In the past, patients with ALK fusion mutations accounted for about 3%-7% of NSCLC patients in my country, but 20%-40% of the patients had brain metastases at the first diagnosis, and the incidence rate increased with time, and often had poor prognosis.

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Recalculate the considerations of first-line treatment choices for ALK-TKI

ALK is a common driver gene for non-small cell lung cancer (NSCLC). In the past, patients with ALK fusion mutations accounted for about 3%-7% of NSCLC patients in my country, but 20%-40% of the patients had brain metastases at the first diagnosis, and the incidence rate increased with time, and often had poor prognosis.

Until 2011, the first generation of ALK inhibitor (ALK-TKI) crizotinib was approved for marketing by US Food and Drug Administration (FDA), filling the gap in targeted drugs in the field of ALK gene fusion-positive NSCLC and greatly extending the survival of this type of patients.

On November 8, 2022, the 25th National Clinical Oncology Conference and the 2022 CSCO Non-small Cell Lung Cancer Committee targeted therapy session have come to a successful conclusion. At the conference, Professor Wang Zhehai from , Shandong Cancer Hospital , , , gave us a special speech on "First-line Treatment Choice for Late-stage NSCLC in ALK Fusion".

Professor Wang Zhehai delivered a report at the CSCO conference

What are the considerations for first-line treatment selection ALK-TKI?

In just over 10 years, ALK-TKI has undergone three generations of changes, and its clinical accessibility has also been greatly improved. More importantly, ALK-TKI has brought great improvements in the treatment and prognosis of patients with ALK fusion mutation NSCLC, and has even gained the reputation of "diamond mutation", which means that its incidence rate is low, but its effect is good.

For NSCLC with ALK fusion mutations, all of them are corresponding targeted drugs in the first-line recommendations of authoritative guidelines at home and abroad. However, facing so many targeted drugs, how should we choose when first-line treatment? What indicators should be used as the main consideration criteria?

Professor Wang Zhehai’s report screenshot

PFS is one of the main considerations for the first-line treatment of ALK-TKI

Except for the first-generation crizotinib, the existing PFS of the second-generation and third-generation ALK-TKI have basically remained between 25-30 months, and performed outstandingly among targeted drugs.

Screenshot of Professor Wang Zhehai’s report

ALK-TKI has achieved good results in PFS, but it has repeatedly hit a wall in the “gold standard” overall survival (OS) of efficacy evaluation. Since the use of ALK-TKI for ALK-positive patients has a good effect and the OS is generally long, the NSCLC guidelines of the United States National Comprehensive Cancer Network (NCCN) have changed the statements of "first-line treatment plans" and "second-line treatment plans" to "initial treatment plans" and "subsequent treatment plans". However, the subsequent selection of multiple treatment options introduced a large number of confounding factors, which caused the evaluation of OS to be disturbed by many factors. In addition, the large differences in the design of first-line Phase III clinical research by different ALK-TKIs will also affect the final results of OS.

Since the factors affected by OS are complex and it is quite challenging to use OS as the main research endpoint, can PFS benefits be truly converted into OS benefits? The research on bugtertinib ALTA-1L may give us some inspiration.

▌ ALTA-1L: Improving survival benefits

•ALTA-1L is a randomized, open-label phase III multicenter clinical study with the main purpose to compare the efficacy and safety of bugtinib and crizotinib (first-generation ALK-TKI) in patients with advanced NSCLC without ALK-TKI treatment. The study results showed that the median PFS in the bugtinib group and the crizotinib group were 24.0 months vs 11.1 months (HR 0.48; 95%CI 0.35-0.66; P <>

ALTA-1L The OS

ALTA-1L study of Final OS and MSN sensitivity analysis prompts that for patients with ALK fusion mutations, their OS is longer and there are many interference factors during the measurement process. Therefore, it is more reasonable to use PFS as the main research endpoint and the main clinical consideration indicators.

Remission depth is the second major consideration for the first-line treatment choice of ALK-TKI

In the chemotherapy era, it has been clear that the degree of tumor remission is closely related to survival benefits. For example, the median OS of patients with complete remission (CR) or partial remission (PR) is far better than those with stable disease (SD).

screenshot from Professor Wang Haizhe’s report

The relationship between the depth of relief brought by ALK-TKI treatment and survival were reported in the 2022 American Society of Clinical Oncology (ASCO) Conference.

2022 ASCO Conference, in addition to announcing the survival benefits of populations after bugtinib treatment, the ALTA-1L study also reported exploratory analysis results on the link between the depth of tumor target lesions and clinical outcomes.

▌ ALTA-1L: There is a positive correlation between tumor remission depth and survival benefit

•ALTA-1L study results show that the proportion of patients with deep remission (76%-100% remission) in bugtinib and crizotinib groups were 56% and 34%; the proportion of patients with moderate remission (51%-75% remission) was 27% and 30% respectively; the proportion of patients with mild remission (0%-50% remission) was 16% and 35% respectively.

• From the results, it can be seen that the patients in the deep remission group had different degrees of prolongation, with the OS rate reaching 81% in 4 years, which is far higher than those with poor remission.

exploratory analysis of ALTA-1L PFS and OS

are targeted at patients with ALK fusion mutations. Targeted therapy, chemotherapy, immune , anti-tumor blood vessels and other treatment methods coexist, and various drugs are blooming. Whether these drugs can achieve deep remission will be an important reference factor for clinical decision makers to accurately select treatment methods.

Prevention and control of brain metastasis is the main consideration for the first-line treatment of ALK-TKI

Brain metastasis is one of the common distant metastasis sites in lung cancer. The probability of brain metastasis in patients with ALK-positive advanced NSCLC is as high as 30%. Studies have shown that more than 40% of patients treated with crizotinib use brain metastasis as the first site of progression, and 60% of patients will still experience brain metastasis during the treatment process [1], which is related to the characteristics of the ALK driver gene itself.

For the choice of first-line treatment of ALK-TKI, the prevention and control of brain metastasis is a very important consideration.

▌ ALTA-1L: Bugitinib can improve the survival rate of patients with brain metastasis

•ALTA-1L final analysis showed that for patients with brain metastasis at baseline, the median PFS of the bugitinib group (evaluated by the independent review committee) was 24.0 months, which significantly prolonged survival compared with the crizotinib group (5.6 months), and the risk of disease progression or death was reduced by 75% compared with the crizotinib group (HR 0.25; 95% CI 0.14-0.46; P <>

ALTA-1L final analysis cORR, PFS

•For patients with arbitrary brain metastasis at baseline, the 4-year OS rate of first-line treatment of bugtinib can reach 71% (71% vs 44%; HR 0.43; P=0.020), which can reduce the risk of death by 57%.

ALTA-1L Final Analysis OS

▌CROWN: Ultra-long follow-up, unprecedentedly end-

•CROWN study is a randomized, open-label, phase III multicenter clinical study comparing the efficacy and safety of lorlatinib and crizotinib in patients with ALK-positive advanced NSCLC systemic treatment without metastatic disease. The study was followed up for more than 3 years (36.7 months), but the median PFS still did not reach the academic amazement.

•Study results show that for patients with baseline with brain metastasis, lorlatinib can effectively delay the progression of central nervous system compared with crizotinib (NE vs 7.2 months), and the objective intracranial response rate (ORR) can reach 83.3% (23.1% in vs crizotinib group);

CROWN study intracranial ORR, DOR, and PFS

•In patients without brain metastasis at baseline, the rate of intracranial progression without brain metastasis for 3 years was as high as 99.1%, while the rate of crizotinib in crizotinib was 49.8%.

CROWN study CNS progress rate

ALTA-1L study and CROWN study suggest that buugitinib and lorlatinib have good efficacy in preventing brain metastasis and preventing and treating brain metastasis progress.

Currently, many studies have shown that second/third generation ALK-TKI have good results in improving the ORR of patients with ALK-positive NSCLC brain metastasis compared with first generation, and can significantly prolong the patient's survival.However, there are certain differences in PFS, remission depth, and brain metastasis effects of second- and third-generation ALK inhibitors. Currently, there is a lack of direct comparison between second- and third-generation drugs. Adverse reactions of

drugs are the main considerations for the first-line treatment choice of ALK-TKI

Although ALK-TKI is generally tolerated compared with traditional cytotoxic drugs, previous studies have shown that various types of ALK-TKI still have adverse reactions in gastrointestinal tract (diarrhea, nausea, vomiting), drug-induced liver injury , cardiovascular adverse reactions and anemia .

In the clinical practice process, attention should be paid to the adverse reactions specific to different ALK-TKIs. When choosing treatment plans, the patient's physical condition and underlying diseases should be fully considered, and different drugs should be individually selected to improve the patient's quality of life and survival benefits.

Accuracy and holistic are the main considerations for the first-line treatment choice of ALK-TKI

ALK fusion mutation patients have relatively long overall survival and more selective treatment drugs. It is of great significance to patients to formulate a set of accurate and holistic plans.

In recent years, more and more research data suggest that the subtype of ALK fusion gene variants will affect the biological characteristics of ALK-positive lung cancer, and the efficacy of different variants in receiving ALK inhibitors also varies. In addition, different ALK gene variants, different ALK inhibitors, and the application of different drug lines will lead to different drug resistance mechanisms. Therefore, the concept of full-process and overall management should be carried out throughout the process, which is also an extremely important consideration for the first-line selection of ALK inhibitors.

screenshot from Professor Wang Zhehai's report

comprehensively considers the factors of drugs, patient factors, accessibility of clinical medication, policies and regulations, as well as guidelines and consensus, making our medication more reasonable. "Being more accurate than precision, and at the same time, the overall concept and full-process management concept make the maximum optimization of backline treatment" is the direction of our future efforts.

Expert Profile

Wang Zhehai

Chief Physician

  • Standing Director of the Chinese Society of Clinical Oncology;

  • Deputy Chairman of the Expert Committee of the Non-small Cell Lung Cancer of the Chinese Society of Clinical Oncology;

  • Deputy Chairman of the Expert Committee of the Anti-tumor Drug Safety of the Chinese Society of Clinical Oncology;

  • Deputy Chairman of the Expert Committee of the Chinese Society of Clinical Oncology;

  • Deputy Chairman of the Expert Committee of the Chinese Society of Clinical Oncology;

  • Deputy Chairman of the Chest Cancer Branch of the Chinese Medical Promotion Association;

  • Deputy Chairman of the Lung Cancer Professional Committee of China Primary Health Care Foundation;

  • Executive Director of Shandong Anti-Cancer Association;

  • Deputy Director of Shandong Cancer Center;

  • Deputy Director of Shandong Cancer Center;

  • Chairman of the Lung Cancer Branch of Shandong Anti-Cancer Association

References:

[1] Zhang I, Zaorsky NG, Palmer JD, et al.Targeting brain metastases in ALK-rearranged non-small-cell lung cancer.Lancet Oncol 2015;16:e510-e521.

This article was first published: Medical tumor channel

Author: Su Xuhan

Editor: Sweet

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