Background: A transmembrane tyrosine kinase, belonging to the insulin receptor superfamily, found across several tumor types. While more commonly found in NSCLC (3-7%), ALK-positive mutations have also been found in a small number of patients with small-cell lung cancer. Three types of ALK mutations have been identified in NSCLC — rearrangement, amplification and point mutations — with the most common being ALK rearrangements. ALK rearrangements, often in combination with EGFR mutations or ROS1 rearrangements, lead to activation of various signaling pathways associated with cell proliferation and survival. Similar to what is seen in EGFR, ALK mutations can form as a secondary resistance to treatment with ALK-TKIs.
Clinical Features Associated: younger age, minimal/no smoking history, adenocarcinoma histology
Detection Methods: FISH, IHC, NGS
Most Common Alterations:
- ALK Rearrangements involve a portion of the ALK gene breaking and attaching to another gene to form fusion oncogene. ALK rearrangements exhibit lower response rates to immunotherapy, specifically immune checkpoint inhibitors. Due to the approval of targeted therapies, 5-year OS has increased for patients with NSCLC with ALK rearrangements.
- EML4-ALK Fusion Oncogene (Echinoderm microtubule-associated protein like-4) was the first and major ALK-fusion partner identified. This inversion rearrangement involving a portion of EML4 gene fusing with a portion of the ALK gene leads to constitutively active ALK kinase resulting in malignant growth and proliferation. Multiple variants of this fusion oncogene have been identified and are found in 3%-7% of patients with NSCLC.
- Over 90 ALK-fusion partners have been reported in NSCLC, the majority of which have been identified from 2018 onward due, in part, to the adoption of NGS for molecular profiling.
Table 2. ALK-Fusion Partners Identified in NSCLC (01/2007- 01/2020)
- Secondary Acquired Resistance Mutations: Secondary ALK kinase domain resistance mutations have been identified after progression on ALK-TKIs.
- Crizotinib resistance is commonly associated with the following secondary ALK mutations: G1269A, gatekeep mutation L1196M, T1151R, C1156Y, R1192P, G1202R, S1206Y, A1280V, and L1535Q.
*Targeted therapy is the preferred first-line treatment and is not recommended in combination with immunotherapy.
- Crizotinib (Xalkori; Pfizer, EMD Serono):
- First-generation multi-targeted ATP-competitive TKI that confers activity againstMET, ALK and ROS1. FDA granted accelerated approval in 2011, with full approval granted in 2013 for patients with metastatic NSCLC positive for ALK rearrangements. Approval was based on the PROFILE 1014 study. At time of approval, an overall response rate (ORR) of 74% was found with median PFS of over 10 months. Of note, nearly all patients treated with front-line crizontinib eventually progress and develop resistance mechanisms.
- Most Common Adverse Events: vision disorders, nausea, diarrhea, vomiting, swelling, constipation, elevated liver enzymes, fatigue, decreased appetite, upper respiratory infection, dizziness/numbness/tingling in the hands and/or feet
- Ceritinib (Zykadia, Novartis):
- Second-generation multi-targeted, brain-penetrable inhibitor againstALK and ROS1 was granted approval by FDA in 2014 as second-line therapy for patients with metastatic ALK-fusion-positive NSCLC post-crizotinib. In 2017, the FDA broadened approval to the first-line setting for these patients based on the ASCEND-4 study of treatment-naive, metastatic ALK-positive NSCLC with stable brain metastasis. Median PFS of 16.6 months was found with ceritinib vs. 8.1 months in the chemotherapy cohort. The ASCEND-8 trial evaluated a lower dose of ceritinib, with median PFS of 17.6 months compared with 10.9 months in the higher dose cohort and reduction in adverse events reported.
- Most Common Adverse Events: diarrhea, nausea, vomiting, fatigue, abdominal pain, decreased appetite, cough — Of note, serious adverse reactions occurred in 38% of patients treated with ceritinib in the above trial.
- Alectinib (Alecensa, Genentech):
- Second-generation potent, brain-penetrable ALK inhibitor was granted approval by FDA in 2015 as second-line therapy for patients with metastaticALK-fusion-positive NSCLC post-crizotinib. In 2017, the FDA expanded approval to first-line setting for these patients. The approval was based on the ALEX study of treatment-naive patients with advanced/metastatic ALK-positive NSCLC. At the time of approval, a PFS of 34.8 months was found with alectinib vs. 10.9 months with crizotinib. Alectinib has shown superior efficacy duration with low incidence of serious adverse events after long-term use compared with crizotinib. Due to alectinib’s blood-brain barrier permeability, studies have shown enhanced prevention of brain metastases and longer PFS.
- Most Common Adverse Events: fatigue, constipation, swelling, muscle pain, anemia — Of note, serious adverse reactions occurred in 28% of patients treated with alectinib in the above study.
- Brigatinib (Alunbrig, Takeda):
- Second-generation, brain-penetrable, multitargeted TKI against ALK, mutant EGFR, and ROS1 was approved by the FDA in 2017 as second-line therapy for patients with metastatic ALK-fusion-positive NSCLC after crizotinib. In 2020, the FDA broadened approval to the front-line setting based on the ALTA-1L study. At the time of approval, a median PFS of 24 months was found in patients treated with brigatinib compared with 11 months in those treated with crizotinib and an ORR of 74% compared with 62%, respectively.
- Most Common Adverse Events: diarrhea, fatigue, nausea, rash, cough, myalgia, headache, hypertension, vomiting, shortness of breath
- Lorlatinib (Lorbrena, Pfizer):
- Third-generation multi-kinase inhibitor against ALK and ROS1 was approved by FDA in 2018 for patients with metastatic ALK-positive NSCLC for patients previously treated on one or more ALK-TKIs. Lorlatinib was designed specifically against ALK drug resistance mutation sites and with high blood-brain permeability. In 2021, full approval was granted by the FDA in the front-line setting based on the CROWN study of treatment-naive, ALK-positive stage IIIB/IV NSCLC. At the time of approval, an ORR of 76% was found with lorlatinib compared with 58% with crizotinib. Median PFS and OS data were still immature, but initial results suggested improvement with lorlatinib compared with crizotinib.
- Most Common Adverse Events: grade 3 laboratory abnormalities, swelling, dizziness/numbness/tingling in the hands or feet, weight gain, cognitive effects, fatigue, shortness of breath, joint paint, diarrhea, mood effects, high blood cholesterol and triglycerides, cough — Of note, serious adverse events that required discontinuation of therapy were 7% and 9% in lorlatinib and crizotinib, respectively, in the above trial.
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