*Only for reading and reference by medical professionals
The fourth generation EGFR-TKI track is "rolled up"!
Since lung cancer entered the era of targeted therapy, the overall survival (OS) of patients with driver gene mutation-positive non-small cell lung cancer (NSCLC) has been prolonged. After more than 20 years of development, targeted drugs for NSCLC have achieved fruitful results. First-, second-, and third-generation EGFR-TKIs provide a variety of treatment options for patients with EGFR mutation-positive NSCLC.
The annual World Conference on Lung Cancer (WCLC) was held in Vienna, Austria, from August 6 to 9. WCLC is one of the most watched international academic conferences in the field of lung cancer and the world's largest dedicated to lung cancer and other thoracic malignancies. Multidisciplinary Oncology Meeting. This meeting announced the research progress of 2 fourth-generation EGFR-TKIs. "Medical Tumor Channel" takes you to study the latest developments.
The mutation rate is about 50%, and EGFR-TKI resistance is still a problem
Among all NSCLC, EGFR is the most common gene mutation, and the incidence rate in Asian populations is about 40%~50%[1]. EGFR-TKI is the first-line standard treatment for patients with advanced NSCLC with EGFR mutations. The third-generation EGFR-TKI osimertinib brings a median OS of 38.9 months to patients with advanced NSCLC.[2].
Although EGFR-targeting therapy has been widely used in lung cancer patients with EGFR mutations. However, after 12-18 months of use, no matter which generation of EGFR-TKI it is, patients will inevitably develop drug resistance. Is there any solution that can last longer to benefit? What new treatments are there for drug resistance?
targets EGFR C797S, and the preclinical and phase I research results of the fourth generation EGFR-TKI are beginning to appear
Some studies have shown that the EGFR C797S mutation is one of the potential mechanisms leading to irreversible resistance to EGFR-TKI. Currently, there are no drugs targeting the EGFR C797S mutation, and the treatment needs of this group of patients remain unmet.
This WCLC meeting announced the results of two studies on fourth-generation EGFR-TKI. Both studies can target NSCLC tumor cells with EGFR C797S and show good anti-tumor activity.
JIN-A02, a Highly Effective 4th Generation EGFR-TKI, Targeting EGFR C797S Triple Mutation in NSCLC
Abstract number: MA07.08
JIN-A02 is A novel, orally targeted EGFR Fourth-generation EGFR-TKI with C797S mutation. In preclinical studies, JIN-A02 demonstrated anti-tumor activity against EGFR double mutations (ex 19del/T970M) or triple mutations (ex 19del/T970M/C797S).
This WCLC explored the anti-tumor activity of JIN-A02 in human EGFR mutant overexpression or EGFR wild-type (WT) cell lines, as well as EGFR mutant cell (PDC) lines derived from patients. In the in vivo efficacy testing experiment, tumor cells with triple EGFR mutations (Ex19del/T790M/C797S or L858R/T790M/C797S) were transplanted into mice.
research results found that:
JIN-A02 in EGFR Ex19del/T790M/C797S (IC50=51.0 nM) and EGFR L858R/T790M/C797S (IC50=49.2 nM) exhibits anti-tumor activity in Ba/F3 cells;
exhibits anti-tumor activity in EGFR ex19del/T790M double mutation (IC50=12.3), EGFR L858R/T790M (IC50=5.3 nM) mutation and EGFR ex19del (IC50=3.2 nM), EGFR L858R (IC50=9.1 nM), the activity in mutated tumor cells is comparable to osimertinib;
for rare EGFR mutations, such as EGFR ex19del/T790M/L718Q (IC50=102 nM), EGFR L858R/T790M/L718Q (IC50=62.1), JIN-A02 also showed anti-tumor activity.
▎ In PDC, JIN-A02 also showed significant anti-tumor activity:
In Yu-1097 tumor cells with EGFR ex19del/T790M/C797S mutation, JIN-A02 has a better inhibitory effect than osimertinib (JIN -A02 IC50=61.5 nM vs osimertinib IC50=3360 nM);
JIN-A02 also retained the greatest anti-tumor activity in EGFR WT A549 tumor cells (IC50=742.4 nM).
▎ The results of in vivo efficacy testing experiments show:
mice that received EGFR ex19del/T790M/C797S (Ba/F3 cell line) tumor cell transplantation were given JIN-A02 orally every day (50 mg/kg and 60 mg/kg), can inhibit tumor growth, [tumor growth inhibition rates (TGI) are 91.7% and 95.7% respectively];
In a mouse model that received YU-1097 PDC xenograft tumor transplantation, JIN-A02 (50 mg/kg, Orally), significant tumor shrinkage (TGI 132.9%);
JIN-A02 exerts anti-tumor effects at 10mg/kg and 50mg/kg, and the efficacy is dose-dependent.
No significant toxicity was observed in any treatment group.
Based on the current results, JIN-A02 has demonstrated ideal anti-tumor activity in preclinical studies and is also effective against the EGFR L718Q mutation. JIN-A02 may become another treatment option for NSCLC patients who have previously progressed after EGFR-TKI. Currently, researchers plan to launch human trials to test the efficacy and safety of JIN-A02.
BBT-176, a 4th generation EGFR-TKI, a phase I clinical trial to evaluate the pharmacokinetics (PK), safety and efficacy in NSCLC patients who have progressed on previous EGFR-TKI
BBT-176, a 4th generation EGFR TKI, for Progressed NSCLC after EGFR TKI Therapy: PK, Safety and Efficacy from Phase 1 Study
Abstract number: MA07.09
BBT-176 is a reversible ATP competitive inhibitor that can target the EGFR C797S mutation and has shown good anti-tumor activity in preclinical studies. This time WCLC announced the results of the Phase I clinical trial of this study.
The main purpose of the Phase I clinical study is to determine PK, safety and determine the recommended Phase II dose (RP2D). The study included patients with EGFR mutations who had previously received at least one EGFR-TKI treatment, and underwent imaging evaluation and Guardant liquid biopsy every 6 weeks. The enrolled patients were given BBT-176 treatment (dose ranging from 20 mg to 600 mg, taken orally, once a day) until disease progression or intolerable treatment-related adverse events (TRAE) occurred. The study used an Bayesian linear regression model to guide dose escalation and allow patients to move up to the next dose level.
As of March 10, 2022, a total of 18 patients have received BBT-176 treatment. Among them, EGFR triple mutations (ex 19del/T790M/C797S or L858R/T790M/C797S) were detected in the blood samples of 5 cases. Drug exposure is dose proportional and is within the Qd dose range at therapeutic doses.
Common TRAEs include nausea (5 cases), vomiting (3 cases), diarrhea (3 cases), rash (4 cases), pruritus (2 cases), increased amylase (2 cases), increased lipase (2 cases) example). There were no dose-limiting toxicities or treatment discontinuations due to TRAEs.
Reduced EGFR mutation allele frequencies were observed in 3 patients, including non-classical EGFR ex 19del/T790M mutation and EGFR T790M mutation. These changes were associated with tumor shrinkage in two of the patients. Two patients with EGFR ex 19del/T790M/C797S triple mutations experienced radiological response in target lesions and non-target lesions. The specific patient mutational status, target lesion shrinkage, and investigator-assessed overall response are as follows:
Table 1 Clinical Outcomes of Representative Patients
Results of the Phase I clinical study of BBT-176 show the tolerability of continuous daily administration of BBT-176 Good, toxicity controllable. In addition, molecular screening and dynamic monitoring of liquid biopsy may further improve the efficacy of BBT-176 in patients. In the future, researchers will further explore the recommended dose for Phase II.
EGFR-TKI resistance treatment strategies are being explored to provide patients with more treatment options
In order to solve the clinical dilemma of EGFR-TKI resistance and rare mutation targets, the research and development and clinical trials of fourth-generation EGFR-TKI are progressing rapidly. JIN-A02 and BBT-176 announced by WCLC this time both show good application prospects. Currently, multiple fourth-generation EGFR-TKIs at home and abroad are in the preclinical/clinical trial stage. In addition, various combination treatment options for EGFR-TKI resistance are also being explored.
believes that in the near future, we will be able to usher in good new drugs and new therapies, providing more treatment options for EGFR-TKI-resistant NSCLC patients and helping to further realize the chronic disease of lung cancer.
This material is supported by AstraZeneca and is for reference only by medical professionals.
Approval number: CN-100601 Expiration date: 2023-8-9
Reference:
[1] Mao, Linlin, et al. Pathology and Oncology Researchnbsp;(2021): 63.
[2] Ramalingam, Suresh S et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. The New England journal of medicine vol. 382,1 (2020): 41-50. doi:10.1056/NEJMoa1913662.
[3] M.R. Yun, et al .WCLC 2022, MA07.08.
[4] S.M. Lim, et al. WCLC 2022, MA07.09.
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform
