Editor's Note: Uveal melanoma (UM) is a severe ocular malignant tumor that threatens patients' vision and survival. Despite some progress in treatment methods in recent years, the survival rate of patients has not significantly improved due to the lack of effective drugs, especially those that inhibit metastasis. At the ongoing 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, several rapid oral reports focused on the challenges of UM treatment and presented the latest research findings. Oncology Frontier has compiled relevant studies for readers.01. Phase II Multi-Center Study of Adjuvant Nivolumab in Combination with Ipilimumab in Patients with High-Risk Uveal Melanoma (HCRN MEL17-309)
Background: More than 50% of high-risk uveal melanoma (UM) patients experience distant recurrence within 3 years (median distant metastasis-free survival [DMFS] of 32 months). Currently, there are no effective treatments to reduce the risk of metastatic disease. Patients with metastasis have poor prognosis and limited treatment options. Although the efficacy of nivolumab/ipilimumab (Nivo/Ipi) in metastatic UM patients is limited, preclinical data suggest biological differences between localized and metastatic UM. This prospective, multi-center phase II study (NCT03528408) was conducted to evaluate the efficacy of adjuvant Nivo/Ipi in high-risk UM patients and compare their DMFS with a cohort of UM patients with similar tumor characteristics.
Methods: This investigator-initiated study enrolled high-risk UM patients with a predicted 3-year DMFS rate of approximately 50% (based on gene expression profile [GEP, DecisionDx-UM] class 2, largest basal diameter [LBD] of 12 mm or larger). Patients received Nivo (240 mg, q2w) and Ipi (1 mg/kg, q6w) for up to 48 weeks. The target sample size was 50 evaluable patients. The primary endpoint was 3-year DMFS. Secondary endpoints included median DMFS, overall survival (OS), and toxicity (AEs). A propensity score method was used to estimate the mean DMFS and compare the DMFS between the non-randomized treatment group and control patients. The control cohort consisted of 119 high-risk patients from the Collaborative Ocular Oncology Group (COOG) database, matched based on tumor characteristics (GEP class 2, LBD ≥12 mm).
Results: A total of 52 patients were enrolled, with 50 patients treated between December 18, 2018, and September 29, 2021. As of November 6, 2023, the median follow-up was 36 months. The 3-year DMFS rates for the treatment and COOG control groups were 69.1% and 45.1%, respectively (bilateral P = 0.012), without any adjustments; using the propensity score method, the 3-year DMFS rates were 70.4% vs. 43.4%. The median DMFS was not reached in the treatment group but was 33.8 months in the control group. Nivo/Ipi reduced the risk of distant recurrence compared to the control group (RR 0.52, 95% CI: 0.309-0.888). Seven patients in the treatment group died from UM, with the median OS not reached. Twenty-seven patients (54%) experienced grade 3 or higher AEs of any cause. Forty-eight percent of patients had grade 3 or higher treatment-related AEs (TRAEs). Twenty-two patients (44%) discontinued treatment due to toxicity. One patient died from immune-related myocarditis.
Conclusion: This phase II study demonstrated that adjuvant Nivo/Ipi significantly improved the 3-year DMFS rate (70.4% vs. 43.4%) in high-risk UM patients compared to the COOG database. Further research is needed to confirm the feasibility of this regimen as an adjuvant treatment for high-risk UM.
02. A Phase II Safety and Efficacy Study of Neoadjuvant/Adjuvant Darovasertib for Localized Ocular Melanoma
Background: Darovasertib is a protein kinase C (PKC) inhibitor that has shown meaningful activity in metastatic uveal melanoma (UM) due to its effect on PKC delta downstream of GNAQ/GNA11 mutations. However, its clinical activity in neoadjuvant or adjuvant treatment for localized primary disease has not been evaluated.
Methods: Patients with localized UM scheduled for enucleation were included in an initial safety cohort, receiving Darovasertib 300 mg BID for 1 month (n=3). Following approval by the Data Safety Monitoring Board (DSMB), an expansion cohort at three centers in Australia received up to 6 months of neoadjuvant treatment (n=12), followed by definitive treatment (enucleation, brachytherapy, or external beam radiotherapy [EBRT]). After definitive treatment, all patients received adjuvant Darovasertib for up to 6 months as decided by the investigator. Tumor volume was calculated using the rotational ellipsoid method.
Results: Fifteen patients were enrolled (7 males, 8 females; median age 62 years, range 33-76). Baseline AJCC tumor stages were T3a (n=5), T3b (n=4), T4a (n=4), T4b (n=2), with a median tumor size (maximum thickness/diameter/volume) of 9.7 mm/15.6 mm/2463 mm³. As of data cutoff, 11/15 patients had completed initial treatment, 4/15 were still receiving neoadjuvant treatment, and 6 patients had started adjuvant Darovasertib treatment post-initial UM treatment, with 3 completing the planned 6-month course. After 1 month of treatment, median tumor reduction (maximum height/base/volume change) was 11.2%/7.6%/22.7%, and after 6 months, it was 31.7%/11.9%/45.3%. Six out of nine (66%) patients who completed neoadjuvant treatment converted to brachytherapy (n=5) or EBRT (n=1), with three still ongoing. One patient with high-risk cytogenetic features developed metastatic disease recurrence after 6 months of neoadjuvant and 6 months of adjuvant Darovasertib. Treatment-emergent adverse events (TEAEs) included orthostatic hypotension (grades 1/2: 13%/13%), syncope (grade 3: 13%), rash (grades 1/2: 33%/5%), pruritus (grade 1: 13%), dizziness (grade 1: 27%), fatigue (grades 1/2: 30%/5%), nausea (grades 1/2: 73%/6%), vomiting (grade 1: 40%), and diarrhea (grade 1: 60%).
Conclusion: The NADOM study is the first to demonstrate that a neoadjuvant treatment strategy for UM is feasible, safe, and effective. The results indicate that PKC inhibition with Darovasertib can significantly shrink primary UM tumors initially requiring enucleation, which is clinically meaningful. Ongoing larger trials (NCT05907954) are further quantifying visual and oncological outcomes.
References:
- Suthee Rapisuwon, Richard D. Carvajal, George Ansstas, et al. Phase II multi-center study of adjuvant nivolumab in combination with ipilimumab in patients with high-risk uveal melanoma (HCRN MEL17-309). ASCO 2024; Abstract 9509.
- Anthony M. Joshua, Roderick O’day, William Glasson, et al. A phase 2 safety and efficacy study of neoadjuvant/adjuvant darovasertib for localized ocular melanoma. ASCO 2024; Abstract 9510.
