RWS of Tunlametinib in NRAS-Mutant Advanced Melanoma

This study is a prospective, open-label, multicenter, real-world clinical study designed to evaluate the efficacy and safety of tunlametinib in patients with NRAS-mutant advanced melanoma who have failed prior anti-PD-1/PD-L1 therapy.

The study consists of a screening period (from the subject signing the informed consent form to enrollment, no more than 28 days), a treatment period (treatment discontinuation is defined as the inability to continue treatment for any reason, such as confirmed disease progression per imaging, intolerable toxicity despite dose adjustment, initiation of new anti-tumor therapy, death, or withdrawal for any reason), and treatment completion and follow-up period (including safety visits and survival follow-up).

Subjects' eligibility will be determined based on information collected within 28 days prior to enrollment. Subjects who meet the study criteria will enter the treatment period. This study plans to enroll 110 subjects with NRAS-mutant advanced melanoma:

Tunlametinib will be administered at a dose of 12 mg orally, twice daily, continuously, in 4-week treatment cycles. Study treatment will continue until the occurrence of intolerable toxicity, PD, withdrawal of consent, initiation of new anti-tumor therapy, death, or when the investigator judges the risk outweighs the benefit, or the study is terminated/ends (whichever occurs first). Survival follow-up will continue after treatment discontinuation until the subject's death.

• Dose adjustments for tunlametinib are permitted and must be performed in a stepwise manner.
• In case of intolerance, the 12 mg dose should first be reduced to 9 mg twice daily, and then to 6 mg twice daily.
• Dose re-escalation depends on the specific situation. If tolerability improves significantly after dose reduction due to reasons such as AE intolerance, and the AE leading to dose reduction resolves to ≤ Grade 1 or baseline level, and no other intolerable toxicities occur after at least 6 weeks of treatment at the lower dose level, the previous dose level may be resumed. For example, if the dose is continuously reduced from 12 mg to 6 mg, re-escalation to 9 mg is recommended; re-escalation to 12 mg is generally not recommended.

Imaging assessments for efficacy evaluation will be performed every 8 weeks from the start of treatment, regardless of dose delays. Treatment continues until imaging progression, intolerable toxicity, withdrawal of consent, death, or other situations where the investigator deems treatment should end (whichever occurs first). Imaging evaluation will be based on RECIST 1.1 criteria. For subjects who discontinue treatment without progression, subsequent imaging assessments will be performed every 3 months (±7 days) until disease progression or initiation of other anti-tumor therapies, whichever occurs first. At treatment completion or subject withdrawal, an imaging examination is required if no tumor assessment was performed within the previous 4 weeks. Unscheduled imaging examinations may be performed if disease progression is suspected (e.g., symptom worsening).

Subjects will enter the follow-up period after disease progression. The safety follow-up period is 30 days (±7 days) after the last dose, with a single visit to perform protocol-required examinations including vital signs, laboratory tests, and to assess AEs, concomitant medications, concomitant treatments, and whether new anti-tumor therapy has been initiated.

After the safety follow-up period, subjects enter the survival follow-up period, with visits every 3 months. These visits can be conducted through effective methods such as telephone follow-up to collect survival information and subsequent treatment information. The survival follow-up period continues until subject death, loss to follow-up, withdrawal of consent, or investigator termination of the study.

Inclusion criteria

• Aged ≥18 years (inclusive), male or female;
• Patients with histologically or cytologically confirmed locally advanced or metastatic melanoma;
• Prior genetic testing results showing positive NRAS mutation;
• Patients who have failed prior anti-PD-1/PD-L1 therapy;
• Able to take oral medications;
• Voluntarily participate and sign the informed consent form, expected to have good compliance, and able to cooperate with the study according to the protocol requirements.

Exclusion criteria

• Currently participating in other clinical trials of drugs;
• Patients who are pregnant or breastfeeding;
• Other conditions deemed unsuitable for targeted therapy after multidisciplinary discussion;
• Other conditions considered inappropriate for inclusion by the investigator, such as familial or social factors that may affect the safety of the subject or the collection of data.