Research

RET Studies Presented at the IASLC 2025 World Conference on Lung Cancer

By September 12, 2025March 2nd, 2026No Comments

The 2025 IASLC World Conference on Lung Cancer was held in Barcelona, Spain, from September 6–9, where some important studies on RET were presented.

P3.03.12 

YAP-Driven Modulation of HER3-Mediated Adaptive Resistance to RET Inhibitors in RET-Altered Cancer

Tadaaki Yamada

This study investigates mechanisms of resistance to RET tyrosine kinase inhibitors (RET-TKIs) in RET-altered cancers, particularly lung and thyroid cancers harboring RET fusions or mutations. 

This study showed that adaptive resistance to RET TKIs emerges via reactivation of ERK signaling mediated by HER3 activation following RET-TKI treatment. YAP, a key Hippo pathway effector, is translocated to the nucleus upon RET inhibition, driving HER3 gene expression and thus enabling ERK reactivation and resistance. Cell lines with high YAP expression display reduced sensitivity to RET-TKIs, whereas YAP knockdown suppresses proliferation, suggesting YAP as a potential biomarker for RET-TKI responsiveness.

Importantly, combining the pan-HER inhibitor afatinib with selpercatinib effectively suppresses ERK reactivation and cell proliferation in RET-TKI resistant, YAP-high cancer cells in vitro and in vivo. This combination therapy shows superior tumor control compared to single agents.

Clinical analysis of 23 RET-positive non-small cell lung cancer patients treated with selpercatinib indicates that low intratumoral cytoplasmic YAP expression correlates with longer progression-free and overall survival, supporting YAP’s role as a predictive biomarker.

In conclusion, YAP-driven HER3 activation constitutes a key adaptive resistance mechanism to RET-TKIs. Early combination therapy targeting both RET and HER3 pathways may overcome resistance, and assessing tumor YAP levels can guide treatment stratification for improved outcomes in RET-altered cancers.

 

P3.03.49

Mechanisms of Resistance to Tyrosine Kinase Inhibitors in Lung Cancer Cells Harbouring RET Fusions

Eva Pros

In this study, researchers created RET-fusion lung cancer cells that became resistant to RET inhibitors using 2 RET cancer cell lines: LC-2 and PDC6. They found that in these cell lines, resistance arise mainly from the activation of other growth pathways (AKT, ERK, mTOR) or the development of new mutations in KRAS or NRAS genes. Some cells also developed a brand-new gene fusion that helped them survive.

These results show that RET-positive lung cancers often escape treatment by turning on backup pathways, meaning combination therapies will likely be needed to block resistance and improve outcomes.

 

P3.12.06 

Pralsetinib (Phase 1/2 ARROW Trial) Compared With Best Available Therapy (External Control) in Pretreated RET Fusion+ NSCLC

Domenico Galetta

This study compares the outcomes of pralsetinib, to best available therapy (BAT) (tyrosine kinase inhibitors (e.g., cabozantinib, vandetanib) and chemotherapy) in patients with previously treated, advanced RET fusion-positive lung cancer, using data from the Phase 1/2 ARROW trial and a real-world (RW) external control cohort. 

Key findings:

  • Objective response rate (ORR) was significantly higher with pralsetinib (61.4%) than BAT (25.9%). 
  • Median progression-free survival (PFS) was 16.8 months for pralsetinib versus 3.5 months for BAT. 
  • Median overall survival (OS) was not reached in the pralsetinib group but was 9.1 months in the RW cohort, with 12-month survival rates of 74.6% versus 58.4%.

Limitations: The study had a small real-world comparison group and some differences between patient groups.

In conclusion, pralsetinib demonstrated superior efficacy over BAT as second-line or later therapy in RET fusion-positive NSCLC, with higher response rates, and significantly improved progression-free and overall survival, supporting its use in this population following prior treatment.

 

P3.12.36 

Multicenter Retrospective Study of Selpercatinib Treatment for Advanced or Recurrent RET Fusion-Positive NSCLC in Japan

Yasuhiro Mihashi

This multicenter retrospective cohort study in Japan evaluated the effectiveness and safety of selpercatinib in 27 patients with advanced or recurrent RET fusion-positive lung cancer. 

Key findings:

  • Overall objective response rate (ORR) of 78% (21/27 patients). 
  • ORRs were 80% in the previously treated group and 76% in the treatment-naïve group. 
  • Median progression-free survival (mPFS) was 23.5 months overall, with treatment-naïve patients showing a longer mPFS (23.5 months) compared to previously treated patients (13.3 months).
  • Median overall survival (mOS) was not reached, with 1-year OS rates around 88%.

Regarding safety, grade 3 liver enzyme elevation (ALT increase) occurred in 41% of patients, indicating a higher incidence of severe liver dysfunction compared to global clinical trials (LIBRETTO-001 and LIBRETTO-431). This suggests that Japanese patients may experience more pronounced hepatic adverse events from selpercatinib.

In summary, selpercatinib demonstrated high efficacy in Japanese patients with RET fusion-positive NSCLC regardless of prior treatment or PD-L1 status. However, increased liver toxicity highlights the need for careful monitoring in this population. These findings support selpercatinib as a valuable treatment option while emphasizing the importance of managing adverse events in real-world Japanese clinical settings.

 

P3.12.58

Initial Results From Phase 1/2 Study of the RET-Selective Inhibitor Vepafestinib in Patients With RET-Aberrant Solid Tumors

Kiyotaka Yoh

RET-altered cancers have limited treatment options beyond existing selective RET inhibitors. Vepafestinib (TAS0953/HM06), a new RET-selective inhibitor, is being tested in the ongoing phase 1/2 MARGARET trial (NCT04683250).

As of November 2024, 32 patients were treated in dose escalation and 14 in dose expansion. The maximum tolerated dose was determined to be 500 mg twice daily after dose-limiting toxicities at higher levels. The most common side effects were headache, nausea, and malaise, mostly mild to moderate.

Early signals of antitumor activity were observed: in dose escalation, partial responses were seen in both RET-inhibitor–naïve and pretreated patients with lung and thyroid cancers. In dose expansion, partial responses occurred in 2 of 4 treatment-naïve patients and 3 of 10 pretreated patients, with disease control rates of 50% and 80%, respectively.

Conclusion: Vepafestinib was generally well tolerated and showed promising early activity in both untreated and RET inhibitor–resistant patients, supporting further study.

 

P3.12.71

Efficacy and Safety of Pralsetinib in Patients With Advanced Ret Fusion-Positive NSCLC: Phase 1/2 ARROW Study Final Data

Aaron Mansfield

The phase 1/2 ARROW trial evaluated pralsetinib, a selective RET inhibitor, in patients with RET fusion–positive NSCLC. A total of 281 patients received pralsetinib 400 mg daily, with a median treatment duration of nearly 15 months.

Key findings:

  • Overall response rate (ORR): 70.3% (median duration of response 19.1 months)
  • Progression-free survival (PFS): 13.1 months
  • Overall survival (OS): 44.3 months with almost 4 years of follow-up
  • In the overall population, ORR, median DOR, and median PFS were higher in the US vs. Asia or Europe.
  • Responses were especially strong in patients <65 years (median duration of response 22.6 months)
  • Safety: 95% experienced treatment-related side effects, most commonly elevated liver enzymes, anemia, and hypertension; 66% had grade ≥3 events; 3 deaths were attributed to treatment-related causes. Importantly, no new safety concerns emerged.

Conclusion: Pralsetinib achieved durable, clinically meaningful responses in RET fusion lung cancer across treatment settings, with a manageable safety profile, confirming its role as a standard therapy option.

 

P3.18.63 

Phase 1 Study of FHND5071, a Novel Selective RET Inhibitor, in RET Fusion-Positive Advanced NSCLC

Dechuang Yuan

FHND5071 is a new oral, selective RET inhibitor designed to achieve strong tumor and brain penetration, with preclinical studies showing up to 28× higher tumor exposure and 33× higher brain levels compared to selpercatinib. These properties support its potential for central nervous system (CNS) activity.

In the ongoing phase 1 trial (NCT05818917), 48 patients with advanced RET fusion–positive NSCLC were enrolled (29% with brain metastases; 77% previously treated). Patients received FHND5071 once daily (40–400 mg) in dose escalation or expansion cohorts. One patient did not receive treatment, leaving 47 in the ITT population.

Key findings:

  • Overall response rate (ORR): 68.1% (median duration of response not reached)
  • Progression-free survival (PFS): not reached
  • 4 patients with measurable brain metastases. All of them achieved brain metastases shrinkage. The CNS Overall response rate (ORR) reached 100%.
  • Manageable safety profile

Conclusion: FHND5071 demonstrated robust activity in both systemic disease and brain metastases. Clinical outcomes and safety results are still being evaluated.

 

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