World J Oncol

World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access

Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc

Journal website http://www.wjon.org

Case Report

Volume 9, Number 2, April 2018, pages 50-55

Synchronous Presence of EGFR, ALK Driver Mutations Along With PD L1 Overexpression in a Resected Early Stage Non-Small Cell Lung Cancer: A Case Report and Review of Literature

**Table 1.** Summary of Previously Reported Patient Characteristics and Treatment Outcomes of NSCLC With Concomitant *EGFR* Mutation and *ALK* Fusion [2, 6-19]
Author	Patients	Age	Sex/ethinicity	Smoking status	EGFR mutation	First line	Best response	Second line	Best response	Third line	Best response
AC: adenocarcinoma; A: Asian; Beva: Bevacizumab; C: Caucasian; Carbo: carboplatin; Cis: cisplatin; CR: complete remission; Doc: docetaxel; Gem: gemcitabine; Heavy smoker: more than 1 pack a day; Light smoker: less than 1 pack a day; ND: not done; NR: not reported; Pts: patients; PD: progressive disease; PR: partial response; Pac: paclitaxel; Pem: pemetrexed; SC: squamous carcinoma; SD: stable disease; TKI: tyrosine kinase inhibitor.
Thumallapally et al [2]	1	72	M/C	Heavy	L861Q exon21	Crizotinib	NR	ND
Chiari et al [13]	1	67	F/C	Never	L858R exon 21	Carbo/Pem	SD	Gefitinib/erlotinib/afatinib	PR/PD	Crizotinib	PR
Chen et al [11]	1	56	F/A	Heavy	Del exon 19	Cis/Gem	Toxicity	Erlotinib	SD	Crizotinib	CR
Miyanaga et al [14]	1	55	F/A	Never	Del exon 19	Cis/Pem	SD	Gefitinib/erlotinib	PD	Crizotinib	SD
									SD
Tanaka et al [15]	1	39	M/A	Light	Del exon 19	Cis/Doc	SD	PEM	PR	Erlotinib	PD

Tiseo et al[9]	1	48	M/C	Never	Del exon 19	Cis/Gem	PR	Erlotinib	PD
Popat et al [10]	1	65	F/C	Never	Del exon 19	Carbo/vinorelbine	PR	Erlotinib	CR
Santelmo et al [7]	1	52	F/ C	Heavy	Del exon 19	Gefitinib	PR	ND
Zhao et al [16]	1	48	F/A	Never	L858R exon 21	Erlotinib	SD	Crizotinib	SD
Rossing et al [17]	1	61	M/C	Never	L858R exon 21	Carboplatin/vinorelbine/Beva	PR	Crizotinib	PR	PEM	PD
Lee et al [6]	1	73	M/Asian	Former	Del exon 19	Gefitinib	PD	Crizotinib	PR
Jurgens et al [18]	1	69	M/C	Light smoker	exon 21 L 861	Gefitinib	PD	Carbo/Pem/Beva	PR	Pem	PD
Sasaki et al [19]	2	NR	Asian	NR	Del exon 19 (2)	Erlotinib (2)	PR (2)	ND
Yang et al [8]	11	Median age 59	Female (8)/male (3)/Asian	Never (11)	Del exon 19 (6)	Gefitinib (3)	PR (3)	Crizotinib(2)	PR(1), S D(1)
					L858R exon 21 (4)	Erlotinib (5)	PR (4), PD (1)	Crizotinib(1)	PD(1)
					Exon 20 (1)	Afatinib (2)	PR (1), SD (1)	Crizotinib (1)	PR(1)
Sweiss et al [12]	3	37	Male (2)/female (1)	Never smoker (2)	Exon 23 polymorphism	Carbo/Beva/Pac	PR	Erlotinib/Beva	PD	Crizotinib	SD
		57		Heavy smoker (1)	Exon 19 Del (1)	Erlotinib	PR	Crizotinib	PD	Erlotinib	PD
		52			L858R (1)	Crizotinib	PD	Carbo/Pem	PD
Thumallapally et al (current patient)	1	77	M/C	Light	L858R exon21	Cis/pem	SD	ND

Table 1. Summary of Previously Reported Patient Characteristics and Treatment Outcomes of NSCLC With Concomitant EGFR Mutation and ALK Fusion [2, 6-19]

Author

Patients

Age

Sex/ethinicity

Smoking status

EGFR mutation

First line

Best response

Second line

Best response

Third line

Best response

AC: adenocarcinoma; A: Asian; Beva: Bevacizumab; C: Caucasian; Carbo: carboplatin; Cis: cisplatin; CR: complete remission; Doc: docetaxel; Gem: gemcitabine; Heavy smoker: more than 1 pack a day; Light smoker: less than 1 pack a day; ND: not done; NR: not reported; Pts: patients; PD: progressive disease; PR: partial response; Pac: paclitaxel; Pem: pemetrexed; SC: squamous carcinoma; SD: stable disease; TKI: tyrosine kinase inhibitor.

Thumallapally et al [2]

M/C

Heavy

L861Q exon21

Crizotinib

Chiari et al [13]

F/C

Never

L858R exon 21

Carbo/Pem

Gefitinib/erlotinib/afatinib

PR/PD

Crizotinib

Chen et al [11]

F/A

Heavy

Del exon 19

Cis/Gem

Toxicity

Erlotinib

Crizotinib

Miyanaga et al [14]

F/A

Never

Del exon 19

Cis/Pem

Gefitinib/erlotinib

Crizotinib

Tanaka et al [15]

M/A

Light

Del exon 19

Cis/Doc

PEM

Erlotinib

Tiseo et al[9]

M/C

Never

Del exon 19

Cis/Gem

Erlotinib

Popat et al [10]

F/C

Never

Del exon 19

Carbo/vinorelbine

Erlotinib

Santelmo et al [7]

F/ C

Heavy

Del exon 19

Gefitinib

Zhao et al [16]

F/A

Never

L858R exon 21

Erlotinib

Crizotinib

Rossing et al [17]

M/C

Never

L858R exon 21

Carboplatin/vinorelbine/Beva

Crizotinib

PEM

Lee et al [6]

M/Asian

Former

Del exon 19

Gefitinib

Crizotinib

Jurgens et al [18]

M/C

Light smoker

exon 21 L 861

Gefitinib

Carbo/Pem/Beva

Pem

Sasaki et al [19]

Asian

Del exon 19 (2)

Erlotinib (2)

PR (2)

Yang et al [8]

Median age 59

Female (8)/male (3)/Asian

Never (11)

Del exon 19 (6)

Gefitinib (3)

PR (3)

Crizotinib(2)

PR(1), S D(1)

L858R exon 21 (4)

Erlotinib (5)

PR (4), PD (1)

Crizotinib(1)

PD(1)

Exon 20 (1)

Afatinib (2)

PR (1), SD (1)

Crizotinib (1)

PR(1)

Sweiss et al [12]

Male (2)/female (1)

Never smoker (2)

Exon 23 polymorphism

Carbo/Beva/Pac

Erlotinib/Beva

Crizotinib

Heavy smoker (1)

Exon 19 Del (1)

Erlotinib

Crizotinib

Erlotinib

L858R (1)

Crizotinib

Carbo/Pem

Thumallapally et al (current patient)

M/C

Light

L858R exon21

Cis/pem

**Table 2.** Adjuvant Targeted Therapy in Resected NSCLC [25, 28-30]
PFS: progression-free survival; DFS: disease-free survival; OS: overall survival.
Zhong et al [25] (ADJUVANT trial)	Phase III	Resected stage II-IIIA EGFR mutant NSCLC	N = 222	Gefitinib vs. cisplatin plus vinorelbine	Median PFS was 28.7 months with gefitinib and 18 months with cisplatin plus vinorelbine.
Kelly et al [28] (RADIANT trial)	Phase III	Resected stage Ib-IIIA NSCLC. Tumors expressed EGFR protein by IHC or FISH	N = 973	Erlotinib vs. placebo	Median PFS was 50.7 months with erlotinib and 48.2 months with placebo.
Pennell et al [29] (SELECT trial)	Single arm Phase II	Resected stage IA-IIIA EGFR mutant NSCLC	N = 100	Erlotinib 150 mg/day for 2 years after adjuvant chemotherapy	Two-year DFS was 90%. Median time to recurrence after stopping erlotinib was 12 months.
Goss et al [30] (NCIC CTG BR19 trial)	Phase III	Resected stage IB-IIIA NSCLC	N = 503	Gefitinb 250 mg daily or placebo after adjuvant chemotherapy	Median DFS and OS were similar in both the groups.
ALCHEMIST (NCT02193282)	Randomized phase III	Resected stage IB-IIIA EGFR mutant NSCLC	N = 450 estimation	Adjuvant erlotinib vs. placebo	Currently ongoing
ADAURA (NCT02511106)	Randomized phase III	Resected stage IB-IIIA EGFR mutant NSCLC	N = 700 estimation	Adjuvant AZD9291 vs. placebo	Currently ongoing

Table 2. Adjuvant Targeted Therapy in Resected NSCLC [25, 28-30]

PFS: progression-free survival; DFS: disease-free survival; OS: overall survival.

Zhong et al [25] (ADJUVANT trial)

Phase III

Resected stage II-IIIA EGFR mutant NSCLC

N = 222

Gefitinib vs. cisplatin plus vinorelbine

Median PFS was 28.7 months with gefitinib and 18 months with cisplatin plus vinorelbine.

Kelly et al [28] (RADIANT trial)

Phase III

Resected stage Ib-IIIA NSCLC. Tumors expressed EGFR protein by IHC or FISH

N = 973

Erlotinib vs. placebo

Median PFS was 50.7 months with erlotinib and 48.2 months with placebo.

Pennell et al [29] (SELECT trial)

Single arm Phase II

Resected stage IA-IIIA EGFR mutant NSCLC

N = 100

Erlotinib 150 mg/day for 2 years after adjuvant chemotherapy

Two-year DFS was 90%. Median time to recurrence after stopping erlotinib was 12 months.

Goss et al [30] (NCIC CTG BR19 trial)

Phase III

Resected stage IB-IIIA NSCLC

N = 503

Gefitinb 250 mg daily or placebo after adjuvant chemotherapy

Median DFS and OS were similar in both the groups.

ALCHEMIST (NCT02193282)

Randomized phase III

Resected stage IB-IIIA EGFR mutant NSCLC

N = 450 estimation

Adjuvant erlotinib vs. placebo

Currently ongoing

ADAURA (NCT02511106)

Randomized phase III

Resected stage IB-IIIA EGFR mutant NSCLC

N = 700 estimation

Adjuvant AZD9291 vs. placebo

Currently ongoing

**Table 3.** Adjuvant Immunotherapy Trials in NSCLC [31, 32]
PEARLS trial [31] (NCT02504372)	Randomized phase III	Resected stage IB-IIIA NSCLC	N = 1,380	Pembrolizumab 200 mg IV every 3 weeks for 1 year vs. placebo after standard adjuvant treatment	Currently ongoing
ANVIL trial [32] NCT02595944	Randomized phase III	Resected stage IB-IIIA NSCLC	N = 714	Nivolumab every 2 weeks for 1 year vs. observation after standard adjuvant treatment	Currently ongoing
NCT02273375	Randomized phase III	Resected stage IB-IIIA NSCLC	N = 1,360	MEDI4736 IV infusion for 12 months vs. placebo infusion after standard adjuvant treatment	Currently ongoing
NCT02486718	Randomized phase III	Resected stage IB-IIIA NSCLC	N = 1,127	Atezolizumab IV infusion Q3 weeks for 16 cycles vs. observation after standard platinum based chemotherapy	Currently ongoing

Table 3. Adjuvant Immunotherapy Trials in NSCLC [31, 32]

PEARLS trial [31] (NCT02504372)

Randomized phase III

Resected stage IB-IIIA NSCLC

N = 1,380

Pembrolizumab 200 mg IV every 3 weeks for 1 year vs. placebo after standard adjuvant treatment

Currently ongoing

ANVIL trial [32] NCT02595944

Randomized phase III

Resected stage IB-IIIA NSCLC

N = 714

Nivolumab every 2 weeks for 1 year vs. observation after standard adjuvant treatment

Currently ongoing

NCT02273375

Randomized phase III

Resected stage IB-IIIA NSCLC

N = 1,360

MEDI4736 IV infusion for 12 months vs. placebo infusion after standard adjuvant treatment

Currently ongoing

NCT02486718

Randomized phase III

Resected stage IB-IIIA NSCLC

N = 1,127

Atezolizumab IV infusion Q3 weeks for 16 cycles vs. observation after standard platinum based chemotherapy

Currently ongoing