Outcome of uncommon EGFR mutation positive newly diagnosed advanced non-small cell lung cancer patients: a single center retrospective analysis

Figures & data

Table 1 Demographic and clinical profile of the study cohort

Variables	N=83 (%)	EGFR TKI sensitizing (%) activating mutations^Citation7 N=227
Median age (in years)
Median	55	56
Range	25–82	50–63
Sex
Male	49 (59)	141 (62.1)
Female	34 (41)	86 (37.9)
Performance status
0, 1	53 (63.8)	110 (48.5)
2	21 (25.3)	>1=117 (51.5)
3	8 (9.6)
4	1 (1.2)
Smoking habitus
Current or past smokers	17 (20.5)
Never-smokers	54 (65.1)	168 (74.0)
Oral tobacco users	12 (14.5)
Brain metastases
Present	26 (31.3)	29 (12.8)
Absent	57 (68.6)	198 (87.2)
Histology
Adenocarcinomas	80 (96.4)
Squamous	1 (1.2)
Poorly differentiated	2 (2.4)
Mixed histology	0
Sampling method used for EGFR testing
Tissue block	56 (67.4)
Pleura/pericardial fluid block	12 (14.4)
Blood	15 (18.0)

Note: Copyright ©2017. Dove Medical Press. Adapted from Noronha V, Choughule A, Patil VM, et al. Epidermal growth factor receptor exon 20 mutation in lung cancer: types, incidence, clinical features and impact on treatment. Onco Targets Ther. 2017;10:2903–2908.⁷

Abbreviation: TKI, tyrosine kinase inhibitor.

Figure 1 Distribution of uncommon EGFR mutations.

Table 2 Uncommon EGFR mutation frequency and their distribution according to predicted sensitivity to oral TKI

Uncommon EGFR mutation types	N=83	%
Uncommon EGFR single mutations
Exon 18 G719X	8	9.6
Exon 20 insertion	15	19.3
Exon T790M	10	12.0
Exon 20 768I	3	3.6
Exon 21 L861Q	3	3.6
Complex dual mutation positivity	43	50.6
Exon 19 deletion + exon 20 T790M	17	20.4
Exon 21 L858R + exon 20 T790M	15	18.0
Exon 18 G719X + exon 20768I	03	3.6
Exon 20 S768I + exon 21 L858R	02	2.4
Exon 18 G719X + exon 20 T790M	01	1.2
Exon 18 G719X + exon 21 L858R	01	1.2
Exon 20 insertion + exon 19 deletion	01	1.2
Exon 21 L858R + L861Q	01	1.2
Exon 20 T790M + exon 20 S768I	01	1.2
Exon 21 L861I + exon 20 T790M	01	1.2
Complex triple mutation	1	1.2
Positivity (exon 18 G719X + exon 20 S768I + exon 21 L858R)
Uncommon mutation frequency as per predicted TKI sensitivity
TKI sensitive single mutations (G719X, S768I, and L861Q)	14	16.8
TKI insensitive single mutations (exon 20 insertion/T790M)	25	30.1
TKI sensitive dual mutations	4	4.8
TKI sensitive/insensitive complex mutations	40	48.2

Abbreviation: TKI, tyrosine kinase inhibitor.

Figure 2 Graphs of survival for different types of uncommon mutations.

Notes: (A) OS by type of mutation. (B) OS by type of mutation by predicted TKI sensitivity.
Abbreviations: OS, overall survival; TKI, tyrosine kinase inhibitor.

Table 3 mPFS and mOS of the cohort by mutation type and predicted TKI sensitivity

Mutation types	N=83	mPFS (months) first line therapy	95% CI	Log rank (Mantel–Cox)	mOS (months)	95% CI	Log-rank (Mantel–Cox)
Specific mutation types	Entire cohort	6.7	4.7–8.6		15.8	10.1–21.5
	Exon 18 G719X	8.4	1.8–15.1	0.82	13.5	0–29.9	P=0.005
	Exon 20 insertion	6.0	2.4–9.6		15.8	6.2–25.3
	Exon T790M	8.2	3.4–13.1		12.3	9.4–15.2
	Exon 20 768I	2.0	NE		2.0	0.9–3.1
	Exon 21 L861Q	1.0	NE		1.8	0–2.6
	Exon 18 G719X, exon 20 S768I, and exon 21 L858R	4.8	NE		4.8	NE
	Dual mutations	6.9	3.2–10.7		22.6	8.2–37.0
Mutation types by TKI sensitivity	TKI sensitive single mutation (exon 18/20 768I/21 L861Q)	6.5	0.6–12.4	P=0.68	12.7	0.0–30.5	P=0.039
	TKI insensitive single (exon 20 insertion/T790M)	6.0	5.5–6.5		12.9	11.1–14.7
	TKI sensitive dual	4.6	0–9.5		9.6	3.6–15.6
	TKI sensitive + insensitive complex mutation	7.8	3.1–12.4		28.2	15.2–41.2

Abbreviations: mOS, median overall survival; mPFS, median progression-free survival; NE, not estimable; TKI, tyrosine kinase inhibitor.

Figure 3 Bar graphs show responses observed with TKI in different uncommon mutations.

Notes: (A) Different types of EGFR mutations and response to EGFR TKIs. (B) Different types of EGFR mutations and response to EGFR TKI as per predicted sensitivity.
Abbreviations: PD, progressive disease; PR, partial response; SD, stable disease; TKI, tyrosine kinase inhibitor.

Table 4 Responsiveness to oral TKI

Mutation types		n	RR (%)	mPFS (months) TKI	95% CI	P-value
Specific mutation types	Overall			9.1	6.2–12.0
	Exon 18 G719X	5	50	9.0	NE	0.60
	Exon 20 insertion	7	0	1.9	0.3–3.5
	Exon 20 T790M	4	24	8.2	2.9–13.5
	Exon 20 S768I	2	0	1.0	NE
	Exon 21 L861Q	2	0	1.8	NE
	Complex dual mutations	36	47.2	9.4	3.3–15.5
	Complex triple mutation (Exon 18 G719X, exon 20 S768I, and exon 21 L858R)	1	0	4.2	NE
Mutation type by TKI sensitivity	TKI sensitive single mutations (exon 18/20 768I/21 L861Q)	9	37.5	12.8	4.7–20.9	0.29
	TKI insensitive single mutations (exon 20 insertion / T790M)	12	16.6	3.7	0–11.5
	TKI sensitive dual mutations	3	66.6	9.1	1.0–17.1
	TKI sensitive / insensitive dual mutations	33	45.7	9.9	0.9–18.9

Abbreviations: mPFS, median progression-free survival; NE, not estimable; RR, response rates; TKI, tyrosine kinase inhibitor.

Table 5 Type of TKI and survival

Types of TKI	N	RR (%)	mPFS in months (95% CI)	mOS in months (95% CI)
First generation TKI	41	48.7	9.4 (7.9–10.9)	18.3 (5.7–30.9)	P=0.65
Second generation TKI	1	100	15.28	NR
Third generation TKI	15	33.3	6.0 (5.1–7.0)	15.9 (6.6–25.2)
Total	57

Abbreviations: mOS, median overall survival; mPFS, median progression-free survival; NR, not reached; RR, response rates; TKI, tyrosine kinase inhibitor.

Table 6 List of all patients who received TKI therapy, their response, and survival

Serial number	Mutation type	TKI received	Response	mPFS (months)	mOS (months)
1	Exon 19 deletion + exon 20 T790M	GEF	PR	25.36	85.42
2	Exon 21 L858R + exon 20 T790M	GEF	PR	63.80	65.71
3	Exon 19 deletion + exon 20 T790M	ERLO	PR	5.19	5.19
4	Exon 18 G719X	GEF	PR	9.03	28.98
5	Exon 20 insertion	GEF	PD	2.79	22.24
6	Exon 19 deletion + exon 20 T790M	GEF	PD	1.77	28.42
7	Exon 18 G719X	GEF	PR	6.77	13.50
8	Exon 19 deletion + exon 20 T790M	GEF	PR	29.90	32.99
9	Exon 19 deletion + exon 20 T790M	ERLO	PR	19.38	33.02
10	Exon 20 insertion	ERLO	PD	1.48	1.48
11	Exon 20 T790M and exon 21 L858	GEF	PD	1.64	28.32
12	Exon 19 deletion + exon 20 T790M	ERLO	PR	9.95	34.92
13	Exon 19 deletion + exon 20 T790M	GEF	PR	24.57	29.83
14	Exon 19 deletion + exon 20 T790M	GEF	PR	27.79	27.79
15	Exon 19 deletion + exon 20 T790M	ERLO	PR	15.51	22.67
16	Exon 20+ VE, exon 21+ VE	ERLO	SD	5.85	5.85
17	Exon T790M	GEF	PR	8.28	11.04
18	Exon 19 deletion + exon 20 T790M	GEF	PR	12.09	26.22
19	Exon 18 G719X + exon 20 T790M	ERLO	SD	7.49	10.25
20	Exon 20 T790M mutant	ERLO	PR	11.01	12.35
21	Exon 19 deletion + exon 20 T790M	ERLO	SD	3.09	9.26
22	Exon 18+ VE + exon 20 768I	ERLO	PR	9.13	9.69
23	Exon 18 G719X	ERLO	PR	16.53	16.53
24	Exon 18 G719X + exon 21 L858R	GEF	PR	9.43	18.37
25	Exon 18 G719X + exon 20 768I	ERLO	PR	15.28	15.28
26	Exon 18 G719X, exon 20 S768I, and exon 21 L858R	GEF	PR	15.34	15.34
27	Exon 21 L858R, L861Q	GEF	*	1.51	1.51
28	Exon 21 L861Q	ERLO	PD	0.92	1.05
29	Exon 20 insertion	ERLO	SD	5.75	14.09
30	Exon 21 L858R + exon 20 T790M	ERLO	*	4.83	4.83
31	Exon 20 S768IT	ERLO	*	4.93	9.56
32	Exon 21 L858R + exon 20 T790M	GEF	*	4.11	5.95
33	Exon 21 L858R + exon 20 T790M	GEF	SD	12.81	20.21
34	Exon 18 G719X + exon 20 768I	GEF	*	0.26	0.26
35	Exon 18 G719X	GEF	*	3.15	3.15
36	Exon 20 S768I, exon 21 L858R	GEF	*	2.04	2.04
37	Exon 19 deletion + exon 20 T790M	GEF	PR	7.98	7.98
38	Exon 21 L861Q	ERLO	*	0.66	0.66
39	Exon 21 L858R + exon 20 T790M	GEF	*	1.94	2.96
40	Exon 20 S768I	ERLO	*	4.34	6.44
41	Exon 18 G719X	GEF	*	3.35	3.35
42	Exon 20 insertion	AFA	SD	5.22	5.22
43	Exon 21 L858R + exon 20 T790M	OSI	PD	2.40	2.40
44	Exon 21 L858R + exon 20 T790M	OSI	PR	6.08	6.54
45	Exon 20 insertion	OSI	*	1.54	1.54
46	Exon 19 deletion + exon 20 T790M	OSI	PD	2.73	25.63
47	Exon 21 L858R + exon 20 T790M	OSI	*	1.05	1.05
48	Exon 20 insertion	OSI	*	3.75	3.75
49	Exon 21 L858R + exon 20 T790M	OSI	PR	3.68	7.92
50	Exon 19 deletion + exon 20 T790M	OSI	PD	1.35	1.35
51	Exon 20 insertion	OSI	PD	0.56	0.56
52	Exon 21 L861I + exon 20 T790M	OSI	SD	13.04	13.04
53	Exon 19 deletion + exon 20 T790M	OSI	PR	15.57	40.51
54	Exon 20 T790M and exon 21 L861	OSI	*	3.35	3.35
55	Exon 20 insertion	OSI	PR	15.28	15.28
56	Exon 21 L858R + exon 20 T790M	OSI	PR	5.49	21.98
57	Exon 21 L858R + exon 20 T790M	OSI	PR	12.71	15.93

Note:

* Response could not be assessed.

Abbreviations: AFA, afatinib; ERLO, erlotinib; GEF, gefitinib; mOS, median overall survival; mPFS, median progression-free survival; OSI, osimertinib; PR, partial response; PD, progressive disease; SD, stable disease; TKI, tyrosine kinase inhibitor.

Table 7 Comparison of survival times of patients with uncommon EGFR mutations

Mutation types	mPFS on TKI Yang et al^Citation15 months (n)	mPFS on TKI Wu et al^Citation14 months (n)	mPFS on TKI Shi et al^Citation13 months (n)	mPFS on TKI in this study months (n)
Exon 18 G8719X	10.7 (38)	3.9 (10)	8.2 (27)	9.0 (5)
Exon 21 L861Q		8.7 (7)	7.6 (17)	1.8 (2)
Exon 20 S768I			3.4 (9)	1.0 (2)
Dual mutations	2.9 (14)a	5.3 (20)	4.2	9.4 (36)
Exon 20 insertion	2.7 (23)	1.4 (25)		1.9 (7)
Exon 20 T790M				8.2 (6)

Notes:

a This study by Yang et al, included T790M mutation alone or in combination with other mutations.

Abbreviations: mPFS, median progression-free survival; TKI, tyrosine kinase inhibitor.

NoronhaVChoughuleAPatilVMEpidermal growth factor receptor exon 20 mutation in lung cancer: types, incidence, clinical features and impact on treatmentOnco Targets Ther2017102903290828652772

 PubMed Web of Science ®Google Scholar

YangJCSequistLVGeaterSLClinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6Lancet Oncol201516783083826051236

 PubMed Web of Science ®Google Scholar

WuJYYuCJChangYCYangCHShihJYYangPCEffectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancerClin Cancer Res201117113812382121531810

 PubMed Web of Science ®Google Scholar

ShiJYangHJiangTUncommon EGFR mutations in a cohort of Chinese NSCLC patients and outcomes of first-line EGFR-TKIs and platinum-based chemotherapyChin J Cancer Res201729654355229353977

 PubMed Web of Science ®Google Scholar