Overcoming crizotinib resistance in ALK-rearranged NSCLC with the second-generation ALK-inhibitor ceritinib

Figures & data

Figure 1. EML4-ALK fusion oncogene and downstream signaling pathways. Information from Shaw et al. [3] and Roskosky.[6]

Figure 2. Information for structural formulas of crizotinib, the lead compound TAE684 and ceritinib (LDK378) taken from Chen et al. (2013) [17]; other structures from references cited in the text.

Figure 3. Structure of human ALK. The left structure (A) represents a dormant enzyme, with in the N-lobe the β-strands labelled at 1-5. Beneath the glycine rich-loop a space-filling model of staurosporine (a general protein kinase inhibitor) is shown, which occupies the ATP binding site. In the middle structure (B) the C- spine and R-spine denote the residues that constitute the catalytic and regulatory spines. The ALK gatekeeper Leu1196 contacts both spines. In this gate-keeper the Met side group of the L1196M mutation can still interact with the Cl moiety of ceritinib but not with the 2-amino group and the alkoxy moiety of crizotinib because of steric interference. The right structure (C) shows the interactions between the human ALK catalytic core residues, ATP and the protein substrate. The G1269M mutation is just proximal of D1270 in the activation DFG motif; steric hindrance of phenyl ring of crizotinib leads to resistance, but can still be inhibited by ceritinib. Reproduced with permission from Roskosky.[6]

Table 1. Common (>10%) or >2% NCI CTCAE* grade 3–4 adverse reactions.

	Crizotinib		Ceritinib
Adverse drug reactions	All grades (%)	Grade 3–4 (%)	All grades (%)	Grade 3–4 (%)
Gastrointestinal disorders
Diarrhea	60	0	86	6
Nausea	55	1	80	4
Vomiting	47	1	60	4
Abdominal pain	8	0	54	2
Constipation	42	2	29	0
Esophageal disorder^a	8	0	16	1
Neurological disorders
Neuropathy	19	na	17	na
Eye disorders
Vision disorder	60	0	9	na
Metabolic disorders
Decreased appetite	27	na	34	1
General disorders
Fatigue^b	27	na	52	5
Skin and subcutaneous disorders
Rash^c	9	na	16	0
Respiratory disorders
Interstitial pneumonitis	26	0	4	3

*National Cancer Institute Common Terminology Criteria for Adverse Events.

^aEsophageal disorder (dyspepsia, gastroesophageal reflux disease, dysphagia).

^bFatigue (fatigue, asthenia)

^cRash (rash, maculopapular rash, acneiform dermatitis).

na: data not available.

Table 2. Pharmacokinetics.

	Crizotinib (250 mg daily)	Ceritinib (750 mg daily)
Time to maximum concentration (Tmax)	4–6 hours	4–6 hours
Time to steady state (Tss)	15 days	15 days
Steady state concentration (ng/mL; µM)	100 – 135 ng/ml	800 ng/ml
AUCinf (ng/mL/h)	2192 – 2946 ng.h/ml	-
AUC0-24 h (ng/mL/h)	-	16500 ng/ml/h
Half-life (T1/2)	42 h	41 h
Clearance (Cl) single dose Steady state	100 L/h	88.5 L/h
	60 L/h	33.2 L/h
Bioavailability (F)	43%*	NR
Plasma protein binding	91%	97%
Volume of distribution after single dose (Vd/F)	1772 L (50 mg I.V.)	4230 L (750 mg orally)
Mean accumulation ratio	4.5	6.2
Excretion (unchanged)	53%feces/2.3% urine	68%feces/1.3%urine
Metabolization	CYP3A4/5	CYP3A

*Calculated by comparing I.V. and oral administration with the assumption that hepatic clearance was identical [23]

Table 3. Selectivity and target mutations of next-generation ALK-inhibitors.

Drug	IC50 ALK in vitro NSCLC	Target kinases	Selective activity against crizotinib-resistant mutations	Reference
Ceritinib	25 nM	ALK, IGF-1R, INSR, STK22D	LL119M(+), G1269A(+), I1171T(+), S1206Y (+), G1202R(−), F1174C(−)	[22]
Alectinib	53 nM	ALK, LTK, GAK	L1196M(+), C1156Y(+), F1174L(+), R1275Q(+)	[27]
Brigatinib	21 nM	ALK, EGFR, ROS1	L1196M(+) (ALK), T790M(+), (EGFR)	[29,30]
PF-06463922	2.7 nM	ALK,ROS	L1196M, G1269A, 1151Tins, F1147L, C1156Y, L1152R, S12026Y	[31]

GAK = cyclin-G-associated kinase; LTK = leukocyte tyrosine kinase.

Table 4. Overview of clinical trials currently in progress for next-generation ALK inhibitors (>20 patients).

Drug	Trial design	Crizotinib-resistant, naïve, or both	ALK-Positive patients	PFS (months)	Objective response rate (%)	Common adverse effects	Source
Crizotinib	Phase 2	–	172	7.7	65	Vision disorder, diarrhea, nausea	[41]
Ceritinib	Phase 1/2	Both	114		58	Nausea, diarrhea, fatigue	[14,22]
		resistant	80	6.9	56
	Phase 2	Naïve	124	11.1	63.7	Nausea, diarrhea, vomiting	[42,43]
		resistant	140	5.7	38.6
Alectinib	Phase 1/2	Naïve	46	NR	93.5	Dysgeusia, AST, Bili	[26]
	Phase 1/2	Resistant	37	NR	59	NR	[40]
	Phase 1/2	Resistant	47	NR	55	Fatigue, myalgia	[28]
Brigatinib	Phase 1/2	Both	24	NR	62.5	Fatigue, nausea, diarrhea	[33]
PF-06463922	Phase I/2	Both	15*	NR	40%	Hypercholesteremia, peripheral edema	[37]

*Included: 18 ALK and 4 ROS patients, 19 pretreated with crizotinib/ceritinib and 17 patients having a CNS metastasis.

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