Table 2:

Examples of therapies targeting EGFR and ERBB2 exon 20 alterations, mechanism of response, and response rate.

Drug/therapy	Alteration(s) of interest	Mechanism of response	Response rate (all NSCLC)	Citation/Year
EGFR or ErbB2/HER2 exon 20 insertions
Lapatinib + trastuzumab + based regimen	ErbB2/HER2 exon 20 insertion (ErbB2 774–775 AYVM)	Similar to EGFR, ErbB2/HER2 mAb (trastuzumab) may interfere with dimerization	Case report, objective response in 1 of 1 patient	[11] 2013
Cetuximab-based regimen	EGFR exon 20 insertion (EGFR D770_P772del_insKG and D770>GY)	EGFR mAb (cetuximab) interferes with dimerization of receptors (modeling showed EGFR exon 20 insertions brought dimerization domains closer together)	Objective response in 2 of 2 patients, previously resistant to EGFR tyrosine kinase inhibitors	[9] 2015
Osimertinib	EGFR exon 20 insertion (V769_D770InsASV)	Small molecular TKI	Case report, single patient with clinical improvement and tumor shrinkage	[3] 2017
Poziotinib	EGFR and ERBB2 exon 20 insertion	Small molecule TKI Smaller size of poziotinib versus other EGFR TKIs allows binding despite restricted drug-binding pocket caused by exon 20 insertion	Objective response in 7 of 11 parents with EGFR exon 20 mutations (64%)	[2] 2018
			Objective response in 23 of 40 patients with EGFR exon 20 mutations (58%) Objective response in 6 of 12 patients with HER2 exon 20 mutations (50%)	[5] 2018
			Objective response in 17 of 115 patients (15%)	[6] 2019
Cetuximab + afatinib combination	EGFR exon 20 insertion	Dual EGFR inhibition via irreversible TKI (afatinib) and antibody binding to extracellular domain (cetuximab)	Objective response in 3 out of 4 patients	[10] 2018
Osimertinib	EGFR exon 20 insertion	Small molecular TKI	Objective response in 1 of 17 patients (6%)	[4] 2018
Luminespib	EGFR exon 20 insertion	Heat shock protein 90 inhibition	Overall response in 5 of 29 patients (17%); median progression-free survival of 2.9 mos	[7] 2017
TAK-788	EGFR exon 20 insertion	EGFR/HER2 TKI	Objective response in 14 of 26 patients (54%)	[8]
TAS6417	EGFR exon 20 insertion	EGFR/HER2 inhibitor	Preclinical in vitro and in vivo activity	[17]–[19]
Tarloxotinib	EGFR exon 20 insertion	EGFR/HER2 TKI in hypoxia	Preclinical in vivo activity	[20]
EGFR exon 20 T790M or C797S
Cetuximab + afatinib combination	T790M	Dual EGFR inhibition via irreversible TKI (afatinib) and antibody binding to extracellular domain (cetuximab)	Objective response in 32% of T790M-positive patients for afatinib plus cetuximab; (Objective response in ∼7% for afatinib alone)	[12], [13] 2012, 2014
Osimertinib	T790M	Osimertinib is a third generation TKI	Objective response rates of ∼60–70%	[14]
Brigatinib + cetuximab	C797S	Dual EGFR inhibition via TKI (brigatinib) and antibody binding to extracellular domain (cetuximab)	Preclinical in vitro and in vivo activity	[15] 2017

Abbreviations: EGFR = epidermal growth factor receptor; ErbB2/HER2 = human epidermal growth factor receptor 2; NSCLC = non-small cell lung cancer; PFS = progression-free survival; TKI = tyrosine kinase inhibitor