Reference Detail

Ref Type

Abstract

PMID

Authors

Y-K. Shi Y. Zheng J. Chen X. Yu J. Fang Y. Liu D. Huang T. Liu H. Shen S. Luo H. Yu Y. Cao X. Zhang

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Annals of Oncology	34	Supplement 2	October 2023	S790

URL

https://www.annalsofoncology.org/article/S0923-7534(23)03248-9/fulltext

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600X	colorectal cancer	predicted - sensitive	Tunlametinib + Vemurafenib	Phase I	Actionable	In a Phase I trial, the combination of Tunlametinib (HL-085) and Zelboraf (vemurafenib) demonstrated safety and resulted in an objective response rate of 25.0% (6/24), a median duration of response of 5.5 months, and a median progression free survival of 6.2 months in patients with advanced colorectal cancer harboring a BRAF V600 mutation (Ann Oncol (2023) 34 (suppl_2): S790; NCT03781219).	detail...
BRAF V600X	lung non-small cell carcinoma	predicted - sensitive	Tunlametinib + Vemurafenib	Phase I	Actionable	In a Phase I trial, the combination of Tunlametinib (HL-085) and Zelboraf (vemurafenib) demonstrated safety and resulted in an objective response rate of 60.6% (20/33), a median duration of response of 11.3 months, and a median progression free survival of 11.7 months in patients with advanced non-small cell lung cancer harboring a BRAF V600 mutation (Ann Oncol (2023) 34 (suppl_2): S790; NCT03781219).	detail...