The Evolution of Frontline Therapy in ALK-Positive Advanced NSCLC: Which ALK TKI to Use Upfront?

Jeffrey Zweig, MD, and Heather Wakelee, MD
Published: Monday, Jan 01, 2018

Therapeutic options for advanced anaplastic lymphoma kinase (ALK)–positive non–small-cell lung cancer have changed dramatically since the 2011 approval of crizotinib. Since then, 3 additional agents have received FDA approval for use in the second-line setting after progression on crizotinib: ceritinib, alectinib, and brigatinib. Other investigational ALK inhibitors are under evaluation. As these agents represent newer-generation, more potent ALK inhibitors, interest in their use in the frontline setting has quickly grown. Here, we review frontline trials of ceritinib and alectinib, with comparisons drawn with crizotinib, the only FDA-approved frontline choice until the recent approval of ceritinib. With several new promising options, we attempt to better answer the question of which ALK tyrosine kinase inhibitor (TKI) should be favored upfront.
Introduction The identification of the EML4-ALK fusion oncogene in 2007 as a driver of pathogenesis, in the 2% to 7% of patients with non– small-cell lung cancer (NSCLC) who express it, has led to the development over the last decade of several targeted anaplastic lymphoma kinase (ALK) inhibitors.1 The use of ALK inhibitors in advanced disease has transformed the treatment strategy of ALKpositive NSCLC, providing targeted therapeutic options that show significant progression-free survival (PFS) and overall survival (OS) benefit, with an impactful influence on patients and their disease course. There are currently 4 approved agents—crizotinib (Xalkori), ceritinib (Zykadia), alectinib (Alecensa), and brigatinib (Alunbrig)—with several others in active development.2 Although crizotinib has historically represented the first-line agent of choice, it has quickly been challenged by the newer, more potent, second-generation ALK inhibitors ceritinib and alectinib, with ceritinib recently gaining FDA approval as a first-line option in May 2017. In order to best answer the question of which agent to use upfront, one must consider a variety of factors, including comparative trial data, adverse event (AE) profiles, and response rates, which will be reviewed here.

The use of crizotinib in ALK-positive lung cancer interestingly evolved when the drug, initially developed as a c-MET inhibitor, was in phase I development at the same time the EML4-ALK fusion oncogene was discovered. It was soon found that crizotinib was also a strong inhibitor of ALK phosphorylation and downstream signaling.3 Crizotinib was first tested in a phase I trial evaluating 143 ALK-positive patients treated with escalating doses, reaching a recommended dose of 250 mg twice daily. Results showed an overall response rate (ORR) of 60.8% (95% CI, 52.3%-68.9%), a median duration of response (DOR) of 49.1 weeks (95% CI, 39.3- 75.4 weeks), and a PFS of 9.7 months (95% CI, 7.7-12.8 months), with a well-tolerated profile.4,5 In August 2011, crizotinib was granted accelerated approval by the FDA for treatment in patients with ALK-positive advanced NSCLC.

Crizotinib was later tested in 2 landmark phase III trials. In the PROFILE 1007 trial, 347 previously treated ALK-positive patients were randomized to either crizotinib or single-agent pemetrexed or docetaxel. At a follow-up of 1 year, crizotinib showed a statistically significant PFS benefit of 7.7 versus 3 months for single-agent chemotherapy (HR, 0.49; 95% CI, 0.37-0.64; P <.001) as well as improved ORR and DOR. Patients reported improved lung cancer symptoms and also greater global quality of life with crizotinib rather than chemotherapy. No significant difference in OS was found (20.3 vs 22.8 months; hazard ratio [HR], 1.02; 95% CI, 0.68-1.54; P = .54), likely a result of 64% crossover.6 With evident success in the second-line setting, crizotinib was then tested in the first-line setting in the PROFILE 1014 trial, in which 343 patients who were ALK-positive with no prior systemic treatment were randomized to crizotinib 250 mg twice daily or standard platinum doublet with cisplatin or carboplatin plus pemetrexed. The primary endpoint was PFS, which was met with a statistically significant benefit with crizotinib of 10.9 versus 7 months with chemotherapy (HR, 0.45; 95% CI, 0.35-0.60; P <.001). The ORR was 74% for crizotinib versus 45% for chemotherapy (P <.001), though the difference in OS was not significant (HR, 0.82; 95% CI, 0.54-1.26; P = .36), again likely due to a high crossover rate of 70% of patients. The most frequently occurring AEs in the crizotinib arm compared with chemotherapy were visual disturbances (71%), diarrhea (61%), and edema (49%). Overall, there was less permanent discontinuation of the drug compared with chemotherapy and a greater improvement in quality-of-life measures.7

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