| Objective: To observe the effect of the first-line treatment of Yiqi Yangyin Jiedu Decoction combined with the first-generation EGFR-TKIs on the progression-free survival and long-term survival of patients with EGFR mutation-positive advanced lung adenocarcinoma with deficiency of both qi and yin,so as to observe the effect of Yiqi Yangyin Jiedu Decoction on the prognosis of EGFR-TKIs combined therapy.Methods: A multi-center,randomized controlled and blind prospective study was conducted.With Yueyang Hospital of Integrated Traditional Chinese and Western Medicine,Shanghai Chest Hospital and Shanghai Pulmonary Hospital as multi-center research units.A total of 187 patients with lung adenoma with deficiency of both qi and Yin with EGFR-positive mutation were included in the first-line treatment and randomly divided into two groups: EGFR-TKI+ CHM group(91 cases)(first-generation EGFR-TKI+ Yiqi Yangyin Jie du granules)and EGFR-TKI group(96 cases)(first-generation EGFR-TKI+ placebo granules).Patients were treated until disease progression or intolerance followed by long-term follow-up.The main observation: PFS(progression-free survival).Secondary observation: clinical progression pattern,drug resistance gene detection of T790 M,tumor related polygene detection,PFS2(second progress free survival),TD-TKI(time to discontinuation of any EGFR-TKI),TD-3rd TKI(time to discontinuation of any third generation of EGFR-TKI),time to progression after second-line chemotherapy,OS(overall survival time)and survival rate.Result:1.PFS: The median PFS of the EGFR-TKI+CHM group was 16.100 months,and the median PFS of the EGFR-TKI group was 11.000 months,with statistical difference between the two groups(P=0.044,HR =0.711,95% CI: 0.509-0.992).Subgroup stratified analysis of age and EGFR-TKI type showed that the median PFS of patients aged < 65 years(13.700 vs.8.800 months,P=0.046,HR= 0.658,95% CI: 0.434-0.996)and those treated with Icotinib(16.433 vs.10.633 months,P=0.044,HR= 0.643,95%CI;0.418-0.991)in the EGFR-TKI+CHM group was longer than that in the EGFR-TKI group,and the difference was statistically significant.2.Clinical progression pattern: In patients with disease progression,the rate of dramatic progression was 39.3%,the rate of gradual progression was 47.5%,and the rate of local progression was 13.1% in the EGFR-TKI+CHM group(N=61).The rate of dramatic progression was 61.4%,the rate of gradual progression was 31.4%,and the rate of local progression was 7.1% in the EGFR-TKI group(N=70).The difference between the two groups was statistically significant(P=0.040).3.Drug resistance gene detection of T790M: Among the 106 patients who underwent T790 M mutation detection after disease progression,the T790 M positive mutation rate of EGFR-TKI+CHM group(N=45)was 57.8%.The positive rate of T790 M mutation in EGFR-TKI group(N=61)was 44.3%.There was no significant difference between the two groups(P=0.169).There was no significant difference in T790 M mutation rate between the two subgroups(P >0.05).There were no significant differences in gender,age class,clinical stage,EGFR-TKI drug and mutation type between the two groups in53 patients with T790 M mutation(P >0.05).4.Tumor related polygene detection: The mutation detection rate of TP53 gene was the highest(66.7%),except EGFR gene,among the 15 patients who underwent polygenic testing after disease progression.The mutation frequency of PTEN gene and PIK3 CA gene related to PI3K/ Akt pathway activation in EGFR-TKI group was 25.0% and12.5%,respectively,and the mutation frequency in EGFR-TKI+CHM group was 0.0%.5.PFS 2: The median PFS 2 of the EGFR-TKI+CHM group(N=91)was 34.967 months,and that of the EGFR-TKI group(N=96)was 28.500 months.There was no significant difference between the two groups(P=0.586).6.TD-TKI: The median TDTKI in the EGFR-TKI+CHM group(N=91)was 35.467 months,and that of the EGFR-TKI group(N=96)was 24.733 months,and there was no statistical significance between the two groups(P=0.057).7.TD-3rd TKI: Among the 61 patients who entered the third generation of EGFR-TKI treatment,the median TD-3rd TKI in the EGFR-TKI+CHM group(N=31)was 34.967 months and the median TD-3rd TKI in the EGFR-TKI group(N=30)was 28.467 months.There was no significant difference between the two groups(P=0.618).8.Time to progression after second-line chemotherapy: In 37 patients who received second-line chemotherapy,the median second progression time of EGFR-TKI+CHM group(N=11)was 23.033 months.The median time to secondary progression in the EGFR-TKI group(N=26)was 22.167 months.There was no statistical difference between the two groups(P=0.839).9.OS: As of February 18,2021,a total of 46 deaths.The median OS of the two groups was not reached.The mean survival time of the EGFR-TKI+CHM group was 39.449 months,and the mean survival time of the EGFR-TKI group was 36.328 months.10.Survival rate: The 1-year,2-year and 3-year cumulative survival rates of EGFR-TKI combined Chinese medicine group were 93%,77% and 71% respectively.The 1-year,2-year and 3-year cumulative survival rates of EGFR-TKI group were 91%,77% and58%,respectively.There was no significant difference between the two groups(P=0.844).Conclusion:1.The combination of Yiqi Yangyin Jiedu Decoction and first-line treatment with EGFR-TKIs can prolong the progression-free survival time of patients with EGFR-mutation-positive advanced lung adenocarcinoma with deficiency of both Qi and Yin,which is related to reducing the dramatic progression type of patients after EGFR-TKI treatment,increasing the proportion of gradual progression type,and influencing the progression type of drug resistance.2.The combination of Yiqi Yangyin Jiedu Decoction and EGFR-TKI treatment might affect the change of EGFR T790 M drug resistance gene,which provides an opportunity for EGFR-TKI future treatment.3.The combination of Yiqi Yangyin Jiedu Decoction and first-line treatment of EGFR-TKIs showed a trend of long-term survival benefit in patients with EGFR-mutation positive and advanced lung adenocarcinoma with deficiency of both Qi and Yin. |
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