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It is well known that neurotrophic tyrosine receptor kinase (NTRK) gene fusion is called the "diamond" target, and the number of new cases of NTRK gene fusion solid tumors is still high every year due to the large Chinese base
.
On April 8, 2022, the National Medical Products Administration (NMPA) approved the precision tumor therapy drug larotinib (Vitec) ® for the treatment
of adult and pediatric solid tumor patients with NTRK gene fusion.
Larotinib is the world's first precision targeted drug with no tumor types, covering all ages (including infants and young children), and is the first choice
for patients with advanced NTRK gene fusion tumors.
On December 24, 2022, the 2022 Pan-tumor Precision Diagnosis and Treatment Summit Forum and Vitekai ® China Listing Conference was successfully held
.
At the meeting, Professor Qi Changsong of Peking University Cancer Hospital introduced the new practice of pan-tumor precision treatment to us.
Expert profiles
Professor Qi Changsong
Deputy Chief Physician of Phase I Clinical Ward, Beijing Cancer Hospital
M.
DMainly engaged in solid tumor cell immunotherapy, standardized diagnosis and treatment of digestive system tumors and individualized treatment
.Member and Secretary of the Chinese Society of Clinical Oncology (CSCO) Gastrointestinal Stromal Tumor Committee
Member of the Young Expert Committee of the Chinese Society of Clinical Oncology (CSCO).
Secretary-General of the Gastric Cancer Prevention and Control Committee of Beijing Cancer Prevention and Control Society
Member of Oncology Branch of Chinese Geriatrics Society
Member of Gastrointestinal Surgery Branch of Chinese Medical Association
Editorial Board Member of Electronic Journal of Comprehensive Oncology Therapy
Young Editorial Board Member of Health Care Science
precision guidance,
Prolong survival of patients with different genetic profiles
With the development of China's economy, the improvement of medical and health conditions, and the wide application of a variety of treatment methods, the survival period of cancer patients has been significantly extended and the quality of life has been improved.
For example, chemotherapy prolongs median overall survival (OS) 1 to 4 in patients with advanced lung squamous cell carcinoma (2.
3 versus 11 months), advanced gastric cancer (1.
9 versus 7.
0 months), and advanced bowel cancer (5 versus 10 to 22.
2 months) compared with natural prognosis
。 Professor Qi said that in recent years, with the deepening of our understanding of genomics, we have gradually realized that most tumor patients have driver gene mutations, and commonly used chemotherapy drugs in clinical practice do not have the ability to target and recognize tumor cells, so traditional chemotherapy has certain limitations
.
Patients have different types of gene mutations, different treatment options, and different prognosis, and individualized targeted treatment plans according to the genetic characteristics of tumor patients, which can help prolong the survival
of patients.
Professor Qi pointed out that NTRK gene fusion is a newly discovered pan-tumor target, with a low positive rate in common tumors and high
in some rare pathological subtypes.
Under normal circumstances, TRK receptors are involved in the regulation of pain, appetite and mood, and NTRK gene fusion leads to the production of abnormal conformational TRK fusion protein, which continues to overactivate downstream signaling pathways, resulting in tumor cell proliferation and growth
.
The emergence of the highly selective NTRK gene fusion targeted drug lalotinib has successfully opened a new era
of tumor treatment that "only looks at the target, regardless of tumor type".
Fig.
1 Incidence of NTRK gene fusion in different tumor species
- Larotinib is effective
The rarotinib registry clinical trial consists of three clinical trials: phase I adults, phase I/II children, phase II adolescents and adults (NCT02122913, NCT02637687, NCT02576431).
The study analysis was conducted according to the intention-to-treat principle, and the main dosing regimen for patients was 100 mg BID for 28 consecutive days
.
The primary endpoint was objective response rate (ORR) and secondary endpoints were duration of response (DoR), progression-free survival (PFS), OS, and safety
.
The three trials included 25 tumor types, totaling 244 patients with
NTRK gene fusion tumors.
Fig.
2 Clinical trial design for rarotinib registration
4 months (95% CI 19.
3-34.
3), and a 4-year OS rate of 64% as of July 20215
。 To rule out the confounding effect of continued enrollment on median DoR, the investigators also exploratorily analyzed 164 patients with a minimum follow-up of 28 months, with an ORR and median DoR of 74% and 34.
5 months, respectively.
5.
A number of large-scale clinical studies have shown that larotinib has a significant
effect in the treatment of NTRK gene fusion tumors.
Fig.
3 Efficacy data of larotinib
- Larotinib has a good safety profile
In addition, lalotinib was well tolerated in the treatment of NTRK gene fusion solid tumors, and most of the treatment-related adverse events (TRAEs) were grade 1-2, and 32 patients (20%) had grade 3-4 TRAEs, mainly neutrophil decline and elevated alanine aminotransferase and aspartate aminotransferase, and 3 (2%) patients stopped treatment due to TRAEs5
。 In summary, larotinib has a good long-term safety profile
.
Fig.
4 Safety data of larotinib
- Authoritative guidelines recommend larotinib
Based on the good survival benefit of larotinib, the National Comprehensive Cancer Network (NCCN) clinical practice guidelines recommend lalotinib for the treatment
of NTRK gene fusion-positive non-small cell lung cancer, colorectal cancer, thyroid cancer, soft tissue sarcoma and other tumors.
The Chinese Society of Clinical Oncology (CSCO) lung cancer guidelines recommend larotinib for first-line treatment of NTRK gene fusion-positive patients, and the Chinese Anti-Cancer Association (CACA) bowel cancer guidelines recommend lalotinib for NTRK gene fusion-positive patients
.
On August 25, 2022, China's first "Expert Consensus on Clinical Diagnosis and Treatment of NTRK Fusion Gene in Solid Tumors in China" was officially released, which strongly recommended larotinib for the treatment of NTRK gene fusion-positive patients
.
The formulation of this consensus aims to promote the standardized diagnosis and treatment of NTRK gene fusion and provide clinicians with more practical guidance
.
- Larotinib case sharing
Professor Qi introduced a case of lalotinib in the treatment of neuroendocrine carcinoma, in which the disease progressed after receiving chemotherapy and immunotherapy, and then enrolled in the rarotinib clinical trial, during which the efficacy of multiple lesions was assessed as partial remission (PR), overall tumor burden PR, and tumor shrinkage
.
This case suggests that larotinib can see a rapid, efficient and sustained response
to NTRK gene fusion tumor patients, regardless of the location of the tumor lesion.
Fig.
5 Larotinib case sharing - neuroendocrine carcinoma
orderly medication,
Maximize benefits for patients across different treatment lines
With the continuous enrichment of the "weapon" of tumor targeted therapy, we need to think about how to arrange the application order of drugs more reasonably to maximize the benefits of patients.
Professor Qi said that taking colorectal cancer (mCRC) as an example, there are many targeted therapy options for mCRC in clinical practice, mainly including targeted therapy
targeting vascular endothelial growth factor and receptor (VEGF/VEGFR) and epidermal growth factor receptor (EGFR).
Then, how to select and arrange mCRC drugs has become a clinical difficulty
.
The study data suggest that the median OS of patients with regorafenib sequential fruquintinib is significantly longer by 9.
7 months (28.
1 versus 18.
4 months) in patients with regorafenib sequential compared with fruquintinib sequential regorafenib in the later line of mCRC6
。 The FRESCO-2 study, which published results this year, further confirmed that patients with third-line regorafenib and fourth-line fruquintinib had a greater risk of death (38 versus 28 percent) compared with third-line TAS-102 and fourth-line fruquintinib.
7
More and more evidence leads us to believe that rational planning and orderly application of precision therapy drugs can lead to better survival outcomes for cancer patients
.
Fig.
6 Regorafenib sequential fruquintinib prolongs OS
combination therapy,
Synergies benefit more patients
With the advent of the era of precision tumor treatment, real-world studies suggest that a single treatment method has not achieved satisfactory results, and the combination therapy model has become a current research hotspot and treatment direction.
Professor Qi said that on the basis of the previous ten tumor marker features, 4 new features will be added to tumor markers in 2022, including unlocking phenotypic plasticity, non-mutant epigenetic reprogramming, peptide microbiome and senescent cell concepts, and our understanding of the tumor microenvironment is still enriching
.
In this context, how to achieve "1+1>2" through the combination of different treatment methods is particularly important
.
Professor Qi said that still taking mCRC as an example, multiple studies have found that small molecule TKI combined with immunotherapy has significantly improved
OS compared with immunotherapy alone.
The REGONIVO "enhanced" study, which published results from ESMO in 2022, further confirmed that the median OS of regorafenib in combination with double-free regimen in patients with microsatellite stable (MSS) mCRC reached nearly 20 months8
.
Professor Qi emphasized that tumor combination therapy and MDT model are current hot spots and future trends, and the synergy of different types of drugs has played an important role
in the field of tumors.
FIG.
7 RESULTS OF THE REGONIVO "ENHANCED" STUDY
summary
Finally, Professor Qi concluded that in the past decade, healthy China has risen to the level of a national strategy and become a new concept
of governance.
In the field of tumors, radical treatment or maximum control of tumors, prolonging the survival of patients, and improving the quality of life are still important goals
of treatment.
Under this goal, tumor treatment selection with more precise targets, more reasonable drug sequencing and more standardized combination regimens will ultimately help patients get more benefits
.
We firmly believe that the listing of lalotinib is a revolution in the treatment of pan-tumors in China and an opportunity
to improve clinical drug use.
References:
1.
Seung SJ, et al.
Curr Oncol.
2020 Aug; 27(4):e361-e367.
2.
Hu HM, et al.
Sci Rep.
2021 Nov 30; 11(1):23142.
3.
Omura K.
Digestion2008; 77(suppl 1):13–22.
4.
Wang et al.
Chin J Cancer (2016) 35:8.
5.
A Drilon,et al.
2022 ASCO Abstract 3100.
6.
Zhang Q, et al.
Clin Colorectal Cancer.
2022 Jan 20; S1533-0028(22)00007-X.
7.
Pietrantonio F, et al.
2022 ESMO invited discussant LBA25 and 316O.
8.
Fakih M, et al.
2022 ESMO abstract 320MO.
Edited by Kristen
Revised: Shirley
Typesetting: Yuna
Execution: Babel
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