Non-small-cell lung cancer: how to manage ALK-, ROS1- and NTRK-rearranged disease

Abstract

Oncogene addiction in non-small-cell lung cancer (NSCLC) has profound diagnostic and therapeutic implications. ALK , ROS1 and NTRK rearrangements are found in about 2–7%, 1–2% and 0.2% of unselected NSCLC samples, respectively; however, their frequency is markedly higher in younger and never-smoker patients with adenocarcinoma histology. Moreover, ALK , ROS1 and NTRK rearrangements are often mutually exclusive with other known driver alterations in NSCLC. Due to such a low frequency, diagnostic screening with accurate and inexpensive techniques such as immunohistochemistry is useful to identify positive cases; however, confirmation with fluorescent in situ hybridization or next-generation sequencing is often required due to higher specificity. In ALK -rearranged NSCLC, sequential treatment with second-generation and third-generation tyrosine kinase inhibitors leads to long-lasting disease control with most patients surviving beyond 5 years with metastatic disease. In ROS1 -rearranged NSCLC, first-line treatment with crizotinib or entrectinib and subsequent treatment with lorlatinib at disease progression leads to similar results in patients with metastatic disease. NTRK1–3 fusions are extremely rare in unselected NSCLC. However, treatment with TRK inhibitors yields high response rates and durable disease control in most patients; diagnostic screening through multigene DNA/RNA-based next-generation sequencing testing is therefore crucial to identify positive cases. This article is part of the Treatment of advanced non-small-cell lung cancer: one size does not fit all Special Issue: https://www.drugsincontext.com/special_issues/treatment-of-advanced-non-small-cell-lung-cancer-one-size-does-not-fit-all/

Adjuvant crizotinib treatment selected by patient-derived organoids in a patient with stage IIIA adenocarcinoma with novel LRRTM4-ALK fusion: a case report

“…Andrea De Giglio: Targeted therapies against the fusion protein represent the standard of care for advanced ALK -positive NSCLC. The first-generation crizotinib improved survival outcomes and quality of life compared to standard platinum-based chemotherapy ( 13 ). Then, second-generation drugs such as alectinib, brigatinib, and ceritinib have proven their superiority to crizotinib ( 13 ), still representing the first-line standard of care in many countries.…”

Advancements in NSCLC

“… 22 ALK signaling in cancer cells is mainly activated through 3 mechanisms: gene fusion, gene amplification, and activating point mutations. 23 In 2007, Professor Manabu Soda of Japan and colleagues first identified the fusion of ALK with EML4 in non-small cell lung cancer specimens. 24 EML4 can promote the activation of the ALK kinase domain, thereby promoting cell proliferation, ultimately leading to tumor initiation and progression.…”

The expanding scenario of advanced non-small-cell lung cancer between emerging evidence and clinical tasks

“… 2 At the same time, new third-generation TKIs offered encouraging progression-free survival benefits but overall-survival data are still immature. 3 Other than standard platinum-based doublets, the subsequent therapeutical decision should be driven by tissue or blood-based genotyping for novel targeted agents within clinical trials. Treatment of ALK -rearranged disease overcame the first-generation TKI crizotinib.…”

“…Treatment of ALK -rearranged disease overcame the first-generation TKI crizotinib. 3 An appropriate sequential strategy starts with second-generation TKIs alectinib or brigatinib based on affordable clinical results and a good tolerability profile. Lorlatinib represents a suitable subsequent clinical choice for disease progression due to its remarkable efficacy on typical ALK -resistance mutation during second-generation treatment and need of mature survival data as upfront treatment.…”

“…Finally, several phase II trials are promisingly expanding the therapeutic scenario of rare driver alterations amenable to targeted therapy and, recently, the approbation of agnostic drugs reverted the hierarchy between histology and molecular targets. 3 , 5 – 8 …”