The correlation between the prognosis of lung adenocarcinoma with acquired resistance to the first-generation EGFR TKI and the T790M mutation

doi:10.3969/j.issn.1004-583X.2022.11.004

Abstract

Abstract:

Objective To prospectively analyze the correlation between the prognosis of lung adenocarcinoma with acquired resistance to the first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and the T790M mutation. Methods A total of 93 eligible patients with lung adenocarcinoma were selected. The EGFR-sensitive mutation and T790M mutation status were detected by the next-generation sequencing (NGS). Osimertinib was used as the EGFR-TKI treatment in the second or third-line treatment, and patients in the control group were given chemotherapy and/or radiotherapy. Objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) of the second and third-line treatment were evaluated.Results The ORR was comparable between lung adenocarcinoma patients with positive or negative T790M mutation ( $P$ =0.084); while a significant difference was detected in the DCR ( $P$ =0.01). There were significant differences in the ORR ( $P$ =0.022) and DCR ( $P$ =0.016) in lung adenocarcinoma patients with positive or negative T790M mutation who were treated with the second-line treatment of osimertinib; similar results were obtained in the third-line treatment of osimertinib as well (ORR [ $P$ =0.016] and DCR [ $P$ =0.011]). The Mann-Whitney U test showed that the mutation status of T790M was significantly correlated with PFS in all lung adenocarcinoma patients ( $P$ <0.01), and those treated with the second-line treatment ( $P$ =0.022) and the third-line treatment ( $P$ =0.016). Kaplan-Meier survival analysis showed that the T790M mutation significantly influenced the overall PFS in lung adenocarcinoma patients ( $P$ <0.01). In the T790M-positive group, there was a significant difference in the PFS between those with EGFR exon 19 mutation and exon 21 mutation ( $P$ =0.05). Multivariate Cox proportional hazards regression analysis showed significant differences in EGFR exon 21 vs exon 19 ( $H R$ =0.551, 95% $C I$ =0.357-0.853, $P$ =0.007), T790M-positive mutation vs T790M-negative mutation ( $H R$ =2.972, 95% $C I$ =1.643-5.379, $P$ <0.01), and tumor diameter ≥5 cm vs tumor diameter <5 cm ( $H R$ =0.575, 95% $C I$ =0.373-0.085, $P$ =0.012). Conclusion The prognosis of T790M mutation-positive lung adenocarcinoma patients is better than that of T790M mutation-negative patients. PFS is comparable in T790M-positive lung adenocarcinoma patients treated with the second or third-line treatment of osimertinib. Advanced lung adenocarcinoma patients with the T790M mutation can be treated with the third-generation EGFR-TKI after the development of first-generation EGFR-TKI resistance.

Key words: lung adenocarcinoma, epidermal growth factor receptor tyrosine kinase inhibitor, T790M, efficacy, drug resistance

CLC Number:

R734.2
R563

Li Shufan, Wang Yuxiu, Jiang Zhenghua. The correlation between the prognosis of lung adenocarcinoma with acquired resistance to the first-generation EGFR TKI and the T790M mutation[J]. Clinical Focus, 2022, 37(11): 985-991.

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URL: https://huicui.hebmu.edu.cn/EN/10.3969/j.issn.1004-583X.2022.11.004

https://huicui.hebmu.edu.cn/EN/Y2022/V37/I11/985

Figures/Tables 9

临床特征	T790M阴性 ( $n$ =15)	T790M阳性 ( $n$ =78)	χ²/ $t$ 值	$P$ 值
性别
女男	9(60.0) 6(40.0)	42(53.8) 36(46.2)	0.192	0.661
年龄(岁)
<65 ≥65	11(73.3) 4(26.7)	44(56.4) 34(43.6)	1.491	0.222
吸烟状态
不吸烟吸烟	11(73.3) 4(26.7)	57(73.1) 21(26.9)	0	0.984
ECOG评分
0	2(13.3)	7(9.0)
1	5(33.3)	47(60.3)	4.119	0.249
2	7(46.7)	19(24.4)
3	5(6.7)	1(6.4)
分期
术后复发初诊Ⅳ期	3(20.0) 12(80.0)	16(20.5) 62(79.5)	0.002	0.964
肿瘤大小
<5 cm ≥5 cm	7(46.7) 8(53.3)	39(50.0) 39(50.0)	0.056	0.813
淋巴结状态
N0	2(13.3)	19(24.4)
N1-2	6(40.0)	36(46.2)	1.934	0.380
N3	7(46.7)	23(29.5)
外显子突变
19外显子 21外显子	6(40.0) 9(60.0)	47(60.3) 31(39.7)	2.106	0.147
奥希替尼治疗线数
二线三线及三线以上	3(20.0) 12(80.0)	39(50.0) 39(50.0)	4.572	0.033

临床特征	T790M阴性 ( $n$ =15)	T790M阳性 ( $n$ =78)	χ²/ $t$ 值	$P$ 值
性别
女男	9(60.0) 6(40.0)	42(53.8) 36(46.2)	0.192	0.661
年龄(岁)
<65 ≥65	11(73.3) 4(26.7)	44(56.4) 34(43.6)	1.491	0.222
吸烟状态
不吸烟吸烟	11(73.3) 4(26.7)	57(73.1) 21(26.9)	0	0.984
ECOG评分
0	2(13.3)	7(9.0)
1	5(33.3)	47(60.3)	4.119	0.249
2	7(46.7)	19(24.4)
3	5(6.7)	1(6.4)
分期
术后复发初诊Ⅳ期	3(20.0) 12(80.0)	16(20.5) 62(79.5)	0.002	0.964
肿瘤大小
<5 cm ≥5 cm	7(46.7) 8(53.3)	39(50.0) 39(50.0)	0.056	0.813
淋巴结状态
N0	2(13.3)	19(24.4)
N1-2	6(40.0)	36(46.2)	1.934	0.380
N3	7(46.7)	23(29.5)
外显子突变
19外显子 21外显子	6(40.0) 9(60.0)	47(60.3) 31(39.7)	2.106	0.147
奥希替尼治疗线数
二线三线及三线以上	3(20.0) 12(80.0)	39(50.0) 39(50.0)	4.572	0.033

临床特征	例数	T790M阴性 ( $n$ =15)	T790M阳性 ( $n$ =78)	χ²值	$P$ 值
所有人群ORR
CR+PR SD+PD	50(53.7) 43(46.3)	2(13.3) 13(86.7)	48(61.5) 30(38.5)	11.760	0.001
二线ORR
CR+PR SD+PD	26(61.9) 16(38.1)	0(0.0) 3(100.0)	26(66.7) 13(33.3)	5.250	0.022
三线ORR
CR+PR SD+PD	24(47.1) 27(52.9)	2(16.7) 10(83.3)	22(56.4) 17(43.6)	5.818	0.016
所有人群DCR
CR+PR+SD PD	87(93.5) 6(6.5)	11(73.3) 4(6.4)	76(97.4) 2(2.6)	12.109	0.01
二线DCR
CR+PR+SD PD	40(95.2) 2(4.8)	2(66.7) 1(33.3)	38(97.4) 1(2.6)	5.815	0.016
三线DCR
CR+PR+SD PD	50(53.7) 4(7.8)	9(75.0) 3(25.0)	38(97.4) 1(2.6)	6.391	0.011

临床特征	例数	T790M阴性 ( $n$ =15)	T790M阳性 ( $n$ =78)	χ²值	$P$ 值
所有人群ORR
CR+PR SD+PD	50(53.7) 43(46.3)	2(13.3) 13(86.7)	48(61.5) 30(38.5)	11.760	0.001
二线ORR
CR+PR SD+PD	26(61.9) 16(38.1)	0(0.0) 3(100.0)	26(66.7) 13(33.3)	5.250	0.022
三线ORR
CR+PR SD+PD	24(47.1) 27(52.9)	2(16.7) 10(83.3)	22(56.4) 17(43.6)	5.818	0.016
所有人群DCR
CR+PR+SD PD	87(93.5) 6(6.5)	11(73.3) 4(6.4)	76(97.4) 2(2.6)	12.109	0.01
二线DCR
CR+PR+SD PD	40(95.2) 2(4.8)	2(66.7) 1(33.3)	38(97.4) 1(2.6)	5.815	0.016
三线DCR
CR+PR+SD PD	50(53.7) 4(7.8)	9(75.0) 3(25.0)	38(97.4) 1(2.6)	6.391	0.011

PFS	T790M阴性 ( $n$ =15)	T790M阳性 ( $n$ =78)	$Z$ 值	$P$ 值
所有人群	6.0(1.5~8.0)	12.5(9.4~17.3)	-4.155	<0.01
二线	6.5(1.5~8.0) ( $n$ =3)	12.5(9.5~17.0) ( $n$ =39)	-2.150	0.022
三线	6.0(1.9~7.9) ( $n$ =12)	12.5(9.4~18.0) ( $n$ =39)	-3.322	0.016

PFS	T790M阴性 ( $n$ =15)	T790M阳性 ( $n$ =78)	$Z$ 值	$P$ 值
所有人群	6.0(1.5~8.0)	12.5(9.4~17.3)	-4.155	<0.01
二线	6.5(1.5~8.0) ( $n$ =3)	12.5(9.5~17.0) ( $n$ =39)	-2.150	0.022
三线	6.0(1.9~7.9) ( $n$ =12)	12.5(9.4~18.0) ( $n$ =39)	-3.322	0.016

变量	单因素分析		多因素分析
变量	HR(95% $C I$ )	$P$ 值	HR(95% $C I$ )	$P$ 值
性别
女	1.00
男	1.083 (0.717~1.634)	0.706
年龄(岁)
<65	1.00
≥65	1.346 (0.881~2.057)	0.170
吸烟状态
不吸烟	1.00
吸烟	1.076 (0.667~1.710)	0.757
ECOG评分
0	1.00
1	0.447 (0.152~1.317)	0.144
2	0.485 (0.206~1.142)	0.098
3	0.591 (0.241~1.448)	0.250
分期	0.724 (0.218~2.401)	0.597
术后复发	1.00
初诊Ⅳ期	1.128 (0.670~1.899)	0.650
肿瘤大小
<5 cm	1.00		1.00
≥5 cm	0.661 (0.433~1.010)	0.056	0.575 (0.373~0.885)	0.012
淋巴结状态
N0	1.00
N1~2	0.946 (0.536~1.669)	0.848
N3	1.229 (0.762~1.983)	0.398
外显子突变
19外显子	1.00		1.00
21外显子	0.580 (0.378~0.890)	0.013	0.551 (0.357~0.853)	0.007
奥希替尼治疗线数
二线	1.00
三线及三线以上	0.950 (0.630~1.433)	0.806
T790M状态
T790M-	1.00		1.00
T790M+	2.747 (1.545~4.886)	0.01	2.972 (1.643~5.379)	<0.01

变量	单因素分析		多因素分析
变量	HR(95% $C I$ )	$P$ 值	HR(95% $C I$ )	$P$ 值
性别
女	1.00
男	1.083 (0.717~1.634)	0.706
年龄(岁)
<65	1.00
≥65	1.346 (0.881~2.057)	0.170
吸烟状态
不吸烟	1.00
吸烟	1.076 (0.667~1.710)	0.757
ECOG评分
0	1.00
1	0.447 (0.152~1.317)	0.144
2	0.485 (0.206~1.142)	0.098
3	0.591 (0.241~1.448)	0.250
分期	0.724 (0.218~2.401)	0.597
术后复发	1.00
初诊Ⅳ期	1.128 (0.670~1.899)	0.650
肿瘤大小
<5 cm	1.00		1.00
≥5 cm	0.661 (0.433~1.010)	0.056	0.575 (0.373~0.885)	0.012
淋巴结状态
N0	1.00
N1~2	0.946 (0.536~1.669)	0.848
N3	1.229 (0.762~1.983)	0.398
外显子突变
19外显子	1.00		1.00
21外显子	0.580 (0.378~0.890)	0.013	0.551 (0.357~0.853)	0.007
奥希替尼治疗线数
二线	1.00
三线及三线以上	0.950 (0.630~1.433)	0.806
T790M状态
T790M-	1.00		1.00
T790M+	2.747 (1.545~4.886)	0.01	2.972 (1.643~5.379)	<0.01

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