Personalized treatment options for ALK-positive metastatic non-small-cell lung cancer: potential role for Ceritinib

Figures & data

Table 1 Mechanisms of crizotinib resistance

Mechanism	Example	Comments
Secondary mutation in the ALK gene	L1196M, G1202R, G1269A, L1152R, C1156Y, F1174L, G1206Y, 1151Tins	L1196M and G1269A are the two most common mutations and confer a sensitivity to ceritinib, whereas G1202R is refractory to ceritinib.
ALK gene amplification
Activation of an alternative escape pathway	EGFR mutation or amplification(br)c-KIT amplification(br)KRAS mutation(br)MET amplification	Studies evaluating ALK inhibitor in combination with agents that suppress these bypass signaling pathways are needed.

Data from studies: ^22–26

Abbreviations: ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor.

Figure 1 Chemical structure of TAE684 (A) and LDK378 (B).

Notes: This figure depicts the structural determinants of Ceritinib potency. The group isopropoxy at the aniline ring confers an improved kinase selectivity of Ceritinib, whereas the reversal of piperidine along with the methyl group para the isopropoxy are thought to minimize the possibility of reactive adducts formation.

Table 2 Most common adverse reactions associated with the usage of ceritinib

	All grades (%)	Grades 3–4 (%)	Dose reduction or discontinuation (%)
Most common clinical adverse reaction
Diarrhea	86	6	16
Nausea	80	4	20
Vomiting	60	4	16
Abdominal pain	54	2
Fatigue	52	5
Decreased appetite	34	1
Constipation	29	0
Most common laboratory adverse reaction
Decreased Hg	84	5
Increased ALT	80	27	29
Increased AST	75	13	16
Increased creatinine	58	2
Hyperglycemia	49	13
Hypophosphatemia	36	7
Increased lipase	29	10
Less common clinical and laboratory adverse reactions
Neuropathy	17
Vision disturbances	9
Prolonged QT interval	4
Bradycardia	3
ILD/pneumonitis	4	3
Increased bilirubin	15	1
Rash	16	0

Data from studies: ^31,35,36

Abbreviations: ILD, interstitial lung disease; ALT, alanine transaminase; AST, aspartate aminotransferase.

Table 3 Some of the major ongoing clinical trials investigating the efficacy of ceritinib against different malignancies

Clinical trial identifier	Study design	Treatment setting	Intervention	Primary endpoint
NCT01828099	Phase III RCT	Metastatic treatment naïve ALK + NSCLC	Ceritinib versus platinum/Pemetrexed	PFS
NCT01828112	Phase III RCT	Metastatic previously treated (with chemo and crizotinib) ALK + NSCLC	Ceritinib versus Docetaxel or Pemetrexed	PFS
NCT02289144	Phase II	Locally advanced or metastatic ALK + anaplastic thyroid cancer	Ceritinib	PFS
NCT02374489	Phase II	ROS1 or ALK overexpressed advanced cholangiocarcinoma	Ceritinib	ORR
NCT01964157	Phase II	Unresectable NSCLC carrying ROS1 rearrangement	Ceritinib	ORR
NCT02393625	Phase I	Relapsed locally advanced or metastatic ALK + NSCLC	Ceritinib plus nivolumab	MTD(br)ORR
NCT02321501	Phase I	Locally advanced or metastatic previously treated solid tumor with an expansion in ALK + NSCLC	Ceritinib plus everolimus	MTD
NCT01685138	Phase II	ALK + crizotinib naïve metastatic NSCLC	Ceritinib	ORR
NCT02336451	Phase II	ALK + NSCLC with CNS metastasis	Ceritinib	ORR
NCT02299505	Phase I	ALK + metastatic NSCLC	Low dose ceritinib taken with low-fat meal versus standard dose ceritinib at fasting	PK
NCT02227940	Phase I	Advanced solid tumor or locally advanced/metastatic pancreatic cancer	Ceritinib combined with gemcitabine-based chemotherapy	MTD
NCT02343679	Phase II	ALK + refractory/relapsed hematological malignancies	Ceritinib	ORR

Abbreviations: PFS, progression free survival; ORR, overall response rate; MTD, maximum tolerated dose; CNS, central nervous system; NSCLC, Non-small-cell lung carcinoma; ALK, anaplastic lymphoma kinase; PK, pharmacokinetic.

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