Optimal First-line Treatment for Metastatic ALK+ Non-Small Cell Lung Cancer

A Narrative Review

Grace Chazan; Benjamin J. Solomon

Transl Lung Cancer Res. 2023;12(2):369-378.

Abstract and Introduction

Abstract

Background and Objective: First-line treatment options for patients with advanced non-small cell lung cancer (aNSCLC) whose tumors harbour anaplastic lymphoma kinase (ALK) gene rearrangements have rapidly evolved from chemotherapy, to the first in class ALK-targeted tyrosine kinase inhibitor (TKI) crizotinib in 2011, and now include no fewer than five Food and Drug Administration (FDA)-approved ALK inhibitors. However, while superiority to crizotinib has been established, head-to-head clinical trials comparing newer generation ALK inhibitors are lacking, and decisions on optimal first-line treatment must be based on analysis of the relevant trials, with attention to systemic and intracranial efficacy, toxicity profile as well as consideration of patient factors and preferences. Here we aim to synthesise findings from review of these trials and to describe options for optimal first-line treatment for ALK+ NSCLC.

Methods: A literature review of relevant randomised clinical trials was undertaken using Embase database. There were no limitations to time frame or language applied.

Key Content and Findings: Crizotinib was established as the standard of care first-line treatment for patients with ALK+ aNSCLC in 2011. Since this time, alectinib, brigatinib, ensartinib and lorlatinib have all demonstrated superiority as first-line treatments compared to crizotinib, based on progression free survival, intra-cranial efficacy, and side-effect profiles.

Conclusions: Options for optimal first-line treatment for ALK+ aNSCLC include alectinib, brigatinib and lorlatinib. This review serves as a resource summarizing data from key clinical trials with ALK inhibitors to aid in decision making when tailoring treatment for patients. Future research in the field includes real world analysis of efficacy and toxicity of next-generation ALK-inhibitors, identification of mechanisms of tumor persistence and acquired resistance, development of novel ALK inhibitors, and use of ALK-TKIs in earlier stage disease.

Introduction

Background

Anaplastic lymphoma kinase (ALK) gene rearrangements were first identified as an oncogenic driver in a subset of non-small cell lung cancers in 2007.^[1] A phase I study with the first in class ALK tyrosine kinase inhibitor (TKI) crizotinib, demonstrated that tumours harbouring ALK gene rearrangements were sensitive to ALK inhibition.^[2] The PROFILE1014 study comparing crizotinib to standard of care platinum doublet chemotherapy established first-line ALK-TKI as a new standard of care and in turn created a requirement for testing of tumors from newly diagnosed non-small cell lung cancer (NSCLC) for ALK rearrangements.^[3] Although this represented a significant advance in the treatment of ALK+ aNSCLC, tumors eventually develop resistance to crizotinib. Additionally, crizotinib has limited penetration of the blood-brain barrier and central nervous system (CNS) progression on crizotinib is common.^[4,5] Thus, newer generation ALK-inhibitors, with improved activity against crizotinib resistance mutations, increased potency and improved CNS penetrance, continue to be developed. A phase III randomised controlled trial (RCT) investigating the second generation ALK inhibitor ceritinib demonstrated superiority of ceritinib over chemotherapy in the first-line setting.^[6] Subsequent RCTs with second generation ALK inhibitors alectinib, brigatinib, ensartinib and most recently third generation ALK inhibitor lorlatinib have demonstrated superiority over crizotinib on the basis of overall and CNS efficacy.

Rationale and Knowledge gap

Despite the multitude of available therapies, there are no RCTs comparing next-generation ALK inhibitors to one another. Thus, selecting the optimal treatment in the first-line setting requires detailed analysis of available evidence, with attention to systemic and intracranial efficacy and to toxicity as well as patient factors and preferences. Previous reviews addressing this topic have included a Cochrane Review by Cameron et al., which concluded that next-generation ALK-inhibitors improve PFS and likely OS when compared to crizotinib, but again this study did not compare next-generation ALK-inhibitors to one another.^[7] Additionally, the pace of drug development means that previous relevant narrative reviews do not discuss all of the currently available ALK-TKIs.^[8,9]

Objective

In this narrative review, we aim to analyse and summarise contemporary relevant evidence from clinical trials and to synthesise recommendations for first-line treatment for patients with ALK+ NSCLC. We present the following article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-656/rc).

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Abstract and Introduction
Methods
Discussion/Summary
Conclusions
References

Table 1. Search strategy summary
Items	Specification
Date of search	12/08/2022
Databases and other sources searched	Embase
Search terms used	Embase <1974 to 2022 August 12>
	1. ((anaplastic lymphoma kinase or ALK positive or ALK rearrang) adj4 (non-small cell lung cancer or nonsmall cell lung cancer* or NSCLC)).tw,kw. 2819
	2. ((anaplastic lymphoma kinase or ALK positive or ALK rearrang) adj4 lung adj3 adenocarcinoma).tw,kw. 436
	3. 1 or 2 3170
	4. exp randomized controlled trial/723233
	5. (random* or RCT or placebo).tw. 1943632
	6. 4 or 5 2041197
	7. 3 and 6 305
	8. 7 not (conference abstract.pt. or (systematic review or meta-analysis).ti.) 128
Timeframe	Unlimited
Inclusion criteria	Randomised controlled trials
Selection process	All abstracts reviewed by first author. Only randomised clinical trials including patients who were treatment naïve were included (8 studies in total). Updated analysis relating to these 8 studies were also included

ALK, anaplastic lymphoma kinase; NSCLC, non-small cell lung cancer; RCT, randomised controlled trial.

Table 2. Summary of randomised controlled trials investigating first-line treatment of ALK+ aNSCLC, as of August 2022
ALK inhibitor	Study, year of publication	Treatments being compared	Hazard ratio for disease progression or death [95% CI]	Intracranial activity (variable endpoints)	Objective response rates % [95% CI]	1^st line approval	Ref
Crizotinib (1^st generation)	PROFILE 1014, 2014	Crizotinib vs. chemotherapy	0.45 [0.35–0.60], P<0.001**	All patients: IC disease progression 5% vs. 15%;	74 [67–81] vs. 45 [37–53], P<0.001	US: 2011; Europe: 2015	(3)
Crizotinib (1^st generation)	PROFILE 1029, 2018	Crizotinib vs. chemotherapy	0.40 [0.29–0.56]; P<0.001**	median IC TTP NR (95% CI, 20.8–NR) vs. 16.0 months (95% CI, 12.6–NR)	87.5 [79.6–93.2] vs. 45.6 [35.8–55.7], P<0.001	US: 2011; Europe: 2015	(12)
Ceritinib (2^nd generation)	ASCEND-4, 2017	Ceritinib vs. chemotherapy	0.55 [0.42–0.73], P<0.00001**	For those with measurable baseline brain metastases: IC ORR 72.7% (95% CI, 49.8–89.3) vs. 27.3% (95% CI, 10.7–50.2); IC CR 9.1% vs. 9.1%	72.5 [65.5–78.7] vs. 26.7 [20.5–33.7]	US: 2017; Europe: 2017	(6)
Alectinib (2^nd generation)	ALEX, 2017	Alectinib vs. crizotinib	0.47 [0.34–0.65], log-rank P<0.001*	For those with measurable baseline brain metastases: IC ORR 81% (95% CI, 58–95) vs. 50% (95% CI, 28–72); IC CR 38% vs. 5%	82.9 [76.0–88.5] vs. 75.5 [67.8–82.1], P=0.09	US: 2017; Europe: 2017	(13)
	J-ALEX, 2017^#	Alectinib vs. crizotinib	0.34 [0.17–0.71], log-rank P<0.0001**	For those with baseline brain metastases: HR for TTP of brain metastatic lesion or death 0.16 (95% CI, 0.02–1.28); No baseline brain metastases: HR for time to onset of new brain metastases or death 0.41 (95% CI, 0.17–1.01)	92 [85.6–97.5] vs. 79 [70.5–87.3]		(14)
	ALESIA, 2018	Alectinib vs. crizotinib	0.37 [0.22–0.61], P<0.0001*	Time to CNS progression cause-specific HR 0.14	91 vs. 77 (HR 0.22, 95% CI: 0.12–0.40; P<0.0001)		(15)
Brigatinib (2^nd generation)	ALTA-1L, 2018^#	Brigatinib vs. crizotinib	0.49 [0.33–0.74], log-rank P<0.001**	For those with measurable baseline brain metastases: IC ORR 78% (95% CI, 52–94) vs. 29% (95% CI, 11–52); IC CR 11% vs. 0%	71 [62–78] vs. 60 [51–68]	US: 2020; Europe: 2020	(16)
Lorlatinib (3^rd generation)	CROWN, 2020	Lorlatinib vs. crizotinib	0.28 [0.19–0.41], P<0.001**	For those with measurable baseline brain metastases: IC ORR 82% (95% CI, 57–96) vs. 23% (95% CI, 5–54); IC CR 71% vs. 8%	76 [68–83] vs. 58 [49–66]	US: 2021; Europe: 2022	(17)
Ensartinib (2^nd generation)	eXalt3, 2021^#	Ensartinib vs. crizotinib	0.51 [0.35–0.72], log-rank P<0.001**	For those without baseline brain metastases in mITTgroup: ^ Development of new brain metastases rate: 4.2% vs. 23.9%; cause specific HR 0.32 (95% CI, 0.16–0.63), P=0.001	74 [66–81] vs. 67 [58–74]	China: 2022	(18)

*, as assessed by investigators; **, as assessed by blinded independent committee review or independent radiology review; ^#, patients may have had up to one prior line of treatment, excluding ALK-directed tyrosine kinase inhibitors; ^, mITT population in eXalt3 study was used to describe the efficacy among patients with central laboratory-confirmed ALK-positive status. ALK, anaplastic lymphoma kinase; aNSCLC, advanced non-small cell lung cancer; DoR, duration of response; CR, complete response; IC, intracranial; ORR, overall response rate; NE, not evaluable; NR, not reached; RR, response rate; TTP, time to progression; US, United States; mITT, modified intention to treat.