Luvometinib in Combination With Serplulimab for NF2-Related Tumors

NF2-related schwannomatosis (NF2-SWN) is a rare autosomal dominant disorder characterized by multiple central nervous system tumors, most commonly vestibular schwannomas and meningiomas. Although current treatments such as surgery and radiotherapy can provide disease control, they are not curative and are associated with cumulative neurological morbidity and potential risk of secondary malignancies. There remains a significant unmet need for effective systemic therapies.

This investigator-initiated study is conducted as a substudy within the Platform Research for Innovative Medicines in NF2-SWN (PRIME-NF2). The trial evaluates luvometinib in combination with serplulimab in patients with progressive NF2-SWN.

Luvometinib (FCN-159) is a selective MEK1/2 inhibitor with antitumor activity in NF1-associated tumors. Serplulimab (HLX10) is an anti-PD-1 monoclonal antibody approved for multiple solid tumors. Preclinical evidence suggests that MEK inhibition may enhance tumor immunogenicity and synergize with immune checkpoint blockade.

The study aims to assess the safety, tolerability, and preliminary efficacy of this combination in NF2-SWN.

• Luvometinib (Drug), also known as FCN-159: Oral once daily per predetermined dosage per protocol.
• Serplulimab (Drug), also known as HLX10: Intravenous infusion per predetermined dosage per protocol.

Primary outcomes

• Objective Response Rate (ORR) or Hearing Response Rate (HRR) [12 months]: Vestibular schwannoma: HRR is defined as WRS improvement exceeding the 95% critical difference from baseline; if baseline WRS is <20%, HRR is defined as a PTA decrease of at least 10 dB. Meningioma: ORR is defined as at least a 20% reduction in target tumor volume from baseline.

Secondary outcomes

• Incidence of Adverse Events [From first dose through 30 days after last dose (up to 12 months)]: Percentage of participants who experience at least one adverse event. Adverse events will be coded and graded according to NCI CTCAE v5.0.
• Maximum Severity Grade of Adverse Events [From first dose through 30 days after last dose (up to 12 months)]: Maximum NCI CTCAE v5.0 grade of adverse events experienced by each participant during the reporting period.
• Incidence of Serious Adverse Events [From first dose through 30 days after last dose (up to 12 months)]: Percentage of participants who experience at least one serious adverse event.
• Incidence of Dose Modifications [From first dose through 30 days after last dose (up to 12 months)]: Percentage of participants who require at least one dose modification due to an adverse event.
• Incidence of Treatment Interruptions [From first dose through 30 days after last dose.]: Percentage of participants who require at least one treatment interruption due to an adverse event.
• Incidence of Treatment Discontinuations [From first dose through 30 days after last dose.]: Percentage of participants who discontinue study treatment due to an adverse event.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Participants must meet the diagnostic criteria for NF2-SWN.
2. Presence of at least one measurable target tumor, either vestibular schwannoma or meningioma, with MRI-documented volumetric progression within the past 36 months or clinical symptom progression related to the target tumor.
3. The target tumor is considered unsuitable for surgery because of high risk.
4. Age >=18 years at the time of screening.
5. KPS >=70 or ECOG performance status 0 or 1.
6. Adequate organ function based on laboratory tests obtained within 14 days before screening.
7. Participant must be able to understand the study and voluntarily sign informed consent.

Exclusion Criteria:

1. Pregnant, planning to become pregnant, or currently breastfeeding.
2. Participation in another interventional clinical trial within the past 4 weeks, or radiation therapy to target lesion(s) within the past 3 years.
3. Severe adverse reactions or intolerable toxicity from prior immune checkpoint inhibitors or MEK inhibitors.
4. Concomitant active malignancies, uncontrolled infections, or active autoimmune diseases.
5. Severe cardiac, hepatic, renal, gastrointestinal, or ophthalmic diseases.
6. Any other factor that may compromise participant safety or study integrity.