A400/EP0031 NDA Accepted for Review in China for RET Fusion–Positive NSCLC

A new drug application (NDA) seeking the approval of A400/EP0031 (also known as KL590586) in adult patients with RET fusion–positive, locally advanced or metastatic non–small cell lung cancer (NSCLC) has been accepted for review by the National Medical Products Administration of China.1

The NDA is supported by findings from two phase 2 cohorts of the KL400-I/II-01 study (NCT05265091). When the RET kinase inhibitor was given at a once-daily dose of 90 mg, it was found to have manageable tolerability and show early efficacy in patients with pretreated and treatment-naive NSCLC, including those with brain metastases or who had prior exposure to immunotherapy. The primary efficacy end points for both cohorts were met, according to Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.

“We are pleased to report positive results from the clinical study of A400/EP0031 in treating RET fusion–positive NSCLC, which gives us confidence in its future clinical potential. As a tumor agnostic precision therapy, A400/EP0031 represents our significant strategic positioning in the solid tumor field,” Michael Ge, chief executive officer of Kelun-Biotech, stated in a news release. “We look forward to working closely with regulatory authorities to expedite the review process for A400/EP0031, bringing this innovative therapy to patients with RET fusion–positive NSCLC as soon as possible.”

What Is A400/EP0031? What Is the Rationale for Development of Next-Generation Selective RET Inhibitors?

A400/EP0031 is a potent next-generation brain-penetrant selective RET inhibitor (SRI) that has demonstrated activity against acquired resistance mutations to first-generation SRIs.2 Preclinical data have shown that the agent was 93-fold more selective for RET than VEGFR2, 10-fold more selective for RET than JAK1, and 22-fold more selective for RET than JAK2.3

A400/EP0031 also demonstrated a greater potency against common and resistant mutations vs first-generation SRIs such as selpercatinib (Retevmo) and pralsetinib (Gavreto). Moreover, the agent demonstrated greater efficacy compared with first-generation SRIs in a G810R patient xenograft model, and better exposure and survival than those products in an intracranial tumor xenograft model.

What Did the Phase 1 KL400-I/II-01 Study Examine?

The phase 1 dose-escalation and -expansion study enrolled patients with locally advanced or metastatic solid tumors harboring RET alterations. These patients were at least 18 years of age, had an ECOG performance status of 0 or 1, and an expected survival time of at least 3 months. A400/EP0031 was evaluated at the following once-daily dose levels: 10 mg (n = 1), 20 mg (n = 3), 40 mg (n = 3), 60 mg (n = 3), 90 mg (n = 3), and 120 mg (n = 6).

The 60- (n = 23) and 90-mg (n = 67) dose levels were selected for exploration in expansion cohorts. Of those who received the agent at 60 mg once daily, 21 had NSCLC and 5 had medullary thyroid cancer (MTC). Of those who received the once-daily 90-mg dose, 48 had NSCLC, 19 had MTC, and 3 had pancreatic or ovarian cancer.

What Data With A400/EP0031 Have Previously Been Reported?

Across all tumor types and doses ranging from 40 mg to 120 mg once daily, the agent elicited an objective response rate (ORR) of 60% with a disease control rate (DCR) of 94%. In those who specifically received the agent at the 90-mg dose, the ORR was 63% and the DCR was 95%. In those who were treatment naive (n = 26), the ORR was 80.8% (95% CI, 60.7%-93.5%), which comprised a complete response (CR) rate of 1% and a partial response (PR) rate of 20%; the DCR was 96.2% (95% CI, 80.4%-99.9%). In those who received prior treatment (n = 33), the ORR was 69.7% (95% CI, 51.3%-84.4%), which comprised a CR rate of 1% and a PR rate of 22%; the DCR was 97.0% (95% CI, 84.2%-99.9%).

Responses were also noted to be durable, with a median duration of response (DOR) that was not yet reached. Specifically, 71% of 76 evaluable patients remained on treatment, with the longest on-treatment duration running beyond 14.5 months.

Notably, the drug was found to have activity against intracranial metastases; the majority of patients who had baseline intracranial target lesions (n = 5/6) experienced intracranial responses. Moreover, 100% tumor shrinkage was noted in 3 patients.

In terms of safety, no dose-limiting toxicities were reported. Most patients experienced a treatment-related adverse effect (TRAE; 94.5%), although the majority were grade 1 or 2 in severity. The only grade 3 TRAE that occurred in 2% or more of patients was anemia. Additionally, toxicities led to dose interruptions, reductions, and discontinuations for 36.7%, 6.4%, and 2.8% of patients, respectively.

What Were the Preliminary Safety and Efficacy Data With A400/EP0031 in RET-Mutant Medullary Thyroid Cancer?

Data presented at the 2025 ASCO Annual Meeting shed light on the use of the RET inhibitor in patients with RET-mutant MTC enrolled on the trial (n = 25).2 At a median follow-up of 23.7 months (95% CI, 21.8-27.1), the agent induced a confirmed ORR of 66.7% and had a DCR of 100%. The median DOR was not reached (NR; 95% CI, 7.4-not evaluable [NE]), and the median progression-free survival was also NR (95% CI, 22.1-NE). Additionally, the 24-month PFS rate was 67.8% (95% CI, 45.1%-82.7%).

Regarding safety, all patients experienced TRAEs and 22.2% of cases were grade 3 or higher. Serious TRAEs were observed in 7.4% of patients. TRAEs resulted in dose reductions for 59.3% of patients and dose interruptions for 66.7% of patients. The most common TRAEs included increased alanine aminotransferase level (any grade, 77.8%; grade ≥ 3; 7.4%), increased aspartate aminotransferase level(70.4%; 3.7%), headache (48.1%; 0%), increased blood creatine phosphokinase (40.7%; 0%), hyperuricemia (37.0%; 0%), increased blood lactate dehydrogenase (37.0%; 0%), anemia (37.0%; 0%), hypertriglyceridemia (33.3%; 3.7%), xerophthalmia (33.3%; 3.7%), and blurred vision (33.3%; 3.7%).

Has A400/EP0031 Received Prior Designations?

In March 2024, the FDA granted fast track designation to A400/EP0031 for use as a potential therapeutic option in patients with RET fusion–positive NSCLC.4 In November 2023, the RET inhibitor also received orphan drug designation from the FDA for the treatment of RET fusion–positive solid tumors.5

References

1. Kelun-Biotech’s new drug application for its novel next-generation selective RET inhibitor A400/EP0031 accepted for review by the NMPA for the treatment of RET-fusion positive NSCLC. News release. Sichuan Kelun-Biotech Biopharmaceutical Co, Ltd. September 22, 2025. Accessed September 25, 2025. https://www.prnewswire.com/news-releases/kelun-biotechs-new-drug-application-for-its-novel-next-generation-selective-ret-inhibitor-a400ep0031-accepted-for-review-by-the-nmpa-for-the-treatment-of-ret-fusion-positive-nsclc-302563729.html
2. Zhou Q, Wu Y-L, Zheng X, et al. A phase I study of KL590586, a next-generation selective RET inhibitor, in patients with RET-altered solid tumors. J Clin Oncol. 2023;41(suppl 16):3007. doi:10.1200/JCO.2023.41.16_suppl.3007
3. Zheng X, Wu Y-L, Zhou Q, et al. Results from a phase I study of KL590586 in patients with advanced RET-mutant medullary thyroid cancer. J Clin Oncol. 2025;43(suppl 16):6098. doi:10.1200/JCO.2025.43.16_suppl.6098
4. Ellipses’ next generation selective RET inhibitor EP0031/A400 granted fast track designation by FDA. News release. Ellipses Pharma. Accessed September 25, 2025. https://ellipses.life/ellipses-next-generation-selective-ret-inhibitor-ep0031-a400-granted-fast-track-designation-by-fda/
5. Kelun-Biotech announced that A400/EP0031 has been granted orphan drug designation from the US Food and Drug Administration by ex-China partner Ellipses Pharma. News release. November 27, 2023. Accessed September 25, 2025. https://en.kelun-biotech.com/newsCenter.aspx?mid=18&sv=A400/EP0031%20#search_top_table