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Professor Zheng Qianqian: The data of 2022 ESMO platinib for the treatment of RET mutant thyroid cancer have been updated again to continue to write a longer survival

 Last Update: 2022-11-01
 Source: Internet
 Author: User

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The European Society of Medical Oncology (ESMO), Europe's most prestigious and influential oncology conference, recently concluded successfully in Paris, France, and the stars of thyroid cancer (TC) system treatment shined, not only the continuous digging of basic research, but also the progress of innovative therapies
.
Among them, the TC study data in the ARROW study continued to be updated, once again confirming the efficacy and safety
of platinib in patients with RET mutant thyroid cancer.
Yimaitong invited Professor Zheng Qianqian of Tianjin Medical University Cancer Hospital to interpret
the data update.

Expert profiles

Professor Zheng Qianqian

Director of the Department of Thyroid and Neck Oncology, Tianjin Medical University Cancer Hospital

Chief physician and doctoral supervisor

Member of the Standing Committee and Secretary-General of the Thyroid Cancer Professional Committee of the Chinese Anti-Cancer Association

Member of the Standing Committee and Secretary-General of the Head and Neck Cancer Professional Committee of the Chinese Anti-Cancer Association

Standing member of the Youth Council of China Anti-Cancer Association

Youth Committee Member of Oncology Branch of Chinese Medical Association

Standing Director of China Medical Education Association

Vice Chairman of the Head and Neck Oncology Professional Committee of China Medical Education Association

Member of the Asia-Pacific Thyroid Society (AOTA).

Pratinib is a potent, highly selective, panneoplastic RET inhibitor that has been approved at home and abroad for the treatment
of advanced or metastatic RET mutant MTC requiring systemic therapy and adults with advanced or metastatic RET fusion-positive TC requiring systemic therapy and refractory to radioactive iodine (if radioactive iodine is applicable) and children 12 years of age and older.
The results of platinib in the treatment of advanced TC of RET mutation have been successively landed in top international journals and academic events
.
At this ESMO Annual Meeting, the ARROW study continued to update the objective
response rate (ORR), median duration of response (mDoR) and median progression-free survival (mPFS) of the three cohorts.

As of October 18, 2021, the intention-to-treat population (ITT) included 145 patients with RET-mutated MTC (vandetanib/cabozantinib [C/V] treated patients: n=67; patients treated with other systems: n=11; untreated patients: n=67) and 25 patients
with treated (including radioactive iodine) RET fusion-positive TC.
Of the patients treated with C/V RET mutations, 82.
1% received 1 or 2 lines and 10.
4% had baseline central nervous system (CNS) metastases
.
Forty percent of patients with RET fusion-positive TC had received ≥ third-line therapy, and forty percent had baseline CNS metastases
.

Table 1 Baseline characteristics of the ITT population 1

Table 2 Updated results of the disease evaluable population and the ITT population1

Pratinib helps patients with RET mutant MTC survive for a long time

The results showed that the ORR and 18-month DoR rates of Pratinib in patients with C/V treated RET mutant MTC were similar to those of 55.
7% and 67.
5%, respectively, with mDoR extended from 21.
7 months to 25.
8 months and mPFS updated to 25.
8 months
.

Fig.
1 Target lesion remission in patients with C/V treated RET mutant MTC

In patients with treatment-new RET mutation MTC, the ORR and mDoR of platinib were consistent with the previous ones, 77.
4% and NR, respectively, and the mDoR rate was updated from 74% to 79.
8%
at 18 months.
In addition, the mPFS and mOS of this cohort are still not reached
in this update.

Fig.
2 Target lesion remission in treatment-newly-treated RET-mutant MTC patients

The waterfall plot shows that in the C/V treated and treatment-naïve RET mutation MTC population, platinib is effective
for RET M818T, cysteine domain mutations and other types.

Table 3 mPFS and mOS update results for ITT population

Fig.
3 PFS results of RET mutant MTC population

Pratinib has a strong and sustained remission in the treatment of RET fusion thyroid cancer, providing a new option for patients refractory to iodine

In this update, the cohort of patients with RET fusion TC expanded from 21 to 25, and the population baseline was similar
to the past.
The updated results showed that the ORR and 18-month DoR rates for this cohort were 90.
9% and 50.
2%, respectively, and the mDoR and mPFS were 23.
6 months and 25.
4 months
, respectively.

In terms of safety, the overall tolerability of platinib was controllable and manageable, and the incidence of dose reduction or interruption due to treatment-related adverse events (TRAEs) was 52.
6% and 5.
7%,
respectively.
The results of this update are consistent
with previously reported safety profiles of platinib.

Professor Zheng Qianqian's comments:

Precise detection helps precise diagnosis and treatment

Targeted drug-based systemic therapy has emerged as an important treatment option
for patients with inoperable or iodine-refractory (RAIR) thyroid cancer.
Multi-kinase inhibitors (MKIs) are widely used targeted drugs in clinical practice, but because MKI sometimes has a stronger effect on other receptors than it does on TC oncogenes, "off-targeting" can lead to some adverse events (AEs), which in turn leads to dose reduction or discontinuation, affecting the quality of life and prognosis of patients2-3
.
Tyrosine kinase inhibitors (TKIs) that target specific oncogene alterations are currently a research hotspot
in the field of TC.

RET gene regulates cell proliferation, growth, differentiation, migration and apoptosis, and RET gene variants are considered to be important factors in the formation and development of multiple tumor species such as thyroid cancer4-5
.
Studies have shown RET mutations in almost all hereditary MTCs and about 50% of sporadic MTCs, RET fusion in about 10%-20% of patients with papillary thyroid carcinoma (PTC), and RET/PTC rearrangement 6-7
in 19.
4% of RAIR PTCs.
Therefore, accurate detection of TC-related genetic changes not only helps to understand its pathogenesis, but also facilitates the formulation
of treatment plans.

Pratinib continues to maintain first-line benefits, and more clinical application scenarios will be explored in the future

Data updated at this ESMO Annual Meeting show that platinib continues to maintain excellent clinical efficacy and manageable safety
in RET variant TC.
As of October 18, 2021, both mDoR and mPFS in patients with C/V treated RET-mutated MTC were 25.
8 months, but not achieved in treatment-new-treated RET-mutated MTC, suggesting that platinib will bring longer survival benefits
to treatment-new MTC.
In addition, both for the M918T site mutation with a poor prognosis, or for other mutant subtypes, platinib has shown significant anti-tumor effects
.

The sample size of the RET fusion-positive TC cohort continues to expand in this update, from 21 to 25 in
the previous case.
Baseline showed that 40% of patients had received ≥ 3-line system therapy, and 40% of patients had baseline CNS metastases
.
Even with many adverse prognostic factors, platinib achieved 90.
9% ORR, 23.
6-month mDoR, and 25.
4-month mPFS
in patients treated with RET fusion-positive TC.
Notably, the median to first response time in this patient population was 1.
9 months8, suggesting that platinib provides rapid and sustained anti-tumor effects
。 With its precise clinical advantages, platinib has been included in a number of authoritative diagnosis and treatment guidelines, including NCCN Thyroid Cancer Guidelines, Chinese Guidelines for Integrated Diagnosis and Treatment of Tumor (CACA)—Thyroid Cancer, CSCO Differentiated Thyroid Cancer Diagnosis and Treatment Guidelines (2021), Expert Consensus on RET Gene Testing and Clinical Application of Thyroid Cancer 2021 Edition, and the upcoming CSCO Guidelines for the Diagnosis and Treatment of Medullary Thyroid Cancer (2022), and the Chinese Expert Consensus on the Application of Targeted Drugs for Advanced Thyroid Cancer ( 2022 edition)" and other guideline consensus, which has become an important part of the standardized treatment of
thyroid cancer in China.

From a surgical perspective, a high ORR of pratinib suggests that it may provide an option
for neoadjuvant therapy in patients with RET variant TC.
Preliminary studies have shown that short-term neoadjuvant targeted therapy can shrink tumors, reduce tumor invasion of surrounding tissues and organs, transform inoperable into operable, reduce the difficulty and risk of surgery, and improve the curative properties of surgery9
.
It is expected that platinib can explore its use in the perioperative period and in combination with other targeted and immune drugs in the future, so as to expand the application population and benefit more patients
.

References

1、 Mimi I.
Hu, Vivek Subbiah, Aaron S.
Mansfield, et al.
Updated ARROW data: pralsetinib in patients with advanced or metastatic RET-altered thyroid cancer.
2022ESMO 1654P.

2.
Zhang Yingchao,Deng Xianzhao,Guo Bomin,Ding Zheng,Yang Zhili,Wu Bo,Fan Youben.
New progress and application of molecular diagnosis and targeted therapy for thyroid cancer[J].
Chinese Journal of Endocrine Surgery,2021,15(05):546-550.
)

3、 Subbiah V, Hu MI, Wirth LJ, et al.
Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study [published correction appears in Lancet Diabetes Endocrinol.
2021 Oct; 9(10):e4].
Lancet Diabetes Endocrinol.
2021; 9(8):491-501.

4.
SONG Chuangye, YAN Li, MENG Yanlin, SHANG Peizhong, LV Ruichang, LIU Bing, ZHANG Jianghua, ZHANG Kejian.
Influencing factors related to the occurrence, development and prognosis of thyroid cancer[J].
Chinese Journal of General Surgery(Electronic Edition),2020,14(01):72-75.
)

5.
LUO Dingyuan, LIAO Jianwei.
Expert consensus on RET gene detection and clinical application of thyroid cancer (2021 edition)[J].
Chinese Journal of General Surgery(Electronic Edition),2022,16(01):1-8.
)

6、 Subbiah V, Gainor JF, Rahal R, et al.
Precision Targeted Therapy with BLU-667 for RET-Driven Cancers.
Cancer Discov.
2018; 8(7):836-849.

7、 Romei C, Ciampi R, Faviana P, et al.
BRAFV600E mutation, but not RET/PTC rearrangements, is correlated with a lower expression of both thyroperoxidase and sodium iodide symporter genes in papillary thyroid cancer.
Endocr Relat Cancer.
2008; 15(2):511-520.

8、 Subbiah V, Hu MI, Wirth LJ, et al.
Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study [published correction appears in Lancet Diabetes Endocrinol.
2021 Oct; 9(10):e4].
Lancet Diabetes Endocrinol.
2021; 9(8):491-501.

9.
Zhang Yingchao, Deng Xianzhao, Guo Bomin, Ding Zheng, Yang Zhili, Wu Bo, Fan Youben.
New progress and application of molecular diagnosis and targeted therapy for thyroid cancer[J].
Chinese Journal of Endocrine Surgery,2021,15(05):546-550.
)

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