RET Target - A new dawn in the treatment of non-small cell lung cancer.

Lilly recently announced the FDA's approval of the listing of its new drug, Selpercatinib, for the treatment of RET gene fusion-positive non-small cell lung cancer (NSCLC) adult patients, RET gene mutation sylomyelin cancer (MTC) patients and RET gene fusion-positive thyroid cancer patients.
non-small cell lung cancer treatment ushered in their own another important target, this paper makes a simple summary.
1985, the high molecular weight DNA of human T-cell lymphoma was transfected to NIH3T3 cells and RET was discovered to be a new conversion gene. The gene is activated by DNA rearrangement, in which two unconnected fragments of human DNA are recombined to produce a new transcription unit. The study then located RET on chromosome 10q11.2, where it encoded a receptor tyrosine kinase. RET is a one-way transmembrane protein with a typical intracellular tyrosine kinase domain (Figure 1). Although the "classic" activation of the receptor tyrosine kinase (RTK) is due to ligand-receptor interactions, RET activation requires the interaction between its ligand (glioblastic-derived neurotrophic factor family ligand, GFLS) and the auxiliary receptor (GFLS family receptor-alpha). The GFL-GFR alpha complex binds to Ret's extracellular domain, causing phosphorylation of the intracellular tyrosine kinase domain, thus activating several pathways, including MAPK, PI3K, JAK-STAT, PKAand PKC, as shown in Figure 1 below.. RET rearrangement was first discovered in 2011 in a young male who did not smoke for lung adenocarcinoma. 1% to 2% of NSCLCs have RET rearrangement. In NSCLC, the correlation between ion radiation and RET rearrangement is still unclear, even though in vitro experiments have demonstrated the possibility of rearrangement of radiation-induced human lung cancer cells. The first RET rearrangement found in Patients with NSCLC was a box fusion transcript of the Kinesin family 5B gene (KIF5B) and the RET gene (KIF5B-RET). Other upstream fusion partners of RET rearrangement were also found in NSCLC, such as protein 6 (CCDC6), nucleoreceptor co-activation factor 4 (NCOA4), 33 (TRIM33) with tripartite base sequence, myoglobin VC gene (MYO5C), adrenal hormone corticosteroid A5 gene (EPHA5), CAP-G-P Three-body base sequence (TRIM24) containing 24 genes. All of these fusion counterparts have a dipolymerized domain that induces ligand-independent activation of RET kinases, as shown in Figure 1 above. The most common RET fusion in lung cancer is driven protein family members 5B (KIF5B) - RET and CCDC6-RET, followed by NCOA4-RET, TRIM33-RET, ZNF477P-RET, ERCC1-RET, HTR4-RET, CLIP1-RET, as shown in Figure 2 below.
. Most anti-RET drugs are polykinase inhibitors. The approval of these drugs is not limited to patients with CHANGEs in the RET gene. Among these drugs are approved for the treatment of thyroid cancer, such as Cabozantinib, Vandetanib, Lenvatinib and Sorafenib, and are also used in polykinase inhibitors for other malignant tumors, including Alectinib, Sunitinib, Inetedanib, Rego-rafenib and Ponatinib. In 2015, a retrospective analysis of data from the Global Multicenter RET Registry (GLORY), which collected experiencein in the treatment of NSCLC patients with RET rearranged NSCLC. Of the various drugs, only Cabozantinib, Vandetanib, Sunitinib, Lenvatinib and Nintedanib achieved a tumor response rate of up to 30%, while Alectinib, Regorafenib, Sorafenib or Ponatinib did not observe a reaction, as shown in figure 3A. The upstream fusion partners of the RET gene (e.g. KIF5B, CCDC6, EPHA5) had no significant effect on the efficacy indicators (response rate, progression-free survival (PFS), total survival (OS)).. Median PFS is 2.3 months and median OS is 6.8 months. Most patients (about 80%) received only one multikinase RET inhibitor. In addition, the registry provides information on the efficacy of RET re-elongating of platinum-based chemotherapy for non-small cell lung cancer, which is approximately 50%. These results are partially consistent with the results of Phase II trials in terms of response rates and PFS.
so far, five Phase II trials using polykinase RET inhibitors have been completed in this subgroup, as shown in Figure 3B above. A one-arm Phase II trial studied Cabozantinib, a multikinase inhibitor that is active on VEGFR2, MET, ROS1, AX1, KIT and TIE2, but has low activity on RET (IC50 s 5.2nm). Patients in this study had not previously been treated with RET inhibitors. About one-third of these patients responded to Cabozantinib, but no full response was observed. In addition, the early response, tumor reduction rate is high (70% of patients tumor reduction rate of 30%). The median total lifetime was 9.9 months.
Vandetanib is another multikinase inhibitor for VEG-FRS, EGFR and RET, with IC50 higher than Cabozantinib. It conducted studies in two Phase II trials in South Korea and Japan. The median PFS was 4.5 and 4.7 months, with an objective response rate (ORR) of 18% and 53%, respectively. In these studies, differences in the types of upstream fusion partners of the RET gene were recorded. In the Study in Korea, kIF5B-RET rearrangement was associated with no objective response, unlike CCDC6-RET fusion. In the Japanese trials, CCDC6-RET rearrangement scored higher ORRs (83 percent vs. 20 percent) and longer PFS (8.3 vs. 2.9 months) than KIF5B-RET rearrangement.
Sorafenib was also studied in a Phase II trial for patients with ret-rearranged non-small cell lung cancer. Solafenib is a polykinase inhibitor for molecules within cells (i.e. BraF, BRAF and mutations) and cell surfaces (i.e. KIT, FLT3, VEGFRs, and RET). With anti-RET activity, IC50 is 5.9-47nm. In the preclinical model, Solafenib actively combats KIF5B-RET fusion. In this study, only three patients treated with sorafenib did not respond significantly, but one patient observed tumor reduction and improved symptoms, accompanied by persistent and stable disease.
ic50 value of the multikine inhibitor Lenvatinib, which is resistant to VEGFRs, PDGFR-beta, and RET, is 35nM. Antitumor activity was assessed in patients with RET fusion-positive lung adenocarcinoma in The Stage II study. Of the 25 patients, the ORR was 16% and the median PFS was 7.3 months. Ninety-two percent of patients experienced adverse events of 3-4, with the most common adverse reactions being high blood pressure, nausea, anorexia, diarrhea, proteinuria and vomiting.
clinical trials of these polykinase inhibitors show that not all RET re-emission patients respond to these drugs. First, the type of RET fusion partner appears to affect the treatment response, as documented by Vandetanib, and the KIF5B-RET fusion group had worse results than the CCDC6-RET fusion group. In the KIF5B-RET fusion group, the results of the KIF5B-RET fusion group were worse than those of the CCDC6-RET fusion group. So the type of gene fusion has an effect on drug sensitivity. Other causes such as increased expression of EGFR gene pathways, MDM2 enhancement, etc.
in terms of activity and tolerance, various polykinase inhibitors are active but nonspecific to RET, and drug researchers have developed a new anti-RET-specific kinase inhibitor RXDX-105. The IC_ (50) of wild RET, RET rearrangement and mutant RET were 0.3, 0.3 to 0.8 and 5 to 15 nm, respectively. Vascular endothelial growth factor receptors are not inhibited by this drug. It was evaluated in Phase I trials involving 28 RET fusion-positive NSCLC patients. The most common G3 adverse events are no more than 10% and no G4 toxicity is reported. None of the patients with KIF5B-RET fusion had an response, compared with 75 percent in non-KIF5B-RET fusion patients, suggesting that selecting patients based on the rearrangement type had a related effect.
BLU-667 is a new type of small molecule RET inhibitor. It is designed to fight cancer-causing RET mutations, including the most frequent RET rearrangements (e.g. KIF5B-RET and CCDC6-RET), and is highly potency and selective. Compared to Vandetanib, Cabozantinib and RXDX-105, the BLU-667 is 8 to 28 times more lethal to wild RETs, and the BLU-667 is more lethal to RETV804L/M, RETM918T and CCDC6-RET than MKIs. Blu-667 also has anti-RETV804L, RETV804M and RETV804E, these three mutations can produce MKI resistance, thereby inhibiting in vitro proliferation. The BLU-667 has more than 96% selectivity to RET, and the inhibition effect of BLU-667 is at least 10 times that of Vandetanib, Cabozantinib and RXDX-105 in the self-phosphorylation of Ba/F3 cell RET, which inhibits KIF5B-RET fusion. BLU-667 maintains this anti-tumor activity and RET selectivity in the body. Preliminary results from the I/II ARRAW study showed significant anti-tumor activity in the late-stage NSCLC, with ANR of 58% (95% CI, 43-72) and 96% DCR (95% CI, 86-99) of all 48 selected assessable patients. This activity appears to be more pronounced in treating sensitive patients, with an ORR of 71% in a small number of patients (n-7), with the results shown in Figure 4 below. The response to treatment was sustained, with the median DOR not achieved in the first mid-term analysis, and 82% of patients were still receiving treatment at the data cut-off point. It is also worth mentioning that the fusion type of RET does not affect the efficacy, whether or not to accept PD-1/PD-L1 does not affect the efficacy, whether brain metastasis does not affect the efficacy. Safety: Treatment-related toxicity is controllable and reversible at the starting dose of 400 mgQD. The main side effects above level 3 are neutrophil reduction (13%), hypertension (13%), anemia (7%), and a rise in AST (5%). The expanded trial queue is still being recruited, and based on these impressive results, further evaluation of the activity of BLU-667 in treating immature patients is necessary.
. Selpercatinib is another highly selective ATP competitive RET inhibitor with Namor efficacy against multiple RET changes, including the expected acquired drug-resistant mutation. It has the pharmacodynamic characteristics of high bioavailability, strong penetration ability of central nervous system and low potential of drug interaction. May 8, 2020 was approved by the FDA for the treatment of adult syllita cancer of non-small cell lung cancer that is positive for metastatic RET gene fusion, adults with advanced or metastatic RET gene mutations requiring systemic treatment, and pediatric patients over 12 years of age, as well as adults with advanced or metastatic RET gene fusion who require systemic treatment and radioactive iodine incurability, and children over 12 years of age who require systemic treatment and radioactive iodine gene fusion. Based on data from LIBRETTO-001 in Phase I/II clinical studies. The study is the largest clinical study to evaluate a RET inhibitor for patients with RET mutations. The reT target mutation distribution of the main analytical data set of non-small cell lung cancer is shown in Figure 5, which shows that KIF5B and CCDC6 dominate the distribution.. Selpercatinib had an ORR of 59% and 56% of patients with previously untreated (initial) and previously treated (previously treated) RET mutant thyroid myelin cancer (MTC). Previously published NSCLC queue data show that Selpercatinib in the initial treatment, treatment of RET fusion-positive NSCLC patients in the ORR of 85%, 68%, the specific treatment results are shown in Figure 6.. In addition, Selpercatinib is the first RET inhibitor to show strong central nervous system (CNS) activity, with CNSORR up to 91%. The specific treatment results are shown in Figure 7 below.. Most AEs have a lower level and are not related to Selpercatinib treatment, with only 1.7% of AEs due to treatment-related discontinuation, as shown in Figure 8 below.
. In routine clinical care, Klempner SJ,12, etc., conducted a comprehensive genomic mapping (CGP) analysis based on hybrid capture on NSCLC tumor specimens with EGFR mutations before and after the progression of EGFRTKI. Two pairs of NSCLC patients with EGFR mutations before and after EGFRTKI progression were identified, of which both samples after EGFRTKI progression contained box CCDC6-RET rearrangement, while none of the tumor samples before EGFRTKI progresses were found. In addition, analysis of the clinical database showed that in non-small cell lung cancer patients taking Theafinib mutation, another case of NCOA4-RET rearrangement coexisted with activated EGFR mutations. EGFRTKI resistance mechanisms were not found, including EGFRT790M and EGFR.