Ivesa (furmonertinib)

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

P1, N=170, Recruiting, ArriVent BioPharma, Inc. | Phase classification: P1b --> P1

P=N/A, N=30, Not yet recruiting, Daping Hospital and the Research Institute of Surgery of the Third Military Medical University

As of August 23, 2023, the first generation EGFR-TKIs, gefitinib, icotinib, and erlotinib; the second generation EGFR-TKIs, afatinib and dacomitinib; and the third generation EGFR-TKIs, osimertinib, almonertinib, furmonertinib and befotertinib were all approved for marketing by China National Medical Products Administration (NMPA). In addition, multiple domestic third-generation EGFR-TKIs are undergoing clinical trials, such as rezivertinib (BPI-7711), limertinib (ASK120067), and oritinib (SH-1028). Meanwhile, mobocertinib and sunvozertinib, which targets EGFR 20ins mutations, were also approved by NMPA. With the increasing variety of EGFR-TKIs approved for marketing subsequently, it brings confusion to clinicians when choosing specific medications, and there is an urgent need to develop relevant treatment guidelines. Hence, the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care and the Chinese Association for Clinical Oncologists convened experts to integrate the research results of various EGFR-TKIs, and proposed the "China clinical practice guideline for epidermal growth factor receptor tyrosine kinase inhibitors in stage Ⅳ non-small cell lung cancer (version 2023)", to provide reference for better clinical practice.

The safety profiles were consistent with previous reports for furmonertinib. Conclusions Furmonertinib 240mg/day has demonstrated clinically significant efficacy as first line and salvage therapy in patients with EGFR-mutant NSCLC and leptomeningeal metastases.

There was no significant difference in the incidence of TRAEs of any grade in patients aged ≥ 65 years and < 65 years (30.9% and 47.8%, p=0.08, respectively). Conclusions This is the first real-world study to demonstrate that furmonertinib has good efficacy and a tolerable safety profile in elderly patients (≥ 65 years) with completely resected stage I-III NSCLC harboring EGFR mutations.

Furmonertinib 160 mg is an optional regimen for patients with advanced NSCLC who develop resistance after treatment with third-generation EGFR-TKIs, especially those developing resistance due to the progression of intracranial lesions, with good efficacy and an acceptable safety profile that warrants further exploration.

P2, N=40, Not yet recruiting, Shanghai Zhongshan Hospital

This retrospective study aimed to evaluate the efficacy and safety of high dose furmonertinib combined with intrathecal injection methotrexate (MTX) or pemetrexed (PEM) in EGFR-mutated NSCLC patients with LM site-specific resistance to osimertinib. Nograde 3 or higher TRAEs observed. Conclusions High dose furmonertinib combined with intrathecal injection showed encouraging efficacy in EGFR-mutated advanced NSCLC patients progressed on osimertinib or other third-generation TKI.

Furmonertinib 160mg orally once daily has shown encouraging efficacy as first-line therapy in EGFR-mutated advanced NSCLC patients with CNS metastases. Patients were well tolerated and the AEs were consistent with previous studies.

Approximately 375 patients will be randomized 1:1:1 to receive furmonertinib 160 mg daily, furmonertinib 240 mg daily, or platinum-based chemotherapy (cisplatin or carboplatin plus pemetrexed for 4 cycles followed by pemetrexed maintenance therapy). Study enrollment is ongoing. Clinical trial information: NCT05607550.

For patients with EGFR20ins mutation, ICI+Chemo significantly prolonged PFS, and after chemotherapy progression, bevacizumab combined with chemotherapy is markedly better than Furmonertinib-based targeted therapy. For HER2-20ins mutation, Beva+Chemo is a better choice.

Treatment regimens involved in the included studies included first, second, and third-generation tyrosine kinase inhibitors (TKIs), TKIs plus chemotherapy, TKIs plus angiogenesis inhibitors, and platinum-containing doublet chemotherapy with or without bevacizumab...The highest-ranking therapies were erlotinib (Erl) plus Bev (SUCRA: 0.94) and Erl plus ramucirumab (Ram) (SUCRA: 0.93). Regarding OS, no significant differences was observed between first-line treatment strategies; the top four treatments based on SUCRA, in rank order, were Bev + Ch (0.87), gefitinib (Gef) plus Ch (0.81), dacomitinib (Dac) (0.79), and osimertinib (Osi) (0.69)... Based on these analyses of survival benefits, tumor burden response, and safety, furmonertinib (Fur), Osi, and aumolertinib (Aum) may represent the best treatment regimen options for Asian patients, significantly prolonging survival (as measured by median PFS/OS), eliciting a greater tumor burden response, and exposing patients to a lower risk of adverse events...Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php? ID=CRD42023407994, identifier CRD42023407994.

P3, N=375, Recruiting, ArriVent BioPharma, Inc. | Initiation date: Dec 2022 --> Jun 2023

P2, N=95, Not yet recruiting, Sun Yat-sen University

Furmonertinib showed promising CNS efficacy in doses of 80 mg orally once daily or higher in patients with EGFR T790M mutated NSCLC.

EGFR-TTs evaluated were erlotinib, gefitinib, icotinib, afatinib, dacomitinib, osimertinib, zorifertinib, and furmonertinib. In the largest cohort of NSCLC LM treated with EGFR TT compiled to date, osimertinib is associated with marginally improved outcomes compared to other EGFR TTs. ECOG performance status is an independent predictor of prognosis in these patients. These results highlight the need for prospective studies for this difficult to treat patient population.

Furthermore, rather than erlotinib (GlideScore: -5.564; MM/GBSA: -52.8044), gefitinib (-7.68; -47.317), and afatinib (-5.075; -44.64), furmonertinib (-11.085; -68.1575) and osimertinib (-10.031; -63.87) revealed favorable binding activity to EGFRex20ins, with furmonertinib being the most significant. Furmonertinib might have positive clinical efficacy to advanced NSCLC pts with EGFRex20ins on account of its favorable binding activity to EGFRex20ins. It may be the optimal choice for these pts in the future.

Furmonertinib demonstrated favorable PROs as measured by the EORTC QLQ-C30 and QLQ-L13 versus gefitinib. These data presented the positive benefit risk profile of first-line furmonertinib and further support this novel third generation EGFR-TKI as a new standard of first line treatment in EGFR mutation-positive NSCLC. Clinical trial information: NCT03787992.

Furmonertinib (AST2818), a potent, orally bioavailable, highly brain penetrant, third generation EGFR-TKI with unique chemical structure designed to improve potency and specificity, showed superior efficacy compared with gefitinib as first-line therapy in EGFR mutant NSCLC along with an acceptable safety profile without new signals (Shi, YK et al.; Lancet Respir Med 2022)...Eligible patients with uncleared EGFR 19Del or L858R ctDNA after 3 weeks furmonertinib treatment will be stratified according to EGFR mutation (19Del or L858R), central nervous system metastases (with or without) and detectable accompanying gene aberrances in plasma (with or without) and randomly assigned (2: 2: 1) to receive furmonertinib or furmonertinib plus chemotherapy (pemetrexed and carboplatin for 4 cycles followed by maintenance pemetrexed) or furmonertinib plus chemotherapy plus bevacizumab (pemetrexed, carboplatin and bevacizumab for 4 cycles followed by maintenance pemetrexed and bevacizumab) in 21-day cycles until disease progression, the occurrence of intolerable toxicities, withdrawal of consent, or other discontinuation reasons judged by the investigators...34 patients had been enrolled till 2nd Feb 2023. Clinical trial information: NCT05334277.

P1/2, N=106, Not yet recruiting, RemeGen Co., Ltd.

Furmonertinib has shown encouraging antitumor activity and CNS activity in patients with advanced NSCLC with EGFR ex20ins. Moreover, furmonertinib had a good safety profile and no dose-dependent toxicity.

P2, N=114, Recruiting, Peking Union Medical College Hospital | Not yet recruiting --> Recruiting

Furthermore, rather than erlotinib (GlideScore: −5.564; MM/GBSA: −52.8044), gefitinib (−7.68; −47.317), and afatinib (−5.075; −44.64), furmonertinib (−11.085; −68.1575) and osimertinib (−10.031; −63.87) revealed favorable binding activity to EGFRex20ins, with furmonertinib being the most significant. Conclusions Furmonertinib has positive clinical efficacy to advanced NSCLC pts with EGFRex20ins probably based on its favorable binding activity to EGFRex20ins. Furmonertinib may be the optimal choice for these pts in the future.

The observed AEs were consistent with those previously reported. This study is still ongoing and more results will be evaluated in the future, which may contribute to definite the role of dual EGFR TKI therapy in first-line setting.

P2, N=100, Recruiting, Allist Pharmaceuticals, Inc. | Not yet recruiting --> Recruiting

Furthermore, rather than erlotinib (GlideScore: -5.564; MM/GBSA: -52.8044), gefitinib (-7.68; -47.317), and afatinib (-5.075; -44.64), furmonertinib (-11.085; -68.1575) and osimertinib (-10.031; -63.87) revealed favorable binding activity to EGFRex20ins, with furmonertinib being the most significant. Conclusions Furmonertinib has positive clinical efficacy to advanced NSCLC pts with EGFRex20ins probably based on its favorable binding activity to EGFRex20ins. Furmonertinib may be the optimal choice for these pts in the future.

P1, N=30, Recruiting, Allist Pharmaceuticals, Inc. | Trial completion date: Dec 2021 --> Dec 2023 | Trial primary completion date: Oct 2021 --> Mar 2023

P2, N=40, Recruiting, Shanghai Chest Hospital | Trial primary completion date: Nov 2022 --> Nov 2023

P3, N=375, Recruiting, ArriVent BioPharma, Inc. | Not yet recruiting --> Recruiting

P1b, N=170, Recruiting, ArriVent BioPharma, Inc. | N=108 --> 170