Anaplastic lymphoma kinase inhibition in metastatic non-small cell lung cancer: clinical impact of alectinib

Figures & data

Figure 1 EML4–ALK pathways and the mechanism of resistance to crizotinib.

Notes: (A) Crizotinib binds to the ALK-TKI domain of the EML4–ALK fusion protein and inhibits downstream signaling of canonical oncogenic pathways such as the PI3K pathway and RAS pathway. (B) Acquired resistance to crizotinib occurs after crizotinib treatment due to mutations in ALK. In addition, amplification of C-KIT and/or increased EGFR signaling can cause progression, independent of EML4–ALK. Cells remain ALK driven, and alectinib successfully improves PFS by inhibiting several ALK mutations that cause crizotinib resistance.
Abbreviations: EML4–ALK, echinoderm microtubule-associated protein-like–anaplastic lymphoma kinase; ALK, anaplastic lymphoma kinase; TKI, tyrosine kinase inhibitor; PI3K, phosphoinositide 3-kinase; RAS, rat sarcoma protein; C-KIT, proto-oncogene C-KIT; EGFR, epidermal growth factor receptor; PFS, progression-free survival; mTOR, mechanistic target of rapamycin; Mek, mitogen-activated protein kinase; Erk, extracellular signal-regulated kinase.

Table 1 Resistance mutations in ALK

Mutation	Sensitive to			Reference
	Crizotinib	Ceritinib	Alectinib	Preclinicala	Biopsy after progression on	Clinical response on second drug
1151Tins	−	−	+	18,39	NR	NR
L1196M	−	+	+	18,39	Crizotinib/ceritinib/alectinib^Citation19	NR
G1202R	−	−	−	18,39	Crizotinib/ceritinib/alectinib^Citation19	NR
G1269A	−	+	+	18,39	Crizotinib^Citation19	NR
S1206Y	−	+	+	18,39	Crizotinib^Citation19	NR
L1152R	−	−	+	18	NR	Ceritinib^Citation38
F1174L	−	NRb	+	18	Ceritinib^Citation19	NR
C1156Y	−	−	+	18	Crizotinib^Citation19	NR
l1171Tc	−	+	(+)	18	Alectinib^Citation36	Ceritinib^Citation36
F1174Cc	−	(+)	+	19	Ceritinib^Citation19	NR
L1152P	+	−	NR	39	NR	NR
V1180L	−	+	−	35	Alectinib^Citation19	NR
I1171T/N/S	−	+	−	35	Alectinib^Citation19	NR
F1245C	−	+	NR	NR	NR	Crizotinib^Citation34
G1123S	NR	−	+	NR	NR	Ceritinib^Citation37

Notes: Biopsy after regression: ALK-positive NSCLC was biopsied after progression. Biopsies were analyzed for ALK mutations.

a Based on BA/F3 in vitro models.

b Reported efficacy in neuroblastoma cells.⁴⁰

c Clinical reports indicate no efficacy of I1171T + alectinib and F1174C + ceritinib (between bracket results for ceritinib).¹⁹

Abbreviations: ALK, anaplastic lymphoma kinase; NR, not reported; +, sensitive; −, not sensitive.

Table 2 Pharmacokinetics of ALK inhibitors

Parameter	Crizotinib^Citation26 (250 mg daily)	Ceritinib^Citation30 (750 mg daily)	Alectinib^Citation31 (600 mg twice daily)
			Alectinib	M4
Tmax (hours)	4–6	4–6	3–5	5–10
Tss (days)	15	15	7	7
Css (ng/mL)	100–135	800	665	246
AUCinf (ng⋅mL/h)	2,192–2,946	NR	6,430	3,450
T1/2 (hours)	42	41	33	31
Cl (L/h) single dose	100	88.5	N/A	N/A
Cl (L/h) steady state	60	33	81.9	217
F (%)	43*	NR	36.9	NR
f b (%)	91	97	99	99
Vd/F (L)	1,772 (50 mg IV)	4,230 (750 mg orally)	4,016	10,093
R	4.5	6.2	6	6
Excretion (unchanged)	NR (53% feces/2.3% urine)	NR (68% feces/1.3% urine)	98% feces/0.5% urine
			84% feces	6% feces
Metabolization	CYP3A4/5	CYP3A	CYP3A4	CYP3A4

Notes: T_max, time to maximum concentration; T_ss, time to steady state; C_ss, steady state concentration (ng/mL; µM); AUC_inf, area under the curve from 0 to infinity; T_1/2, half-life; Cl, clearance; F, bioavailability; f_b, fraction bound to plasma protein; V_d/F, volume of distribution; R, accumulation ratio.

* Calculated by comparing IV and oral administration with the assumption that hepatic clearance was identical.

Abbreviations: NR, not reported; N/A, not applicable; IV, intravenous; CYP3A4/5, cytochrome P450 3A4/5; CYP3A, cytochrome P450 3A; CYP3A4, cytochrome P450 3A4.

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