Non-small-cell lung cancer: how to manage RET-positive disease

Abstract

Targeted therapy has dramatically changed the history and outcomes of oncogene-addicted non-small-cell lung cancer (NSCLC). RET rearrangements are typically observed in about 1-2% of NSCLC, resulting in constitutive activation of downstream signalling pathways commonly involved in cell growth and survival. RET-positive NSCLCs are generally associated with young age, non-smoking history, a high rate of brain metastases at diagnosis and an immunologically 'cold' tumour microenvironment. Multi-kinase inhibitors, such as cabozantinib, lenvatinib and vandetanib, showed limited efficacy but significant toxicity mainly linked to off-target effects. In contrast, two RET-selective tyrosine kinase inhibitors (TKIs), selpercatinib and pralsetinib, demonstrated high response rates and manageable safety profiles, and have received FDA approval for the treatment of advanced RET-positive NSCLC regardless of previous lines of treatment. Despite the initial high response rate to RET-TKIs, most patients inevitably develop disease progression due to acquired resistance mechanisms by both on-target or off-target mechanisms. To date, new potent and selective next-generation RET-TKIs are currently being evaluated in ongoing clinical trials in order to overcome resistance and improve efficacy and blood-brain barrier crossing. Genomic recharacterization at progression could help guide treatment choice or enrolment in clinical trials of specific next-generation RET inhibitors. Here, we review the biology, clinicopathological characteristics, targeted therapies and mechanisms of resistance of advanced NSCLC harbouring RET fusions to provide treatment guidance for these patients.

Keywords: RET; next-generation sequencing; non-small-cell lung cancer; pralsetinib; selpercatinib; tyrosine kinase inhibitors.

Figure 1

RET molecular mechanism of activation and corresponding targeted therapies. The RET proto-oncogene encodes a single-pass transmembrane tyrosine kinase normally activated by the interaction with a soluble neurotrophic factor (GDNF, NRTN or ARTN) and requires a co-receptor of the GDNF family receptor-α (GFRα). The complex formed by GDNF–NRTN–ARTN and GFRα binds RET extracellular domain determining heterodimerization and auto-phosphorylation of intracellular tyrosine kinase domains with consequent activation of downstream signalling pathways, including RAS–MAPK, PI3K–AKT, PKC and JAK–STAT. RET rearrangements are the result of the fusion between the C-terminal region of RET and the N-terminal region of partner genes as KIF5B, CCDC6, NCOA4 and others. The resulting chimeric fusion protein lacks the extracellular portion, is constitutively active, and activates downstream signalling pathways with consequent aberrant cell proliferation. AKT, protein kinase B; ARTN, artemin; BRAF, V-Raf murine sarcoma viral oncogene homolog B; ERK, extracellular signal-regulated kinases; GDNF, glial cell line-derived neurotrophic factor; JAK, Janus kinase; KRAS, Kirsten rat sarcoma viral oncogene homolog; MEK, Mitogen-activated and extracellular signal regulated kinase; mTOR, mammalian target of rapamycin; NRTN, neurturin; PI3K, phosphatidylinositol-3-kinase; PKC, protein kinase C; STAT3, signal transducer and activator of transcription 3; TKI, tyrosine kinase inhibitor. Created with BioRender.com

Figure 2

Resistance mechanisms to RET-TKIs. A. On-target mechanisms. Missense mutations can occur in the RET kinase domain conferring resistance to multi-kinase inhibitors (MKI) or tyrosine kinase inhibitors (TKIs). Most of these mutations are located in the Gly-rich loop (L730, E732 and V738), the gatekeeper residue (V804) or the hinge strand (Y806, A807 and G810). In some cases, mutations determine pan-resistance to MKI/TKIs preventing drug binding whereas, in other cases, RET kinase domain mutations (L730V, E732K, A807V, G810A, V871I, M918T, F998V) cause selective resistance to one or more drugs. B. Off-target mechanisms. MET and KRAS amplifications determine resistance to RET by activating downstream signal translation pathways, which stimulate cell proliferation and survival, regardless of MKI/TKIs binding to RET kinase domain. GAB1: Growth factor receptor binding protein 2-associated binding protein 1; SHP2: Src homology-2 domain containing protein tyrosine phosphatase-2; KRAS: Kirsten rat sarcoma viral oncogene homolog; SOS: son of sevenless guanine nucleotide exchange factor; GRB2: growth factor receptor-bound protein 2; BRAF: V-Raf murine sarcoma viral oncogene homolog B; MEK: mitogen-activated and extracellular signal-regulated kinase; ERK: extracellular signal-regulated kinases; PI3K: phosphatidylinositol-3-kinase; AKT: protein kinase B; mTOR: mammalian target of rapamycin; JAK: Janus kinase; STAT3: signal transducer and activator of transcription 3. Created with BioRender.com

Figure 3

Proposed therapeutic algorithms for RET-positive advanced NSCLC. *If not previously administered. RET-selective TKI: pralsetinib or selpercatinib. ICIs: nivolumab or atezolizumab (regardless of PD-L1), or pembrolizumab (if PD-L1 ≥1%). ICIs, immune-checkpoint inhibitors; TKI, tyrosine kinase inhibitor.