Toward precision medicine with next-generation EGFR inhibitors in non-small-cell lung cancer

Figures & data

Table 1 Summary of clinical trials of commercially available EGFR tyrosine kinase inhibitors versus chemotherapy as first-line therapy in non-small-cell lung carcinoma with activating EGFR mutations

Clinical trial	Epidermal growth factor receptor tyrosine kinase inhibitor	Number of patients	Median progression-free survival in tyrosine kinase inhibitor group (months)	P-value	Hazard ratio
OPTIMAL^Citation52	Erlotinib	154	13.1	<0.0001	0.16
First Signal^Citation53	Gefitinib	42	8.4	0.084	0.61
IPASS^Citation54	Gefitinib	261	9.5	<0.0001	0.48
WJTOG3405^Citation55	Gefitinib	177	9.2	<0.001	0.48
NEJSG 002^Citation56	Gefitinib	200	10.8	<0.001	0.36
EURTAC^Citation57	Erlotinib	174	9.4	<0.0001	0.42
LUX-Lung 3^Citation11,Citation12	Afatinib	308	13.6	<0.0001	0.47

Abbreviation: EGFR, epidermal growth factor receptor.

Figure 1 EGFR is part of a family of receptor tyrosine kinases (RTKs) that also includes HER2 (ERBB2), HER3 (ERBB3) and HER4 (ERBB4).

Notes: These RTKs comprise a ligand-binding extracellular domain, a transmembrane link and an intracellular catalytic domain. Binding of growth factors to the extracellular domain leads to homo- or hetero-dimerization of the respective receptor, with subsequent activation of RTK activity and regulation of multiple key intracellular signaling substrates as shown in the Figure.
Abbreviations: EGFR, epidermal growth factor receptor; HER, human epidermal growth factor receptor.

Table 2 Summary of clinical trials of EGFR tyrosine kinase inhibitors in development in NSCLC with EGFR mutations

EGFR tyrosine kinase inhibitor	Phase	Trial registration	Targets	Trial design
Lapatinib	II	NCT00528281	EGFR, HER2	Single-arm study with pemetrexed
Neratinib	II	NCT00266877	EGFR, HER2	Three-group study
Icotinib (BPI-2009H)	II, III	NCT01690390 NCT01707329 NCT01516983 NCT01719536	EGFR	Monotherapy and with chemotherapy, radiation or other targeted therapies
Afatinib	II, III	Multiple studies	Pan-HER family
Dacomitinib (PF00299804)	III	NCT01774721 NCT01360554	Pan-HER family	Monotherapy versus gefitinib or erlotinib
Poziotinib (HM781-36B)	II	NCT01819428 NCT01718847	Pan-HER and TEC family	First- and second-line monotherapy
AZD9291	I	NCT01802632	EGFR mutation specific	Monotherapy in previously treated EGFR mutant NSCLC
CO-1686	I, II	NCT01526928	EGFR mutation specific	Monotherapy in previously treated EGFR mutant NSCLC
HM61713	I	NCT01588145	EGFR mutation specific	Monotherapy in previously treated EGFR mutant NSCLC
AP26113	I, II	NCT01449461	Dual ALK and EGFR inhibitor	Monotherapy in NSCLC with ALK gene rearrangement or mutant EGFR

Abbreviations: EGFR, epidermal growth factor receptor; HER, human epidermal growth factor receptor; NSCLC, non-small-cell lung carcinoma.

Table 3 Summary of clinical trials of afatinib in advanced non-small-cell lung carcinoma (LUX-Lung clinical trial program)

LUX-Lung trial	Phase	EGFR mutation mandated	Line of treatment	Design	Primary endpoint	Efficacy results	Toxicity results
LUX-Lung 1, NCT00656136^Citation13,Citation14	IIb/III	N/R	Third-/fourth-line after patient-based chemotherapy and first-generation EGFR TKI	Afatinib + BSC versus placebo + BSC	Overall survival	Primary endpoint of overall survival not met (median, 10.8 months versus 12.0 months; P=0.74); PFS, 3.3 months in the treatment group versus 1.1 months in the placebo group (P<0.0001); 29 (7%) patients achieved a partial response versus one patient in the placebo group	Diarrhea in 339 (87%) of 390 patients (17% grade 3) and acneiform rash in 305 (78%) patients (14% grade 3)
LUX-Lung 2, NCT00525148^Citation15	II	Yes	First-/second-line after chemotherapy only; no prior EGFR TKI	Afatinib monotherapy	Objective response (complete response or partial response)	70 (66%) of 106 patients harboring the two common activating EGFR mutations (deletion 19 or L858R) had objective antitumor responses, whereas 9 (39%) of 23 patients with less common mutations also had objective responses	The two most common toxicities were diarrhea and rash, with grade 3 events more common in patients receiving 50 mg afatinib daily compared with 40 mg daily
LUX-Lung 3, NCT00949650^Citation11,Citation12	III	Yes	First-line	Afatinib versus cisplatin/pemetrexed	PFS	PFS of 11.1 months versus 6.9 months (P=0.001); patients with common EGFR mutations had PFS of 13.6 months versus 6.9 months (P=0.001); response rate, 56% versus 23% (P=0.001)	Diarrhea in 95.2% of patients, (G3 14.4%); rash in 89.1% of patients (G3 16.2%); mucositis in 72.1% (G3 in 8.7%; G4 in 0.4%) and paronychia in 56.8% (G3 in 11.4%) of patients; four deaths in the afatinib group in this study
LUX-Lung 4, NCT00711594^Citation10	I/II	N/R	Third-/fourth-line after patient-based chemotherapy and first-generation EGFR TKI	Afatinib monotherapy	Phase I: safety, dose-limiting toxicity; Phase II: objective response (complete response or partial response)	8.2% had a confirmed partial response. PFS was 4.4 months, whereas median overall survival was 19 months; two patients with acquired T790M mutations had SD for 9 months and 1 month, respectively	The most common afatinib-related toxicities were diarrhea in all patients and rash/acne in 91.9% of patients
LUX-Lung 5, NCT01085136^Citation38	III	N/R	Third-/fourth-line after chemotherapy ± first-generation EGFR TKI	Part A: afatinib monotherapy Part B: Afatinib + weekly paclitaxel versus investigators’ choice of chemotherapy	PFS	PFS for afatinib was 3.3 months; 8% overall response rate, with 56% SD at 6 weeks; PFS for EGFR-mutated patients was 4.2 months versus 2.6 months in non-EGFR-mutated patients (n=35)	–
LUX-Lung 6, NCT01121393	III	Yes	First-line	Afatinib versus cisplatin/gemcitabine	PFS	PFS 11.0 versus 5.6 months; hazard ratio, 0.28 (P<0.0001); overall response rate, 66.9% versus 23.0% (P<0.0001); and DCR, 92.6% versus 76.2% (P<0.0001)	≥G3 drug-related toxicities in 36.0% versus 60.2% of patients in each group; the most common toxicities included rash/acne (14.6%), diarrhea (5.4%); stomatitis/mucositis (5.4%) with afatinib; and neutropenia (17.7%), vomiting (15.9%), and leukopenia (13.3%) with gemcitabine-cisplatin
LUX-Lung 7, NCT01466660	IIb	Yes	First-line	Afatinib versus gefitinib	PFS; DCR	–	–
LUX-Lung 8, NCT01523587	III	N/R	Second-line after patient-based chemotherapy; squamous cell histology	Afatinib versus erlotinib	PFS	–	–

Abbreviations: BSC, best supportive care; DCR, disease control rate; G3, grade 3; N/R, not recorded; PFS, progression-free survival; EGFR, epidermal growth factor receptor; SD, stable disease; TKI, tyrosine kinase inhibitor.

ZhouCWuYLChenGErlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 studyLancet Oncol201112873574221783417

 PubMed Web of Science ®Google Scholar

HanJYParkKKimSWFirst-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lungJ Clin Oncol201230101122112822370314

 PubMed Web of Science ®Google Scholar

MokTSWuYLThongprasertSGefitinib or carboplatin-paclitaxel in pulmonary adenocarcinomaN Engl J Med20093611094795719692680

 PubMed Web of Science ®Google Scholar

MitsudomiTMoritaSYatabeYWest Japan Oncology GroupGefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trialLancet Oncol201011212112820022809

 PubMed Web of Science ®Google Scholar

MaemondoMInoueAKobayashiKNorth-East Japan Study GroupGefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFRN Engl J Med2010362252380238820573926

 PubMed Web of Science ®Google Scholar

RosellRCarcerenyEGervaisRSpanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia ToracicaErlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trialLancet Oncol201213323924622285168

 PubMed Web of Science ®Google Scholar

YangJCHirshVSchulerMSymptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutationsJ Clin Oncol201331273342335023816967

 PubMed Web of Science ®Google Scholar

SequistLVYangJCYamamotoNPhase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutationsJ Clin Oncol201331273327333423816960

 PubMed Web of Science ®Google Scholar

MillerVAHirshVCadranelJAfatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trialLancet Oncol201213552853822452896

 PubMed Web of Science ®Google Scholar

HirshVCadranelJCongXJSymptom and quality of life benefit of afatinib in advanced non-small-cell lung cancer patients previously treated with erlotinib or gefitinib: results of a randomized phase IIb/III trial (LUX-Lung 1)J Thorac Oncol20138222923723328549

 PubMed Web of Science ®Google Scholar

SchulerMHPlanchardDYangJCHInterim analysis of afatinib monotherapy in patients with metastatic NSCLC progressing after chemotherapy and erlotinib/gefitinib (E/G) in a trial of afatinib plus paclitaxel versus investigator’s choice chemotherapy following progression on afatinib monotherapyPresented at: 2012 Annual Meeting of the American Society of Clinical Oncology2012Chicago, IL

 Google Scholar

KatakamiNAtagiSGotoKLUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or bothJ Clin Oncol201331273335334123816963

 PubMed Web of Science ®Google Scholar

SchulerMHYangCHParkKContinuation of afatinib beyond progression: Results of a randomized, open-label, phase III trial of afatanib plus paclitaxel (P) versus investigator’s choice chemotherapy (CT) in patients (pts) with metastatic non-small cell lung cancer (NSCLC) progressed on erlotinib/gefitinib (E/G) and afatanib – LUX-Lung 5 (LL5)Presented at: 2014 Annual Meeting of the American Society of Clinical Oncology2014Chicago, IL

 Google Scholar