Meta-analysis of the impact of de novo and acquired EGFR T790M mutations on the prognosis of patients with non-small cell lung cancer receiving EGFR-TKIs

Figures & data

Figure 1 Flowchart of the literature search procedure.

Table 1 Studies of pretreatment T790M mutation

Study	Published year	Number of patients	T790M detection method	Detection limit (%)	Specimen	TKI treatment	EGFR mutation: Del19+/L858R+	TKI treatment line: first/second	Histology: Ade/non-Ade	Prevalence of T790M (%)	Extracted data
Costa et al^Citation26	2014	50	PNA-clamping PCR	0.02	Tumor tissue	Erlotinib	33/17	50/0	47/3	68.00	ORR, PFS
Fujita et al^Citation27	2012	35	CH	0.01	Tumor tissue	Gefitinib	22/13	35/0	35/0	80.00	PFS
Karachaliou et al^Citation28	2013	91	TaqMan assay	0.02	Tumor tissue	Erlotinib	57/34	49/42	70/21	38.46	OS
Lee et al^Citation29	2014	124	MALDI-TOF MS	2.50	Tumor tissue	Gefitinib (n=108), erlotinib (n=16)	78/46	50/74	120/4	25.00	ORR, OS, PFS
Maheswaran et al^Citation30	2008	26	SARMs assay	0.10	Tumor tissue	Gefitinib, erlotinib	15/7/others	26/0	26/0	38.46	ORR, PFS
Rosell et al^Citation31	2011	129	TaqMan assay	0.02	Tumor tissue	Erlotinib	81/48	65/64	129/0	34.88	ORR, PFS
Su et al^Citation25	2012	56	MALDI-TOF MS	0.4–2.2	Tumor tissue	Erlotinib (n=17), gefitinib (n=55)	24/32	56/0	53/3	41.07	ORR, OS, PFS
Zhao et al^Citation32	2016	27	ACB-ARMS PCR	0.01	Tumor tissue	Gefitinib	13/14	9/18	26/1	22.22	PFS, OS

Abbreviations: ACB-ARMS PCR, allele-specific competitive blocker-amplification refractory mutation system polymerase chain reaction; Ade, adenocarcinoma; CH, colony hybridization; EGFR, epidermal growth factor receptor; MALDI-TOF MS, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PNA-clamping PCR, peptide nucleic acid-clamping polymerase chain reaction; SARMs, scorpion amplification refractory mutation system; TKI, tyrosine kinase inhibitor.

Table 2 Studies of posttreatment-acquired T790M mutation

Study	Number of patients	T790M detection method	Detection limit (%)	Specimens	TKI treatment	EGFR mutation: Del19+/L858R+/other	TKI treatment line: first/second	Histology: Ade/non-Ade	Prevalence of T790M (%)	Extracted data
Hata et al^Citation9	78	PNA-LNA clamp PCR assay	Unclear	Tumor tissue	Gefitinib (n=65), erlotinib (=13)	42/33/3	31/47	71/6	33.33	ORR, PPS
He et al^Citation10,*	33	Mutant-enriched PCR	0.10	ctDNA	Gefitinib	Del19+/L858R+: 16, others: 17	Unclear	29/4	36.36	ORR, PFS
Isobe et al^Citation11	12	Direct sequence method or PNA-LNA PCR	Unclear	Tumor tissue	Gefitinib	8/4/0	3/9	12/0	33.33	ORR, OS, PFS
Ji et al^Citation12	26	Asan-Panel assay	1–5	Tumor tissue	Gefitinib	16/10/0	Unclear	25/1	42.30	OS, PFS
Li et al^Citation13	54	PCR-based testing	Unclear	Tumor tissue	Gefitinib (n=15), erlotinib (n=36), icotinib (n=3)	29/24/1	11/43	48/6	53.70	OS, PFS, PPS
Nakamura et al^Citation14,*	19	MBP-QP assay	0.30	ctDNA	EGFR-TKIs	9/5/5	Unclear	19/0	52.63	TTP
Oxnard et al^Citation15	93	LNA-PCR assay	0.1	Tumor tissue	Gefitinib (n=23), erlotinib (n=64)	70/23/0	72/21	93/0	62.36	OS, PPS, TTP
Sakai et al^Citation16,*	75	SABER technique	0.30	ctDNA	Gefitinib or erlotinib	Del19+/L858R+: 60 others: 15	Unclear	71/4	28	ORR, PFS
Sorensen et al^Citation17	23	Allele-specific PCR assay	Unclear	ctDNA	Erlotinib	17/5/1	0/23	23/0	39.13	TTP
Soria et al^Citation18	247	BEAMing	Unclear	ctDNA	Gefitinib	Unclear	247/0	Unclear	57.49	OS
Sueoka- Aragane et al^Citation19	58	MBP-QP assay	0.30	ctDNA	EGFR-TKIs	31/27/0	47/11	58/0	39.66	OS
Sun et al^Citation20,*	70	DS-PCR and PNA- clamping PCR	0.01	Tumor tissue	Gefitinib (n=38), erlotinib (n=32)	31/18/21	13/57	67/3	51.43	OS, PFS, PPS
Uramoto et al^Citation21	19	PCR-based analyses	Unclear	Tumor tissue	Gefitinib	7/12/0	9/10	18/1	42.10	ORR, OS
Zheng et al^Citation22	117	ddPCR	0.04	ctDNA	EGFR-TKIs	Activating EGFR mutation	29/88	108/9	47	OS

Notes:

* Contained EGFR wild-type or EGFR status unknown patients. Asan-Panel, mass spectrometric genotyping technology.

Abbreviations: Ade, adenocarcinoma; ctDNA, circulating tumor DNA; ddPCR, droplet digital polymerase chain reaction; DS-PCR, directional sequencing of polymerase chain reaction; EGFR, epidermal growth factor receptor; LNA, locked nucleic acid; MBP-QP assay, mutation-biased polymerase chain reaction and quenching probe assay; ORR, objective response rate; OS, overall survival; PCR, polymerase chain reaction; PFS, progression-free survival; PNA-LNA clamp PCR, peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method; PPS, post-progression survival; SABER technique, single allele base extension reaction technique; TKI, tyrosine kinase inhibitor; TTP, time-to-progression.

Table 3 Quality assessment of studies included in the pretreatment T790M mutation group

Study	Costa et al^Citation26	Fujita et al^Citation27	Karachaliou et al^Citation28	Lee et al^Citation29	Maheswaran et al^Citation30	Rosell et al^Citation31	Su et al^Citation25	Zhao et al^Citation32
Was the sample representative of the target population?	No	No	Yes	Yes	Yes	Yes	Yes	Yes
Were the study participants recruited in an appropriate way?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Was the sample size adequate?	Not applicable (not designed to explore the prevalence of T790M)
Were the study subjects and the setting described in detail?	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes
Was the data analysis conducted with sufficient coverage of the identified sample?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Were objective, standard criteria used for the measurement of the condition?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Was the condition measured reliably?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Was there appropriate statistical analysis?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Are all important confounding factors/subgroups/differences identified and accounted for?	Yes	No	Yes	Yes	No	Yes	Yes	Yes
Were subpopulations identified using objective criteria?	Yes	No	Yes	Yes	No	Yes	Yes	Yes

Table 4 Quality assessment of studies included in the posttreatment-acquired T790M mutation group

Study	Hata et al^Citation9	He et al^Citation10	Isobe et al^Citation11	Ji et al^Citation12	Li et al^Citation13	Nakamura et al^Citation14	Oxnard et al^Citation15	Sakai et al^Citation16	Sorensen et al^Citation17	Soria et al^Citation18	Sueoka-Aragane et al^Citation19	Sun et al^Citation20	Uramoto et al^Citation21	Zheng et al^Citation22
Was the sample representative of the target population?	Yes	Yes	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Were the study participants recruited in an appropriate way?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Was the sample size adequate?		Not applicable (not designed to explore the prevalence of T790M)
Were the study subjects and the setting described in detail?	Yes	Yes	Yes	Yes*	Yes	Yes*	Yes	Yes*	Yes	Yes	Yes	Yes	Yes	Yes
Was the data analysis conducted with sufficient coverage of the identified sample?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Were objective, standard criteria used for the measurement of the condition?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Was the condition measured reliably?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Was there appropriate statistical analysis?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Are all important confounding factors/subgroups/differences identified and accounted for?	Yes	Yes	No	No	No	No	Yes	Yes	No	Yes	Yes	Yes	No	No
Were subpopulations identified using objective criteria?	Yes	Yes	Yes	No	Yes	No	Yes	Yes	No	Yes	Yes	Yes	No	Yes

Note:

* No available information about lines of tyrosine kinase inhibitor therapy.

Table 5 Summary of heterogeneity and publication bias in all studies included in the meta-analysis

	Study number	Pooled HR with 95% CI	HRs (P-value)	Heterogeneity (I^2, %)	Heterogeneity (P-value)	Analysis model	Begg’s test (P-value)	Egger’s test (P-value)
Pretreatment T790M group
PFStotal	7	2.23 (1.44–3.45)	<0.001	60.60	0.019	Random	0.548	0.606
PFSfirst-line	6	1.91 (1.23–2.97)	0.004	56.50	0.042	Random	0.452	0.396
OStotal	4	1.55 (1.16–2.07)	0.003	23.30	0.271	Fixed	0.734	0.319
ORRtotal	5	0.86 (0.74–1.00)	0.051	0.00	0.499	Fixed	0.806	0.494
Posttreatment-acquired T790M group
PFS	9	0.75 (0.61–0.92)	0.006	30.20	0.177	Fixed	0.175	0.113
PFStissue	5	0.76 (0.59–0.98)	0.037	38.50	0.164	Fixed
PFSctDNA	4	0.73 (0.51–1.03)	0.072	38.90	0.178	Fixed
OS	9	0.86 (0.55–1.36)	0.526	84.30	<0.001	Random	1.000	0.719
OStissue	6	0.60 (0.48–0.77)	<0.001	2.50	0.401	Random
OSctDNA	3	1.87 (1.49–2.36)	<0.001	0.00	0.874	Random
PPS	4	0.57 (0.44–0.73)	<0.001	44.70	0.143	Fixed	0.308	0.192
ORR	5	1.21 (0.87–1.70)	0.256	66.90	0.017	Random	0.806	0.712
ORRtissue	3	0.93 (0.58–1.49)	0.759	53.00	0.119	Random
ORRctDNA	2	2.02 (0.59–6.87)	0.262	88.80	0.003	Random

Abbreviations: CI, confidence interval; HR, hazard ratio; ORR, objective response rate; ORR_ctDNA, objective response rate according to the mutation status assessed by rebiopsy with liquid ctDNA; ORR_tissue, objective response rate according to the mutation status assessed by rebiopsy with tissue sample; ORR_total, objective response rate for all lines of epidermal growth factor-tyrosine kinase inhibitor treatment; OS, overall survival; OS_ctDNA, overall survival according to the mutation status assessed by rebiopsy with ctDNA; OS_tissue, overall survival according to the mutation status assessed by rebiopsy with tissue sample; OS_total, overall survival for all lines of epidermal growth factor-tyrosine kinase inhibitor treatment; PFS, progression-free survival; PFS_first-line, progression-free survival for first-line epidermal growth factor-tyrosine kinase inhibitor treatment; PFS_total, progression-free survival for all lines of epidermal growth factor-tyrosine kinase inhibitor treatment; PPS, post-progression survival; PFS_tissue, progression-free survival according to the mutation status assessed by rebiopsy with tissue sample; PFS_ctDNA, progression-free survival according to the mutation status assessed by rebiopsy with ctDNA.

Figure 2 Forest plots of pooled HRs and 95% CIs for PFS_total (A) and OS_total (B) according to pretreatment de novo T790M mutation status.

Note: Weights are from random effects analysis.
Abbreviations: CI, confidence interval; HR, hazard ratio; OS_total, overall survival for all lines of epidermal growth factor-tyrosine kinase inhibitor treatment; PFS_total, progression-free survival for all lines of epidermal growth factor-tyrosine kinase inhibitor treatment.

Figure 3 Forest plots of pooled HRs for all PFS_first-line (A) and RRs for ORR_total (B) according to pretreatment de novo T790M mutation status.

Note: Weights are from random effects analysis.
Abbreviations: CI, confidence interval; HRs, hazard ratios; PFS_first-line, progression-free survival for first-line of epidermal growth factor-tyrosine kinase inhibitor treatment; ORR_total, objective response rate for all lines of epidermal growth factor-tyrosine kinase inhibitor treatment; RR, relative ratio.

Figure 4 Forest plots of HRs and 95% CIs for PFS (A) and PPS (B) according to acquired T790M mutation status.

Abbreviations: CI, confidence interval; ctDNA, circulating tumor DNA; HRs, hazard ratios; PFS, progression-free survival; PPS, post-progression survival.

Figure 5 Forest plots of HRs for OS (A) and RR for ORR (B) according to acquired T790M mutation status.

Note: Weights are from random effects analysis.
Abbreviations: CI, confidence interval; ctDNA, circulating tumor DNA; HRs, hazard ratios; ORR, objective response rate; OS, overall survival; RR, relative ratio.

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