HA121-28 Shows Promising Efficacy in Advanced RET Fusion+ NSCLC

The observed safety profile of HA121-28 was similar to that of other multi-targeted RET tyrosine kinase inhibitors.

HA121-28, a multikinase inhibitor targeting RET fusions and VEGFR-2, showed promising efficacy in patients with advanced RET fusion-positive non–small cell lung cancer (NSCLC), according to findings from an open-label, single-arm phase 1/2 trial (NCT03994484; NCT05117658) published in Signal Transduction and Targeted Therapy.¹

Across the phase 1/2 trial, 97 patients with RET fusion-positive NSCLC received at least 450 mg of HA121-28 and were evaluable for efficacy. The confirmed objective response rate (ORR) in this patient population was 26.8% (95% CI, 18.3%-36.8%) per investigator assessment. All responses were partial responses (PRs), and the disease control rate (DCR) was 72.2% (95% CI, 62.1%-80.8%).

Additionally, among patients with CCDC6-RET fusions, the confirmed ORR per investigator assessment was 46.7% (95% CI, 21.3%-73.4%), and the median duration of response (DOR) was 14.0 months (95% CI, 5.8-not estimable [NE]). Furthermore, those with KIF5B-RET fusions had an investigator-assessed ORR of 25.4% (95% CI, 15.8%-37.1%) and a median DOR of 7.7 months (95% CI, 3.7-NE).

The median progression-free survival (PFS) in this patient cohort was 5.5 months (95% CI, 3.8-7.6), including 14.9 months (95% CI, 6.5-NE) among those with CCDC6-RET fusions and 5.5 months (95% CI, 3.6-7.0) in patients with KIF5B-RET fusions. ORR was generally similar across patient subgroups, with numerically higher ORR in patients younger than 60 (30.9%), those with an ECOG performance status score of 0 (35.5%), and those with liver metastases (37.5%).

“[O]ur results demonstrated that HA121-28 was tolerated across the dose range of 25 [to] 600 mg in patients who had advanced solid tumors,” Dan-Yun Ruan, of the Department of Clinical Research of the Sun Yat-sen University Cancer Center in Guangzhou, China, wrote in the publication with study coinvestigators.¹ “HA121-28 demonstrated promising antitumor activity in NSCLC with RET fusion; especially, patients [with CCDC6-RET fusion] showed a numerically higher response, and the cardiac risk associated with HA121-28 should be noted. Further studies are warranted to evaluate HA121-28 and its combination with other active drugs in [patients with] cancer with RET fusion.”

The phase 1 trial enrolled patients ages 18 to 75 years with locally advanced or metastatic histopathologically or cytologically confirmed solid tumors. In the dose-escalation portion, dosing initially started out with single-patient titration at doses of 25 mg and 50 mg of HA121-28, followed by escalation at a 3+3 design, with doses ranging from 100 mg to 800 mg. A dose-expansion portion will seek to assess the safety and efficacy of HA121-28 at the recommended phase 2 dose level assessed during the escalation phase.

The phase 2 trial enrolled patients ages 18 to 75 with locally advanced or metastatic histopathologically or cytologically confirmed NSCLC with documented RET fusions with disease progression following at least 1 previous line of therapy.

Patients in the phase 1 (n = 160) and phase 2 (n = 48) studies had a median age of 54.0 years (IQR, 48.0-61.5) and 53.0 years (IQR, 46.0-60.0). Most patients in both phases were female (53.1% vs 66.7%), had an ECOG performance status score of 1 (73.1% vs 72.9%), and received prior antitumor medication (93.8% vs 100%). The median body mass index in each arm was 23.5 (IQR, 21.3-26.0) and 23.2 (IQR, 20.4-25.6), 13.8% vs 45.8% of patients had brain metastases, and 54.4% vs 22.9% had 3 or more previous lines of systemic treatment.

The primary end point of the phase 2 study was ORR per independent review committee (IRC) assessment.² Secondary end points included investigator-assessed ORR, PFS, overall survival, DCR per IRC and investigator assessment, DOR per IRC and investigator assessment, and safety.

In the phase 1 study, 99.4% of patients experienced at least 1 treatment-emergent adverse effect (TEAE), with 48.8% of patients reporting grade 3 or higher TEAEs. A total of 98.1% of patients reported treatment-related AEs (TRAEs), with grade 3 or higher TRAEs observed in 40.0% of patients.

In the phase 2 trial, all patients reported at least 1 TEAE, with 95.8% reporting at least 1 TRAE. Additionally, 62.5% of patients reported grade 3 or higher TRAEs. Across phases 1 and 2 of the trial, the most common grade 3 or higher TRAEs included prolonged QT interval (15.0% vs 29.2%), diarrhea (6.9% vs 10.4%), rash (5.6% vs 2.1%), and hypokalemia (2.5% vs 6.3%).

References

1. Ruan D-Y, Huang W-W, Li Y, et al. Safety, pharmacokinetics and efficacy of HA121-28 in patients with advanced solid tumors and RET fusion-positive non-small-cell lung cancer: a multicenter, open-label, single-arm phase 1/2 trial. Signal Transduct Target Ther. 2025;10(62). doi:10.1038/s41392-025-02155-5
2. Study of HA121-28 in patients with non-small cell lung cancer. ClinicalTrials.gov. Updated August 4, 2025. Accessed February 28, 2025. https://tinyurl.com/57ab2kju