Qilu Pharmaceutical Submits First Clinical Application for Fourth-Generation EGFR Inhibitor QLH11811

On June 16, according to the CDE official website, Qilu Pharmaceutical's fourth-generation EGFR inhibitor QLH11811 was submitted for clinical trial for the first time.

Source: CDE Official Website

Previously, at the 2022 AACR Annual Meeting, Qilu Pharmaceutical Co., Ltd. (Qilu) first announced the preclinical data of QLH11811. The data shows that QLH1811 can reverse the C797S mutation and also inhibit common mutations such as ex19del, L858R, and T790M. Additionally, studies have shown that QLH11811 reduces tumor growth in multiple tumor xenograft models.

QLH11811 Preclinical Data

The Third Generation of EGFR Inhibitors Faces Numerous Challenges

Regarding EGFR inhibitors, since the FDA approved the first EGFR inhibitor in 2003, they have evolved from the first generation to the second and third generations.

However, the current third-generation EGFR inhibitor market has become extremely crowded, with competition reaching a fever pitch. Products in the same field are also highly active. Ameitinib, the first domestically produced third-generation EGFR-TKI approved for marketing in China, was just submitted for marketing approval in the UK yesterday, becoming the first innovative drug in its class to expand overseas.

However, third-generation inhibitors also face the issue of drug resistance, and their resistance mechanisms are complex, including various situations: it may be due to acquired mutations at target sites such as C797S and G796D, or mutations in oncogenes like MET and K-ras leading to the activation of downstream EGFR signaling pathways. Additionally, there may be cases of non-small cell lung cancer transforming into small cell lung cancer and epithelial-mesenchymal transition.

Among the reasons, the most important one is the EGFR C797S mutation, which prevents third-generation inhibitors from forming a covalent irreversible bond with the protein, reducing the drug's competitive activity with ATP. Consequently, fourth-generation EGFR-TKI inhibitors primarily targeting the C797S mutation have emerged.

Seven Products Enter Clinical Stage Globally

According to the Insight database, there are currently 18 inhibitors targeting EGFR-C797S globally. Among them, 7 have entered the clinical stage.

7 Targeted EGFR-C797S Products That Have Entered the Clinical Stage

Source: Insight Database Global New Drug Module (http://db.dxy.cn/v5/home/)

Blueprint Medicines：

BLU-945 and BLU-701

Blueprint Medicines currently has two oral, reversible, selective fourth-generation EGFR inhibitors: BLU-945 and BLU-701. These inhibitors target both activating and resistance mutations of EGFR while sparing the activity of wild-type kinases. Zai Lab holds the development rights for these two products in Greater China.

BLU-945 Pharmaceutical Deal

Source: Insight Database (http://db.dxy.cn/v5/home/)

Currently, both BLU-945 and BLU-701 have entered the clinical stage. At the recent ASCO meeting, Blueprint Medicines reported on the progress of the clinical trials for BLU-945 and BLU-701, as well as the inclusion and exclusion criteria. The study designs for these two products were also disclosed.

The Phase I/II Study of BLU-945 (SYMPHONY) (Abstract No.: TPS9156) aims to evaluate the safety and efficacy data of BLU-945 as a monotherapy or in combination with osimertinib.

The Phase I/II Clinical Study of BLU-701 (Abstract No.: TPS9142) Aims to Evaluate the Safety and Efficacy of BLU-701 as Monotherapy, in Combination with Osimertinib, and in Combination with Chemotherapy (Carboplatin + Pemetrexed).

The phase I/II SYMPHONY trial data (registration number: NCT04862780) for BLU-945 was first disclosed at this year’s American Association for Cancer Research (AACR) meeting, marking the world's first release of clinical data for a fourth-generation EGFR inhibitor.

SYMPHONY Trial

Source: Insight Database (http://db.dxy.cn/v5/home/)

In the dose-escalation phase of the trial, a total of 33 patients with EGFR-mutated NSCLC were enrolled, including 55% Asians. Among these patients, 97% had previously received osimertinib treatment, 21% had undergone 1-2 treatment regimens, and 79% had received three or more treatment methods.

Thirty-three percent of these patients had EGFR common mutations + T790M + C797S, and 27% of the patients did not detect EGFR mutations.

Baseline Characteristics of Patients

In terms of safety, any grade of treatment-related adverse events occurred in 33 patients as follows: nausea (21%), headache (3%), fatigue (15%), cough (3%), vomiting (9%), and dry mouth (9%). Additionally, treatment-related grade 3 adverse events included nausea (3%) and vomiting (3%). No grade 4 or 5 adverse events were reported. Serious adverse events occurred in 8 patients (24%), of which only 2 cases (6%) were considered related to grade 3 vomiting and grade 3 elevated transaminases. Overall, adverse events associated with wild-type EGFR were generally milder.

Adverse Reactions of BLU-95 in the Treatment of EGFR-Mutant NSCLC Patients

Pharmacokinetic analysis showed that the half-life of BLU-945 in humans was 24.1 hours, and the higher the dose, the more likely it was to reach the drug concentration required to overcome resistance mutations.

For the EGFR 19del/L858R+T790M+C797S triple mutation, lower doses such as 25mg and 50mg can achieve 90% inhibitory concentration (IC 90) after 15 days of medication. For L858R +/- C797S, at least a 100mg dose is required to reach IC 90 after 15 days of medication. However, for 19del +/- C797S, even a 400mg dose taken for 15 days still fails to reach IC 90, which is consistent with preclinical study results.

Pharmacokinetic Results

In terms of clinical efficacy, the trial results showed that 83% of patients with the T790M mutation who took BLU-945 experienced a reduction in T790M ctDNA, and 81% of patients with the C797S mutation who took BLU-945 experienced a reduction in C797S ctDNA. At the dose level of 400 mg, all patients showed a decrease in T790M and C797S ctDNA, with three cases achieving complete clearance.

Clinical Efficacy of BLU-945 in EGFR Patients

Tumor volume assessment showed that two patients with triple mutations of 19del + T790M + C797S had significant tumor shrinkage when treated with 400 mg of BLU-945 once daily, but whether partial response was achieved remains to be confirmed.

Tumor Changes Over Time in Patients with Different Doses

Overall, BLU-945 is a highly effective and selective fourth-generation oral inhibitor. It can reduce ctDNA of resistance mutations such as C797S, and significant tumor shrinkage in patients can be observed at doses of 200mg or higher. However, due to its weaker inhibitory effect on ex19del, it needs to be used in combination with other drugs. Fortunately, BLU-945 is well-tolerated with mild adverse reactions, supporting its use in combination with other therapies.

It is reported that BLU-945 will subsequently be administered in combination with Osimertinib, and the two companies have signed a clinical cooperation agreement.

Betta Pharmaceuticals: BPI-361175

In May last year, BPI-361175 was first initiated in clinical trials in China, launching a Phase I/II dose-escalation, open-label study (registration number: CTR20210966) to evaluate the safety, tolerability, pharmacokinetics, and efficacy of BPI-361175 tablets in patients with advanced solid tumors. The trial is still ongoing.

In December of the same year, the FDA approved the clinical trial application for BPI-361175, used to treat non-small cell lung cancer carrying the EGFR C797S mutation and other EGFR-related mutations. Currently, two clinical trials (registration numbers: NCT05393466, NCT05329298) have been registered on ClinicalTrials.gov.

Gantt Chart of Global R&D Progress for BPI-361175

Source: Insight Database (http://db.dxy.cn/v5/home/)

Mechanism of Action of BPI-361175

Source: Official WeChat Account of Betta Pharmaceuticals

Previously disclosed preclinical data showed that BPI-361175 demonstrated consistent biological activity in vitro and in vivo, effectively inhibited the proliferation of tumor cells carrying the EGFR C797S mutation, and exhibited potent antitumor effects in multiple xenograft models with EGFR-related mutations.

BPI-361175 significantly inhibits the activity of various EGFR kinase mutants, including triple, double, and single mutations, as well as EGFR phosphorylation and cell proliferation in cells carrying the corresponding mutations.

Meanwhile, BPI-361175 showed no significant inhibition on EGFRWT and IGF1R at both cellular and kinase levels, demonstrating good selectivity. In vivo, oral administration of BPI-361175 effectively inhibited the growth of various tumors with different EGFR mutations and induced their regression.

Notably, BPI-361175 demonstrates excellent blood-brain barrier penetration and significantly extends the survival of mice in an orthotopic BaF3 EGFRDel19/T790M/C797S brain model.

Bridge Biotherapeutics：BBT-176

BBT-176 is also an EGFR-C797S inhibitor. Studies have shown that BBT-176 exhibits potent anticancer activity in xenograft animal models harboring triple mutations including C797S (Del19/T790M/C797S, and L858R/T790M/C797S). The combination of BBT-176 with anti-EGFR antibodies significantly enhances its activity.

Currently, Bridge Biotherapeutics is conducting a Phase I/II clinical trial to explore the safety, tolerability, and efficacy of BBT-176 as a monotherapy and in combination with rituximab.

BBT-176 Global R&D Progress Gantt Chart

Source: Insight Database (http://db.dxy.cn/v5/home/)

Zhengda Tianqing: TQB3804

According to the Insight database, TQB3804 from Zhengda Tianqing was first submitted for clinical trials in April 2019, and clinical trials were initiated in November of the same year.

Source: Insight Database (http://db.dxy.cn/v5/home/)

TQB3804 can not only address resistance to Osimertinib but also shows efficacy against the T790M double mutation following resistance to 1st/2nd generation TKIs. Previous studies have demonstrated that the IC50 values of TQB3804 for d746-750(19del)/T790M/C797S, L858R/T790M/C797S, d746-750/T790M, and L858R/T790M are 0.46, 0.13, 0.26, and 0.19 nM, respectively, indicating significant inhibitory effects on tumor cells with EGFR triple and double mutations that arise after resistance to 1st/2nd/3rd generation TKIs.

TQB3804 demonstrated significant tumor growth delay across various models of 19del/T790M/C797S. A Phase I dose-escalation and expansion clinical trial of TQB3804 is currently ongoing in patients with advanced malignancies.

Gantt Chart of Global R&D Progress for TQB3804

Source: Insight Database (http://db.dxy.cn/v5/home/)

Black Diamond Therapeutics：BDTX-1535

Black Diamond Therapeutics’ BDTX-1535 was approved by the FDA to enter the clinical stage in January this year, and about a month later, a Phase 1 study (Registration Number: NCT05256290) evaluating the efficacy of the oral EGFR inhibitor BDTX-1535 in patients with glioblastoma or non-small cell lung cancer was initiated. The current trial is recruiting patients and is expected to be completed in September 2024.

NCT05256290 Clinical Trial

Source: Insight Database (http://db.dxy.cn/v5/home/)

Hansoh Pharma: HS-10375

HS-10375 is a fourth-generation EGFR inhibitor independently developed by Hansoh Pharma. A Phase I/II clinical study (registration number: CTR20220045) evaluating the safety, tolerability, pharmacokinetics, and efficacy of HS-10375 in patients with advanced non-small cell lung cancer is currently underway.

Source: Insight Database (http://db.dxy.cn/v5/home/)

In addition to small molecule inhibitors, other therapies such as ADCs are also expected to provide solutions for resistance to third-generation EGFR inhibitors, such as Daiichi Sankyo's HER3 ADC drug Patritumab deruxtecan (U3-1402). U3-1402 is designed using Daiichi Sankyo's proprietary DXd ADC technology, linking the anti-HER3 antibody Patritumab with the topoisomerase inhibitor DX-8951 (exatecan) via a tetrapeptide linker.

Introduction to Patritumab Deruxtecan (U3-1402)

Source: Daiichi Sankyo Official Website

At this year's ASCO conference, U3-1402 disclosed clinical data targeting breast cancer. Previously, the early clinical data (NCT03260491) released in the NSCLC field was also very impressive, and this set of data was presented at the 2021 ASCO conference.

In the trial, a total of 57 NSCLC patients received U3-1402 5.6 mg/kg once every three weeks. All patients had previously been treated with EGFR TKI, 86% with osimertinib, 91% with platinum-based chemotherapy, 40% with immunotherapy, with a median of 4 treatment lines, and 27 cases (47%) with brain metastases.

The confirmed objective response rate was 39%, the disease control rate was 72%, the median duration of response was 6.9 months, and the median progression-free survival was 8.2 months. Among the 44 patients previously treated with osimertinib and platinum-based chemotherapy, the confirmed objective response rate was 39%, the disease control rate was 68%, the median duration of response was 7.0 months, and the median progression-free survival was 8.2 months.

Notably, the study observed partial tumor responses in patients with EGFR C797S mutations, MET gene amplification, HER2 mutations, and BRAF fusions. This suggests that if subsequent development proceeds smoothly, this product is likely to have "universal" potential. For patients resistant to EGFR inhibitors, this is undoubtedly good news.

In December last year, the FDA granted patritumab deruxtecan (HER3-DXd; U3-1402) Breakthrough Therapy Designation (BTD) for the treatment of patients with metastatic or locally advanced non-small cell lung cancer (NSCLC) who have experienced disease progression during or after treatment with a third-generation tyrosine kinase inhibitor (TKI) and platinum-based therapy, and who carry resistance EGFR mutations.

According to the Insight database, a Phase III clinical trial (registration number: NCT05338970) for the NSCLC indication of patritumab deruxtecan was just initiated on May 10.

Patritumab Deruxtecan Phase III Clinical Trial

Source: Insight Database (http://db.dxy.cn/v5/home/)

*Disclaimer: This article was written by an author who has settled in Sina Medicine News. The views expressed represent those of the author and do not reflect the position of Sina Medicine News.