Ivesa (firmonertinib)

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.

Firstly, we describe the patient's treatment history, including failed third-line combination treatments of systemic chemotherapy with bevacizumab or carrelizumab or anlotinib, primary lung tumor recurrence, bilateral lung metastases progression, and new brain metastatic lesion detection. Next, we detail the patient's fourth-line treatment with radiotherapy for brain metastases and two cycles of bevacizumab plus Abraxane and cisplatin, however, the disease progressed and relapsed...However, the patient died due to hypoproteinemia combined with severe pneumonia in December 2023. Furmonertinib may be effective for NSCLC patients with HER2 T8962A and L869R mutations and further studies are needed to confirm these results in prospective clinical trials.

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

P2, N=54, Not yet recruiting, Abbisko Therapeutics Co, Ltd

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

The patient had progressed after targeted therapy with oxitinib, ametinib, and vometinib. Although peripheral neurotoxicity occurred during treatment, it improved after symptomatic treatment. The treatment of EGFR mutant stage IV NSCLC with utidelone combined with pabolizumab has good effect and mild adverse reactions.

P=N/A, N=60, Not yet recruiting, Henan Cancer Hospital

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

P=N/A, N=51, Not yet recruiting, hunan cancer hospital; hunan cancer hospital

P2, N=88, Not yet recruiting, Shanghai Chest Hospital; Shanghai Chest Hospital

P1, N=60, Not yet recruiting, Jiangsu Cancer Hospital; Jiangsu Cancer Hospital

P2, N=40, Recruiting, Hunan Province Tumor Hospital | Trial primary completion date: Jul 2024 --> Dec 2024

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

In the real world, the high-dose furmonertinib-based treatment may potentially have clinical efficacy and tolerable safety in patients of EGFR-mutated NSCLC with LM, even in patients previously treated with other third-generation EGFR-TKIs. Methylation and CNB analysis of cfDNA in CSF may be considered objective indicators for the diagnosis of LM and evaluation of treatment response.

P2, N=44, Not yet recruiting, Shanghai Pulmonary Hospital, Shanghai, China

Despite maintaining a prolonged progression-free survival (PFS) with first-generation EGFR-TKI Afatinib, disease progression occurred in 2022 without detectable resistance mutations. Transition to second-generation TKI Furmonertinib resulted in poor control, with rapid progression including unusual bilateral breast metastases that exhibited inflammatory breast cancer-like peau d'orange changes...This case underscores the importance of continuous genetic profiling and tailored treatment approaches in managing advanced lung adenocarcinoma, particularly when presenting with rare metastatic sites and complex genetic landscapes. The successful application of Savolitinib following the identification of a MET amplification mutation highlights its potential in overcoming resistance mechanisms in NSCLC, providing a significant therapeutic option for similarly challenging cases.

Ba/F3 cells with an osimertinib-resistant secondary mutation were refractory to all 3G TKIs tested (alflutinib, lazertinib, rezivertinib, almonertinib, and befotertinib)...HCC827BIR cells had MET gene amplification and were sensitive to a combination of capmatinib (MET-TKI) and BI4020...This study suggests that erlotinib may be more suitable than 4G TKIs to overcome secondary mutations after front-line osimertinib. We found that off-target mechanisms that cause resistance to earlier-generation TKIs will also cause resistance to 4G TKIs.

P1, N=170, Active, not recruiting, ArriVent BioPharma, Inc. | Recruiting --> Active, not recruiting

P4, N=300, Not yet recruiting, The Second Affiliated Hospital of Army Medical University.; The Second Affiliated Hospital of Army Medical University.

P4, N=40, Recruiting, Beijing Tiantan Hospital, Capital Medical University; Beijing Tiantan Hospital, Capital Medical University

P2, N=25, Not yet recruiting, Anhui Provincial Cancer Hospital; Anhui Provincial Cancer Hospital

P2, N=144, Not yet recruiting, Peking Union Medical College Hospital; Peking Union Medical College Hospital

In patients with locally advanced or metastatic EGFR mutation-positive NSCLC, furmonertinib showed improved scores and delayed deterioration in several functioning and symptoms compared to gefitinib. Shanghai Allist Pharmaceutical Technology Co., Ltd and the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015).

This report provided direct evidence for the treatment of EGFR-KDD to use furmonertinib. A Large-scale study is needed to confirm this preliminary finding.

P2, N=27, Not yet recruiting, Cancer Institute and Hospital, Chinese Academy of Medical Sciences

This study will evaluate the efficacy and tolerability of furmonertinib plus carboplatin and pemetrexed with or without bevacizumab verses furmonertinib alone in untreated patients with advanced EGFR mutant NSCLC without EGFR clearance.

The current study demonstrated that high-dose furmonertinib plus IVC as salvage treatment for patients with LM harboring EGFR ex20ins mutations had promising clinical benefits and a manageable safety profile.

P2, N=91, Not yet recruiting, Cancer Institute and Hospital, Chinese Academy of Medical Sciences

P2, N=6000, Recruiting, Hunan Province Tumor Hospital | Phase classification: P --> P2 | N=100 --> 6000 | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Dec 2024 --> Dec 2026

These findings suggest that almonertinib and alflutinib may be potential therapeutic options for non-small cell lung cancer patients with the EGFR S768I mutation.

P2, N=84, Recruiting, Changhai Hospital

The study proved the potential efficacy of 160mg furmonertinib in patients with advanced NSCLC with EGFR ex20ins. Meanwhile, 160mg furmonertinib had a good safety profile.

Besides, there is also a subtype of EGFR mutations, known as EGFR 20 exon insertion (EGFR 20ins) mutation. The authors summarized the treatment of a lung adenocarcinoma patient with EGFR 20ins mutation accepting Furmonertinib mesylate, in order to provide effective references for clinical diagnosis and treatment..

For patients with EGFR20ins mutation, compared to chemotherapy, ICI+Chemo prolongs PFS, and after chemotherapy progression, bevacizumab combined with chemotherapy seems better than Furmonertinib-based targeted therapy on PFS. For HER2-20ins mutation, Beva+Chemo may be a better choice.

Regrettably, the patient eventually died from heart disease. This report provides the first reported evidence for the use of furmonertinib and intrathecal pemetrexed chemotherapy in NSCLC patients harboring EGFR R776S/C797S/L858R mutations who progressed on previous EGFR-TKIs.

In a real-world setting, furmonertinib appears to be a favorable treatment option for EGFR-mutated patients. The manageable nature of adverse events further supports its use in clinical practice.

EGFR-C797S in cis to all EGFR mutations evaluated generated dependent cells that were resistant to the covalent EGFR tyrosine kinase inhibitors mobocertinib, zipalertinib, furmonertinib, sunvozertinib, poziotinib, and osimertinib. This report highlights that poziotinib and mobocertinib are susceptible to on-target resistance mediated by EGFR-T790M or -C797S in the background of the most prevalent EGFR exon 20 insertion mutations. Furmonertinib, sunvozertinib, and to a less extent zipalertinib can overcome EGFR-T790M compound mutants, whereas EGFR-C797S leads to covalent inhibitor cross-resistance-robust data that support the limitations of mobocertinib and should further spawn the development of next-generation covalent and reversible EGFR exon 20 insertion mutation active inhibitors with favorable therapeutic windows that are less vulnerable to on-target resistance.

The present study indicates that furmonertinib may be a first-line treatment option for patients with non-small cell lung cancer harboring EGFR ex20ins mutation.

P2, N=108, Not yet recruiting, Cancer Institute and Hospital, Chinese Academy of Medical Sciences

P1, N=170, Recruiting, ArriVent BioPharma, Inc.

P1/2, N=106, Recruiting, RemeGen Co., Ltd. | Not yet recruiting --> Recruiting