Treatment Paradigm Shift in ALK-Positive NSCLC Raises Further Questions Regarding ALK Inhibitor Sequencing

Web Exclusives - Lung Cancer

Changes to the treatment landscape for non–small-cell lung cancer (NSCLC) with advanced anaplastic lymphoma kinase (ALK) rearrangements are necessitating more nuanced decision-making by clinicians to determine the best line of action for a particular patient’s tumor characteristics.

The results of the PROFILE clinical trials solidified the status of crizotinib (Xalkori) as the standard of care in the first-line treatment of ALK-positive NSCLC.1

One size does not fit all, however, as demonstrated by Yoshida and colleagues in a recent study that identified the varied activity of crizotinib in tumors with different ALK variants, as defined by the size of the EML4 gene involved in the ALK fusion gene.2 The study showed a median progression-free survival (PFS) of 11 months in patients with the most common ALK variant (variant 1), and a PFS of 4.2 months in patients whose tumors had other ALK variants.1,2

Regardless of its varying efficacy among patients with ALK-positive NSCLC, one factor holds true for almost all crizotinib-treated patients—eventual disease progression. Occurring through 1 of 3 major mechanisms of resistance, and often manifested by metastatic disease in the central nervous system (CNS), crizotinib resistance has paved the way for next-generation ALK inhibitors.1

The superior potency demonstrated by the next generation of ALK inhibitors, including their CNS activity, gave rise to the question of whether these new agents—ceritinib (Zykadia), alectinib (Alecensa), and brigatinib (Alunbrig)—could have a place in the frontline setting. The results of the phase 3 ALEX study answered that question, at least in the case of alectinib, showing the drug more than doubled PFS compared with crizotinib (25.7 months vs 10.4 months, respectively) and significantly reduced the risk for CNS progression versus crizotinib by 84% (hazard ratio, 0.16; 95% confidence interval, 0.10-0.28; P <.0001).3 Based on these results, the FDA approved alectinib as a first-line treatment for ALK-positive NSCLC on November 6, 2017.3

Recent results from the phase 3 ASCEND-4 trial, which randomized treatment-naїve patients with ALK-positive NSCLC to receive either ceritinib or chemotherapy, showed significantly improved PFS (16.6 months vs 8.1 months, respectively), quality of life, and lung cancer symptom scores with ceritinib.1 These data could point to ceritinib as a future first-line treatment, as well.

Just as is the case with crizotinib, patients still experience disease progression with the next-generation ALK inhibitors, albeit at varying degrees. Gainor and colleagues conducted molecular profiling of tumors in 46 patients with ALK-positive NSCLC whose disease progressed with crizotinib and with a next-generation ALK inhibitor. Among the patients—of whom 23 had progressed with ceritinib, 17 had progressed with alectinib, and 6 had progressed with brigatinib—56% showed ALK resistance mutations, the most common of which was G1202R. The researchers determined that the frequency of the ALK G1202R mutation increases significantly after treatment with a next-generation ALK inhibitor.4 It is worth noting, however, that brigatinib has shown the potential to overcome the ALK G1202R resistance mutation.5

With alectinib as the new first-line standard of care, the question of whether patients treated under this new indication will develop similar mechanisms of resistance to crizotinib-refractory patients treated with the drug is one that warrants investigation. In addition, due to the newness of alectinib as a first-line ALK inhibitor, data on treatment options for alectinib-treated patients are sparse. This raises the concern that starting a patient with alectinib could limit subsequent treatment options.1

Lorlatinib, an investigational third-generation ALK/ROS1 inhibitor, has shown promise in patients who have received ≥2 ALK inhibitors, with a median PFS of 9.2 months, along with CNS activity and the ability to overcome the ALK G1202R resistance mutation.1,5 When Gainor and colleagues studied the activity of lorlatinib in ceritinib-resistant tumors in preclinical models, however, they determined that lorlatinib only showed antitumor activity in patients with ALK resistance mutations. This points to the possibility of lorlatinib, once approved, becoming a treatment indicated for patients who have developed ALK resistance mutations.

For patients without ALK resistance mutations who have received ≥2 ALK inhibitors, non–ALK-directed therapy could be the best course of action, with cytotoxic chemotherapy and PD-1–directed agents as considerations.1                                                             
1. Gadgeel SM. Sequencing of ALK inhibitors in ALK+ non-small cell lung cancer. Curr Treat Options Oncol. 2017;18:36.
2. Yoshida T, Oya Y, Tanaka K, et al. Differential crizotinib response duration among ALK fusion variants in ALK-positive non-small-cell lung cancer. J Clin Oncol. 2016;34:3383-3389.
3. FDA approves Genentech’s Alecensa (Alectinib) as first-line treatment for people with specific type of lung cancer. November 6, 2017.’s-Alecensa-Alectinib-First-Line-Treatment. Accessed February 26, 2018.
4. Gainor JF, Dardaei L, Yoda S, et al. Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer. Cancer Discov. 2016;6:1118-1133.
5. Metro G, Tazza M, Matocci R, et al. Optimal management of ALK-positive NSCLC progressing on crizotinib. Lung Cancer. 2017;106:58-66.

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Last modified: February 19, 2019

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