Cancer Res Treat.  2023 Jul;55(3):841-850. 10.4143/crt.2022.1438.

EGFR-TKI Combined with Pemetrexed versus EGFR-TKI Monotherapy in Advanced EGFR-mutated NSCLC: A Prospective, Randomized, Exploratory Study

• Gu W
• Zhang H
• Lu Y
• Li M
• Yang S
• Liang J
• Ye Z
• Li Z
• He M
• Shi X
• Wang F
• You D
• Gu W
• Feng W

• KMID: 2544165
• DOI: http://doi.org/10.4143/crt.2022.1438

Abstract

Purpose
We aimed to evaluate whether the addition of pemetrexed is effective in improving progression-free survival (PFS) in epidermal growth factor receptor (EGFR)–mutated patients with or without concomitant alterations.
Materials and Methods
This multicenter clinical trial was conducted in China from June 15, 2018, to May 31, 2019. A total of 92 non–small cell lung cancer (NSCLC) patients harboring EGFR-sensitive mutations were included and divided into concomitant and non-concomitant groups. Patients in each group were randomly treated with EGFR–tyrosine kinase inhibitor (TKI) monotherapy or EGFR-TKI combined with pemetrexed in a ratio of 1:1. PFS was recorded as the primary endpoint.
Results
The overall median PFS of this cohort was 10.1 months. There were no significant differences in PFS between patients with and without concomitant and between patients received TKI monotherapy and TKI combined with pemetrexed (p=0.210 and p=0.085, respectively). Stratification analysis indicated that patients received TKI monotherapy had a significantly longer PFS in non-concomitant group than that in concomitant group (p=0.002). In concomitant group, patients received TKI combined with pemetrexed had a significantly longer PFS than patients received TKI monotherapy (p=0.013). Molecular dynamic analysis showed rapidly emerging EGFR T790M in patients received TKI monotherapy. EGFR mutation abundance decreased in patients received TKI combined chemotherapy, which supports better efficacy for a TKI combined chemotherapy as compared to TKI monotherapy. A good correlation between therapeutic efficacy and a change in circulating tumor DNA (ctDNA) status was found in 66% of patients, supporting the guiding role of ctDNA minimal residual disease (MRD) in NSCLC treatment.
Conclusion
EGFR-TKI monotherapy is applicable to EGFR-sensitive patients without concomitant alterations, while a TKI combined chemotherapy is applicable to EGFR-sensitive patients with concomitant alterations. CtDNA MRD may be a potential biomarker for predicting therapeutic efficacy.

Keyword

Non-small cell lung carcinoma; Tyrosine kinase inhibitors; Dynamic detection; Minimal residual disease

Figure

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  Fig. 1 The randomization and trial profile. EGFR, epidermal growth factor receptor; NSCLC, non–small cell lung cancer; TKI, tyrosine kinase inhibitor.

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  Fig. 2 Kaplan-Meier curves for progression free survival (PFS) in patients. (A) Comparison analysis of PFS treated with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and EGFR-TKI combined with pemetrexed in patients without concomitant alterations. (B) Comparison analysis of PFS treated with EGFR-TKI and EGFR-TKI combined with pemetrexed in patients with concomitant alterations. (C) A comparison analysis of PFS between EGFR-TKI treated patients with and without concomitant alterations. (D) A comparison analysis of PFS between EGFR-TKI combined with pemetrexed treated patients with and without concomitant alterations. CI, confidence interval. (E) A comparison analysis of PFS between patients with EGFR-TKI and EGFR-TKI combined with pemetrexed treatments. “Yes” indicates patients with concomitant alterations. “No” indicates patients without concomitant alterations. “TKI” indicates patients that received an EGFR-TKI treatment. “TKI+chemo” indicates patients that received an EGFR-TKI combined with pemetrexed treatment.

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  Fig. 3 Dynamic circulating tumor DNA (ctDNA) monitoring for epidermal growth factor receptor (EGFR) mutations. (A) The detection rate of EGFR T790M mutation in patients with and without concomitant alterations. (B) The detection rate of EGFR T790M mutation in patients with an EGFR–tyrosine kinase inhibitor (TKI) monotherapy treatment and with EGFR-TKI combined with pemetrexed treatment. (C) Dynamic ctDNA monitoring for EGFR mutation abundance in patients with an EGFR-TKI monotherapy treatment and with EGFR-TKI combined with pemetrexed treatment. “Yes” indicates patients with concomitant alterations. “No” indicates patients without concomitant alterations. “TKI” indicates that patients received an EGFR-TKI treatment. “TKI+chemo” indicates that patients recei-ved an EGFR-TKI combined with pemetrexed treatment.

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  Fig. 4 Dynamic circulating tumor DNA (ctDNA) status and clinical outcomes. The x-axis represents the follow-up time (months). The y-axis represents each patient. Circles represent the time point of ctDNA detection. Sizes for individual circles represent different values of ctDNA variant allele frequency (VAF). Red crosses indicate the progress of disease. Green arrows indicate the stability of disease.

Reference

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