Key points

Introduction

First described in 2007, echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) gene rearrangements are chromosomal inversions that lead to constitutive oncogenic activation. Cells harboring ALK rearrangements are sensitive to tyrosine kinase inhibitors (TKIs), which have dramatically improved patient outcomes, with up to 50% of patients surviving 6.8 years after diagnosis.

The proportion of patients with ALK-positive disease varies depending on the population. ALK rearrangements are detected in approximately 3% to 7% of adenocarcinomas, translating to 60,000 new cases annually worldwide. This incidence is similar in Asian (4.2%) and Western (3.4%) populations. ALK-positive disease occurs almost exclusively in adenocarcinomas, is associated with younger age (median age of diagnosis of 52), male sex, and never-smoking or light-smoking history.

ALK-positive patients with stage I–III disease are managed similarly to those with wild-type disease. They may receive surgery, radiation, chemotherapy, or multimodal therapy as appropriate for the patient’s stage. It remains to be determined whether TKIs will play a role for these early-stage patients (see later discussion). For patients with previously untreated metastatic ALK-positive disease, multiple TKIs are available ( Table 1 ). Drug resistance inevitably emerges, and has led to the development of more potent next-generation ALK inhibitors ( Table 2 ).

Diagnostic testing

All patients with metastatic lung adenocarcinoma should be tested for ALK rearrangements using fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), or next-generation sequencing (NGS). FISH is the gold standard for detecting ALK rearrangements, and uses red and green probes to hybridize with either side of the ALK translocation breakpoint. These probes either overlay to form a yellow signal for wild-type samples or separate with independent red and green signals if a fusion mutation is present.

An alternative to FISH is IHC, which involves the use of monoclonal antibodies to the ALK fusion oncogene. NGS is performed with extraction of genomic DNA from tumor cells, with probes targeting cancer-specific genes using either plasma or tissue. Comparing these 3 methods, IHC had the greatest positive rate (94.5%), with similar results from NGS (92.7%), followed by FISH (82.4%).

Tyrosine kinase inhibitors

Tyrosine kinase inhibitors in development

Ensartinib (X-396) is a novel inhibitor with activity against ALK and ROS1 crizotinib resistance mutations, including L1196M and C1156Y. In a recent phase 1/2 study (N = 60), relative response (RR) rate was 60% with a median PFS of 26.2 months. Activity was seen in patients who had previously received a second-generation ALK TKI (n = 16, ORR 23%, DCR 50%), as well as in patients who had received between 2 and 5 prior regimens of ALK TKIs. Intracranial RR (64%) and IC DCR (92.9%) were particularly promising. A phase 3 trial, eXalt3, is currently comparing ensartinib with crizotinib.

Entrectinib is another novel inhibitor of ALK. A recent phase 1 study found that entrectinib had rapid and durable benefit in patients harboring rearrangements of NTRK, ROS1, and ALK. However, no responses were observed in patients previously treated with ALK inhibitors.

Repotrectinib is a next-generation ROS, TRK-A, and ALK inhibitor that has shown meaningful preliminary clinical activity. The current phase 1/2 trial (Trident-1) is still ongoing.

Resistance mechanisms

Mutations in the ALK kinase domain are the best described mechanism of TKI resistance, occurring in both crizotinib-treated patients (20%–36%) ^, and patients treated with a second-generation ALK inhibitor (>50%). Each TKI is associated with an individual spectrum of mutations. ^, Gainor and colleagues analyzed 103 biopsies from ALK-positive patients progressing on various ALK inhibitors. L1196M is the most common mutation found in crizotinib resistance (7%). G1202R occurs frequently after second-generation agents, including ceritinib (21%), alectinib (29%), and brigatinib (43%). ^{, , ,} Even though G1202R confers high-level resistance, it can be overcome by lorlatinib. ^, Little is known regarding lorlatinib resistance.

Resistance mechanisms outside of the ALK kinase domain also occur. Amplification of the ALK domain occurs in about 10% of crizotinib-resistant samples, either in isolation or with other mutations. ^, Bypass signaling pathway activation is another resistance mechanism, with activation of the epidermal growth factor receptor (EGFR) most commonly reported. ^, Transformation to both spindle-cell morphology and squamous cell lung cancer have also been described. ^,

Systemic therapy after tyrosine kinase inhibitors

Treatment with chemotherapy, with or without immunotherapy, is used after targeted therapies have been exhausted. The use of combination chemoimmunotherapy is supported by a subgroup analysis of 111 patients with EGFR and ALK mutations from the IMpower150 study. The combination of carboplatin, paclitaxel, bevacizumab, and atezolizumab demonstrated an improvement of PFS in patients with EGFR and ALK mutations over carboplatin, paclitaxel, and bevacizumab (9.7 months vs 6.1 months; HR 0.59, 95% confidence interval 0.37–0.94).

Outside of IMpower150, data supporting the use of immunotherapy in ALK-mutated patients is scarce. Patients with ALK mutations were excluded from KEYNOTE-189, which studied the combination of carboplatin, pemetrexed, and pembrolizumab. Negative clinical trial results were seen for ALK patients with carboplatin/nab-paclitaxel/atezolizumab, ^, nivolumab, pembrolizumab, and atezolizumab. In addition, extrapolation of EGFR data lead to safety concerns in giving TKI therapy either with or following immunotherapy. Testing for ALK should be completed before the administration of chemoimmunotherapy in the untreated setting to avoid this increased toxicity risk.

Discussion

Alectinib is the current preferred first-line treatment for ALK-positive, metastatic NSCLC. This preference is based on improved efficacy, side-effect profile, and CNS activity when compared with crizotinib. ^, Brigatinib, ceritinib, and crizotinib remain options for front-line treatment, and may be considered based on individual clinical circumstances. Lorlatinib should be considered after progression on alectinib.

Excellent CNS activity of alectinib and brigatinib has allowed for treatment of CNS metastasis with TKI therapy and has allowed patients to delay or avoid the use of radiotherapy or surgery for local control. ^{, , , ,} For patients with CNS progression on alectinib, lorlatinib remains an option.

Future directions

Long-term follow-up data for brigatinib await maturity, and how this drug will compare with alectinib remains to be seen. Ensartinib, entrectinib, and repotrectinib are all being investigated in clinical trials, and the role they will play is yet to be determined. Additional data are needed regarding the optimal treatment following TKI therapy, whether it be chemotherapy or chemoimmunotherapy.

The role of TKIs in the perioperative setting is under investigation. Crizotinib is being studied in the neoadjuvant setting as well as the adjuvant setting as part of the larger, multi-institutional Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST). ^, An ongoing phase 3 study (ALINA) is evaluating the efficacy and safety of alectinib compared with platinum-based chemotherapy in patients with completed resected IB to stage IIIA tumors as an adjuvant therapy.

In summary, excellent progress has been made over the past decade in the treatment of ALK-positive NSCLC, with 4 TKIs now approved in the front-line setting, with additional options available at time of progression. Next-generation ALK inhibitors demonstrate excellent CNS response rates. Future areas of research include additional next-generation TKIs, the perioperative role of TKIs, and the optimal systemic treatment once TKI options have been exhausted.