinical Medical Association

The 1st "Guangzhou Strength Young and Middle-Aged Doctors", the 2nd "People's Good Doctor - Outstanding Contribution Award in the Field of Lung Cancer", the 5th "Yangcheng Good Doctor"

 

References:[1] Sang Zi,Liu Xiaohui,Huang Xiaoyu,Geng Mingfei.
Expression of ALK and KRAS Proteins in Non-Small Cell Lung Cancer and Its Clinical Significance[J].
Practical Oncology, 2022, 37(08):1246-1249.[2] S-H.I.
Ou, M.Nishio, T.Yoshida, et al.
Integrated Efficacy and Safety of Brigatinib Following Alectinib Treatment in the ALTA-2 and J-ALTA Studies.
WCLC 2022 MA13.03.[3]Z.Zou, P.Xing, X.Hao, et al.
Progression Pattern, Resistance Mechanism and Subsequent Therapy for ALK Positive NSCLC in the Era of Second—Generation ALK—TKIs.
WCLC 2022 EP08.02-009.[4]D.
Montague.Real-World Data on the Side Effects of Alectinib, Brigatinib andLorlatinib.
WCLC 2022 EP08.02-066.[5]J.M.LEE, B.Sepesi, E.M.Toloza, et al.
Phase II NAUTIKA1 Study of Targeted Therapies in Stage II-III NSCLC: Preliminary Data of Neoadjuvant Alectinib for ALK+ NSCLC.
WCLC 2022 EP02.04-005.
[6]A.Leonetti, R.Minari, L.Boni, et al.
Alectinib as Neoadjuvant Treatment in Surgically Resectable Stage III ALK-Positive NSCLC: ALNEO Phase II Trial (GOIRC-01-2020).
WCLC 2022 EP02.04-001.
*This article is for the sole purpose of providing scientific information to medical professionals and does not represent the views of the Platform