MET, RET and NTRK in NSCLC: A new era for targeted therapies

The understanding of molecular alterations in non-small cell lung cancer (NSCLC) has opened the door to new therapeutic strategies that have led to improved outcomes in patients in terms of better survival with decreased toxicity. MET, RET and NTRK are mutations/fusions with an incidence of 3–4%, 1–2% and <1% respectively. Although these mutations are rare, it is essential to identify patients who have them by doing comprehensive oncogene profiling upfront, to ensure that the appropriate therapies are selected.

Mesenchymal epithelial transition (MET) pathway

Under normal conditions, the MET gene is activated by its ligand, hepatocyte growth factor (HGF), and is responsible for embryonic development, cellular survival and wound healing. MET can have many different alterations. MET exon 14 skipping mutation (METex14) is the most common and is generally caused through a gain of function by hundreds of different mechanisms such as gene amplifications, insertions, deletions or overexpression. This leads to activation of downstream signalling pathways which lead to cell proliferation, survival and metastases. Normally, Exon 14 is the key region which prevents oversignalling. METex14 is the specific mutation which leads to a predictive benefit for response to tyrosine kinase inhibitors such as capmatinib, tepotinib and savolitinib. METex14 is usually mutually exclusive and associated with a poorer prognosis, thus it is important to be identified as initiating appropriate targeted therapy improves overall response rates.METex14 has also been identified in patients with epidermal growth factor receptor(EGFR)-positive NSCLC as a mechanism of resistance.

The clinical characteristics of patients with METex14 skipping mutations are not typical compared to the usual population of patients seen with other driver mutations. METex14 occurs more frequently in patients with sarcomatoid type histology (up to 30%). In a retrospective analysis, a large proportion of patients with sarcomatoid histology, compared to adenocarcinoma, had a higher programmed cell death protein 1 (PD-L1) expression, however, a poor and shorter response to immunotherapy. A lower tumour mutational burden is generally seen and perhaps accounts for this. Patients with METex14 also tend to be of older age (median age of 65–76 years), are often smokers and common metastatic sites appear to be lymph nodes (67%), lung (53%), pleura/pericardium or malignant effusions (51%), bone (49%) or brain (37%).

MET inhibitors: crizotinib, capmatinib, tepotinib and savolitinib

There are two types of MET inhibitors, type 1 and type 2, based on where they bind to the MET tyrosine kinase.

Crizotinib, a multikinase TKI, is a non-selective type 1a drug and was the first drug to show activity in MET mutations in PROFILE 1001, a multicohort, open label phase I study. Efficacy of crizotinib (Overall response rate [ORR] 32%) inMETex14 patients paved the way for additional research for MET inhibitors. Specific limitation of crizotinib is its limited central nervous system (CNS) penetrance, as seen in the treatment of other mutations such as ALK.

Capmatinib, tepotinib and savolitinib are selective type 1b drugs that are adenosine triphosphate (ATP) competitors that bind to ATP-binding pocket of the active form and block phosphotransferase activity. They are more specific and potent inhibitors of METex14, which also have good CNS disease control.

Capmatinib was approved for use based on the data from the open-label, multicohort, prospective GEOMETRY mono-1 trial, which was a non-randomised phase II trial that included patients with advanced or metastatic NSCLC and MET dysregulation status, which included METex14 and other MET amplifications. Patients were stratified according to the type of MET mutation and whether they were treatment naïve or not. The biggest benefit for capmatinib was noted in patients that were METex14 treatment naïve (ORR 68%, median duration of response [DoR] of more than one year). In the pre-treated METex14 patients, the ORR was 41%, which is impressive compared to other treatments in the second-line setting.

Capmatinib showed limited activity in patients with MET-amplified NSCLC and a low gene copy number of less than 10. In GEOMETRY mono-1, the incidence of brain metastases in patients with METex14 was 11–23%. Capmatinib showed good efficacy and of the 13 patients included, 7 had responses, of which 4 had a complete response.

The efficacy of tepotinib was shown in the phase II VISION trial that enrolled patients with a confirmed METex14 status. This trial did not include patients with active brain metastases or brain metastases as the only measurable lesion. Patients were analyzed according to the detection of the mutation on either liquid or tissue biopsy. The combined ORR was 46%. This trial also showed durable clinical activity and good correlation between the different types of biopsies. This validates that liquid biopsy is not inferior to tissue biopsy and may also be a viable option to monitor response to therapy. Savolitinib had similar response rates as tepotinib in a single arm phase II study.

MET inhibitors show a very good safety profile with the most frequent side effect being peripheral oedema, which was also the most common reason for discontinuation or dose reduction and interruptions. Peripheral oedema can usually be managed conservatively.

Resistance to type 1 MET inhibitors occurs via two main mechanisms – either on-target or off-target. On-target mutations happen by the development of clones or by mechanisms which cause interference with binding of ATP-binding pocket. The use of type 2 inhibitors such as cabozantinib, merestinib and glesatinib could potentially be considered as they bind differently. Off-target resistance can be very diverse and includes activation of alternate pathway gene amplifications such as acquired KRAS/EGFR/HER3/MAPK or BRAF mutations. The management of patients after developing resistance is not yet clear in the data. A consideration to repeat the biopsy when patients develop disease progression can be advocated for to see if there are possibly alternate targets.

RET pathway

The normal role of RET in the body is in developmental functions. RET mutations are often seen in various other solid tumours such as thyroid carcinomas or patients with MEN2(multiple endocrine neoplasia type 2)-syndromes. RET mutations can cause tumour proliferation, invasion, and migration. In NSCLC, RET are chromosomal rearrangements or fusions between the RET gene and another domain. The most common fusion is between kinesin family member 5B (KIF5; 70–90%) and coiled coil domain containing 6 (CCD6; 10–25%), amongst others. This leads to overexpression of the RET protein and the heterodimerization of ligand co-receptors complexes. RET leads to autophosphorylation and downstream activation of signalling pathways. Like MET, it is usually mutually exclusive. RET fusions can be detected in various methods, but DNA/RNA-based next-generation sequencing (NGS) is the most sensitive. Liquid biopsies are validated as well.

The patient population with RET fusions is more in keeping with what we usually expect in oncogene-addicted NSCLC. Patients are usually younger (mean age 62 years), non-smokers, generally have a better performance status and adenocarcinoma histology. Unlike MET, RET-rearranged tumors usually have low PD-L1 expression but also low tumour mutational burden (TMB) and thus also show poor responses to immune checkpoint inhibitors. Patients with a RET-fusion have a higher risk of metastases to the brain compared to other NSCLC patients.

RET inhibitors: Selpercatinib & pralsetinib

The drugs shown to have activity in RET gene-rearranged NSCLC are selpercatinib and pralsetinib, both highly selective small-molecule inhibitors of RET kinase. They have activity against multiple RET rearrangements and have very good CNS penetrance and activity.

In the LIBRETTO-001 phase I/II study, selpercatinib was shown to have an ORR of 64% in patients with advanced RET-fusion-positive NSCLC who had received prior platinum based chemotherapy, and of 85% in untreated patients with a durable duration of response of up to 17.5 months. LIBRETTO-001 included patients with CNS metastases and showed very high CNS response rates of selpercatinib, 91%.

Pralsetinib showed similar results in the phase I/II ARROW trial, regardless of the fusion partner. ORR was 65%, but slightly higher in patients with no prior systemic treatment (73%). The drugs are very similar, and it is not established if one is better than the other. Patient preference can also be considered in drug choice, as selpercatinib is a twice-daily dose with food and pralsetinib once-daily without food. Both drugs also have an excellent safety profile and patients rarely have discontinuation of therapy. Both drugs have excellent CNS activity. The side effects usually include gastrointestinal abnormalities, liver function derangements and fatigue. Drug-specific side effects are a prolonged QT interval for selpercatinib and interstitial lung disease/pneumonitis for pralsetinib. Resistance to RET inhibitors are reported in patients, but the mechanisms are not well known.

Neurotropic tropomyosin-related kinases (NTRK) pathway

NTRK mutations are exceptionally rare and have an incidence little as 0.2–0.3%. NTRK has a role in neuronal development in utero and post-neuronal differentiation survival and function. It is expressed in higher incidence in many different types of cancers including intrahepatic cholangiocarcinoma, papillary thyroid cancer, glioblastoma, sarcoma, salivary gland cancer and secretory type breast cancers. NTRK genes – NTRK1, NTRK2, NTRK3 –encode the tropomyosin receptor kinases TRKA, TRKB and TRKC respectively. NGS is preferred as it can detect NTRK1/2/3 and multiple fusion partners. In patients with NSCLC harbouring NTRK fusions, no other known oncogenic drivers were identified.

Clinical characteristics of NTRK mutated NSCLC, although evaluated in small numbers, are very young age (median 47.6 years), equal male/female predominance, smokers or non-smokers and usually more advanced stage at presentation. Adenocarcinoma is the most common histological subtype, but NTRK fusions have been documented in different histological subtypes such as squamous carcinoma and adenocarcinoma with neuroendocrine features. Common sites of metastases are lymph nodes, bone, pleura, and lung.

TRK inhibitors: Entrectinib & larotrectinib

The efficacy of pan-TRK inhibitors (entrectinib and larotrectinib) were evaluated in basket trials which included many different types of cancer, thus the numbers for patients with NSCLC are very small. However, the patients who were treated have exceptionally impressive response rates (70–80%) despite many of them having received two or three lines of prior therapy. Patients also experienced durable responses, some of them up to 35 months. Both drugs have good CNS activity, with entrectinib potentially having better CNS penetrance as it has decreased interaction with p-glycoprotein, which is essential in efflux of drugs across the blood-brain barrier.

Entrectinib and larotrectinib are very well tolerated. Toxicities of interest are weight gain and hyperphasia, peri-oral numbness and hyperalgia or pain syndrome when the drug is stopped or withheld. It is important to educate patients about possible adverse event and encourage them to watch their weight. If the drug is stopped, it is important to note that occurring pain is unlikely to be cancer-related.

Resistance to the drugs can occur through on- or off-target cause, such as NTRK gene mutations. More recently it has also been shown that other genomic pathway alterations can be activated. This can usually be overcome with second-generation TRK inhibitors, e.g. investigational agents like selitrectinib and repotrectinib.

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