Treatment of ALK‐rearranged non‐small cell lung cancer: A review of the landscape and approach to emerging patterns of treatment resistance in the Australian context

Abstract

Since the identification of anaplastic lymphoma kinase (ALK) gene rearrangements in non-small cell lung cancer (NSCLC) in 2005, the treatment of ALK-rearranged NSCLC (ALK+ NSCLC) has evolved at a rapid pace. This molecularly distinct subset of NSCLC has uniquely important biology, clinicopathologic features and mechanisms of drug resistance which impact on the choice of treatment for a patient with this disease. There are multiple ALK tyrosine kinase inhibitors now available in clinical practice with efficacy data continuing to emerge and guide the optimal treatment algorithm. A detailed search of medical databases and clinical trial registries was conducted to capture all relevant articles on this topic enabling an updated detailed overview of the landscape of management of ALK-rearranged NSCLC.

An Update on Predictive Biomarkers for Treatment Selection in Non-Small Cell Lung Cancer

“…The ALK gene encodes for a receptor tyrosine kinase that is thought to transmit growth activating signals [ 27 ]. Activating ALK gene rearrangements that produce an abnormally, constitutively expressed and activated ALK protein led to abnormal cell growth and proliferation.…”

“…The most common rearrangement occurs when the ALK gene fuses with the echinoderm microtubule-associated protein like 4 ( EML4 ) gene through an inversion, producing the EML4-ALK fusion oncogene. ALK rearrangement is more commonly found in younger patients with adenocarcinoma histology who are light smokers or who have never smoked, and they are almost always mutually exclusive with other oncogenic drivers such as EGFR mutations [ 16 , 20 , 27 ].…”

“…Biomarkers to detect ALK rearranged NSCLC include immunohistochemistry (IHC) [ 29 ] and fluorescence in situ hybridization (FISH) using a break apart assay [ 25 , 27 , 28 , 29 , 30 ]. Molecular methods such as reverse transcriptase-polymerase chain reaction (RT-PCR) or next generation sequencing (NGS) can also be utilized but unusual or novel fusion partners or isoforms are not detected by RT-PCR or amplicon-based NGS techniques.…”

Systematic review and meta-analysis of selected toxicities of approved ALK inhibitors in metastatic non-small cell lung cancer

“…ORR were 7% for the chemotherapy group as compared with 39% for the Ceritinib group, indicating that ALK rearrangements are predictive of benefit to targeted therapy after progression on first line treatment [ 11 ]. Resistance mechanisms including mutation of the kinase domain, amplification of the gene copy number, bypass signaling, transformation to small cell lung cancer, have been previously described [ 17 ].…”

Precision medicine and actionable alterations in lung cancer: A single institution experience

“…While our data recapitulates that broad-based sequencing panels were not independently associated with better median OS, our results also show that patients with actionable alterations had a discernibly improved median OS as compared to wild-type patients who did not have an actionable alteration. Most notably ALK rearrangement patients had an improved OS as compared to tested ALK rearrangement negative (median OS 82.6 vs 26.6 months), which is suspected due to appropriate molecular testing at presentation and apt selection of therapy based on results [35,36]. While Presley et al include ALK in their small routine panel it should be noted that in a study evaluating the methods of ALK rearrangement testing it was found that comprehensive genomic profiling by NGS was able to identify a number of patients who had previously tested negative using the standard ALK fluorescence in situ hybridization (FISH) assay [37].…”