Uveal Melanoma: Emerging Therapies

Educational Objectives

The goal of this program is to improve management of uveal melanoma (UM). After hearing and assimilating this program, the clinician will be better able to:

1. Explain data regarding effectiveness of melphalan and Hepatic Delivery System in metastatic UM.
2. Follow guided treatment of tumors in UM provided by the Collaborative Ocular Melanoma Study.

Summary

Uveal melanoma (UM): effective treatments include enucleation (100% local control) and radiotherapy (RT; eg, plaque brachytherapy); however, metastatic UM (mUM) remains a concern

mUM: recently, the US Food and Drug Administration has approved 2 new therapies for mUM; melphalan and Hepatic Delivery System — the melphalan liver-directed hepatic artery infusion for unresectable hepatic metastasis (no extrahepatic disease) involves cannulation of the hepatic vasculature and isolated perfusion of the liver; the FOCUS trial (Zager et al [2024]) showed an objective response rate (RR) of 31%, with complete remission in ≈7% of patients; progression-free survival was >65%; tebentafusp — a bispecific T-cell redirection therapy; targets gp100-positive melanoma cells and activates gp100-specific and native T cells; a human leukocyte antigen-restricted therapy (limits the treated patient population); in a trial, overall survival was statistically significant with tebentafusp compared with investigator’s choice, with a reduction in circulating tumor DNA (a marker of benefit)

Management of UM: evidence from the Collaborative Ocular Melanoma Study (Margo [2004]) guides the treatment of small, medium, and large tumors; small tumors are managed by observation and RT; medium-sized tumors are managed by RT; large tumors are mostly managed by enucleation; limitations of UM management include delay in initiation of RT because of observation, radiation retinopathy, and vision loss in small tumors and radiation retinopathy, vision loss, and loss of the eye in medium and large tumors; use of RT has increased as a globe-sparing option

Belzupacap sarotalocan (bel-sar): a highly targeted antitumor treatment and a first-in-cancer molecule; bel-sar is an inactivated papillomavirus, delivered by intravitreal injection (IVTI) or suprachoroidal injection (SCI); dual mechanism of action — after the virus-like drug conjugate (bel-sar) attaches to the heparan sulfate proteoglycans on the tumor surface, activation by a 689 nm light source induces direct tumor cell necrosis; the release of neoantigens primes the immune system and provides long-term immunosurveillance and immune-mediated tumor cell killing; the phase 1b/2 trial used IVTI to treat small tumors; SCI — has the potential to treat small- and medium-sized tumors and allows maximizing bioavailability; a phase 3 trial that treats indeterminate lesions and small choroidal melanoma (showing active growth) is ongoing; results from the phase 2 trial with SCI showed good tumor control rates (≈90%) with the highest-dose regimen; safety signals were reduced with SCI compared with IVTI; the aforementioned phase 3 trial involves 2:1:2 (high dose: low dose: sham control) randomization, with composite end points (tumor control and vision loss)

Adjuvant and neoadjuvant therapy: after definitive surgery, adjuvant chemotherapy is administered to eradicate micrometastatic disease; neoadjuvant chemotherapy intends to shrink a large tumor before definitive treatment (may be altered), which may be followed by adjuvant therapy

Darovasertib: a protein kinase C (PKC) inhibitor; mutations in GNAQ and GNA11 active PKC signaling, which regulates RAF, MEK, and ERK pathways; in clinical trials, darovasertib produced ≈50% reduction in tumors as first-line treatment in mUM; in a phase 2 trial that compared darovasertib plus crizotinib (DC) vs standard of care (immune checkpoint inhibitors), DC produced good tumor response; overall RR was 45% in the DC group; in some patients, a reduction in size of the primary tumor was observed with DC; neoadjuvant darovasertib — in a phase 2 trial (NCT05907954) in patients with UM scheduled for enucleation, darovasertib produced a reduction in size of the tumor and enucleation was no longer indicated (preliminary results); in patients with mUM, the primary tumor improved with darovasertib; the trial consisted of a large tumor arm and a medium tumor arm; in the large tumor arm, the neoadjuvant darovasertib was followed by primary local therapy (eg, RT) and, if required, adjuvant therapy; in the medium tumor arm, patients who were scheduled for brachytherapy were administered neoadjuvant darovasertib; a reduction in tumor size allowed for reduction in radiation dose and toxicity

Questions and Answers

Sham control: in small tumors, the risk for metastasis is very low; patients are closely monitored, and adequate treatment may be initiated if the tumor progresses

Readings

Brănişteanu DE, Porumb-Andrese E, Porumb V, et al. New treatment horizons in uveal and cutaneous melanoma. Life (Basel). 2023;13(8):1666. doi:10.3390/life13081666; Cao L, Chen S, Sun R, et al. Darovasertib, a novel treatment for metastatic uveal melanoma. Front Pharmacol. 2023;14:1232787. doi:10.3389/fphar.2023.1232787; Honavar SG. Is Collaborative Ocular Melanoma Study (COMS) still relevant?. Indian Journal of Ophthalmology. 2018;66(10):1385. doi:10.4103/ijo.IJO_1588_18; Margo CE. The Collaborative Ocular Melanoma Study: an overview. Cancer Control. 2004;11(5):304-309. doi:10.1177/107327480401100504; McCannel TA, Bhavsar A, Capone A, et al. Two year results of a phase 1b/2 open-label clinical trial of AU-011 for the treatment of small to medium choroidal melanoma. Investigative Ophthalmology & Visual Science. 2019;60(9):719; Nathan P, Hassel JC, Rutkowski P, et al. Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med. 2021;385(13):1196-1206. doi:10.1056/NEJMoa2103485; Plasseraud KM, Wilkinson JK, Oelschlager KM, et al. Gene expression profiling in uveal melanoma: technical reliability and correlation of molecular class with pathologic characteristics. Diagn Pathol. 2017;12(1):59. doi:10.1186/s13000-017-0650-3; Sen M, Demirci H, Honavar SG. Targeted therapy in ophthalmic oncology: The current status. Asia Pac J Ophthalmol (Phila). 2024;13(2):100062. doi:10.1016/j.apjo.2024.100062; Synoradzki KJ, Paduszyńska N, Solnik M, et al. From molecular biology to novel immunotherapies and nanomedicine in uveal melanoma. Curr Oncol. 2024;31(2):778-800. doi:10.3390/curroncol31020058; Zager JS, Orloff M, Ferrucci PF, et al. Efficacy and safety of the melphalan/Hepatic Delivery System in patients with unresectable metastatic uveal melanoma: results from an open-label, single-arm, multicenter phase 3 study. Ann Surg Oncol. Published online May 4, 2024. doi:10.1245/s10434-024-15293-x.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Mruthyunjaya is a consultant for Aura Biosciences. Members of the planning committee reported nothing relevant to disclose. Dr. Mruthyunjaya's lecture includes information related to the off-label or investigational use of a product, therapy, or device.

Acknowledgements

Dr. Mruthyunjaya was recorded at the Ohio Ocular Oncology Symposium, held September 23-24, 2023, in Cleveland, OH, and presented by the Cleveland Clinic Foundation. For more information about upcoming CME activities from this presenter, please visit www.clevelandclinicmeded.com. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0.75 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0.75 CE contact hours.

Lecture ID:

OP621701

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.