The IASLC 2026 Targeted Therapies of Lung Cancer (TTLC) Meeting was held on February 18th. The meeting convened leading experts in thoracic oncology to share the latest breakthroughs in clinical research and targeted therapies.
The IASLC Targeted Therapies of Lung Cancer Meeting 2025 is one of the most engaging meetings summarizing data on new therapies across thoracic malignancies — and this year’s dynamic event was no exception. Held annually, this lung cancer meeting brings together medical oncologists, radiation oncologists, and researchers to summarize data on relevant targets and the drugs directed at them. From early clinical trials to practice-changing approvals, the meeting presenters distill the latest advances in targeted therapies of lung into a focused, high-yield forum. Below is a summary of key highlights from the 2026 IASLC TTLC meeting covering therapies of lung cancer with RET as a focus, complementing a broader overview of current treatment options for RET-positive NSCLC.
Dr. Kamya Sankar: The Future of RET Therapy for NSCLC
Dr. Kamya Sankar, Assistant Professor at Cedars-Sinai Medical Center presented a detailed summary of the latest developments in RET therapies. The presentation outlined the rapid evolution of treatment for RET-positive non-small cell lung cancer (NSCLC), highlighting both major advances and ongoing challenges in the field.
Selective RET inhibitors
Dr. Sankar highlighted the strong responses observed with selective RET inhibitors, selpercatinib and pralsetinib, presenting data from the LIBRETTO-001 and ARROW clinical trials. These studies demonstrated high overall response rates (approximately 64–70%) and durable progression-free survival exceeding 20 months in both treatment-naïve and previously treated patients, echoing findings from RET-focused studies at the 2025 IASLC World Conference. She also emphasized their significant intracranial activity.
She showed some data of other selective RET inhibitor trials, including LIBRETTO-431 and AcceleRET Lung, that were evaluating selective RET inhibitors in the first-line setting compared to chemotherapy and immunotherapy. The results of the LIBRETTO-431 trial support the use of RET inhibitors as preferred frontline therapy, with improved progression-free survival and patient-reported outcomes.
Resistance Mechanisms
Dr. Sankar emphasized the different resistance mechanisms seen in RET patients, among which bypass resistance appears to be particularly common:
- On-target RET resistance: mutations in the RET gene that interfere with drug binding
- Bypass resistance: activation of alternative pathways, including mutations in genes such as KRAS, BRAF or the emergence of other oncogenic fusions (e.g., ALK or NTRK). Other alterations may be included here such as MET amplifications. More info about this here.
Emerging and Next-Generation RET Therapies
Dr. Sankar highlighted some of the new agents for RET that are under investigation in clinical trials:
EP0031 (Ellipses Pharma), currently in Phase II studies, has demonstrated meaningful responses in patients with RET-altered cancers, including NSCLC. In patients previously treated with RET inhibitors, it achieved an overall response rate (ORR) of 42% and a disease control rate (DCR) of around 83%, Responses have also been observed in treatment-naïve patients. Notably, EP0031 has shown encouraging central nervous system (CNS) activity, with some patients achieving complete intracranial responses, consistent with encouraging Phase 1 data on EP0031. More info here and here.
- HA121-28
HA121-28 is a multi-target tyrosine kinase inhibitor that targets RET as well as EGFR and VEGFR2, has shown more modest activity in previously treated RET-positive NSCLC patients, with an ORR of approximately 27% and a median PFS of 5.5 months. This highlights a different therapeutic approach, suggesting that multi-target inhibition may have a role as a way to combat bypass resistance mutation and complements ongoing funded research into resistance mechanisms in RET-driven cancers. More info here.
- Resencatinib (HS-10365)
Resencatinib has been evaluated in Phase 1/2 studies in China and has demonstrated strong efficacy, with ORRs of approximately 80% in previously treated patients and 83% in treatment-naïve patients, along with a disease control rate of around 96%. Reported toxicities include elevated liver enzymes, QTc prolongation, and decreased white blood cell counts, underscoring how next-generation RET inhibitors and combination approaches are expanding options beyond first-generation TKIs. More info here and here.
- SY-5007
SY-5007 has reported strong results. Phase II data from studies in China showed high response rates, with ORRs of ~89% in treatment-naïve patients and ~81% in previously treated patients, and a median PFS of 19.3 months, aligning with RET-focused updates from the 2024 ASCO Annual Meeting on selective RET therapies. More info here and here.
Conclusions
Selective RET inhibitors such as selpercatinib and pralsetinib have become the standard first-line treatment for patients with advanced RET fusion positive NSCLC. Ongoing research is now exploring their use in earlier stages of disease, with the goal of improving long-term outcomes. However, treatment resistance, both on-target and through bypass pathways, remains a significant challenge. While next-generation RET inhibitors are being developed to address on-target resistance, bypass mechanisms continue to limit durability of response. In addition, brain metastases are highly prevalent and represent an ongoing clinical hurdle. Ultimately, the future of RET therapy will depend on developing effective strategies to overcome resistance, including innovative combination approaches that can deliver more durable and comprehensive disease control.
Dr. Jaime Rubio-Perez: Intestinal Lymphangiectasia with Selective RET TKI Therapy
Dr. Jaime Rubio-Perez, Research Fellow from Memorial Sloan Kettering Cancer Center, presented data on intestinal lymphangiectasia (IL), a gastroenteropathy caused by dilation or rupture of the lymphatic vessels. This condition can occur as a side effect of RET therapy and is associated with symptoms such as abdominal pain, nausea, diarrhea, protein loss, and constipation between other symptoms. Dr. Rubio-Perez conducted a retrospective study that included a total of 113 patients with RET-altered NSCLC treated with selective RET TKIs between 2015 and 2025. IL was radiologically identified in 33/110 patients treated with selpercatinib and 1/3 treated with pralsetinib (29.2% of all patients). Interestingly, patients with IL received RET TKIs in later lines (≥3) (p = 0.028) more frequently than those without, but no other differences in clinical and molecular characteristics were observed.
Radiologic features found in all 33 patients with IL including:
- Bowel wall thickening (100%)
- Mesenteric fat stranding and local congestion (42%)
- Nodular protrusions on mucosal folds (11%)
Gastrointestinal symptoms were reported in 66.6% of patients with IL including:
- abdominal pain (42%)
- diarrhea (30%)
- constipation (27%)
- vomiting (21%)
Laboratory findings included:
- hypoalbuminemia (45%)
- hypocalcemia (18%)
Protein loss and third-space fluid accumulation were described in 72.6% of patients and occurred more frequently in those with IL.
Dose reduction or temporary discontinuation of the RET TKI resulted in resolution of findings in 42% of cases (n=14/33 ) with resolution of radiographic findings in 64% of the cases (n=9/14).
Conclusions
IL is a relatively frequent complication of RET TKI therapy, commonly associated with gastrointestinal symptoms and protein loss, highlighting the importance of early detection and individualized management. The data suggest that the incidence rises with increasing time on therapy. Consistent with published reports of drug-induced IL, a definitive diagnosis could not be established in many cases, however, endoscopic biopsies suggest that at a subset of these findings is IL-driven. The mechanism is unknown: potential inflammatory/immune mechanism + VEGFR inhibition. Regardless of etiology, these findings can be reversed with TKI dose modification and/or discontinuation.
The IASLC Targeted Therapies of Lung Cancer meeting continues to serve as an engaging meeting where medical oncologists, radiation oncologists, and researchers come together to summarize data on emerging and established therapies of lung cancer. From early clinical trials of next-generation agents to updated resistance data, the meeting presenters consistently highlight the most clinically relevant targets and the drugs directed at them across thoracic malignancies. This dynamic event reinforces why staying current with this lung cancer meeting – as well as curated RET Lung Cancer Newsletters and expert-led RET Lung Cancer Webinars – is essential for anyone involved in the care of patients with RET-positive and other targetable driver mutations.
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