1378P - Efficacy and safety of tunlametinib (HL-085) combined with vemurafenib in patients with advanced BRAF V600-mutated solid tumors: A multicenter, phase I study

Background

Addition of a MEK inhibitor to a BRAF inhibitor enhances tumour growth inhibition, delays acquired resistance of the MAPK pathway in BRAF V600-mutated cancers. We assessed the safety and efficacy of tunlametinib (HL-085), a novel highly selective MEK1/2 inhibitor, in combination with vemurafenib in patients(pts) with advanced BRAF-mutated solid tumors.

Methods

In this phase I study, pts with advanced solid tumors who had progressed on or shown intolerance to standard treatment were enrolled and received escalating doses of tunlametinib combined with vemurafenib in dose-escalation phase (followed a 3 + 3 design). Patients received tunlametinib at dose levels of 0.5, 6, 9, 12, and 15 mg BID, together with vemurafenib 960 mg BID, in 21-day cycles. In dose-expansion phase, tunlametinib 12mg + vemurafenib 960mg, tunlametinib 12mg + vemurafenib 720mg and tunlametinib 9mg + vemurafenib 720mg dose groups were evaluated. The tunlametinib 9mg + vemurafenib 720mg was determined as the recommended phase 2 dose (RP2D).

Results

As of the data cut-off date on 04, Nov, 2022, a total of 72 pts with solid tumors were enrolled. The most common AE were CK elevation, anemia and rash which were predominantly grade 1/2. 33 pts with non-small cell lung cancer (NSCLC) have been evaluated for response. The objective response rate (ORR) was 60.6% (95%CI: 42.1%, 77.1%), a median duration of response (DoR) was 11.3 months (95% CI: 3.9, NE), and a median progression free survival (PFS) was 11.7 months (95% CI: 5.6, NE) . At the RP2D, ORR was 60.0% (95%CI: 32.3%, 83.7%) and mPFS was 10.4 months (95% CI: 5.6, NE). 24 pts with metastatic colorectal cancer (mCRC) at all doses, ORR was 25.0% (95%CI: 9.8%, 46.7%), mDoR was 5.5 months (95% CI: 2.9, NE), and mPFS was 6.2 months (95% CI: 4.8, 7.6). Antitumor activity was also seen in papillary thyroid carcinoma and pancreatic ductal adenocarcinoma.

Conclusions

Tunlametinib in combination with vemurafenib showed promising antitumor activity and manageable safety profile in pts with BRAF V600-mutated solid tumors. Further studies are ongoing.

Clinical trial identification

NCT03781219.

Editorial acknowledgement

Legal entity responsible for the study

Shanghai Kechow Pharma, Inc.

Funding

Shanghai Kechow Pharma, Inc.

Disclosure

All authors have declared no conflicts of interest.