Response-adapted Luvometinib With or Without Cytarabine in Langerhans Cell Histiocytosis

Objective response rate after six cycles of luvometinib induction by blinded independent central review

Proportion of full analysis set participants achieving complete metabolic response (CMR) or partial metabolic response (PMR) by PET response criteria at the cycle 6 assessment window (target C7D1 +/- 7 days), as determined by blinded independent central review. No subsequent confirmatory PET/CT is required. The analysis is descriptive and will report the point estimate with an exact two-sided 95% confidence interval; no confirmatory hypothesis test is planned. Mild out-of-window assessments may be included with protocol deviation documentation if no major treatment or disease-status change affects interpretation. Clearly out-of-window, non-evaluable, or unreliable assessments, death, progression, treatment discontinuation due to toxicity, withdrawal from study treatment, or non-evaluable imaging before the cycle 6 assessment are counted as non-responders.

Incidence of adverse events and serious adverse events

AEs, TRAEs, grade \>=3 AEs, SAEs, deaths, and clinically significant laboratory abnormalities summarized by NCI-CTCAE v5.0 and MedDRA SOC/PT. All AEs after informed consent will be recorded; treatment-emergent summaries will start at first study treatment and be summarized by actual exposure period, including luvometinib monotherapy, luvometinib plus cytarabine, and post-progression or salvage treatment descriptions as applicable. SAEs, study-related AEs, pregnancy, and important safety information after study treatment discontinuation may be followed during continued follow-up unless follow-up consent is withdrawn.

Kaplan-Meier estimated progression-free survival rate at 24 months

Kaplan-Meier estimated proportion of participants without PRC-defined PMD, investigator-confirmed clinical progression supported by clinically performed imaging or documentation after study treatment discontinuation, or death from any cause. Clinically performed data may be used to record PFS progression events but are not included in ORR/DCR/CBR endpoint analyses. Such PFS events may be investigator-adjudicated, with BICR review or audit when feasible; if BICR review is not feasible, the source, assessment date, adjudicator, rationale, and reason will be documented. A sensitivity analysis will include only BICR-confirmed progression, protocol-window imaging-confirmed progression meeting PRC/BICR requirements, or death from any cause.

Time to response among CMR/PMR responders

Time from first dose to first documented CMR or PMR. TTR will be calculated only for participants who achieve CMR or PMR. SMD is not considered a response for TTR; if SMD precedes later PMR/CMR, TTR is measured from first dose to first documented PMR/CMR. Participants with SMD only are not assigned a TTR value.

Kaplan-Meier estimated overall survival rate at 12 and 24 months

Kaplan-Meier estimated survival rate from first dose to death from any cause. Participants who transition to combination treatment, receive salvage therapy, or discontinue study treatment remain in survival follow-up unless follow-up consent is withdrawn.

Objective response rate at cycles 12, 18, and 24

Proportion of evaluable participants achieving CMR or PMR by PRC/BICR at the cycle 12, 18, and 24 assessment windows. Later ORR is summarized descriptively using the evaluable response set at each time point; the FAS denominator, number evaluable, and reasons for missing or non-evaluable assessments will also be reported. These later visits evaluate durability and subsequent response patterns and do not confirm the primary ORR endpoint.

Duration of response among CMR/PMR responders

Duration of response will be analyzed among responders only, defined as participants who achieve CMR or PMR. DOR is measured from the first documented CMR/PMR to first documented PMD or death from any cause; responders without progression or death will be censored at the date of last evaluable disease assessment. SMD is not considered a response for DOR; if SMD precedes later PMR/CMR, DOR starts at the first documented PMR/CMR. Participants with SMD only are not included in the DOR analysis.

Spearman Correlation Between Changes in MAPK VAF in cfDNA and peripheral blood cell DNA

Change from baseline in the proportion of MAPK pathway variant allele fraction (VAF) in plasma cell-free DNA (cfDNA) and peripheral blood cell DNA, including tumor-derived cfDNA (ctDNA) when detectable, with Spearman's rank correlation coefficient calculated between these proportional changes. These biomarkers will not independently determine treatment assignment or response assessment. After study treatment discontinuation, additional research cfDNA testing is not mandatory; clinically performed or voluntarily completed relevant testing may be recorded descriptively and will not be included in protocol-defined efficacy endpoint analyses unless it occurs within a protocol-defined window and meets applicable protocol requirements.

Spearman Correlation Coefficient for Changes in MAPK VAF in cfDNA/Peripheral Blood Cell DNA and SUVmax change

Spearman's rank correlation coefficient between change from baseline in MAPK pathway VAF in plasma cfDNA/peripheral blood cell DNA and change from baseline in SUVmax of target lesions. Exploratory only, not for treatment assignment or response assessment.

Quality-of-life scores (adults)

EORTC QLQ-C30 for adults