The ASCO Annual Meeting 2025, held in Chicago, brought together oncology experts, researchers, and pharma leaders to discuss the latest advancements in clinical oncology.
Here are the RET lung cancer studies that were presented at the meeting this year.
Final results of a phase 1 study of EP0031, a next generation selective RET inhibitor (SRI) in patients with SRI naïve or pretreated advanced RET-altered tumors
Guzman Alonso. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
Ellipses’ next generation selective RET inhibitor EP0031 is a new specific RET inhibitor with broad activity against common RET fusions and mutations, including RET mutations that confer resistance to the RET inhibitors selpercatinib or pralsetinib and great brain penetration. It has been granted US Food and Drug Administration Orphan Drug and Fast Track Designation.
Final data from patients in the US and Europe was presented at the ASCO 2025 conference. In this study, a total of 40 patients were enrolled across dose cohorts (Most of them had lung cancer (NSCLC, 22 patients)), but over 400 patients have received EP0031 globally.
Among 40 treated patients, 32 were evaluable for response. 24 evaluable patients were previously treated with other RET inhibitors and 8 were naive patients (new to RET treatment).
Among patients previously treated with other RET inhibitors:
- 14 evaluable RET lung cancer patients: 5 patients had confirmed partial response and 5 had stable disease. Overall response rate was 42% and disease control rate was 83%.
- 7 evaluable RET thyroid cancer patients (MTC): 2 had partial response and 2 had stable disease. Duration of response was 6.5 – 9.6 months range.
- 3 evaluable other solid RET tumors the median duration of treatment was in the 1.7 – 3.9 months range.
- 2 non-evaluable patients due to having no measurable disease included a NSCLC patient who had stable disease for 16 weeks and a papillary thyroid carcinoma patient with stable disease for 36 weeks.
Among naive patients (new to RET treatment):
- 2 evaluable RET lung cancer patients: 1 had a complete response and 1 had a partial tumor response.
- 5 evaluable MTC patients: 4 patients had partial response and 1 patient had stable disease.
Brain lesions:
- Among patients previously treated with other RET inhibitors, 3 of 4 evaluable patients with brain lesions had complete resolution of the lesions.
- Among naive patients, 1 patient with brain lesions had complete resolution of the lesions
EP0031 demonstrated an acceptable safety and tolerability profile. Most treatment related side effects were manageable with temporary dose interruption (40% of the cases) and reductions (20%). Treatment related side effects leading to discontinuation was 2.5%.
Conclusions: EP0031-101 demonstrated promising safety and efficacy in a Phase 1 dose escalation and expansion trial, over long durations of treatment. It shows evidence of deep and durable responses in NSCLC regardless of exposure to prior treatment including selpercatinib and pralsetinib. Efficacy extends to patients with brain metastases, with complete resolution in several patients. It also demonstrates encouraging efficacy in other RET driven tumor types such as MTC. Phase 2 trials continue to evaluate EP0031 in the US, Europe, UAE and China.
Rechallenge with first-generation RET inhibitors in RET-rearranged NSCLC pre-treated with selpercatinib or pralsetinib: Results from the RET MAP registry
Arianna Marinello. Cancer Medicine Department, Gustave Roussy
The RET MAP registry is an international, multicenter, retrospective study collecting genomic and clinical information from patients with NSCLC harboring a RET fusion who were diagnosed between February 2012 and April 2022. In this study, investigators examine the efficacy and safety of rechallenging RET NSCLC patients (continuing with the same RET inhibitor or switching the treatment to other same class RET inhibitor as single agent or in combination) who had previously progressed on selpercatinib or pralsetinib.
Out of 369 people who were treated with a first-generation RET inhibitor (selpercatinib or pralsetinib), about 38 people) were treated again with a drug from the same class later on, after their cancer progressed or they had to stop the original drug. The most common reason for stopping the first RET drug was cancer progression (71%). The rest stopped due to side effects (29%).
The same agent was maintained in 63% of the patients and in 27% of cases, doctors switched to a different first-generation RET drug. Most patients with progression received the RET drug alone (52%), while some had it combined with other targeted therapies (33%) or with chemotherapy (15%).
- For patients who got a second RET drug alone after progression, the overall response rate was 18% and the median progression free survival was 2.14 months.
- For those who got a second RET drug with other targeted treatments for bypass RET inhibitor resistance, the overall response rate was 38% and the median progression free survival was 4 months.
- For patients who had to stop the first RET drug due to toxicity and were later given a different RET drug, the overall response rate was 50% and the median progression free survival was 9.89 months. But 3 out of 11 of these patients developed toxicity again.
Conclusions: Rechallenge a different RET inhibitor of the same class is effective after initial discontinuation due to toxicity, though recurrent toxicity may occur in one-third of patients. In contrast, RET inhibitor rechallenge after progression demonstrates limited efficacy, primarily in selected cases treated with combination therapies.
First-in-human phase I/II study of BYS10 in patients (pts) with locally advanced or metastatic RET-altered solid tumors: Preliminary dose escalation results
Jie Wang, CAMS Key Laboratory of Translational Research on Lung Cancer, Cancer Hospital, Chinese Academy of Medical Sciences
BYS10 is a highly potent and RET-specific inhibitor that overcomes common RET resistant mutations (V804 and G810 mutations).
A total of 51 pts were enrolled in the study. In 40 evaluable patients, the confirmed overall response rate (ORR) and disease control rate (DCR) were 62.5% and 85% respectively. In the 30 evaluable patients with RET-fusion NSCLC, the overall response rate (ORR) and disease control rate (DCR) were 60% and 80 respectively. Intracranial antitumor activity was observed by investigators in 4 pts with at least 1 measurable intracranial lesion (one intracranial complete response).
Treatment related adverse events occurred in all subjects, the most common were: liver-related changes (high liver enzymes (AST in 64%, ALT in 58%) and high bilirubin (45%)), blood issues (low white blood cells (43%) and low neutrophils (33%)), and other lab changes (high uric acid (31%), low albumin (26%), and high creatinine (24%)). Other common symptoms included high blood pressure (29%) and headaches (24%). More serious side effects (moderate to severe, or grade 3 or 4) happened in some people, including: high AST (26%), high ALT (14%), High blood pressure (10%). Serious adverse events were recorded in 7 pts.
Conclusions: BYS10 showed preliminary antitumor activity in patients with RET-altered NSCLC. The study is still ongoing.
Efficacy and safety of pralsetinib in patients with advanced RET-fusion-positive NSCLC: Final data from the phase 1/2 ARROW study.
Gilberto Lopes. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Final results of the phase 1/2 ARROW (NCT03037385) study testing pralsetinib, a highly potent selective RET inhibitor for metastatic RET-altered NSCLC were presented.
281 patients with RET-fusion-positive NSCLC received pralsetinib with a median duration of treatment of 14.95 months. The overall response rate was 70% and median duration of response was 19.1 months. The median overall survival was 44.3 months. Median progression free survival was 13.1 months. The overall response rate and median progression free survival were markedly higher in the US (25.9 months, n=64) vs. Asia (12.6 months, n=122) or Europe (12.9 months, n=95).
Nearly all patients (95%) had some side effects from the treatment, and about two-thirds (66%) had more serious ones (moderate to severe). The most common side effects were:
- High liver enzymes (AST in 46% and ALT in 35% of patients)
- Anemia (low red blood cells) in 43%
- High blood pressure in 27%
3 patients died from treatment-related complications:
- 2 from pneumonia
- 1 from lung inflammation (interstitial lung disease)
- 1 from severe muscle breakdown (rhabdomyolysis).
However, no new or unexpected safety issues were found in this update.
Conclusions: Pralsetinib produced clinically meaningful and durable responses in patients with RET-fusion-positive NSCLC (regardless of prior therapies) with a manageable safety profile, confirming with this longer follow up previously published results.
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