With a sharp armor and a decisive victory over thousands of "cases" | donatifonib helps PATIENTS WITH RAIR-DTC survive for a long time

Age: 60 years old

Basics: The patient underwent radical thyroid cancer resection in 2013 and received his last radiation iodine treatment

Personal history: no history of smoking, alcohol consumption, allergies, and substance abuse

• Surgical treatment: radical resection of left thyroid cancer + right lobectomy of the thyroid gland + bilateral lymph node exploration + bilateral recurrent laryngeal anatomy;

• Pathological results: Papillary thyroid carcinoma (PTC), grade of differentiation unknown

  
  

From 30 December 2013 to 2 March 2017, the patient was treated with radioactive iodine

Treatment:

• On December 30, 2013, the patient received 100 mCi radioactive iodine therapy;

• On 6 January 2016, the patient received 150 mCi radioactive iodine therapy

  
  

• On 10 June 2016, the patient received 150mCi radioactive iodine treatment at the local hospital;

• On 2 March 2017, the patient received 150 mCi radioactive iodine treatment

  
  

On 29 August 2017, a patient review revealed disease progression

• On imaging assessment, the upper right lung nodule is 25 mm, and there are multiple nodules in both lungs, and the patient has disease progression (PD

  
  

• After ¹³¹¹I systemic imaging and consultation assessment, no significant iodine uptake was seen in the thyroid area of the patient, and no obvious abnormal concentration was
  seen in other parts of the body.
  
  

• After screening, the patients met the "multicenter, randomized, double-blind, placebo-controlled Phase III clinical trial to evaluate the efficacy and safety of dornafenib tosylate tablets in the treatment of locally advanced/metastatic iodine-refractory differentiated thyroid cancer (RAIR-DTC)" (ZGDD3 study) conducted by Henan Provincial Cancer Hospital, and were enrolled in the clinical trial
  .
  
  

Donafenib treatment

• Patient baseline: height 160 cm, weight 70 kg, BMI 27.
  3 kg/m², Eastern Tumor Collaboration Group Physical Condition Score (ECOG PS)1, no previous history of tyrosine kinase inhibitor (TKI) therapy;

• Tumor baseline: TxN1bM1 (lung metastases), target lesion of the upper right lung 25 mm, multiple nodules in both lungs;
  

• Laboratory baseline: thyroid-stimulating hormone (TSH) 0.
  08mIU/L (local laboratory); Thyroglobulin (Tg) 40.
  79 ng/mL, thyroglobulin antibody (TgAb) 0.
  1 IU/mL (local laboratory).
  
  
  

• On 6 September 2017, the patient was enrolled in a trial and an oral polykinase inhibitor, dornafenib (300 mg twice daily),
  was initiated.
  
  

• At week 8 of enrollment, the patient's Tg level dropped to 22.
  46 ng/ml and the disease was partially relieved (PR);

• At week 120 of enrollment, the patient reached a minimum SOD of the target lesion and retreated to 13 mm
  .
  
  Currently, the patient is still receiving donalfenib (58 months
  of medication).
  

Laboratory evaluation

• Tg levels and target lesion size varied between the screening period and 228 weeks of treatment

Imaging studies

• Baseline to 27 December 2019, imaging changes for lung target lesions

• Baseline to 27 December 2019, radiographic changes in non-target lesions in the lungs

Dornafenib treatment-related adverse reactions (TRAE) occur

• Other TRAEs are CTCAE grade 1 and include arthralgia, elevated aspartame aminotransferase, elevated alanine aminotransferase, hypopigmentation of the skin, stomach pain, weight loss, insomnia, loss of appetite, and diarrhea
  .
  
  

This case was diagnosed with PTC, and after undergoing surgery such as radical resection of left thyroid cancer, the disease progressed after multiple radiation iodine therapy, and the lesion metastasized to the
lungs.

By ¹³¹I systemic imaging, the patient was diagnosed that the disease had progressed to iodine refractory
.

On September 6, 2017, after multiple evaluations, the patient met the admission criteria of the ZGDD3 study and was enrolled in the clinical study
.

At the first evaluation of efficacy, donafenib showed good efficacy: the patient's Tg level decreased significantly at week 4 and fluctuated in a small range of TgAb levels during treatment; At week 8, imaging findings suggest that the patient's tumor has reached PR
.

As of now, patients are still taking donalfenib, have a progression-free survival (PFS) of 58 months, and maintain a PR status
for the tumor.

During the treatment period, the patient developed 3 grade TRAEs (hypertension and oral mucositis), and after symptomatic treatment, the dose was reduced to resume the drug, and other adverse reactions were 1-2 grades, and the overall tolerance was good
.

Professor Yang Hui

• Chief physician, master tutor and department director of the Department of Nuclear Medicine, Henan Provincial Cancer Hospital

• Director of Henan Provincial Key Laboratory of Precision Diagnosis and Treatment of Tumor Nuclear Medicine

• Chairman-elect of the Tumor Nuclear Medicine Professional Committee of the Chinese Anti-Cancer Association

• Vice Chairman of the Nuclear Medicine Expert Committee of the Chinese Society of Clinical Oncology

• Member of the Standing Committee of the Nuclear Medicine Branch of the China Imaging Technology Research Association

• Vice Chairman of the Radioactive Particle Working Committee of the Nuclear Medicine Branch of the Chinese Medical Association

• Vice Chairman of particle therapy branch of the Tumor Minimally Invasive Therapy Professional Committee of the Chinese Anti-Cancer Association

• Member of the Standing Committee of the Editorial Board of the Journal of Tumor Imaging

PTC is the most common pathological type of thyroid cancer, accounting for about 90% of all thyroid cancers, and is often referred to as DTC¹ together with thyroid follicular carcinoma (FTC
).

Most DTC patients achieve a good prognosis with surgery, TSH suppression therapy, and a combination of radioactive iodine, but some DTC patients still develop distant metastases and lose the ability to concentrate polyiodine during the natural course of the disease or treatment, developing RAIN-DTC²
.

Compared with well-iodized DTC patients, the survival time of RAIR-DTC patients was significantly shortened, with an average survival of only 3 to 5 years and a 10-year survival rate of about 10% ³
.

The presence of high expression of VEGF and its receptors in DTC, as well as genetic alterations such as BRAF V600E mutation, RET rearrangement, and RAS point mutation, laid a good foundation for the application of polykinase inhibitors¹
.

Donafenib is a deuterated polykinase inhibitor that can effectively inhibit activities such as VEGFR and PDGFR, and can also directly inhibit a variety of Raf kinases and downstream Raf/MEK/ERK signaling pathways, and significantly inhibit tumor growth and angiogenesis⁴ in preclinical
studies.

In a randomized multicenter, open-label Phase II.
-III study (ZGDH3 study) of 668 patients with advanced hepatocellular carcinoma, the overall survival (OS) of donatin was significantly better than that of sorafenib (full assay: 12.
1 months vs 10.
3 months, HR=0.
831, P=0.
0245)⁵
.

The success of the ZGDH3 study has laid a good foundation
for further expansion of indications for donafenib.

The ZGDD3 study in which patients enrolled in this case evaluated the efficacy and safety
of donatin in patients with locally advanced/metastatic RAIR-DTC.

As analysed by the Independent Data Monitoring Board (IDMC), the mid-term results of the study met the criteria for effective early termination and ended prematurely
.

Part of the results of the study will be announced
next week at the annual meeting of the European Society of Oncology (ESMO).

It is worth mentioning that on August 12, according to the official website of the State Drug Administration of China (NMPA), donafenib was officially approved for the treatment of patients
with progressive, locally advanced or metastatic radioactive iodine refractory differentiated thyroid cancer (RAIR-DTC).

It is believed that in the future, donafenib will bring new treatment options to DTC patients
.

References

1.
Thyroid Cancer Diagnosis and Treatment Guidelines 2022 Edition.

2.
Renfei Wang, Yong Wang, Feng Shi, et al.
Consensus on the Diagnosis and Treatment of Iodine-Refractory Differentiated Thyroid Cancer (2019 Edition).
Chinese Journal of Cancer,2019,29(06):476-480.

3.
Cong Hui,Liang Jun,Lin Yansong.
Diagnosis and targeted therapy of iodine-refractory differentiated thyroid cancer[J].
International Journal of Radiological Nuclear Medicine,2015,39(01):25-31.

4.
Li Su,Qin Shukui.
Deuterated drugs and their application prospects in the research and development of new anti-tumor drugs[J].
Journal of Clinical Oncology,2020,25(12):1138-1143.

5.
Qin S, Bi F, Gu S, et al.
Donafenib Versus Sorafenib in First-Line Treatment of Unresectable or Metastatic Hepatocellular Carcinoma: A Randomized, Open-Label, Parallel-Controlled Phase II-III Trial.
J Clin Oncol.
2021; 39(27):3002-3011.

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