Lung cancer is the third-most common occurring malignancy in men and women in Singapore, accounting for 7.7% to 13.7% of all diagnoses in males and females respectively, and nearly a quarter of all cancer-related deaths.
Non-small cell lung cancer (NSCLC) accounts for 85% of all diseases, of which RET fusions have been identified as oncogenic drivers in 1-2% of all NSCLCs. RET fusions are caused by chromosomal rearrangements consisting of the juxtaposition of the C-terminal region of the RET protein with the N-terminal portion of another protein, with KIF5B being the most common rearrangement, accounting for approximately 70% of RET-positive NSCLC cases. RET-fusion positive lung adenocarcinoma is observed more frequently in young, active, female, non-smoking patients, who are more likely to be present with advanced disease involving multiple sites including central nervous system (CNS) metastases. The presence of RET alterations is therefore associated with a poorer prognosis compared to other lung cancer patients.
Patients with alterations in the RET gene have historically had limited targeted treatment options and many with RET-positive NSCLC were initially treated with first-line chemotherapy as molecular testing for RET rearrangements and targeted therapy were the only recent developments that emerged in late 2020. Non-targeted approaches have demonstrated limited benefit in this clinical setting and are associated with high off-target toxicity.
- Real-world data from a global multicentre RET registry (GLORY) found that complete response or partial response was achieved in 51% of patients with advanced RET-rearranged lung cancers who received first-line platinum-based chemotherapy (N=65), with median progression-free survival (PFS) of 7.8 months and overall survival (OS) of 24.8 months.
- Several Phase II trials have investigated the role of multikinase inhibitors i.e. RET non-selective) in this setting, with unsatisfactory clinical outcomes. Notably, the modest efficacy findings were not comparable to outcomes observed with targeted therapy in patients with other targetable alterations such as EGFR and ALK. The GLORY study also investigated the activity of multikinase inhibitors (MKI) as monotherapy in tyrosine kinase inhibitor (TKI)-naïve patients. The MKIs evaluated include cabozantinib (N=21), vandetanib (N=11), sunitinib (N=10) sorafenib (N=2), alectinib (N=2), lenvatinib (N=2), nintedanib (N=2), ponatinib (N=2) and regorafenib (N=1). Efficacy, however, was limited, with responses observed only with cabozantinib, nintedanib, lenvatinib, vandetinib and sunitinib. Median PFS was 2.3 months, and OS was 6.8 months.
- In terms of immunotherapy, there is presently limited data on its use in patients with targetable alterations. Further, RET fusions have been related to a low response to immune checkpoint inhibitors due to a low tumour mutational burden and low level of PD-L1 expression.
Most recently, landmark FDA approvals of the first selective RET inhibitors have revolutionised the RET-positive NSCLC armamentarium, with Pralsetinib (Gavrelto) and selpercatinib (Retevmo) receiving accelerated approvals following promising results in their registrational trials. In Singapore however, regulatory approval remains uncertain as of mid-2022.
- Selpercatinib was the first RET inhibitor to receive accelerated approval from the US FDA in May 2020 for the indication, based on initial objective response rate (ORR) and duration of response (DOR) endpoints from the single-arm, open-label LINRETTO-001 Phase I/II trial. Updated data was recently presented at the European Lung Cancer Congress (ELCC) in April 2022. The updated analysis utilised a June 15, 2021, data cut-off and included 355 patients who were eligible for efficacy analysis. Among 247 patients previously treated with platinum-based chemotherapy, the confirmed ORR was 61.1% (95% CI: 54.-67.2%) and among 69 treatment-naïve patients, the confirmed ORR was 84.1% (95% CI: 73.3-91.8%). Safety findings remained consistent with selpercatinib’s known safety profile. The most common adverse events (≥25% of patients) were dry mouth, diarrhoea, hypertension, increased liver enzymes, peripheral oedema, constipation, rash, headache and fatigue. A global randomized Phase III trial is currently recruiting and will compare selpercatinib treatment with the current standard care (SoC) in the first-line treatment of advanced or metastatic RET fusion-positive NSCLC.
- Pralsetinib was granted accelerated approval by the US FDA in September 2020 for adult patients with metastatic RET fusion-positive NSCLC based on the results of the open-label multi-cohort ARROW trial. As of November 2019, 354 patients with advanced solid tumours had received pralsetinib at a starting dose of 400mg once daily with a median follow-up of 8.8 months. Of the 116 patients with metastatic RET fusion-positive NSCLC, the ORR was 65% (95% CI: 55-73%), the disease control rate (DCR) was 93% (95% CI, 87-97%) and tumour size reduction was observed in 96% of patients. The ORR was similar regardless of RET fusion partner, prior therapies, or central nervous system involvement. Overall, there were 7 (6%) complete responses, 4 (5%) in previously-treated patients and 3 (12%) in treatment-naïve patients; the median time to response overall was 1.8 months and the median duration of response (DOR) was not reached (95% CI, 11.3–NR). In the safety population (n=354), most treatment-related adverse events (TRAEs) were Grade 1-2 and included increased liver enzymes, anaemia, constipation and hypertension.
Pralsetinib was also FDA-approved for use in RET-mutant medullary thyroid cancer (MTC) and radioactive iodine refractory RET fusion-positive thyroid cancer in December 2020. Its thyroid indications are discussed separately.
Currently, RET is 1 of 7 NSCLC biomarkers that can be targeted with an FDA-approved therapy. In avoidance of unnecessary toxicity associated with cytotoxic chemotherapy and ‘broad spectrum’ multikinase inhibitors, selpercatinib and Pralsetinib represent a therapeutic breakthrough for RET fusion-positive NSCLC, long devoid of precision medicine options. However, in the absence of head-to-head trials evaluating the RET inhibitors, the choice of either agent remains largely dependent on access and their differing toxicity profiles. Ongoing Phase III trials for selpercatinib (LIBRETTO-431) and Pralsetinib (AcceleRET Lung) will provide much-needed information regarding the differential activity of these RET inhibitors and further data on their comparative efficacy over the current standard of care.
