Ignite Creation Date:
2024-10-26 @ 3:42 PM
Last Modification Date:
2024-10-26 @ 3:42 PM
Study NCT ID:
NCT06643000
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-10-14
Brief Title:
Evaluating High-dose Furmonertinib With Bevacizumab and Pemetrexed for EGFRm NSCLC With Leptomeningeal Metastasis
Sponsor:
None
Organization:
None
Study Overview
Official Title:
A Single-center Real-world Study Aimed at Evaluating the Efficacy and Safety of 240 mgd Furmonertinib Combined With Bevacizumab and Pemetrexed in the Treatment of Advanced NSCLC With EGFRm and Leptomeningeal Metastasis
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The primary objective of this clinical study is to evaluate the efficacy of high-dose furmonertinib combined with bevacizumab and pemetrexed triple therapy in the treatment of non-small cell lung cancer NSCLC with leptomeningeal metastasis and epidermal growth factor receptor mutation EGFRm through overall survival OS The secondary objectives are to further assess the efficacy of the triple therapy in patients with EGFRm and leptomeningeal metastasis including time to treatment failure TTF leptomeningeal objective response rate ORR-LM and clinical response rateThe study will also evaluate the impact of the triple therapy on quality of life using the EORTC QLQ-C30 scale and assess the safety of the therapy in EGFRm NSCLC patients with leptomeningeal metastasis focusing primarily on adverse events and their severity graded according to CTCAE v50 as well as their frequencyThe exploratory objectives are to assess changes in intracranial pressure and the improvement rate of cerebrospinal fluid CSF before and after the triple therapy treatment Additionally the study will compare the genomic and epigenomic profile changes in circulating tumor DNA ctDNA from peripheral blood and cell-free DNA cfDNA from cerebrospinal fluid before and after treatment and analyze their correlation with clinical outcomes drug efficacy and other clinical indicators
The primary endpoint of this study is overall survival OS The secondary endpoints include time to treatment failure TTF leptomeningeal objective response rate ORR-LM clinical response rate and quality of life assessment EORTC QLQ-C30The safety endpoints are adverse events and their severity graded according to CTCAE v50 as well as the frequency of occurrence
A total of 60 patients are planned to be enrolled targeting eligible advanced NSCLC patients with EGFR mutations and leptomeningeal metastasis
The intervention consists of furmonertinib 240 mgd po combined with bevacizumab 15 mgkg every 3 weeks ivgtt and pemetrexed 50 mg intrathecal chemotherapy pemetrexed 500 mgm² intravenous chemotherapy administered every 3 weeks
The primary endpoint of this study is overall survival OS The secondary endpoints include time to treatment failure TTF leptomeningeal objective response rate ORR-LM clinical response rate and quality of life assessment EORTC QLQ-C30The safety endpoints are adverse events and their severity graded according to CTCAE v50 as well as the frequency of occurrence
A total of 60 patients are planned to be enrolled targeting eligible advanced NSCLC patients with EGFR mutations and leptomeningeal metastasis
The intervention consists of furmonertinib 240 mgd po combined with bevacizumab 15 mgkg every 3 weeks ivgtt and pemetrexed 50 mg intrathecal chemotherapy pemetrexed 500 mgm² intravenous chemotherapy administered every 3 weeks
Detailed Description:
Leptomeningeal metastasis LM is a fatal complication of advanced lung cancer In recent years with the rapid advancement of precision therapy for lung cancer the survival time of patients with advanced lung cancer has significantly increased leading to a rapid rise in the incidence of LM It is reported that the incidence of LM in patients with advanced non-small cell lung cancer NSCLC reaches 3-5 and as high as 94 among patients with epidermal growth factor receptor EGFR mutations The prognosis of NSCLC patients with LM is extremely poor with a median overall survival OS of only 4-6 weeks without treatment1 Due to the presence of the blood-brain barrier BBB which limits drug penetration as well as the efflux mechanisms of transport proteins on the BBB effectively treating patients with LM remains a significant challenge
For brain or leptomeningeal metastases driven by genetic mutations both the Lung Cancer Brain Leptomeningeal Metastasis Diagnosis and Treatment Consensus 2017 and the 2024 NCCN Guidelines recommend tyrosine kinase inhibitors TKIs as the first-line treatment Most studies on first- and second-generation EGFR-TKIs for leptomeningeal metastasis are retrospective and show relatively limited efficacy Pulse dosing of erlotinib appears to achieve relatively longer overall survival OS but both studies included only a few patients In two prospective studies on afatinib and gefitinib OS did not exceed four months The BLOOM study included 41 patients with CSF-confirmed EGFR-mutant NSCLC with leptomeningeal metastasis who received osimertinib at a dose of 160 mgd The LM objective response rate ORR was 62 progression-free survival PFS was 86 months and OS was 110 months While the overall efficacy showed room for improvement safety concerns were notable 66 of patients experienced grade 3 or higher adverse events 51 experienced serious adverse events SAEs 22 discontinued treatment due to adverse events and 12 required dose reduction In summary improving clinical outcomes for patients with EGFR-mutant NSCLC with LM while reducing toxicity remains a key area for further exploration
Furmonertinib brand name Aifisha formerly known as alflutinibAST2818 is a third-generation EGFR TKI independently developed by Shanghai Allist Pharmaceuticals Furmonertinib has demonstrated strong antitumor activity and manageable safety characteristics in advanced patients with EGFR exon 20 T790M point mutations T790M-positive It was approved by the NMPA in March 2020 In June 2022 furmonertinib received approval from the National Medical Products Administration NMPA for first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer NSCLC harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations
In the Phase I-IIa study furmonertinib demonstrated good tolerability with no dose-related toxic reactions observed across the dose groups ranging from 20 mg to 240 mg At a dose of 240 mgday the safety and tolerability were favorable with an incidence of Grade 3 adverse events AEs at 11 and serious adverse events occurring in 11 of patients Dose reduction due to AEs occurred in 6 of patients and no patients discontinued treatment due to AEs The most common adverse reactions included diarrhea 33 rash 33 decreased white blood cell count 28 elevated serum creatinine 22 and proteinuria 22 all of which were Grade 1-2 The most frequent Grade 3 AE was elevated ALT 6 Overall the drug was well-tolerated and adverse events were relatively manageable
An Ib phase clinical study named FAVOUR enrolled 30 patients with advanced NSCLC harboring EGFR Exon20ins mutations who received furmonertinib at doses of 160 mgday or 240 mgday Data from the initial treatment cohort of 10 patients receiving 240 mgday of furmonertinib have been released The results showed that the objective response rate ORR assessed by independent review committee IRC reached 60 the disease control rate DCR was 100 and progression-free survival PFS has not yet been reached Additionally safety was favorable with no reports of Grade 3 adverse events suggesting that high-dose furmonertinib holds promise for the treatment of patients with EGFR uncommon mutations
In addition to showing good efficacy in patients with advanced NSCLC harboring classic and uncommon EGFR mutations furmonertinib has also demonstrated promising central nervous system CNS activity Preclinical studies indicated that 24 hours after administration in animal models the ratio of furmonertinibs prototype drug and its major active metabolite AST2818 in brain tissue AUC0-24h to plasma AUC0-24h was greater than 1 suggesting that furmonertinib can penetrate the blood-brain barrier BBB In its Phase IIb clinical study furmonertinib achieved a CNS objective response rate ORR of 66 CNS disease control rate DCR of 100 and CNS progression-free survival PFS of 116 months in patients with EGFR T790M mutation and brain metastases Additionally in its Phase III study CNS efficacy increased with higher doses the 80 mgday dose achieved a CNS ORR of 60 and a CNS PFS of 97 months while the 160 mgday dose resulted in a CNS ORR of 846 and a CNS PFS of 193 months For patients with refractory leptomeningeal metastasis LM increasing the dose of furmonertinib may offer enhanced antitumor activity
Based on the above findings researchers conducted a real-world study and data analysis revealed that furmonertinib at a dose of 240 mgday demonstrated significant efficacy in the treatment of leptomeningeal metastasis with patients overall showing good tolerability From May 2021 to December 2023 a total of 48 patients were enrolled of which 35 patients had an ECOG performance status 3 accounting for 729 Of these 35 patients 729 had previously received other third-generation EGFR-TKI treatments Seventeen patients 354 were treated with furmonertinib monotherapy The median follow-up time was 15 months The median overall survival OS was 8433 months 95 CI 5481-11386 months and the median time to treatment discontinuation TTD was 8267 months 95 CI 5395-11138 months The clinical response rate was 75 According to the RANO-LM radiological criteria the leptomeningeal metastasis LM objective response rate ORR and disease control rate DCR were 500 and 921 respectively The treatment was well tolerated overall consistent with previous reports Twenty-two patients 458 experienced treatment-related adverse events TRAEs and three patients 63 experienced Grade 3 TRAEs We found that high-dose TKI monotherapy improved prognosis in patients with leptomeningeal metastasis but the median OS still did not exceed one year Further exploration is needed to extend survival in these patients and more treatment modalities are currently under investigation
In terms of systemic combination therapy studies have shown that bevacizumab can enhance the penetration of TKIs into cerebrospinal fluid increasing their concentration in brain tissue A retrospective analysis of 27 patients receiving osimertinib combined with bevacizumab showed that the median OS in the combination group n16 and the monotherapy group n11 was 180 months and 137 months p 0046 respectively and intracranial PFS iPFS was 106 months and 55 months p 0037 These results suggest that osimertinib combined with bevacizumab may significantly improve the median OS and intracranial PFS in patients with leptomeningeal metastasis compared to osimertinib monotherapy Additionally combining intrathecal chemotherapy to increase local drug concentration can improve efficacy and survival benefits An III phase study showed that intrathecal injection of pemetrexed achieved good efficacy in lung cancer patients with leptomeningeal metastasis who had failed multiple lines of targeted therapy the ORR was 846 and the median OS was 9 months Among patients who achieved a clinical response CR or PR the median OS was 12 months and the safety profile was significantly better than with traditional drugs When pemetrexed was administered intravenously in combination with systemic therapy patients also benefited in terms of survival A retrospective study of 110 patients with EGFR-mutant advanced NSCLC treated with EGFR TKIs found that after leptomeningeal metastasis patients who received systemic pemetrexed chemotherapy had a longer overall survival than those who did not 137 vs 40 months p 0008
Based on the above findings this study aims to explore the efficacy and safety of furmonertinib 240 mgday combined with bevacizumab and pemetrexed in EGFR-mutant NSCLC patients with leptomeningeal metastasis
For brain or leptomeningeal metastases driven by genetic mutations both the Lung Cancer Brain Leptomeningeal Metastasis Diagnosis and Treatment Consensus 2017 and the 2024 NCCN Guidelines recommend tyrosine kinase inhibitors TKIs as the first-line treatment Most studies on first- and second-generation EGFR-TKIs for leptomeningeal metastasis are retrospective and show relatively limited efficacy Pulse dosing of erlotinib appears to achieve relatively longer overall survival OS but both studies included only a few patients In two prospective studies on afatinib and gefitinib OS did not exceed four months The BLOOM study included 41 patients with CSF-confirmed EGFR-mutant NSCLC with leptomeningeal metastasis who received osimertinib at a dose of 160 mgd The LM objective response rate ORR was 62 progression-free survival PFS was 86 months and OS was 110 months While the overall efficacy showed room for improvement safety concerns were notable 66 of patients experienced grade 3 or higher adverse events 51 experienced serious adverse events SAEs 22 discontinued treatment due to adverse events and 12 required dose reduction In summary improving clinical outcomes for patients with EGFR-mutant NSCLC with LM while reducing toxicity remains a key area for further exploration
Furmonertinib brand name Aifisha formerly known as alflutinibAST2818 is a third-generation EGFR TKI independently developed by Shanghai Allist Pharmaceuticals Furmonertinib has demonstrated strong antitumor activity and manageable safety characteristics in advanced patients with EGFR exon 20 T790M point mutations T790M-positive It was approved by the NMPA in March 2020 In June 2022 furmonertinib received approval from the National Medical Products Administration NMPA for first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer NSCLC harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations
In the Phase I-IIa study furmonertinib demonstrated good tolerability with no dose-related toxic reactions observed across the dose groups ranging from 20 mg to 240 mg At a dose of 240 mgday the safety and tolerability were favorable with an incidence of Grade 3 adverse events AEs at 11 and serious adverse events occurring in 11 of patients Dose reduction due to AEs occurred in 6 of patients and no patients discontinued treatment due to AEs The most common adverse reactions included diarrhea 33 rash 33 decreased white blood cell count 28 elevated serum creatinine 22 and proteinuria 22 all of which were Grade 1-2 The most frequent Grade 3 AE was elevated ALT 6 Overall the drug was well-tolerated and adverse events were relatively manageable
An Ib phase clinical study named FAVOUR enrolled 30 patients with advanced NSCLC harboring EGFR Exon20ins mutations who received furmonertinib at doses of 160 mgday or 240 mgday Data from the initial treatment cohort of 10 patients receiving 240 mgday of furmonertinib have been released The results showed that the objective response rate ORR assessed by independent review committee IRC reached 60 the disease control rate DCR was 100 and progression-free survival PFS has not yet been reached Additionally safety was favorable with no reports of Grade 3 adverse events suggesting that high-dose furmonertinib holds promise for the treatment of patients with EGFR uncommon mutations
In addition to showing good efficacy in patients with advanced NSCLC harboring classic and uncommon EGFR mutations furmonertinib has also demonstrated promising central nervous system CNS activity Preclinical studies indicated that 24 hours after administration in animal models the ratio of furmonertinibs prototype drug and its major active metabolite AST2818 in brain tissue AUC0-24h to plasma AUC0-24h was greater than 1 suggesting that furmonertinib can penetrate the blood-brain barrier BBB In its Phase IIb clinical study furmonertinib achieved a CNS objective response rate ORR of 66 CNS disease control rate DCR of 100 and CNS progression-free survival PFS of 116 months in patients with EGFR T790M mutation and brain metastases Additionally in its Phase III study CNS efficacy increased with higher doses the 80 mgday dose achieved a CNS ORR of 60 and a CNS PFS of 97 months while the 160 mgday dose resulted in a CNS ORR of 846 and a CNS PFS of 193 months For patients with refractory leptomeningeal metastasis LM increasing the dose of furmonertinib may offer enhanced antitumor activity
Based on the above findings researchers conducted a real-world study and data analysis revealed that furmonertinib at a dose of 240 mgday demonstrated significant efficacy in the treatment of leptomeningeal metastasis with patients overall showing good tolerability From May 2021 to December 2023 a total of 48 patients were enrolled of which 35 patients had an ECOG performance status 3 accounting for 729 Of these 35 patients 729 had previously received other third-generation EGFR-TKI treatments Seventeen patients 354 were treated with furmonertinib monotherapy The median follow-up time was 15 months The median overall survival OS was 8433 months 95 CI 5481-11386 months and the median time to treatment discontinuation TTD was 8267 months 95 CI 5395-11138 months The clinical response rate was 75 According to the RANO-LM radiological criteria the leptomeningeal metastasis LM objective response rate ORR and disease control rate DCR were 500 and 921 respectively The treatment was well tolerated overall consistent with previous reports Twenty-two patients 458 experienced treatment-related adverse events TRAEs and three patients 63 experienced Grade 3 TRAEs We found that high-dose TKI monotherapy improved prognosis in patients with leptomeningeal metastasis but the median OS still did not exceed one year Further exploration is needed to extend survival in these patients and more treatment modalities are currently under investigation
In terms of systemic combination therapy studies have shown that bevacizumab can enhance the penetration of TKIs into cerebrospinal fluid increasing their concentration in brain tissue A retrospective analysis of 27 patients receiving osimertinib combined with bevacizumab showed that the median OS in the combination group n16 and the monotherapy group n11 was 180 months and 137 months p 0046 respectively and intracranial PFS iPFS was 106 months and 55 months p 0037 These results suggest that osimertinib combined with bevacizumab may significantly improve the median OS and intracranial PFS in patients with leptomeningeal metastasis compared to osimertinib monotherapy Additionally combining intrathecal chemotherapy to increase local drug concentration can improve efficacy and survival benefits An III phase study showed that intrathecal injection of pemetrexed achieved good efficacy in lung cancer patients with leptomeningeal metastasis who had failed multiple lines of targeted therapy the ORR was 846 and the median OS was 9 months Among patients who achieved a clinical response CR or PR the median OS was 12 months and the safety profile was significantly better than with traditional drugs When pemetrexed was administered intravenously in combination with systemic therapy patients also benefited in terms of survival A retrospective study of 110 patients with EGFR-mutant advanced NSCLC treated with EGFR TKIs found that after leptomeningeal metastasis patients who received systemic pemetrexed chemotherapy had a longer overall survival than those who did not 137 vs 40 months p 0008
Based on the above findings this study aims to explore the efficacy and safety of furmonertinib 240 mgday combined with bevacizumab and pemetrexed in EGFR-mutant NSCLC patients with leptomeningeal metastasis
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None