RET target: a new dawn for the treatment of NSCLC

The treatment of non-small cell lung cancer ushers in another important target of its own, this paper makes a brief summaryIn 1985, the high molecular weight DNA of human T cell lymphoma was transfected into NIH3T3 cells, and RET was found to be a new transforming geneThe gene is activated by DNA rearrangement, in which two unconnected fragments of human DNA are recombined to produce a new transcription unitSubsequently, RET was located on chromosome 10q11.2, where it encodes a receptor tyrosine kinaseRET is a one-way transmembrane protein with a typical intracellular tyrosine kinase domain (Fig1)Although the "classical" activation of receptor tyrosine kinase (RTK) is due to ligand receptor interaction, the activation of RET requires the interaction between its ligand (glial cell-derived neurotrophic factor family ligand, GFLs) and its auxiliary receptor (GFLs family receptor - α)Gfl-gfr α complex combines with the extracellular domain of RET, resulting in phosphorylation of the intracellular tyrosine kinase domain, thus activating several pathways, including MAPK, PI3K, JAK-STAT, pkaand PKC, as shown in Figure 1 [1]< br / > Figure 1Schematic structure of wild-type and rearranged RET protein in cancer cells < br / > RET rearrangement was first found in a young male non-smoking lung adenocarcinoma patient in 20111% - 2% of NSCLC have RET rearrangementIn NSCLC, the correlation between ion radiation and RET rearrangement is still unclear, even though the possibility of RET rearrangement induced by radiation in human lung cancer cells has been demonstrated in vitroThe first RET rearrangement found in NSCLC patients is an in frame fusion transcript of kinesin family 5B gene (kif5b) and RET gene (kif5b-ret)Other upstream fusion partners of RET rearrangement were also found in NSCLC, such as protein 6 (ccdc6), nuclear receptor coactivator 4 (ncoa4), 33 (trim33), myosin VC gene (myo5c), adrenocorticotropin receptor A5 gene (EphA5), link protein family member 1 gene (Clip1) with cap Gly domain, elks / Rab6 -A trisomic motif (trim24) containing 24 genesAll these fusion counterparts have a dimerization domain that can induce ligand independent activation of RET kinase, as shown in Figure 1The most common RET fusion in lung cancer is the kinesin family member 5B (kif5b) - RET and ccdc6-ret, followed by ncoa4-ret, trim33-ret, znf477p-ret, ercc1-ret, htr4-ret and clip1-ret The specific proportion distribution is shown in Figure 2 [2] < br / > Fig 2 The proportion distribution of RET fusion in lung cancer < br / > multi kinase inhibitors < br / > most anti RET drugs are multi kinase inhibitors Approval of these drugs is not limited to patients with RET gene changes Among these drugs, there are drugs approved for the treatment of thyroid cancer, such as cabozantinib, vandetanib, lenvatinib and sorafenib, as well as multi kinase inhibitors for other malignant tumors, including alectinib, sunitinib, inetedanib, Rego rafenib and ponatinib In 2015, data from the global polycentric RET Registry (glory) were analyzed retrospectively The center collected the experience of treating NSCLC patients with RET rearrangement with multiple kinase inhibitors Among all kinds of drugs, only cabozantinib, vandetanib, sunitinib, lenvatinib and nintedanib achieved ~ 30% tumor response rate, while alectinib, regorafenib, sorafenib or ponatinib did not, as shown in Figure 3A [3] The upstream fusion partners of RET gene (such as kif5b, ccdc6 and EphA5) had no significant effect on response rate, PFS and OS < br / > Figure 3 (a) the response rate of retrospective analysis of anti RET multi kinase inhibitor was calculated by glory; (b) the response rate of five phase II trials of anti RET multi kinase inhibitor was 2.3 months in median PFS and 6.8 months in median OS Most patients (about 80%) received only one multi kinase RET inhibitor In addition, the registry also provides information on the efficacy of RET rearrangement of first-line platinum chemotherapy for non-small cell lung cancer, which is about 50% These results are partially consistent with the results of phase II test in terms of response rate and PFS < br / > so far, five phase II trials have been completed in this subgroup using a multi kinase RET inhibitor, as shown in Figure 3B above A single arm phase II trial studied the activity of cabozantinib, a multi kinase inhibitor, on VEGFR2, met, ros1, ax1, kit and Tie2, but very low on RET (IC50 = 5.2nm) The patients in this study have not been treated with RET inhibitors before About one third of these patients responded to cabozantinib, but no complete response was observed In addition, the response is early, and the tumor reduction rate is high (70% of patients with tumor reduction rate ≥ 30%) The median overall survival time was 9.9 months [4] < br / > vandetanib is another multiple kinase inhibitor for veg-frs, EGFR and RET, and its IC50 is higher than that of cabozanib It was studied in two phase II experiments in Korea and Japan The median PFS was 4.5 and 4.7 months, and the objective response rate (ORR) was 18% and 53%, respectively In these studies, the differences in the types of fusion partners upstream of RET gene were recorded In Korean studies, unlike ccdc6-ret, kif5b-ret rearrangement was associated with no objective response In the Japanese experiment, ccdc6-ret obtained higher orr (83% vs 20%) and longer PFS (8.3 vs 2.9 months) than kif5b-ret [5] < br / > sorafenib was also studied in a phase II trial in patients with RET rearranged NSCLC Sorafenib is a multi kinase inhibitor for intracellular (i.e craf, BRAF and mutated BRAF) and cell surface (i.e kit, FLT3, VEGFRs and RET) It has anti RET activity, IC50 = 5.9-47 nm In the preclinical model, sorafenib actively antagonized the fusion of kif5b-ret In this study, only three patients treated with sorafenib did not respond significantly, but one patient observed tumor shrinkage and symptom improvement, accompanied by persistent and stable disease [6] < br / > the IC50 value of lenvatinib, a multi kinase inhibitor against VEGFRs, PDGFR - β and RET, was 35 nm The antitumor activity of RET fusion positive lung adenocarcinoma patients was evaluated in the phase II study In 25 patients, Orr was 16% and median PFS was 7.3 months 92% of patients had grade 3-4 adverse events, the most common adverse reactions were hypertension, nausea, anorexia, diarrhea, proteinuria and vomiting [7] < br / > clinical trials of these multi kinase inhibitors have shown that not all RET rearrangement patients respond to these drugs First of all, the type of RET fusion partner seems to affect the response to treatment, and as vandetanib recorded, the results of the kif5b-ret fusion group were worse than those of the ccdc6-ret fusion group In the kif5b-ret fusion group, compared with the ccdc6-ret fusion group, the results of the kif5b-ret fusion group were worse So the type of gene fusion has an effect on the sensitivity of drugs Other reasons such as increased expression of EGFR gene pathway, increased MDM2 and so on [1] < br / > in terms of activity and tolerance, all kinds of multi kinase inhibitors are active but not specific to ret drug researchers have developed a new anti RET specific kinase inhibitor rxdx-105 IC of wild-type RET, RET rearrangement and mutant ret_ (50) were 0.3, 0.3-0.8 and 5-15 nm, respectively Vascular endothelial growth factor receptor is not inhibited by the drug It was evaluated in a phase I trial involving 28 patients with RET fusion positive NSCLC The most common adverse events of G3 were less than 10%, and no toxicity of G4 was reported There was no response in patients with kif5b-ret fusion, but orr was 75% in patients without kif5b-ret fusion, suggesting that patients selected according to the rearrangement type have a related role [8] < br / > blu-667, an efficient RET inhibitor, is a new 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), with high potency and selectivity Compared with vandetanib, cabozantinib and rxdx-105, blu-667 increased the lethality of RET by 8-28 times; compared with MkIS, blu-667 also increased the lethality of RET v804l / m, RET m918t and ccdc6-ret Blu-667 also has the effect of anti RET v804l, RET V804M and RET v804e These three mutations can produce MKI resistance, thus inhibiting proliferation in vitro The selectivity of blu-667 to RET is more than 96% In terms of inhibiting RET autophosphorylation of baf3 cells fused with kif5b-ret, the inhibitory effect of blu-667 is at least 10 times that of vandetanib, cabozantinib and rxdx-105 Blu-667 maintained this antitumor activity and RET selectivity in vivo [9] The preliminary results of the I / II arraw study showed that RET had significant antitumor activity in the late NSCLC with positive RET fusion In all the 48 evaluable patients, the orr was 58% (95% CI, 43-72), and the DCR was 96% (95% CI, 86-99) This activity seems to be more obvious in the treatment sensitive patients, in this small number of patients (n = 7), Orr is 71%, and the specific treatment results are shown in Figure 4 below The response to treatment was long-lasting and did not reach the median dor in the first interim analysis, with 82% of patients still receiving treatment at the data cut-off point In addition, it is worth mentioning that the fusion type of RET does not affect the efficacy, whether PD-1 / PD-L1 was previously accepted does not affect the efficacy, whether brain metastasis does not affect the efficacy In terms of safety: at the initial dose of 400mg QD, the treatment-related toxicity is controllable and reversible The main side effects were neutropenia (13%), hypertension (13%), anemia (7%), AST (5%) [9] Based on these impressive results, further evaluation of the activity of blu-667 in the treatment of immature patients is necessary [10] < br / > Fig 4 Clinical efficacy of blu-667 in 48 patients with evaluable efficacy It has the characteristics of high bioavailability, strong central nervous system penetration, low drug interaction potential and pharmacokinetics On May 8, 2020, it was approved by FDA for the treatment of adult patients with metastatic RET gene fusion positive non-small cell lung cancer, adult patients with advanced or metastatic RET gene mutation requiring systemic treatment and pediatric patients over 12 years old, And advanced or metastatic RET fusion positive thyroid cancer patients in adults and children over 12 years old who need systemic therapy and radioiodine treatment Based on data from phase I / II clinical study libretto-001 This study is the largest clinical study to evaluate the efficacy of a RET inhibitor in patients with RET mutant cancer The distribution of RET target mutations in the main analysis data set of NSCLC is shown in Figure 5 below The results show that kif5b and ccdc6 occupy the main distribution [11] < br / > Figure 5 Population distribution of RET target mutation subtypes in non-small cell lung cancer treated with selpercatinib According to the previously published NSCLC queue data, the orr of selpercatinib in the initial and treated RET fusion positive NSCLC patients is 85% and 68%, respectively The specific treatment results are shown in Figure 6 [11] < br / > Figure 6 Summary of main analysis data of selpercatinib in the treatment of RET fusion non-small cell lung cancer < br / > in addition, selpercatinib is the first RET inhibitor showing strong central nervous system (CNS) activity, with CNS orr up to 91% The specific treatment results are shown in Figure 7 [11] < br / > Figure 7 Data summary of selpcatinib treatment for RET fusion non-small cell lung cancer sensitive population < br / > most AES are of low level and have nothing to do with selpcatinib treatment, only 1.7% AES is due to treatment-related discontinuation, and the specific results are shown in Figure 8 [11] < br / > figure 8 Summary of selpercatinib security data < br / >