CStone Pharmaceuticals recently announced the key research of the RET inhibitor pralsetinib in the global phase I/II ARROW at the 21st World Lung Cancer Conference (WCLC) online conference in 2020 hosted by the International Association for the Research of Lung Cancer. Results of the study of Chinese patients in China. The results show that pralsetinib has superior and long-lasting clinical anti-tumor activity and is well tolerated and safe in Chinese patients with advanced RET fusion-positive non-small cell lung cancer (NSCLC) who have previously received platinum-based chemotherapy.
pralsetinib is a potent and selective RET inhibitor developed by Blueprint Medicines, a partner of CStone Pharmaceuticals. In June 2018, CStone Pharmaceuticals and Blueprint Medicines reached an exclusive cooperation and licensing agreement to obtain the exclusive development and commercialization rights of pralsetinib in Greater China, including Mainland China, Hong Kong, Macau and Taiwan.
It is worth mentioning that in July 2020, Roche and Blueprint Medicines signed a license and cooperation agreement, obtaining the exclusive right to develop and commercialize the oral RET inhibitor pralsetinib outside the United States (excluding Greater China). In the United States, Genentech, a Roche subsidiary, obtained the joint commercialization rights of pralsetinib and shared profits equally.
pralsetinib is an oral, once-a-day, potent and highly selective RET inhibitor, with the trade name Gavreto. At present, the drug has been approved by the US FDA for the treatment of: (1) Adult patients with metastatic RET fusion-positive non-small cell lung cancer confirmed by the FDA-approved detection method; (2) 12 years old and above who require systemic treatment Adults and children with advanced or metastatic RET-mutated medullary thyroid cancer; (3) Adults and children with advanced or metastatic RET fusion-positive thyroid cancer that requires systemic treatment and is refractory to radioiodine (if applicable). pralsetinib has not been approved for other indications in the United States, and neither China nor medical regulatory agencies in other regions have made an approval decision on any indications for pralsetinib.
The ARROW study (NCT03037385) is a global phase I/II clinical study to evaluate the safety of pralsetinib in patients with RET fusion-positive NSCLC, RET mutant medullary thyroid carcinoma (MTC) and other advanced solid tumors with RET fusion , Tolerability and effectiveness. Data show that pralsetinib has extensive and long-lasting anti-tumor activity in a variety of advanced RET variant solid tumors (including RET fusion-positive NSCLC).
The results reported at the meeting showed that for Chinese patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy in the ARROW study, the efficacy and safety of pralsetinib (400 mg once a day) were consistent with previously reported data on global patients. This is the first time that pralsetinib is used to treat Chinese patients with RET fusion-positive NSCLC who have previously received platinum-containing chemotherapy.
As of the data cut-off date (May 22, 2020), a total of 37 patients with advanced RET fusion-positive NSCLC from 10 Chinese research centers were included in the global ARROW study and received a starting dose of 400 mg (once a day) pralsetinib treatment. All patients received at least one platinum-based chemotherapy regimen, about half (49%) of the patients had received >=3 system treatment regimens, and 32% of the patients received >=3 chemotherapy regimens. Tumor remission was evaluated by blinded independent center review (BICR) using "Solid Tumor Response Evaluation Criteria" (RECIST) version 1.1.
Effectiveness: pralsetinib shows strong clinical activity on RET fusion-positive NSCLC after platinum-containing chemotherapy: (1) Among the 32 patients with evaluable lesions at baseline determined by BICR, the confirmed objective response rate (ORR) was 56 % (95% CI: 38-74%), including 1 complete remission and 17 partial remission (PR). In addition, there are 2 PRs to be confirmed. The disease control rate (DCR) was 97%, of which 1 case was not evaluable. (2) Among 18 patients with confirmed remission, the median time to first remission was 1.9 months. (3) As of the data cutoff date, 89% (16/18) of confirmed remission patients are still receiving treatment. (4) The median duration of response (DOR) was not reached, and the 6-month DOR rate was 83%. (5) Regardless of the RET fusion genotype, there is remission.
Safety: pralsetinib is well tolerated and its safety is controllable. In the study, pralsetinib was well tolerated, and there was no treatment termination or death caused by adverse events related to pralsetinib.
The molecular structure of pralsetinib (picture source: aobious.com)
RET-activated fusions and mutations are key disease drivers for many cancer types, including NSCLC and MTC. RET fusion involves about 1-2% of NSCLC patients and about 10-20% of patients with papillary thyroid carcinoma (PTC), while RET mutations involve about 90% of patients with advanced MTC. In addition, low-frequency RET changes have also been observed in colorectal cancer, breast cancer, pancreatic cancer and other cancers, and RET fusion has also been observed in patients with drug-resistant, EGFR-mutated NSCLC.
pralsetinib was designed by the research team of Blueprint Medicines based on its proprietary compound library. In preclinical studies, pralsetinib has always shown sub-nanomolar titers against the most common RET gene fusions, activating mutations and drug resistance mutations. In addition, the selectivity of pralsetinib for RET is significantly improved compared with approved multi-kinase inhibitors. Among them, the effectiveness of pralsetinib is more than 90 times higher than that of VEGFR2. By inhibiting primary and secondary mutations, pralsetinib is expected to overcome and prevent the occurrence of clinical drug resistance. This treatment method is expected to achieve long-lasting clinical remission in patients with different RET variants, and has good safety.
It is worth mentioning that Eli Lilly Retevmo (selpercatinib) is the first approved RET inhibitor. The drug was developed by Loxo Oncology, an oncology company under Eli Lilly and was approved by the U.S. FDA in May 2020. It is used to treat patients with 3 types of tumors with genetic alterations (mutations or fusions) in the RET gene: non-small cell lung cancer (NSCLC) , Medullary Thyroid Cancer (MTC), other types of thyroid cancer.
In terms of medication, Retevmo is taken orally twice a day, with or without food. Retevmo is the first therapeutic drug approved specifically for cancer patients carrying RET genetic changes. The drug is suitable for the treatment of: (1) Adult patients with advanced or metastatic NSCLC; (2) Patients with advanced or metastatic MTC who are ≥12 years old and require systemic treatment; (3) Are ≥12 years old and require systemic treatment and are radioactive Patients with advanced RET fusion-positive thyroid cancer who have stopped responding to iodine therapy or are not suitable for radioactive iodine therapy. It is particularly worth mentioning that up to 50% of RET fusion-positive NSCLC patients may have tumor brain metastases. Among patients with baseline brain metastases, Retevmo has shown a strong effect, with intracranial remission (CNS-ORR) as high as 91% (n =10/11).