Ameile (aumolertinib)

In conclusion, acquired BRAF-V600E mutations may contribute to osimertinib resistance. Aumolertinib plus BRAF inhibitors improves outcomes in patients with EGFR-L858R and acquired BRAF-V600E comutant lung adenocarcinoma in whom osimertinib treatment has failed.

P1, N=20, Recruiting, Jiangsu Hansoh Pharmaceutical Co., Ltd.

Additionally, the invasion of cells in the knockdown group was repressed. These findings indicated that almonertinib and osimertinib exhibited distinct resistance mechanisms in vitro, underscoring the need for tailored treatment approaches.

We conducted a network meta-analysis of randomized controlled trials comparing osimertinib, lazertinib, aumolertinib, befotertinib, furmonertinib, dacomitinib, afatinib, erlotinib, gefitinib, icotinib, and chemotherapy. Osimertinib is the first choice of treatment with considerable efficacy and safety for EGFR mutation-positive NSCLC. The treatments associated with the best PFS in patients with exon 19 deletions and Leu858Arg mutations were furmonertinib and lazertinib, respectively.

P2, N=122, Recruiting, The Affiliated Panyu Central Hospital of Guangzhou Medical University; The Affiliated Panyu Central Hospital of Guangzhou Medical University

RNA-sequencing based analysis revealed increased infiltration of CD8 + T-cells in post-treatment tumors compared to baseline, particularly in responsive and Ex19-Del mutation tumors. Collectively, neoadjuvant Aumolertinib showed promising efficacy and a surgical conversion rate with a tolerable safety profile for unresecable NSCLCm in stage III, potentially involved in the remodeling of tumor microenvironment.

This review delves into the current clinical status, efficacy, safety profiles, and regulatory approvals of third-generation EGFR TKIs, including Osimertinib, Lazertinib, Furmonertinib, Aumolertinib, Rezivertinib, Befotertinib, Sunvozertinib...Notable fourth-generation candidates such as TQB3804, BPI-361175, BDTX-1535, WJ13404, QLH11811, H002, HS-10375, BBT-207, JIN-A02, and HS-10504 are highlighted for their potential to overcome the C797S mutation...By evaluating the therapeutic potential and limitations of these EGFR TKIs, this review aims to guide future research in the management of EGFR-mutant NSCLC. This acts as guiding beacon for the strategic design and development of third and fourth generation EGFR-TK inhibitors to overcome the drug resistance hurdles in the development of EGFR-TK inhibitors.

Aumolertinib plus chemotherapy shows potential as first-line treatment for patients with EGFR-mutant advanced NSCLC, which deserves to be investigated in randomized controlled trials. CtDNA clearance may be a prognostic marker.

P2, N=36, Completed, Cancer Institute and Hospital, Chinese Academy of Medical Sciences | Not yet recruiting --> Completed

A subsequent lung biopsy after progression confirmed the diagnosis of large cell neuroendocrine carcinoma, and subsequently treatment with cisplatin and etoposide was effective. EGFR mutations may persist even after transformation into neuroendocrine carcinoma. For non-small cell lung cancer patients undergoing Almonertinib therapy, this case report emphasizes the importance of performing a timely pathological biopsy upon the emergence of resistance.

We propose that patients with EGFR Ex19del mutation and MET de novo amplification may benefit more from dual-targeted therapy than pemetrexed and carboplatin chemotherapy along with bevacizumab. Timely intervention is needed to avoid greater harm when ILD occurs and, when ILD is effectively controlled, seize the opportunity to rechallenge the dual-targeted therapy may contribute to a better prognosis. In addition, the patients with targeted-induced ILD in the past need more rigorous monitoring and follow-up in the process of rechallenging the targeted drug therapy.

This case underscores the importance of re-challenge using third-generation EGFR-TKI with novel MET-TKI after the failure of second-generation EGFR-TKI plus crizotinib in EGFR-TKI resistant NSCLC patients with MET amplification, especially in patients with brain metastases. The successful application of aumolertinib plus gumarontinib highlights its potential in overcoming MET amplification-induced EGFR-TKI resistance, which warrants further investigation in future large-scale clinical trials.

Whether first-generation EGFR inhibitors (e.g. icotinib or gefitinib) can sustainably control EGFR-sensitive mutations/C797S NSCLC following third-generation EGFR inhibitor treatment remains insufficiently reported. Our case report discusses a female patient with advanced lung adenocarcinoma carrying an EGFR exon 19 E746_A750delELREA mutation who received almonertinib as first-line treatment and developed C797S resistance during therapy. The patient was subsequently treated with a double dose of icotinib for 8 months until disease progression occurred, along with the development of an EGFR exon 20 T790M point mutation and TP53 mutation. This case provides clinical evidence suggesting that first-generation EGFR-TKIs may be an effective treatment strategy for patients with acquired EGFR 19del/C797S resistance following EGFR TKI therapy.

CAFs regulate HK2-mediated glycolysis through SKP2, which promotes almonertinib resistance in NSCLC.

In EMAN patients, osimertinib + CT and amivantamab + lazertinib were associated with optimal PFS and OS, respectively. Among BM patients, osimertinib + CT offered the best PFS benefits. These findings may assist in clinical decision-making and personalized care for EMAN and BM patients. The study is registered on PROSPERO (CRD42024506995).

As of the submission date, the patient achieved significant remission and a LM Progression-Free Survival (PFS) exceeding 20 months. This case highlights the positive impact of high-dose aumolertinib combined with intrathecal pemetrexed on NSCLC patients presenting with severe meningeal symptoms as the initial manifestation, offering a viable therapeutic approach for managing severe meningeal symptoms associated with LM, such as headache, nausea, neck stiffness, and vomiting.

P2, N=770, Recruiting, Cancer Institute and Hospital, Chinese Academy of Medical Sciences | Not yet recruiting --> Recruiting | Trial completion date: Jul 2023 --> Jul 2028 | Trial primary completion date: Jul 2022 --> Jul 2026

Aumolertinib showed potential in treating EGFR-mutated NSCLC patients with LM, with a tolerable safety profile.

P2, N=67, Liaoning Cancer Hospital & Institute; Liaoning Cancer Hospital & Institute

Almonertinib demonstrates good clinical efficacy and safety for the treatment of EGFR mutation-positive residual ground-glass opacities following stage I lung cancer resection.

This study demonstrated that H1975 cells stimulated by almonertinib promoted the accumulation of CAFs in NSCLC cells, likely through increased secretion of TGF-β1. The accumulation of CAFs enhanced the survival of NSCLC cells undergoing almonertinib treatment and induced drug resistance. Additionally, the mechanism underlying CAF-induced drug resistance in NSCLC cells was potentially linked to the activation of the YAP/TAZ signaling pathway.

After receiving dacomitinib and almonertinib sequentially, plasma-based NGS revealed the emergence of EGFR T790M-trans-C797S mutations, prompting a switch to a combination therapy of almonertinib and gefitinib...Larotrectinib was incorporated into the dual EGFR-TKI regimen, forming a triplet therapy...This is the first reported case of a novel, targetable POT1::NTRK3 fusion as a potential off-target mechanism mediating EGFR-TKI resistance, occurring alongside MET amplification in a patient with NSCLC harboring acquired EGFR L858R/T790M/C797S mutations. Concomitant inhibition of EGFR, NTRK, and MET was safe and resulted in a significant response, underscoring the importance of precision medicine guided by matched NGS.

Our study concluded that combination regimens based on third-generation TKIs (osimertinib plus ramucirumab, osimertinib plus chemotherapy, osimertinib plus bevacizumab, amivantamab plus lazertinib and aumolertinib plus apatinib) could be the new and clinically preferable first-line, standard of care for EGFR-mutated advanced non-small cell lung cancer.

Third-generation TKIs, such as osimertinib, almonertinib and furmonertinib, are effective for the treatment of NSCLC that is EGFR-sensitizing mutation-positive and T790M-positive. To the best of our knowledge, the present report describes the first case of a patient with lung adenocarcinoma who had multiple co-existing EGFR resistance mutations, including EGFR L718Q, EGFR C797S, EGFR C797G, EGFR L792H, EGFR V802F and EGFR V689L. These mutations conferred resistance to almonertinib, whilst maintaining sensitivity to afatinib.

P2, N=0, Withdrawn, Sun Yat-sen University | N=85 --> 0 | Recruiting --> Withdrawn

P3, N=624, Active, not recruiting, Jiangsu Hansoh Pharmaceutical Co., Ltd. | Recruiting --> Active, not recruiting | Trial primary completion date: Jan 2024 --> Jun 2024

This review included 23 randomized clinical trials incorporating 7,006 patients and 11 treatments: erlotinib, gefitinib, icotinib, afatinib, dacomitinib, osimertinib, furmonertinib, aumolertinib, pemetrexed-free chemotherapy (PfCT), pemetrexed-based chemotherapy (PbCT) and placebo. Difference in safety between the third-generation EGFR-TKIs was also first investigated comprehensively. Furthermore, this review elaborated the varied predominate spectrum and ranked the toxicity of EGFR-TKIs for providing toxicity rationale for treatment decisions.

Quantitative ion pairs were m/z 569.3 → 72.2 for furmonertinib and m/z 526.5 → 72.2 for aumolertinib, which was used as the internal standard (IS). The established analytical methods showed great sensitivity, simplicity, accuracy and reliability for the analysis of furmonertinib in human plasma and CSF. This assay would be helpful to predict the effectiveness and toxicities of furmonertinib in the pursuit of precision medicine for lung cancer patients.

Aumolertinib combined with anlotinib can effectively inhibit NSCLC cell proliferation by downregulating the PI3K-Akt pathway, suggesting a potentially new option for NSCLC treatment.

P=N/A, N=800, Recruiting, Fudan University | Not yet recruiting --> Recruiting

P3, N=192, Active, not recruiting, Jiangsu Hansoh Pharmaceutical Co., Ltd. | Trial primary completion date: Jan 2026 --> Jul 2024

P=N/A, N=4000, Completed, Fudan University | N=500 --> 4000

This case represents the first documented successful treatment of ARDS induced by EGFR E19 mutated NSCLC using almonertinib. The favorable clinical response observed in this critically ill patient suggests that almonertinib may be a viable therapeutic option for managing severe complications in NSCLC. Further research is necessary to corroborate these findings and optimize dosage and toxicity management strategies for broader clinical application.

Aumolertinib demonstrated superior progression-free survival (PFS) and a well-tolerated toxicity profile compared to gefitinib in front-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in the AENEAS trial. In this real-world study, aumolertinib showed comparable disease control and objective response rates as reported in the AENEAS trial for advanced NSCLC patients with EGFR-sensitizing mutations. Aumolertinib treatment improved PROs, further supporting it in first-line clinical practice.

P=N/A, N=500, Completed, Fudan University

Sensitivity and scenario analyses were performed to explore the robustness of the model. Compared with gefitinib, aumolertinib yielded an additional 0.941 expected life-years and 0.692 quality-adjusted life-years (QALYs), with an incremental cost of $18,855.55 over a 20-year time horizon. The incremental cost-effectiveness ratios were $20,051.67/life-year and $27,272.29/QALY, that below the willing-to-pay threshold of $38,223.34/QALY. Aumolertinib was a cost-effective alternative first-line treatment for patients with epidermal growth factor receptor-positive advanced nonsmall-cell lung cancer in China.

P=N/A, N=800, Not yet recruiting, Fudan University

P1, N=13, Terminated, Jiangsu HengRui Medicine Co., Ltd. | N=345 --> 13 | Recruiting --> Terminated; Sponsor R&D strategy adjustment

P1, N=20, Not yet recruiting, Chia Tai Tianqing Pharmaceutical Group Nanjing Shunxin Pharmaceutical Co., Ltd.

P2, N=85, Recruiting, Sun Yat-sen University | Not yet recruiting --> Recruiting

Overall, the method proved to be sensitive, reliable, and straightforward, enabling successful simultaneous determination of blood concentrations of icotinib, osimertinib, aumolertinib, and anlotinib in patients. The validity of the method has been confirmed across various instruments.

The patient achieved partial remission and did not show any further progression during the follow-up period. For NSCLC patients with both EGFR mutation and HER2 amplification, the combination of almonertinib and pyrotinib is a valuable therapy that can continuously reduce tumor burden and achieve long-term survival.