RET-Fusion NSCLC Clinical Trials — 2026 Pipeline Tracker

Active Phase 2 and Phase 3 trials — RET-fusion NSCLC (March 2026)

The table below reflects key trials targeting RET fusion-positive non-small cell lung cancer registered on ClinicalTrials.gov as of March 2026. With two agents approved (selpercatinib, pralsetinib), current activity focuses on resistance mechanisms, combination strategies, and post-approval real-world evidence generation.

Sources: ClinicalTrials.gov. With two approved agents, many RET-fusion trials have completed or moved to maintenance follow-up. Active drug development is focused on resistance mechanisms and next-generation agents. Table reflects trials with open enrollment or active follow-up as of March 2026.

RET fusions in NSCLC: biology, epidemiology, and clinical context

RET (rearranged during transfection) is a receptor tyrosine kinase with essential roles in kidney development and enteric nervous system formation. In lung cancer, chromosomal rearrangements place the RET kinase domain under constitutive transcriptional control by fusion partner genes, creating an oncogenic driver that activates RAS/MAPK, PI3K/AKT, and JAK/STAT signaling. RET fusions occur in approximately 1–2% of NSCLC cases — roughly 10,000–20,000 new patients per year globally.

The dominant fusion partner in NSCLC is KIF5B (kinesin family member 5B), a motor protein involved in intracellular transport. KIF5B-RET fusions account for approximately 70% of RET+ lung cancers and arise from an inversion or translocation on chromosome 10q. CCDC6-RET accounts for approximately 10–20% of RET+ NSCLC cases; other partners (NCOA4, TRIM33, etc.) are rarer. The KIF5B-RET versus CCDC6-RET distinction has limited clinical significance to date — both respond to selpercatinib and pralsetinib — but may become relevant as next-generation agents with different structural features emerge.

Selpercatinib (Retevmo, Eli Lilly): the current standard

Selpercatinib is a highly selective, ATP-competitive RET kinase inhibitor developed by Loxo Oncology (acquired by Eli Lilly in 2019). It received accelerated FDA approval in May 2020 for RET fusion-positive NSCLC based on LIBRETTO-001 Phase 1/2 data — the first selective RET inhibitor to receive approval — and full FDA approval in September 2022 following confirmatory trial data.

LIBRETTO-431 (NCT04194944): from accelerated to full approval

LIBRETTO-431 was a global Phase 3 randomized trial comparing selpercatinib versus platinum-based chemotherapy (with or without pembrolizumab based on investigator choice) as first-line therapy in RET fusion-positive NSCLC. The trial addressed the regulatory pathway to full approval while also generating the first Phase 3 randomized data in any RET+ NSCLC setting.

The LIBRETTO-431 result was particularly notable because the control arm included pembrolizumab (anti-PD-1) — the backbone of first-line non-oncogene-addicted NSCLC therapy. The fact that selpercatinib significantly outperformed chemo+pembro reinforces the principle established in EGFR+ and ALK+ NSCLC: patients with oncogene-addicted tumors derive minimal benefit from checkpoint inhibitors and should receive targeted therapy first-line.

Pralsetinib (Gavreto, Blueprint Medicines): an alternative approved agent

Pralsetinib received FDA approval in September 2020 for RET fusion-positive NSCLC based on Phase 1/2 ARROW trial data. In previously treated patients, pralsetinib achieved an ORR of 61% with a median duration of response of 16.3 months. In treatment-naive patients, ORR was 70%. Pralsetinib has demonstrated activity against the RET V804M and V804L gatekeeper mutations, which are not effectively inhibited by multikinase RET inhibitors (cabozantinib, vandetanib).

In the competitive landscape, selpercatinib is generally considered the preferred agent — it has longer follow-up data, an approved full label based on a Phase 3 trial, and a cleaner tolerability profile (pralsetinib is associated with higher rates of hypertension and elevated liver enzymes). However, pralsetinib remains a clinically valid option, particularly in settings where selpercatinib is unavailable or not tolerated, and its development continues in combination strategies.

Resistance to selpercatinib: the next drug development frontier

Despite the impressive efficacy of selpercatinib and pralsetinib, acquired resistance is universal. As follow-up matures in the LIBRETTO trials, the landscape of selpercatinib resistance mechanisms is becoming better characterized — and it will drive the next generation of RET-targeted drug development.

G810X mutations: the primary drug development target for post-selpercatinib NSCLC

The G810 position at the RET solvent front is structurally analogous to the G2032 position in ROS1 — both are "gatekeeper-adjacent" residues that provide the dominant resistance mutation for their respective first-generation selective inhibitors. Next-generation RET inhibitors specifically designed to maintain activity against G810R/S/C mutations are in early clinical development, following a design philosophy similar to repotrectinib's development to overcome G2032R in ROS1+ NSCLC.

Several academic and industry programs are in early phase trials targeting G810X-driven selpercatinib resistance. This represents the defining unmet need in RET+ NSCLC drug development for 2026–2028: an approved first-line therapy with excellent outcomes but no standard second-line option for patients who develop on-target resistance.

RET fusions vs. RET mutations: a critical distinction

RET alterations in cancer exist in two distinct categories that require different therapeutic approaches. RET fusions (chromosomal rearrangements creating constitutively active fusion proteins) drive lung cancer and are the subject of this page. RET point mutations (activating substitutions in the kinase domain, ATP-binding pocket, or extracellular domain) are the dominant oncogenic event in medullary thyroid cancer (MTC) — both hereditary (MEN2A/2B) and sporadic forms.

Both selpercatinib and pralsetinib are approved for RET+ NSCLC (fusions) and for RET-mutant MTC (point mutations), reflecting the dual-indication development strategy. However, the clinical management, molecular testing methodology, and resistance landscapes are distinct. Molecular testing in NSCLC uses NGS or FISH to detect chromosomal rearrangements; in thyroid cancer, targeted point mutation panels for the C634, M918T, and other hotspots are used. Pharma BD teams tracking selpercatinib's commercial performance should monitor both indications separately.

Immunotherapy in RET-fusion NSCLC: limited benefit expected

The LIBRETTO-431 control arm included pembrolizumab-based chemoimmunotherapy and was nonetheless statistically inferior to selpercatinib — a result consistent with the broader pattern in oncogene-addicted NSCLC. ALK+ NSCLC trials have similarly shown that checkpoint inhibitors provide limited benefit when tumors harbor a dominant oncogenic driver. The mechanistic explanation is debated but likely involves low tumor mutational burden (RET fusion tumors arise predominantly in never-smokers with few smoking-associated mutations), low neoantigen load, and the possibility that oncogene-driven tumors have less inflammatory tumor microenvironments.

This does not mean immunotherapy combinations are irrelevant in RET+ NSCLC — but it means they are unlikely to improve on front-line selpercatinib monotherapy. More plausible combination opportunities involve targeting resistance bypass pathways (e.g., selpercatinib + MET inhibitor in MET-amplified resistance) or exploiting the immunological changes that accompany RET TKI therapy.

Related clinical trials and monitoring resources

RET-fusion NSCLC is part of the rare fusion-driven NSCLC subgroup. DataLookout monitors related areas including:

• NSCLC clinical trials — full non-small cell lung cancer pipeline, all molecular subgroups
• ALK-positive lung cancer clinical trials — parallel TKI evolution; lorlatinib as current standard with Phase 3 challenge from neladalkib
• ROS1-fusion NSCLC clinical trials — closest structural and clinical analog; shared resistance themes
• EGFR mutant lung cancer clinical trials — largest NSCLC targeted therapy population; most mature TKI resistance literature
• KRAS G12C clinical trials — overlapping NSCLC adenocarcinoma population; mutually exclusive with RET fusions

Frequently asked questions

What is RET-fusion NSCLC?

RET-fusion non-small cell lung cancer is a molecularly defined subgroup (~1–2% of NSCLC) characterized by chromosomal rearrangements creating a constitutively active RET kinase fusion oncogene. KIF5B-RET is the dominant fusion (~70% of cases). Like other fusion-driven NSCLC subgroups (ALK, ROS1), RET+ NSCLC disproportionately affects never-smokers and younger patients, and occurs in adenocarcinoma. Two highly selective RET inhibitors — selpercatinib and pralsetinib — are FDA-approved, with LIBRETTO-431 establishing selpercatinib as the first-line standard of care.

Is selpercatinib better than pralsetinib?

Selpercatinib is generally considered the preferred agent based on more mature data, a Phase 3 randomized trial (LIBRETTO-431), and a somewhat more favorable tolerability profile. However, the two drugs have not been compared head-to-head in a randomized trial. Both are FDA-approved, both achieve ORRs exceeding 60% in previously treated patients, and both cover the V804M/L gatekeeper mutations. The choice between agents may depend on formulary access, tolerability profile, and any specific resistance mutations detected by NGS at the time of treatment.

What is the role of checkpoint inhibitors in RET-fusion NSCLC?

Checkpoint inhibitors (anti-PD-1/PD-L1 agents) have limited efficacy in RET-fusion NSCLC, consistent with the broader pattern in oncogene-driven NSCLC. LIBRETTO-431 demonstrated that selpercatinib significantly outperformed chemo plus pembrolizumab — a regimen that is highly effective in non-driver NSCLC. Current guidelines recommend against combining selective RET inhibitors with checkpoint inhibitors in the front-line setting, due to concerns about overlapping toxicity (hepatotoxicity, pneumonitis) and the absence of additive benefit evidence. RET+ NSCLC patients should receive selpercatinib monotherapy as first-line treatment.