Clinical use of crizotinib for the treatment of non-small cell lung cancer

Figures & data

Figure 1 Aberrant ALK signaling cascade.

Notes: ALK gene rearrangements result in aberrant ALK signaling through PI3K/AKT/mTOR, JAK/STAT, and RAS/MEK/ERK signaling pathways. Constitutive ALK signaling mediates enhanced cell proliferation, cell survival, and metabolism. Current efforts to target aberrant ALK signaling in cancer include inhibition with ALK tyrosine kinase inhibitors and inhibition of the molecular chaperone heat shock protein 90, which leads to reduced ALK expression.

Figure 2 Major events leading to rapid clinical development of crizotinib for ALK-positive NSCLC.

Abbreviations: ALK, anaplastic lymphoma kinase; ASCO, American Society of Clinical Oncology; EML4-ALK, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion-type tyrosine kinase; MET, met proto-oncogene (hepatocyte growth factor receptor); NSCLC, non-small cell lung cancer.

Table 1 Efficacy data for approval by the US Food and Drug Administration^24–26

	Study A (profile 1005)	Study B (A8081001)
Enrolmenta	136	119 (116)b
Complete responses	1 (1%)	2 (2%)
Partial responses	67 (49%)	69 (59%)
ORR (CR + PR)	50% (95% CI 42–59)	61% (95% CI 52–70)
Median duration of response	41.9 weeks	48.1 weeks

Notes:

a Enrolment at the time of regulatory submission;

b 119 patients enrolled, but only 116 evaluable. Response rates calculated based on 116 patients.

Abbreviations: CI, confidence interval; CR, complete response; ORR, overall response rate; PR, partial response.

Table 2 Common adverse events reported in studies A and B

	All grades n (%)	Grades 3–4 n (%)
Eye disorders
Visual disturbance	159 (62)	0
Gastrointestinal disorders
Nausea	136 (53)	0
Diarrhea	109 (43)	0
Vomiting	101 (40)	0
Constipation	69 (27)	1 (<1)
Esophageal disorder	29 (11)	0
Abdominal pain	20 (8)	0
General
Edema	72 (28)	0
Fatigue	51 (20)	4 (2)
Decreased appetite	49 (19)	0
Nervous system disorders
Dizziness	42 (16)	0
Neuropathy	34 (13)	1 (<1)
Dysgeusia	30 (12)	0
Liver disorders
ALT elevation	34 (13)	14 (5)
AST elevation	24 (9)	5 (2)
Skin disorders
Rash	25 (10)	0
Cardiovascular disorder
Bradycardia	12 (5)	0

Note: n=225.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Table 3 Serious adverse events requiring crizotinib dose modification

Toxicity	n (%)a	Recommended dose modification
Hematologic toxicity	43 (17)b
Grade 3		Withhold until recovery to grade ≤ 2, resume at the same dose schedule
Grade 4		Withhold until recovery to grade ≤ 2, then resume at 200 mg twice dailyc
QTc prolongation	4 (1.3)d
Grade 3		Withhold until recovery to grade ≤ 1, then resume at 200 mg twice daily
Grade 4		Permanently discontinue
Hepatotoxicity	19 (7)e
Grade 3 or 4 ALT or AST elevation		Permanently discontinue with grade ≤ 1 total bilirubin
Grade 2, 3, or 4 ALT or AST elevation		Permanently discontinue with grade 2, 3, or 4 total bilirubin
Pulmonary toxicity	4 (1.6)
Pneumonitis (any grade)		Permanently discontinue

Notes:

a incidence of Grade 3 and 4 toxicities reported in study A and study B from a total of 255 evaluable patients;

b lymphopenia 29 (11%); neutropenia 13 (5%); thrombocytopenia 1 (<1%);

c in case of recurrence, withhold until recovery to grade ≤ 2, then resume at 250 mg once daily. Permanently discontinue in case of further grade 4 recurrence;

d four cases of QTc prolongation out of 308 evaluable patients have been documented;

e Grade 3 or 4 ALT elevation, 14 (5%); Grade 3 or 4 AST, 5 (2%).

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Table 4 Mechanisms of acquired crizotinib resistance

Persistent presence of ALK rearrangement	Loss of detectable ALK rearrangement
Secondary ALK mutations	EGFR mutation
ALK copy number gain	KRAS mutation
Upregulation of ErbB signaling	Unknown
KIT amplification
Unknown

Abbreviations: ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; ErbB, avian erythroblastosis oncogene B homolog; KIT, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog; KRAS, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog.

Table 5 ALK-targeted therapies in development

Drug	Manufacturer	Target	Clinical stage
Crizotinib	Pfizer	ALK	FDA approved; Phase II
AP26113	Ariad pharmaceuticals	ALK/EGFRa	Phase I/II
NMS-E628	Nerviano medical	ALK	Preclinical
X-396	Xcovery	ALKb	Phase I
CH5424802	Chugai pharmaceuticals	ALKc	Phase I
LDK378	Novartis	ALK	Phase II
ASP3026	Astellas	ALK	Phase I
Ganetespib (STA-9090)	Synta pharmaceuticals	HSP90	Phase IIb/III
Retaspimycin (IPI-504)	Infinity pharmaceuticals	HSP90	Phase II
AT13387	Astex pharmaceuticals	HSP90	Phase II
AUY922	Novartis	HSP90	Phase II
Debio 0932	Debiopharma	HSP90	Phase I/II
SNX-5422 (PF-04929113)	Esanex	HSP90	Phase I
KW2478	Kyowa Hakko Kirin	HSP90	Phase I/II
PU-H71	Samus therapeutics	HSP90	Phase I
XL888	Exelixis	HSP90	Phase I
DS-2248	Daiichi Sankyo	HSP90	Phase I
BIIB028	Biogen Idec	HSP90	Completed Phase I
NMS-P506	Nerviano medical	HSP90	Preclinical

Notes:

a Effective against L1196M, S1206R, and G1269S ALK secondary mutations;

b effective against L1196 ALK secondary mutations;

c effective against L1196M, C1156Y, and F1174L ALK secondary mutations.

Abbreviations: ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; HSP90, heat shock protein 90; FDA, US Food and Drug Administration.

CamidgeDRBangYKwakELProgression-free survival (PFS) from a Phase I study of crizotinib (PF-02341066) in patients with ALKpositive non-small cell lung cancer (NSCLC)J Clin Oncol201129Suppl 152501

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Xalkori [crizotinib, package insert]New York, NYPfizer Inc2011

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