Neoadjuvant Tebentafusp in Patients With Metastatic Uveal Melanoma

1. RACIONAL Tebentafusp has demonstrated efficacy and safety and is indicated as monotherapy for the treatment of adult patients with human leukocyte antigen (HLA)-A\*02:01-positive unresectable or metastatic uveal melanoma. The main hypothesis is that neoadjuvant treatment with Tebentafusp could achieve ≥20% pathological complete response (pCR) in patients with metastatic uveal melanoma with resectable or potentially resectable liver metastasis and absence of extrahepatic disease. 2. OBJECTIVES Primary Objective: to evaluate the ability of tebentafusp used as a single agent to generate pathological complete responses (pCR) in patients with metastatic uveal melanoma with resectable / potentially resectable liver metastases and absence of extrahepatic disease. Secondary objectives: to assess efficacy and safety of tebentafusp used as a single agent to maintain disease control and delay relapse / progression. Exploratory objectives: * Study mechanisms of resistance to tebentafusp. * Study correlation between pathological response and circulating tumor DNA (ctDNA) dynamics or circulating tumor cells (CTCs). * Evaluate dynamics in T-cell receptor (TCR) populations and peripheral lymphocytes memory cells in blood samples before/after Tebentafusp and in the prospective fresh samples from liver resections. 3. Primary Endpoint The primary endpoint for NEO-TB trial is the pathological complete response (pCR) rate, defined as no presence of residual disease assessed by biopsy or surgical resection at 7 months (+/-1 month) after the start of the scheduled treatment with tebentafusp. 4. Secondary Endpoints * Objective response rate (ORR) according to RECIST 1.1 * Disease control rate (DCR) according to RECIST 1.1 * Relapse-free survival (RFS) according to RECIST 1.1 * Event-free survival (EFS) * Overall survival (OS) * Adverse events (AE) * Treatment-related AEs (TRAEs) * Molecular biomarkers determined from liver biopsies at baseline and fresh samples from liver resections in lesions with viable tumors and samples of peripheral blood. 5. Study Design NEO-TB is a non-randomized, single arm, multi-centre, phase II study of Tebentafusp monotherapy in subjects with resectable / potentially resectable disease within the liver and absence of extra-liver disease. The Neo-TB study is divided into 4 phases: Screening, Treatment, Surgery and Follow-up. After informed consent is obtained, subjects will enter the Treatment phase. All patients will undergo periodic tumor assessments by CT or MRI scan every 8 weeks ± 7 days from the start of study treatment and during the first 48 weeks of study. Tumor assessments will be performed every 12 weeks ± 7 days thereafter until relapse or patient withdrawal. After surgery, CT or MRI scans will be performed every 12 weeks ± 7 days thereafter, regardless of time after study inclusion. Further CT/MRI scans could be performed upon suspicion of disease relapse according to standard clinical practice and physician criteria. The study includes the collection of tumor and blood samples for the determination of exploratory endpoints 6. Study Population The trial will enroll 19 patients; male and female, ≥ 18 years, with ECOG PS 0-1 patients with metastatic uveal melanoma (HLA)-A\*02:01 positive who have resectable or potentially resectable metastatic lesions only in the liver. Patients with extrahepatic disease are not eligible. Patients will have not received previously other anti-tumor treatments. 7. Study Treatment Patients will receive tebentafusp intravenously (IV) weekly for 6 months with liver directed imaging every 2 months to identify rapid progressors. Rapid progressors will discontinue tebentafusp and have surgical resection if considered feasible. After 6 months, patients with complete response (CR) according to RECIST will continue tebentafusp therapy (surgery might be an option if deem appropriate by local PI); while patients achieving partial response or stable disease will be evaluated for tumor resection and will enter into Surgery phase. Surgery will be conducted 7 months (+/- 1 month). If PD occurs earlier surgery can happen earlier. After surgery, patients without pCR or R0 surgery will maintain tebentafusp until disease relapse, unacceptable toxicity or patient withdrawal. Patients with pCR and R0 will continue tebentafusp therapy for 1 additional year or until disease relapse, unacceptable toxicity or patient withdrawal 8. Ethical Considerations Patients with metastatic uveal melanoma have limited therapeutic options. Clinical guidelines recommend considering clinical trials. Tebentafusp is approved for use as monotherapy in patients with uveal melanoma whose tumors are positive for (HLA)-A\*02:01. In the phase 3 clinical trial, tebentafusp showed a significant improvement in overall survival compared to other standard therapies and therefore it is considered the treatment of choice for patients with (HLA)-A\*02:01 positive tumors. NEO-TB aims to use tebentafusp in the pathology for which it is indicated, with the only modification of combining its administration with surgical resection in patients already or potentially candidates for surgery, aiming to evaluate the pathological response. The guidelines also allow this multimodal treatment strategy with tebentafusp and surgery, so the trial could in some way consider the proposed intervention as low impact. Patients will be closely monitored, following an adaptive strategy to allow surgery if necessary, avoiding delays that limit tumor resection. Tebentafusp is the standard therapy for these patients, so its administration in the context of this trial is not expected to increase the risks already described associated with this treatment. Given the mechanism of action of tebentafusp, an increase in its toxicity due to the combination with surgery is not expected. Immunotherapies in combination with surgery are used in the perioperative setting as neoadjuvant and adjuvant strategies in patients with cutaneous melanoma and are safe. However, there is no published data with patients treated with tebentafusp in this context. Given the limited therapeutic options and the current evidence and rationale for the use of tebentafusp and surgery, the risk-benefit ratio of this trial is considered positive. The potential benefit outweighs the risks