A phase 2 study of HLX208, a BRAF^V600E inhibitor, in adult patients with Langerhans cell histiocytosis and/or Erdheim-Chester disease harboring BRAF^V600E mutation.

7574 Background: HLX208 is a novel BRAF V600E inhibitor, exhibiting excellent antitumor efficacy in preclinical studies. This phase 2 study aimed to evaluate the efficacy, safety, and pharmacokinetics of HLX208 in adult patients with Langerhans cell histiocytosis (LCH) and/or Erdheim-Chester disease (ECD) harboring BRAF V600E mutation. Methods: This was a single-arm, open-label, multicenter, phase 2 study. Patients with histologically confirmed LCH and/or ECD were enrolled and received oral administration of HLX208 at 450 mg twice every day. HLX208 was given in 28-day cycles until disease progression, experiencing intolerable toxicity, withdrawal of consent, initiation of new antitumor therapy, or death, whichever occurred first. The primary endpoint was the objective response rate (ORR) assessed by independent review committee (IRC) per PET Response Criteria in Solid Tumors (PERCIST) 1.0. Secondary endpoints included safety, other efficacy measures, and pharmacokinetics of HLX208. Results: As of January 15, 2023, 22 patients with LCH and/or ECD were enrolled. All patients have received at least one dose of HLX208 and were included in the current analysis. The median age was 39 (range 18–69) years. Nine (40.9%) patients were male. 12 (54.5%) patients were diagnosed with LCH, 9 (40.9%) were diagnosed with ECD, and 1 (4.5%) had combined LCH and ECD. 6 (27.3%) patients had single system multifocal disease, while 16 (72.7%) had multisystem disease. The median follow-up duration was 4.8 months (95% CI 2.7–5.7). Among the 10 efficacy evaluable patients, ORR (unconfirmed) assessed by IRC per PERCIST 1.0 was 90.0% (95% CI 55.5–99.7%) (9/10, including 2 complete metabolic response [CMR] and 7 partial metabolic response [PMR]), while that by investigators per PERCIST 1.0 was 100.0% (95% CI 69.2–100.0%) (10/10, including 3 CMR and 7 PMR). Disease control rate was 100.0% (95% CI 69.2–100.0%) as assessed by both IRC and investigators per PERCIST 1.0. The median duration of response, median progression-free survival, and median overall survival were not reached. Of the 22 patients who received the drug, 17 (77.3%) patients experienced treatment-emergent adverse events (TEAEs); 12 (54.5%) reported treatment-related adverse events (TRAEs), most commonly alanine aminotransferase increased (36.4%), aspartate aminotransferase increased (22.7%), γ-glutamyltransferase increased (18.2%), and blood lactate dehydrogenase increased (18.2%). Most TRAEs were grade 1 (27.3%) and 2 (18.2%). Only 2 (9.1%) patients experienced grade ≥3 TRAEs and 1 (4.5%) experienced treatment-related serious adverse event. There were no TEAEs that led to treatment discontinuation or death. Conclusions: In summary, HLX208 was safe and well tolerated, and showed promising efficacy in patients with LCH and/or ECD. Clinical trial information: NCT05092815 .