Optimal Care for Patients with Anaplastic Lymphoma Kinase (ALK)–Positive Non–Small Cell Lung Cancer: A Review on the Role and Utility of ALK Inhibitors

Figures & data

Table 1 Main Mechanisms of Resistance to First- and Next-Generation ALK TKIs

ALK TKIs^Citation29,Citation33,Citation96,Citation97	ALK-Dependent Resistance Mechanism	ALK-Independent Resistance Mechanism
	(Amplification/Mutation Acquisition)	(Bypass of Signaling Pathways)
Crizotinib	Amplification of the ALK fusion gene; L1196M, G1269A/S, I1151Tins, L1152P/R, C1156Y/T, I1171T/N/S, F1174C/L/V, V1180L, G1202R, S1206C/Y, E1210K mutation acquisition	EGFR, NRG1 overexpression,^Citation101 IGF-1R activation^Citation102
Ceritinib	G1202R, F1174C/L/V, G1202del, I1151Tins, L1152P/R, C1156Y/T	cMET-gene amplification; activating mutation of MEK (MAP2K1^K57N), PIK3CA mutations
Alectinib	G1202R, I1171T/N/S, V1180L, L1196M	cMET-gene amplification, PIK3CA mutations
Brigatinib	E1210K + S1206C, E1210K + D1203N, G1202Ra	Not described
Lorlatinib^Citation100	L1198F + C1156Yc, L1196M/D1203N, F1174L/G1202R, C1156Y/G1269A	NF2 loss-of-function mutations^Citation100

Abbreviation: TKI, tyrosine-kinase inhibitor.

Table 2 Major ALK-Inhibitor Clinical Trials for Second- and Next-Line Therapy in ALK-Rearranged Non–Small Cell Lung Cancer

Trial	PROFILE 1007^Citation27	ASCEND-5^Citation51	ASCEND-8^Citation53,Citation54	NP28673^Citation63	ALTA^Citation73	Solomon et al^Citation81
ALK inhibitor	Crizotinib (n=173)	Ceritinib (n=115)	Ceritinib 450 mg with low-fat meal (n=108)	Alectinib (n=138)	Brigatinib 90 mg; arm A (n=112)	Lorlatinib 100 mg (n=276)^$
Comparator	Chemotherapy–pemetrexed or docetaxel (n=174)	Chemotherapy– pemetrexed or docetaxel (n=116)	Ceritinib 750 mg, fasted (n=111)	None (single-arm study)	Brigatinib 180 mg; arm B (n=110)	None (single-arm study)
Primary end point	mPFS	mPFS	ORR	ORR	ORR	ORR
Response rate (%)	65 vs 20	39.1 vs 6.9	78.1% vs 75.7%	50	45 vs 54	EXP (2–3A) 69.5; EXP3B 32.1; EXP (4–5) 38.7
Median PFS (months)	7.7 vs 3 (HR 0.49, 95% CI 0.37–0.64; p<0.001)	5.4 vs 1.6 (HR 0.49, 95% CI 0.36–0.67; p<0.0001)	NE (95% CI 11.8–NE) vs 12.2 (8.2–NE); HR and p-value — NR	8.9 (95% CI 5.6–11.3)	9.2 vs 12.9 (HR 0.55, 95% CI 0.35–0.86, arm B vs A)	Pooled mPFS (EXP2–5): 7.3 (95% CI 5.6–11.0)
Median OS (months)	21.9 vs 21.7 (HR 0.85, 95% CI 0.66–1.10; p=0.11)	18.1 vs 20.1 (HR 1.00, 95% CI 0.67–1.49; p=0.50)	NR	Pooled analysis with another study (NP28761)^Citation57, mOS 29.1 (95% CI 21.3–39.0)	27.6 vs NR (HR 0.67, 95% CI 0.42–1.06; p-value NR	NR

Notes: ^$ALK-positive and pretreated with crizotinib without chemotherapy (n=27; EXP2); ALK-positive and pretreated with crizotinib and chemotherapy (n=32; EXP3A); ALK-positive and one previous non–crizotinib ALK TKI with or without chemotherapy (n=28; EXP3B); ALK-positive and pretreated with two ALK TKIs with or without chemotherapy (n=66; EXP4); ALK-positive and pretreated with three ALK TKIs with or without chemotherapy (n=46; EXP5). Cohorts EXP1 (treatment-naïve ALK+) and EXP6 (ROS1⁺) excluded in this table.

Abbreviations: mOS, median overall survival; mPFS, median progression-free survival; NR, not reported; NR, not reached; ORR, objective response rate.

Table 3 Major ALK Inhibitor Clinical Trials for First-Line Therapy in ALK-Rearranged Non–Small Cell Lung Cancer

Trial	PROFILE 1014^Citation29	ASCEND-4^Citation52	J-ALEX^Citation65	ALEX^Citation67	ALTA 1L^Citation79
ALK inhibitor	Crizotinib (n=172)	Ceritinib (n=189)	Alectinib (n=103)	Alectinib (n=152)	Brigatinib (n=137)
Comparator	Platinum-based chemotherapy (n=171)	Platinum-based chemotherapy (n=187)	Crizotinib (n=104)	Crizotinib (n=151)	Crizotinb (n=138)
Primary end point	Median PFS (months)	Median PFS (months)	Median PFS (months)	Median PFS (months)	Median PFS (months)
Response rate (%)	74 vs 45	72.5 vs 26.7	Not reported	82.9 vs 75.5	71 vs 60
Median PFS (months)	10.9 vs 7 (HR 0.45, 95% CI 0.35–0.60; p<0.001)	16.6 vs 8.1 (HR 0.55, 95% CI 0.42–0.73; p<0.00001)	34.1 vs 10.2 (HR 0.37, 95% CI 0.26–0.52; p<0.0001)	34.8 vs 10.9 (HR 0.43, 95% CI 0.32–0.58; p<0.01)	Not reached vs 9.8 (HR 0.49, 95% CI 0.33–0.74; p=0.0007)
Median OS (months)	Not reached vs 47.5 (HR 0.76, 95% CI 0.548–1.05; p=0.0978	Not reached vs 26.2 (HR 0.73, 95% CI 0.5–1.08; p=0.056	—	Not reached vs not reached (HR 0.76, 95% CI 0.50–1.15)	—

Abbreviations: OS, overall survival; PFS, progression-free survival.

Table 4 Efficacy of Various ALK Inhibitors for Brain Metastases in Patients with ALK-Rearranged NSCLC

Trial	PROFILE 1007^Citation27	ASCEND-4^Citation52	ALEX^Citation67	ALTA^Citation73	Solomon et al^Citation81
ALK inhibitor (ALKi)	Crizotinib	Ceritinib	Alectinib	Brigatinib 90 mg; arm A	Lorlatinib 100 mg
Comparator	Chemotherapy–Pemetrexed or Docetaxel	Chemotherapy- Platinum based plus pemetrexed	Crizotinib	Brigatinib 180 mg; arm B	None (single-arm study)
Prior ALKi	ALKi-naïve	ALKi-naïve	ALKi-naïve	ALKi-pretreated	ALKi-pretreated
ICC-ORR	18%	73%	81%	42% in arm A; 67% in arm B	39%
IC-DoR	26.4 weeks	Not reported	17.3 months for patients with measurable target BM and NR for all patients with BM at baseline	NR (3.7 months–NR) for arm A; 16.6 (5.6 months–NR for arm B)	Not reported
Attainable CSF concentration and CSF to plasma ratio
	Crizotinib	Ceritinib	Alectinib	Brigatinib	Lorlatinib
Attainable CSF concentration (nM/L)	1.4^Citation35,Citation37	NA	2.7	NA	NA
CSF:plasma ratio	~0.003	NA	~0.75^Citation40,Citation98	0.31^Citation40	0.75^Citation99

Abbreviations: BM, brain metastasis; NA, not available; NR, not reached; IC-DoR, intracranial duration of response; IC-ORR, intracranial objective response rate.

Figure 1 Treatment algorithm for ALK-rearranged non–small cell lung cancer.

Note: ^#Absence of ALK-dependent secondary mutations as well as ALK-independent alternate resistance pathways on rebiopsy.

Abbreviations: ICI, immunocheckpoint inhibitor; PD, progressive disease; TKI, tyrosine-kinase inhibitor.

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