RET Therapy for NSCLC, a New Generation of Inhibitors

Therapies for NSCLC have evolved over the past 2 decades to account for the specific biology of the tumor and have improved outcomes for a multitude of patients. Discovery of activating mutations in the EGFR gene initiated the transition toward our understanding of driver mutations and the value of targeted therapy in subsets of patients with NSCLC. Previously, it had been demonstrated that a patient with a tumor harboring a driver mutation who received a targeted therapy experienced improved survival on a patient level.¹ A recent analysis shows this improvement in survival has also occurred at a population level, with a decline in lung cancer incidence–based mortality in NSCLC that is due to the introduction of targeted therapies.² Therefore, we have a critical need to provide upfront testing with a comprehensive genomic panel to identify all oncogenic driver mutations that have targeted agents approved by the U.S. Food and Drug Administration (FDA). This leads us to a discussion of RET inhibition as a new therapy for NSCLC. 
 
The RET gene encodes a protein responsible for cell signaling and normal development of neural and genitourinary development, including autonomic responses.³ The RET proto-oncogene was first identified in lung cancer in 2012, and RET fusions occur in 1% to 2% of nonsquamous NSCLC in patients who are predominantly younger and with light or no prior smoking history.⁴ These fusions promote ligand-independent dimerization and downstream pathway activation.⁵ In RET fusions, the tyrosine kinase domain of the 3’ region of the RET gene, and a number of upstream 5’ fusion partners, have been described, including KIF5B, CCDC6, EML4, and NCOA4.^5-8 Co-mutations are common, and the fusion partner may have clinical significance.^9,10RET fusions have also been identified as potential mechanisms of resistance to TKI therapy in EGFR-mutated11 and ALK-altered¹² NSCLC.

Targeted Agents

Multitargeted TKIs were investigated for RET-altered NSCLC, although response rates were modest and with limited duration, and toxicity could be significant.¹³ Subsequently, RET-specific inhibitors have been developed, which have shown great promise for patients with advanced RET gene–rearranged NSCLC. Selpercatinib is the first RET-specific TKI to be approved by the FDA. The LIBRETTO-001 phase 1/2 trial evaluated selpercatinib in RET-altered cancers and demonstrated significant tumor responses across doses and RET alterations.¹⁴ The subset of patients who have NSCLC with RET fusion included 105 patients with advanced disease who had previously received platinum-based doublet chemotherapy and 39 patients who were treatment-naive.¹⁵ The objective response rate (ORR) in the previously treated group was 64% (95% CI [54%-73%]), and responses occurred regardless of prior immune checkpoint inhibition or prior multitargeted TKI therapy; median duration of response was 17.5 months, and PFS was 16.5 months. The ORR in the treatment-naive group was 85% (95% CI [70%-94%]), and the median duration of response and PFS had not been reached at follow-up of 7.4 and 9.2 months, respectively. Eleven of 38 patients with investigator-assessed central nervous system (CNS) metastases had measurable lesions, and objective intracranial response was 91%. The most common grade 3 or 4 adverse events were hypertension, increased transaminases, hyponatremia, and lymphopenia; 30% required dose reduction, whereas 2% discontinued selpercatinib because of toxicity. 

Pralsetinib is another selective RET TKI with impressive results in RET-fusion NSCLC. The ARROW trial was a phase 1/2 study evaluating pralsetinib in patients with RET-altered tumors.¹⁶ Updated results for 92 previously treated patients showed an ORR of 55% (95% CI [45%-66%]), and 29 treatment-naive patients had an ORR of 66% (95% CI [46%-82%]).¹⁷ Responses were seen regardless of prior immune checkpoint inhibitor therapy or RET-fusion partner. The median duration of response in all patients with NSCLC had not been reached. For 9 patients with measurable CNS metastases, intracranial response rate was 56%, and for 3 patients, the treatment achieved a complete response intracranially. Toxicities are similar across the class of specific RET inhibitors, and the most common adverse events (grade 3 and higher) included neutropenia, hypertension, and anemia, with 7% of patients discontinuing because of treatment-related toxicities. These inhibitors have changed the landscape for the treatment of RET-fusion NSCLC and have replaced chemotherapy combinations as frontline therapy for patients with tumors that harbor the alteration.

Multiple resistance mutations have already been reported in preclinical studies and early clinical reports. Cabozantinib therapy has led to a gatekeeper mutation, V804L, whereas solvent front mutations (G810A/S) have been shown with vandetinib and the selective RET inhibitors.^18,19 TPX-0046 is a selective, next-generation RET/SRC inhibitor with structural differences to selpercatinib and prasetinib that leads to inhibition of cell growth in cells with resistance mutations.²⁰ Clinical studies are anticipated. RET is now included on the growing list of genomic alterations in NSCLC that have approved targeted therapies and should be evaluated at the time of diagnosis for patients with advanced disease, since targeted treatments are leading to improved survival, even in the metastatic setting.  

References:

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