On January 28, the European Commission approved lorlatinib as monotherapy for the treatment of adult patients with ALK-positive advanced NSCLC, confirming the growing importance of the biomarker in the treatment of lung cancer.

The ALK (anaplastic lymphoma kinase) gene encodes for a transmembrane tyrosine kinase receptor. It is physiologically expressed in the nervous system during embryogenesis and subsequently silenced in adult tissues.
In addition to the development of the nervous system, ALK plays an important role in the regulation of cell growth, differentiation and transformation.

Several ALK gene alterations have been identified; fusions between the 5’ portion of a partner gene containing the promoter and the 3’ region of ALK encoding the kinase domain are the most common mutations. These translocations lead to the constitutive activation of the ALK chimeric protein and multiple downstream signalling pathways, resulting in increased cell proliferation and survival.
ALK rearrangements were identified in many different cancers, prevalently lung adenocarcinoma, non-small cell lung cancer (NSCLC), inflammatory myofibroblastic tumour (IMT) and pancreatic adenocarcinoma.

In the NSCLC, where ALK translocations are found in approximately 5% of patients, over 90 different fusion partner genes have been identified.
Generally, ALK translocations are mutually exclusive with mutations in other oncogenic drivers of NSCLC. However, some studies report some degree of overlap between ALK rearrangements and mutations in KRAS or EGFR.
Patients with ALK-positive NSCLC show the following clinicopathological characteristics: young age at diagnosis (50 years or less), female gender, non-smokers/light smokers, histology of adenocarcinoma, tendency to metastasize in pleura or pericardium and often in the central nervous system (CNS).

NSCLC harbouring ALK rearrangements is very sensitive to ALK tyrosine kinase inhibitors (ALK TKI).
Crizotinib was the first ALK TKI to be approved for use in advanced ALK-positive NSCLC, after phase III clinical trials demonstrated its superiority over chemotherapy in this patient setting. However, poor central nervous system penetrance with high incidence of relapse in the brain and acquired resistance with the appearance of secondary ALK mutations have favoured the development and use of second-generation ALK inhibitors. Ceritinib, alectinib and brigatinib have provided not only an increased progression-free survival (PFS) and overall survival (OS) in comparison with chemotherapy, but also an increased CNS activity. These ALK inhibitors, initially used after progression on crizotinib, then have been approved in the first line, where they demonstrated to be highly active.

The need to further improve CNS activity and to target the acquired resistance mutations of ALK, that arise in more than half of patients treated with second-generation ALK inhibitors, has led to the development of lorlatinib.

Lorlatinib is a reversible highly potent inhibitor of ALK and ROS1 kinases, capable of overcoming multiple ALK resistance mutations and penetrating the blood-brain barrier. Already approved by the European Commission on June 2019 for the treatment of ALK-positive NSCLC patients in progression after therapy with other ALK inhibitors, lorlatinib demonstrated improved objective response rate (ORR): 90% in ALK+ treatment-naïve patients, 69.5% in those who had progressed on crizotinib, 32.1% in patients in progression on second-generation ALK TKIs. Moreover, an intracranial response was seen in 87% of patients treated prior with crizotinib alone and in 55.6% of patients who received second-generation ALK TKI.

On January 28, lorlatinib was approved by the European Commission for the first-line treatment as monotherapy of adult patients with ALK-positive advanced NSCLC previously not treated with an ALK inhibitor.
The approval was based on the results of the Phase III CROWN clinical trial, in which lorlatinib reduced the risk of disease progression or death by 72% compared to crizotinib. The confirmed objective response rate (ORR) was 76%. Moreover, 82% of patients with brain metastases experienced an intracranial response, which was complete in 71% of cases. CROWN is an open-label, parallel 2-arm trial in which 296 people with previously untreated advanced ALK-positive NSCLC were randomised 1:1 to receive lorlatinib monotherapy or crizotinib monotherapy.

Given the progress in ALK inhibition and its impact on patient survival and quality of life, it is extremely important to identify any ALK rearrangement in NSCLC.
The analysis of ALK gene translocations can be performed with different methods, the most common are: fluorescent in situ hybridization (FISH), immunohistochemistry (IHC), Real Time RT-PCR and Next Generation Sequencing (NGS).

Diatech Pharmacogenetics offers complete solutions for the detection of ALK fusion variants based on Real Time RT-PCR and NGS. Learn more here.

 

References

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  2. Friedlaender A, Banna G, Patel S, Addeo A. Diagnosis and Treatment of ALK Aberrations in Metastatic NSCLC. Curr Treat Options Oncol. 2019 Sep 4;20(10):79.
  3. ALK Fusion – My Cancer Genome.
  4. Ou SI, Zhu VW, Nagasaka M. Catalog of 5′ Fusion Partners in ALK-positive NSCLC Circa 2020. JTO Clin Res Rep. 2020 Feb 19;1(1):100015.
  5. Gainor JF, Varghese AM, Ou SH, Kabraji S, Awad MM, Katayama R, Pawlak A, Mino-Kenudson M, Yeap BY, Riely GJ, Iafrate AJ, Arcila ME, Ladanyi M, Engelman JA, Dias-Santagata D, Shaw AT. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res. 2013 Aug 1;19(15):4273-81.
  6. Patcas A, Chis AF, Militaru CF, Bordea IR, Rajnoveanu R, Coza OF, Hanna R, Tiberiu T, Todea DA. An insight into lung cancer: a comprehensive review exploring ALK TKI and mechanisms of resistance. Bosn J Basic Med Sci. 2022 Feb 1;22(1):1-13.
  7. Choo JR, Soo RA. Lorlatinib for the treatment of ALK-positive metastatic non-small cell lung cancer. Expert Rev Anticancer Ther. 2020 Apr;20(4):233-240.
  8. Pfizer Press Release, January 28, 2022. European Commission Approves LORVIQUA® (lorlatinib) as a First-Line Treatment for ALK-Positive Advanced Lung Cancer.
  9. Shaw AT, Bauer TM, de Marinis F, Felip E, Goto Y, Liu G, Mazieres J, Kim DW, Mok T, Polli A, Thurm H, Calella AM, Peltz G, Solomon BJ; CROWN Trial Investigators. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. N Engl J Med. 2020 Nov 19;383(21):2018-2029.