First-line treatment of advanced ALK-positive non-small-cell lung cancer

Figures & data

Figure 1 A chromosomal inversion in chromosome 2 juxtaposes the 5′ end of the EML4 gene with the 3′ end of the ALK gene resulting in the fusion oncogene EML4-ALK.

Notes: The resulting chimeric protein, EML4-ALK, contains an N-terminus derived from the EML4 and a C-terminus containing the intracellular tyrosine kinase domain of ALK.
Abbreviations: EML4, echinoderm microtubule–associated protein-like 4; ALK, anaplastic lymphoma kinase.

Figure 2 EML4-ALK fusions are due to small inversions within chromosome 2p.

Notes: These fusions lead to aberrant expression of ALK and constitutive activation of the ALK tyrosine kinase and further downstream signaling pathways. Hence, this results in uncontrolled proliferation and survival of cancer cells.
Abbreviations: EML4, echinoderm microtubule–associated protein-like 4; ALK, anaplastic lymphoma kinase.

Table 1 Trials using crizotinib in ALK-positive non-small-cell lung cancer

Trial	Year	Treatment regimen	Number of patients	Response rate (95% CI)	P-value	PFS (95% CI)	P-value	OS	P-value
PROFILE 1001 (expanded cohort)	2012	Crizotinib	143	60.8% (52.3–68.9)	–	9.7 mo (7.7–12.8)	–	–	–
PROFILE 1007	2013	Crizotinib	173	65% (57–72)	<0.001	7.7 mo (6–8.8)	<0.001	20.3 mo (18.1 – NR)	0.54
		Pemetrexed or docetaxel	174	20% (14–26)		3.0 mo (2–4.3)		22.8 mo (18.6 mo – NR)
PROFILE 1014	2014	Crizotinib	172	74%	<0.001	10.9 mo	<0.001	Not described	0.18
		Pemetrexed + carboplatin or cisplatin	171	45%		7.0 mo		Not described

Abbreviations: PFS, progression-free survival; OS, overall survival; mo, months; NR, not reached.

Table 2 Selected ALK inhibitors currently in the clinic or under clinical development

Drugs	Current phase	Toxicity	Response		CNS response
			Crizotinib-naïve	Crizotinib-resistant	Crizotinib-naïve	Crizotinib-resistant
Crizotinib (PF-02341066)	III	Visual disturbances, nausea, vomiting, constipation, edema	–	–	Untreated: Intracranial DCR – 56% (95% CI, 46–66) Intracranial TTP: 6.7–16.4 mo^Citation85 Treated with radiotherapy: Intracranial DCR – 62% (95% CI, 54–70) mTTP: 13.2 mo (95% CI, 9.9–NR)^Citation85
Ceritinib (LDK378)	II/III	Diarrhea, elevated transaminases	ORR – 41/59 (66%)^Citation41 mPFS: not reached^Citation41	ORR – 67/121 (54.6%)^Citation41 mPFS: 6.9 mo^Citation41	ORR 75% (95% CI, 19.4–99.4)^Citation41	ORR 40% (95% CI, 12.2–73.8)^Citation41
Alectinib (CH542802/RO542802)	II/III	Nausea, fatigue, myalgias, neutropenia, elevated CPK	Phase I/II: ORR – 43/46 (93.5%)^Citation46	Phase I/II: ORR – 24/44 (55%), SD – 16/44 (36%)^Citation47		Phase I/II: ORR – 11/21 (52%)^Citation47
AP26113	I/II	Nausea, fatigue, diarrhea	–	ORR – 24/38 (63%)^Citation86 mPFS: 47 wk^Citation86	–	ORR – 6/10, SD – 2/10, PD – 2/10^Citation86
ASP-3026	IB	Nausea, vomiting, constipation, abdominal pain	–	PR: 7/15 (49%), SD: 8/15 (50%)^Citation87 mPFS: 5.9 mo (95% CI 3.8–9.4)^Citation87	–	–
X-396	I/II	N/A	13 ALK+: 3 crizotinib-naive and 10 crizotinib-resistant – among 6 ALK + patients: SD 17% and PR 83% (unsure of crizotinib-naive or -resistant)^Citation78

Abbreviations: TTP, time to progression; CI, confidence interval; ORR, overall response rate; SD, standard deviation; PFS, progression-free survival; mPFS, median progression-free survival; ALK, anaplastic lymphoma kinase; CNS, central nervous system; CPK, creatine phosphokinase; wk, weeks; mo, months; DCR, disease control rate; NR, not reached; mTTP, median time to progression; N/A, not available; PD, progressive disease.

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