<b><i>Background:</i></b> Uveal melanoma (UM) is a rare subtype of melanoma that generally has a poor prognosis once it has metastasized. Clinical trials evaluating immune checkpoint inhibitors (ICIs) in UM have demonstrated response rates lower than those seen in cutaneous melanoma. Despite lower efficacy demonstrated in initial ICI studies, there are a number of ongoing clinical trials investigating novel immunotherapy approaches in UM. <b><i>Summary:</i></b> This review aims to summarize important ongoing clinical trials investigating immunotherapeutic approaches in UM and previous trials that have evaluated a number of immunologic interventions. A thorough clinical trial investigation was conducted through clinicaltrials.gov using the disease search terms “uveal melanoma” and “ocular melanoma,” excluding non-immunotherapy-related trials. Here, we report on ICI, vaccine, adoptive T cells, and combination immunotherapy trials in UM. <b><i>Key Messages:</i></b> There is an increasing effort in the search for new, effective therapies for this difficult-to-treat disease, with immunotherapeutic approaches being of particular interest. Increasing knowledge of UM biology and development of new biomarkers will direct future drug development and trial design.
Tebentafusp is a gp100xCD3-bispecific ImmTAC designed to redirect polyclonal T cells against cells presenting the melanocyte lineage-specific antigen gp100 on HLA-A∗02:01. Skin-related adverse events, predominantly rash, are frequent and occur within a few hours after initial infusions; yet, the mechanisms are unknown. In this study, we analyzed clinical data from the randomized phase 3 trial (NCT03070392) of tebentafusp (n = 252) versus investigator's choice (n = 126). Translational analyses were performed on paired on-treatment skin samples from 19 patients collected in the phase 1 trial (NCT01211262). Our analyses showed that rash is a clinical manifestation of tebentafusp-induced recruitment of T cells to cutaneous melanocytes. Development of rash depended on baseline expression levels of gp100 and other melanin pathway genes in the skin. On treatment, melanocyte number was reduced, and expression of melanocytic genes decreased, whereas gene expression related to immunity and cytokine signaling increased. When adjusted for baseline prognostic features, patients with rash within the first week of tebentafusp treatment had the same overall survival as patients without a rash in the phase 3 randomized trial IMCgp100-202 (hazard ratio = 0.84, 95% confidence interval = 0.53-1.32). In summary, skin rash is an off-tumor, on-target effect of tebentafusp against gp100+ melanocytes, in line with the mechanism of action.
9535 Background: Metastatic UM is associated with a median overall survival (OS) < 1 year (yr) and overall response rate (RR) to ICI < 18%. SF3B1 mut UM represent a clinically unique subset of UM, distinct from BAP1 mut disease, characterized by aberrant spliceosome machinery which may result in increased neoantigen presentation, increased immunogenicity, and sensitivity to ICI. To assess these hypotheses, we performed a multicenter retrospective analysis to assess the natural history and response to ICI in patients (pts) with SF3B1 mut UM. Methods: Patients were identified from institutional databases and the AACR Project GENIE Consortium. Data collected included: baseline and recurrent disease characteristics, molecular characteristics, treatments received, treatment response, and vital status. Efficacy endpoints included investigator assessed RECIST RR and OS. Results: 58 pts with deleterious SF3B1 mutations were identified: 56 R625; 1 D781G; 1 G742D. Median age at diagnosis (dx) was 52 (range, 14-87). 50% were female. 49 pts developed distant metastases. The median time from initial dx to metastasis was 6.1 years (yrs; range, 0.9 to 26.7). Initial metastatic sites (n = 48) were: liver-only (52%); non-liver-only (29%); mixed liver and non-liver disease (19%). The most common initial metastatic sites were: liver (71%), lung (29%), soft tissue (13%), lymph node (8%), and bone (4%). The median OS for all pts from time of metastasis was 3.9 years (95% confidence interval (CI), 2.3-6.2) with OS for pts with non-liver only disease at 6.2 yrs vs those with liver-only or mixed disease at 3.4 yrs (hazard ratio = 2.12, p = 0.14). 1-year OS rate from time of metastasis was 94% (95% CI, 0.86-0.99). 34 pts received ICI for metastatic disease at which time 27% had received a prior systemic therapy (median, 0; range, 0-3) and 35% had received a prior hepatic regional therapy (median, 0; range, 0-6). 15 pts received single-agent anti-PD1; 4 received ipilimumab alone; 15 received dual ICI. 10 pts received ICI with concurrent hepatic regional tx. Best response among 33 evaluable pts were: 9% partial response; 39% stable disease; 52% progressive disease. Median OS from ICI initiation was 20.2 months (95% CI, 13.1-27.4). 1-year OS from ICI initiation was 74% (95% CI, 0.59-0.90). Conclusions: SF3B1 mut UM is characterized by later development of metastases, more common involvement of extrahepatic sites, and longer OS when compared with historical datasets of molecularly unselected UM. Although a modest RR to ICI was observed, the median OS and 1-year survival rate post-ICI are numerically superior to historical controls. Given the more indolent course of SF3B1 mut UM, stratification by SF3B1 status should be included in future clinical trials.
The 2023 Cure Ocular Melanoma (CURE OM) Global Science Meeting was held in Philadelphia on November 6, 2023. There is increased awareness and dedicated research in uveal melanoma (UM), but unmet needs remain in the prevention, detection, and treatment of UM. The purpose of this meeting was to provide an international forum for the exchange of research ideas, to allow for discussion of basic science as well as clinical research on UM, and to gather input about advocacy and patient needs.
Treatment of advanced and metastatic melanoma is a rapidly changing field. Over the past 10 years, there have been six new drugs approved by the FDA for the treatment of metastatic melanoma. These approved drugs include a number of immune checkpoint inhibitors and MAPK-pathway-targeted therapies. The discovery of such agents as ipilimumab, pembrolizumab, nivolumab, vemurafenib, trametininb and dabrafenib have revolutionized the way in which melanoma in managed. While these agents have succeeded in both early and later phase clinical trials, a large number of investigational therapies have not yet been developed or researched past Phase I clinical studies. Furthermore, there are dozens of potential agents in Phase I and Phase II clinical development that appear promising and are currently being explored. The field currently aims to determine the optimal sequence and combination of these therapies to best overcome such setbacks as toxicity and resistance and build upon the successes previously seen.
Abstract Background Tebentafusp, a TCR-anti-CD3 bispecific fusion protein designed to target a peptide from melanocyte lineage antigen gp100, has shown monotherapy activity in advanced cutaneous and uveal melanoma (UM) [1]. gp100 is expressed in normal melanocytes in skin and hair follicles. We previously reported a possible association between rash and overall survival (OS) in a Ph 1/2 trial of HLA-A*0201 patients with UM [1]. Anti-PD1 therapy for melanoma can induce vitiligo in 10-25% of patients, with one study showing a median time to onset of 126 days (range 52 - 453) and a potential association with clinical benefit [2]. We now investigate the association of melanocyte-related adverse events (MRAEs) and OS following tebentafusp treatment of patients with UM. Methods To test the differential potency of tebentafusp, HLA-A2+ epidermal skin derived melanocytes (5 healthy donors) and gp100+ and gp100- melanoma cell lines were incubated with PBMCs and increasing tebentafusp concentrations, and tested in IFNγ (measure of T cell activation) and GrB (measure of T cell mediated killing) ELISPOT assays. The clinical trial database (NCT02570308; Ph1 n=19, Ph2 n=23) was also queried for AEs suggestive of melanocyte origin, including vitiligo, leukotrichia, and skin hyperpigmentation. Simon-Makuch estimates were derived to visualize the association between MRAEs and OS while adjusting for immortal time bias, and Mantel-Byar method was used to estimate odds of death associated with experiencing MRAEs. Results In vitro, tebentafusp redirected and activated T cells against gp100+ melanoma and skin-derived melanocytes but not gp100- melanoma; in all cases, potency for melanocytes was less than melanoma, potentially reflecting differential peptide presentation. 24 of 42 patients (57%) developed one or more MRAEs including vitiligo/skin hypopigmentation (28%), leukotrichia (33%), and hyperpigmentation (21%), with median time to onset of 67 days (range 24-221). The estimated probability of experiencing a MRAE within 6-months of continuous treatment is 70%. Among the 24 patients with MRAEs, 22 (92%) and 20 (83%) experienced rash and pruritus, respectively. Rash preceded MRAEs in all patients with both events, while pruritus preceded MRAEs in 77% of patients. In a post-hoc analysis, experiencing a MRAE was associated with a 72% lower odds of death compared to those who did not experience these AEs. Conclusion Over half of tebentafusp-treated patients with advanced UM experienced at least one MRAE, supporting the hypothesis that tebentafusp can redirect T cells against gp100+ cells in patients. This rate of MRAEs is higher than historically reported for anti-PD1 based therapies. MRAEs appear to be associated with prior rash, and even accounting for the time bias of onset, may be associated with OS. 1. Sato T. J Clin Oncol 36, 2018, suppl, 9521 2. Hua C. JAMA Dermatol 2016;152:45-51 Citation Format: Marlana Orloff, Joseph J. Sacco, Paul Nathan, Chris Holland, Chris Cohen, Jane Harper, Shaad E. Abdullah, Takami Sato, Richard D. Carvajal. Vitiligo and other clinical melanocyte-related adverse events following tebentafusp (IMCgp100) exposure in patients with uveal melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3295.
9527 Background: Tebe is a bispecific consisting of an affinity-enhanced T cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100+ cells. In this Phase (Ph) 3, randomized trial of first line (1L) metastatic uveal melanoma (mUM) [NCT03070392], tebe significantly improved overall survival (OS) vs. investigator’s choice (IC) in the intention-to-treat population (ITT). In previous trials, tebe-related skin adverse events (AEs), hypothesized to be on-target, off-tumor activity against gp100-expressing melanocytes, were associated with improved OS. This association was tested prospectively as a co-primary endpoint in the Ph3 study. Methods: 378 1L HLA-A*02:01+ mUM pts were randomized 2:1 to tebe (n = 252) or IC (n = 126). Co-primary endpoints were 1) OS in all randomized pts (ITT) and 2) OS in tebe-randomized pts who develop any grade rash in week (wk) 1 vs. all receiving IC. Rash was defined as composite of preferred AE terms. Melanocyte-related AEs (MRAEs) were defined as pigment change AEs in the skin or hair. Overall study-wide alpha was controlled at 0.05, with 90% assigned to ITT and 10% to rash. This analysis was conducted on the first interim analysis (data extracted Nov-2020). Results: In the 245 tebe treated pts, the characteristic skin related AEs included most frequently rash (at any time) in 201 pts (82%), pruritis in 167 pts (68%), MRAEs in 109 pts (45%) and erythema in 69 pts (28%). While rash, erythema and pruritis mostly occurred in the first 4 weeks, MRAEs occurred after a median of 2.7 mo. Rash captures most pts, 201/227 (89%), who have any of these skin related AEs. Rash occurred in 146 pts (60%) by wk 1; 179 pts (73%) by wk 2; and 195 pts (80%) by wk 3. Tebe pts with wk 1 rash had significantly longer OS vs. the IC arm, HR 0.35 (95% CI 0.23, 0.53), p < 0.0001. The estimated 1-yr OS rates were 83% vs 58%, respectively. When expanded to include tebe pts with rash through wk 3, the 1-yr OS rate of 75% was still numerically higher than IC. The 50 (20%) tebe pts who did not experience rash by week 3 had 1-yr OS rate of 55%. Conclusions: In 1L mUM pts, tebe significantly improved OS compared to IC in the ITT analysis. Week 1 rash, presumed due to tebe redirection of T cells to gp100+ skin melanocytes, was associated with a very strong OS benefit. Therefore, rash may be a marker that the immune system can be mobilized by tebe to target gp100+ cells. The vast majority of tebe pts will develop a rash at some point, and tebe pts without rash may still derive benefit. Clinical trial information: NCT03070392.
9569 Background: Uveal melanoma is the most common primary intraocular malignant tumor in adults. Up to 50% of uveal melanoma patients die of metastasis, usually to the liver. Cell free DNA (cfDNA) provides a commercially available, non-invasive mechanism for monitoring disease activity in malignancy. Recently, studies have investigated cfDNA in uveal melanoma and have demonstrated an association with hepatic metastasis, metastatic volume as well as PFS and OS. It remains unclear if cfDNA can predict recurrent metastatic disease in high-risk uveal melanoma patients. Methods: We conductedan exploratory study of cfDNA following treatment for primary intraocular uveal melanoma. Three cohorts were investigated: high-risk patients ( > 50% estimated recurrence rate) with no clinical evidence of metastatic disease (cohort 1), patients with newly developed metastatic disease of the liver by surveillance MRI (cohort 2), patients with previously established metastatic disease (cohort 3). cfDNA profiles were provided by Guardant360 complete exon sequencing and analyzed for the presence of GNAQ/GNA11 mutations and MYC amplification which represent driver mutations present in > 80% of uveal melanomas. cfDNA was evaluated within 1 week of surveillance imaging studies. Results: Cohort 1 revealed no G-protein/MYC abnormalities by cfDNA (0/32). 34.4% (11/32) of patients in cohort 1 had mutations unrelated to G-protein/MYC. Cohort 2 showed a 10% (1/10) G-protein/MYC detection rate. Cohort 3 showed a G-protein MYC detection rate of 75% (18/24) which approaches the expected mutation rate in uveal melanoma. Interestingly, cfDNA did not detect G-protein/MYC abnormalities in hepatic tumors less than 2.0cm in diameter, regardless of cohort. Conclusions: MRI is a more sensitive screening test than cfDNA for detection of hepatic metastasis in uveal melanoma. cfDNA negative for G-protein/MYC alterations correlates with the absence of clinically detectable disease (100% specificity) and a positive result in the adjuvant setting should prompt further evaluation. This study suggests a detection threshold for cfDNA of > 2.0cm hepatic tumor diameter, which may have implications for the utilization of cfDNA across tumor types.
1. Cristofanilli, M, et al., Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004; 351(8): 781-91. 2. Bidard FC, et al., Detection rate and prognostic value of circulating tumor cells and circulating tumor DNA in metastatic uveal melanoma. Int J Cancer. 2014 Mar 1; 134(5):1207-13. 3. Weight RM, et al. Photoacoustic detection of metastatic melanoma cells in the human circulatory system. Opt Lett . 2006 Oct 15; 31(20):2998-3000. 4. O’Brien CM, et al. Capture of circulating tumor cells using photoacoustic flowmetry and two phase flow. J Biomed Opt . 2012 Jun; 17(6):612-21. • Circulating Uveal Melanoma Cells (CUMCs) were successfully quantified by the photoacoustic method including single cell detection. • Recovery rates of pigmented uveal melanoma cells suspended in a neutral density solution approached 25%. • 60% CUMCs are lost during PBMC isolation. Superior isolation techniques should be investigated to increase CUMC recovery. • Recovery rates for CUMCs in whole blood averaged 10% of expected cell yield (23/216 noise adjusted cell detection). • The Photoacoustic Method offers a viable platform for the detection of CUMCs. • Studies analyzing CUMCs from patients with metastatic disease are ongoing.
TPS9588 Background: Despite successful treatment of primary uveal melanomas (UM), up to 50% of patients subsequently develop systemic metastasis, with the liver involved in up to 90% of patients. Currently there is no US FDA-approved treatment for metastatic uveal melanoma (MUM). Activating mutations in genes encoding alpha subunits of the heterotrimeric G proteins, GNAQ and GNA11, are found in 80-90% of UM. Recent information suggests that GNAQ/GNA11-oncogenic signaling involves a non-canonical pathway conferring the activation of YAP1, distinct from the activation of PLCβ and PKC-MEK-ERK, which may explain the failure of MEK inhibitors in MUM patients. Focal Adhesion Kinase (FAK) is a tyrosine kinase that provides a direct link between Gαq and tyrosine phosphorylation networks controlling YAP and UM growth. Interestingly, UM represents the human cancer harboring the highest level of FAK overexpression. Recent kinome-wide CRISPR-Cas9 screens revealed that FAK and RAF/MEK co-targeting may provide a new network-based precision therapeutic strategy for MUM treatment. Methods: This is an investigator-initiated, prospective, single arm, single-institution, phase II trial evaluating the combination of a FAK inhibitor (defactinib, VS-6063) with a RAF/MEK inhibitor (VS-6766, CH5126766) for the treatment of patients with metastatic uveal melanoma [NCT04720417]. The primary endpoint of the study is disease control rate (DCR) of 50% including complete response (CR), partial response (PR), and stable disease (SD) as determined by RECIST criteria version 1.1. Secondary endpoints include progression free survival, overall survival, and causality of adverse events. Exploratory endpoints include analysis of the pharmacodynamic profile, mechanism of resistance to the combination, and investigation of circulating free DNA as a biomarker. The efficacy of this combination treatment will be assessed using the Simon’s two stage design. In stage I, a total number of 8 patients are accrued and if there are 2 or fewer overall responses among these 8 patients, further enrollment of patients may be stopped with the conclusion that DCR cannot be 50% or greater. Otherwise, an additional 10 patients will be accrued in stage II, resulting in a total sample size of 18 patients. Patients at 18 years or older with metastases from uveal melanoma will be eligible (any line of therapy). Defactinib (200 mg) will be administered orally twice a day in combination with VS-6766 (3.2 mg) administered orally twice a week for 3 weeks, in 28-day cycles. Dose modification will be considered based on toxicity. Treatment will be continued until maximum clinical benefit is obtained; disease progression or the development of intolerable side effects. Enrollment to stage 1 began in February 2021. Clinical trial information: NCT04720417.
