Almonertinib Combined With Anlotinib as First-line Treatment for Advanced Non-small Cell Lung Cance

Advanced Non-small Cell Lung Cancer Clinical Trial

Official title: A Prospective Single-center, Single-arm Clinical Study of Almonertinib Combined With Anlotinib as First-line Treatment for Advanced Non-small Cell Lung Cancer With EGFR Sensitive Mutation and TP53 Mutation

Status Recruiting

Clinical Trial Summary

To evaluate the efficacy and safety of almonertinib plus anlotinib as first-line treatment for advanced non-small cell lung cancer with EGFR sensitive mutation and TP53 mutation.

This study is an exploratory single-arm study. The specific treatment regimen is as follows:

Non-squamous NSCLC: almonertinib (110 mg/d) plus anlotinib (12mg/d) is started on the first day of each treatment cycle and administered every three weeks until disease progression or intolerable toxicity. Anlotinib was given for two weeks, followed by one week off.

Patients are assessed for measurable disease at baseline, 6 weeks, 12 weeks after starting treatment, and every 9 weeks thereafter according to RECIST 1.1 criteria during the treatment period until disease progression or intolerable toxicity withdrawal. Following discontinuation of treatment, subjects are followed for survival status every 3 months until death. Subject safety was assessed during treatment according to NCI CTCAE Version 4.0 criteria. Subjects who experience an AE should be followed until the AE returns to baseline. The primary endpoints is Progression-free survival (PFS) . Secondary endpoints include objective response rate (ORR), overall survival (OS) and safety (NCI CTCAE v 4.0).

Statistical methods: The PFS curve was estimated using the Kaplan-Meier method for the largest population to be analyzed. The confidence interval method was used as the criterion for the main analysis. OS was calculated in the same way as the secondary endpoint. Descriptive statistics will be used to analyze ORR, DCR, etc. It is expected that almonertinib plus anlotinib as first-line treatment will prolong median PFS and OS of advanced non-small cell lung cancer with EGFR sensitive mutation and TP53 mutation patients.

Clinical Trial Description

Lung cancer is the most common solid tumor and the leading cause of cancer-related death in the world [1]. According to the Globocan analysis report of global cancer epidemic statistics in 2023, the number of new cases of lung cancer in the world reached 238,400, and the number of deaths reached 127,100, ranking first in all cancers [2]. There are about 815,000 new cases and 715,000 deaths in China every year, accounting for 23.8% of the total cancer deaths [1]. Non-small Cell Lung Cancer (NSCLC) is the most common pathological type of lung cancer, accounting for about 85% of all lung cancers [3]. About 70% of patients are locally advanced or advanced at the time of diagnosis, and only 25% of patients with NSCLC survive for more than 5 years after diagnosis. When patients receive traditional cytotoxic chemotherapy regimens, the 5-year relative survival rate of patients with advanced NSCLC is only 6%[4-6]. However, with the application of targeted therapy and immunotherapy in recent years, the 5-year survival rate of NSCLC patients receiving immunotherapy or targeted therapy can reach 15% to 50%[7-10].

EGFR mutation is one of the most common mutations in NSCLC, especially in lung adenocarcinoma.Since 2014, EGFR-TKI has become the standard first-line treatment for NSCLC patients with EGFR classical mutations.For advanced NSCLC patients with EGFR sensitive mutations and TP53 mutations, the benefit of single drug may be limited. Combination therapy may improve the survival and quality of life of advanced NSCLC patients with EGFR sensitive mutations and TP53 co-mutations, but there is still a lack of sufficient clinical trials to verify.

Almonertinib is a novel irreversible third-generation TKI. It is used for the treatment of adult patients with locally advanced or metastatic NSCLC with T790M mutation positive after prior EGFR-TKI treatment. The AENEAS study [25] is a multicenter, randomized, controlled, double-blind, phase III clinical trial comparing the efficacy and safety of almonertinib and gefitinib as first-line treatment for patients with locally advanced or metastatic NSCLC with EGFR19Del or L858R mutation. 429 untreated patients with locally advanced or metastatic disease harboring the EGFR19Del or L858R mutation were randomized to receive almonertinib at a dose of 110mg daily (n=214) or gefitinib at a dose of 250mg daily (n=215). The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR), and disease control rate (DCR). The results showed that the mPFS of almonertinib group and gefitinib group were 19.3 months and 9.9 months, ORR were 73.8% and 72.1%, DCR were 93.0% and 96.7%, DOR were 18.1 months and 8.3 months. Based on this study, on December 16, 2021, the NMPA officially approved almonertinib for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR19Del or exon 21 L858R mutation.

Anlotinib is a novel multi-target oral tyrosine kinase inhibitor developed by China. It can effectively inhibit VEGFR, PDGFR, FGFR, PDGFRα and β and stem cell growth factor receptor (c-Kit) and other kinases, so it can play an effective role in anti-tumor angiogenesis and inhibition of tumor cell growth [29, 30]. A number of clinical trials have confirmed the significant efficacy of anlotinib in patients with advanced NSCLC. ALTER-0303 trial [31] was a randomized, double-blind, multicenter, controlled phase III clinical trial of anlotinib as a third-line or longer treatment for advanced NSCLC patients. A total of 437 subjects were enrolled in the study and randomly assigned to anlotinib group (n=294) and placebo group (n=143) at a ratio of 2:1. The primary endpoint was overall survival (OS). The secondary endpoints were PFS, ORR, DCR, Quality of Life (QoL), and safety. The results showed that anlotinib was superior to placebo in terms of OS and PFS. The median OS (mOS) and mPFS were 9.6 and 5.4 months, respectively, in the anlotinib group, and 6.3 and 1.4 months, respectively, in the placebo group. Meanwhile, the results of exploratory subgroup analysis showed that advanced NSCLC with EGFR mutation or EGFR wild type could benefit from clinical treatment in terms of OS and PFS. Based on this experimental result, on May 8, 2018, the China Food and Drug Administration (CFDA) officially approved single-agent anlotinib for the third-line and beyond treatment of advanced NSCLC patients.

To evaluate the efficacy and safety of almonertinib plus anlotinib as first-line treatment for advanced non-small cell lung cancer with EGFR sensitive mutation and TP53 mutation.

This study is an exploratory single-arm study. The specific treatment regimen is as follows:

Non-squamous NSCLC: almonertinib (110 mg/d) plus anlotinib (12mg/d) is started on the first day of each treatment cycle and administered every three weeks until disease progression or intolerable toxicity. Anlotinib was given for two weeks, followed by one week off.

Patients are assessed for measurable disease at baseline, 6 weeks, 12 weeks after starting treatment, and every 9 weeks thereafter according to RECIST 1.1 criteria during the treatment period until disease progression or intolerable toxicity withdrawal. Following discontinuation of treatment, subjects are followed for survival status every 3 months until death. Subject safety was assessed during treatment according to NCI CTCAE Version 4.0 criteria. Subjects who experience an AE should be followed until the AE returns to baseline. The primary endpoints is Progression-free survival (PFS) . Secondary endpoints include objective response rate (ORR), overall survival (OS) and safety (NCI CTCAE v 4.0).

Statistical methods: The PFS curve was estimated using the Kaplan-Meier method for the largest population to be analyzed. The confidence interval method was used as the criterion for the main analysis. OS was calculated in the same way as the secondary endpoint. Descriptive statistics will be used to analyze ORR, DCR, etc. It is expected that almonertinib plus anlotinib as first-line treatment will prolong median PFS and OS of advanced non-small cell lung cancer with EGFR sensitive mutation and TP53 mutation patients. ;

Related Conditions & MeSH terms

• Advanced Non-small Cell Lung Cancer
• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms

• NCT number: NCT06043973
• Study type: Interventional
• Source: Qianfoshan Hospital
• Contact: Degan Lu, Professor
• Phone: 18753157623
• Email: deganlu@126.com
• Status: Recruiting
• Phase: Phase 3
• Start date: September 1, 2023
• Completion date: June 30, 2027