Treatment Of Metastatic Uveal Melanoma Research Articles

Association between clinical and disease characteristics and detectable or undetectable baseline ctDNA in patients with metastatic uveal melanoma.

9537 Background: Tebentafusp, a bispecific soluble TCR specific for a gp100 peptide, is licensed for the treatment of metastatic uveal melanoma (mUM) in HLA-A*02:01+ individuals. 82% of patients (pts) with mUM in the IMCgp100-102 (previously treated; 2L+) and 61% in IMCgp100-202 (frontline; 1L) studies, respectively, had detectable baseline ctDNA. There is a strong relationship between decrease in ctDNA by 9 weeks and overall survival (OS) [Carvajal 2022; Hassel & Piperno-Neumann 2023]. Patients with undetectable baseline ctDNA had improved survival despite having macroscopic disease. In this study, we report the characteristics of baseline ctDNA undetectable vs detectable disease. Methods: Disease characteristics of 202 1L (Study 202) and 117 2L+ (Study 102) pts who had baseline undetectable or detectable ctDNA (unDNA vs detDNA) were compared in a post-hoc unplanned analysis. ctDNA detection was analysed at baseline and up to week 9 on tebentafusp using targeted mPCR-NGS assay for mutations in 15 genes including GNAQ, GNA11, SF3B1, CYSLTR2, PLCB4 and EIF1AX. Largest lesion size groups (≤ 3 cm, 3-8 cm, > 8 cm) were defined by American Joint Committee on Cancer 7th Ed. Presence of oncogenic mutations in GNAQ, GNA11, SF3B1 and BAP1 were assessed by WES on metastatic tissue biopsies. Results: Baseline ctDNA levels increased in association with size of largest lesion regardless of number of prior therapies. However, there was an association between disease burden (defined by largest lesion size) and unDNA vs detDNA in both studies, with all pts with largest liver lesion > 8 cm having detDNA. In Study 202, % of the population with unDNA vs detDNA was 50% vs 50% for ≤ 3cm and 27% vs 73% for 3.1-8 cm. While OS was similar for unDNA & detDNA in pts with ≤ 3cm lesions, OS was longer for pts with unDNA vs detDNA who had baseline tumor size 3.1-8 cm in both studies (Table). Within this 3.1-8 cm group, pts with unDNA tended to have lower LDH, AST, and ALP. Initial analysis showed no difference in the frequency of GNAQ, GNA11, SF3B1 or BAP1 mutations between unDNA and detDNA groups. Further data on somatic mutation defined groups and RNAseq gene expression in unDNA and detDNA groups will be presented. Conclusions: Patients with unDNA were more likely to have smaller disease burden than those with detDNA; however, many pts with unDNA had a significant burden of metastatic disease. Baseline unDNA was associated with improved OS outcome vs detDNA in pts with 3.1-8 cm baseline metastatic deposits, but not in pts with ≤ 3cm disease. No association was seen between oncogenic background of GNAQ/GNA11/SF3B1/BAP1 and unDNA vs detDNA. Clinical trial information: NCT02570308 ; NCT03070392 . [Table: see text]

Safety, efficacy, and biomarker results from an open-label, multicenter, phase 1 study of RP2 alone or combined with nivolumab in a cohort of patients with uveal melanoma.

9511 Background: Uveal melanoma is the most common primary intraocular tumor in adults and has a high risk of liver metastasis. Effective treatments for metastatic uveal melanoma (MUM) are limited, as MUM responds poorly to immune checkpoint inhibition. RP2 is an enhanced-potency oncolytic HSV-1–expressing human GM-CSF, a fusogenic glycoprotein (GALV-GP-R−), and an anti–CTLA-4 antibody-like molecule. We present safety, efficacy, and biomarker data for RP2 monotherapy and RP2 +nivolumab (nivo; anti–PD-1) in patients (pts) with MUM (NCT04336241). Methods: Pts ≥18 years old with advanced or metastatic non-neurologic solid tumors (including MUM) who progressed on, or could not tolerate, standard therapy were included in the clinical trial; pts had ≥1 measurable and injectable tumor (≥1 cm). After determination of the recommended phase 2 dose of intratumoral RP2 (1×106 PFU/mL once, then ≤7 doses at 1×107 PFU/mL; ≤10 mL total/treatment day), pts received RP2 Q2W as monotherapy or in addition to nivo (240 mg Q2W/480 mg Q4W). Responses were assessed per modified RECIST v1.1.Tumor biopsies and peripheral blood mononuclear cells were collected pre-treatment and at day 43 and were analyzed by immunohistochemistry (IHC) and/or sequencing of the CDR3β region of the T-cell receptor (TCR) by immunoSEQ. Results: A total of 17 pts with MUM were enrolled (RP2 monotherapy, n = 3; RP2 + nivo, n = 14). Most pts had received both anti–PD-1 and anti–CTLA-4 therapy (12/17 [70.6%]), and 3/17 (17.6%) had received ≥3 prior lines of therapy. The ORR was 29.4% (5/17; all PRs; RP2 monotherapy, 1/3; RP2 + nivo, 4/14). The DCR (CR + PR + SD) was 58.8% (10/17). The median (range) duration of response at the data cutoff was 11.5 (2.8–21.2) months, with some responses and disease stabilizations ongoing. The most common overall grade 1–2 treatment-related AEs (TRAEs; ≥20% overall) were pyrexia, chills, fatigue, hypotension, and pruritus. The only grade 3 TRAE in > 1 pt was hypotension (2 pts receiving RP2 + nivo); no grade 4/5 TRAEs occurred. Evaluable baseline and post-treatment biopsies were used for IHC (n = 8) and TCR sequencing analyses. Paired biopsies from pts with clinical benefit (n = 5; 2 PR, 3 SD) showed an increase in tumor PD-L1 expression by IHC analysis, and 4 of these pts (2 PR, 2 SD) exhibited an increase in CD8+ T-cell infiltration into tumors. TCR sequencing following treatment with RP2 + nivo revealed expansion of pre-existing TCRs and generation of new T-cell clones. Conclusions: RP2 alone or combined with nivo demonstrated a favorable safety profile and meaningful antitumor activity in pts with previously treated MUM. Biomarker data indicated immune cell infiltration and increased PD-L1 expression in tumors and changes in the peripheral T-cell repertoire following RP2 ± nivo therapy. Based on these results, a randomized, controlled clinical development plan is being planned. Clinical trial information: NCT04336241 .

Use of baseline and serial ctDNA dynamics to predict outcomes in patients treated with first-line tebentafusp, including those who were and were not treated beyond progression.

9536 Background: Tebentafusp (tebe), a bispecific soluble T cell receptor specific for a gp100 peptide, is licensed for the treatment of metastatic uveal melanoma (mUM) in HLA-A*02:01+ individuals. As part of the pivotal, Phase 3 IMCgp100-202 study, 378 mUM pts were randomized to receive tebe or investigators choice. Approximately 60% of patients (pts) with metastatic UM in the IMCgp100-202 study had detectable baseline ctDNA. We have reported the strong relationship between change in ctDNA at 9 weeks (wks) and overall survival (OS). Additionally, radiographic treatment response is a poor predictor of who is benefitting from therapy. We hypothesized that ctDNA dynamics would help identify those patients (pts) who benefit from treatment beyond progression (TBP). Methods: Sera (n=202 pts) collected at baseline and wk 9 on tebe were analyzed for ctDNA using a targeted mPCR-NGS assay for 15 genes including GNAQ, GNA11, SF3B1, PLBC4, EIF1AX, and CYSLTR2. RECISTv1.1 was assessed by investigators; TBP was allowed per protocol. OS was analyzed in subsets of pts who were not TBP, and those who were TBP and treated with tebe for < or > 16 wks; the approximate time point where TBP pts would have had confirmatory imaging, although confirmatory scan data is not available. At baseline, pts were determined to be ctDNA detectable or undetectable. At wk 9, pts were determined to have cleared ctDNA, < or ≥ 68% (0.5 log-fold) reduction, < or ≥ 50% reduction. Data cut-off was July 2023. Results: Of 202 pts randomized to tebe and with ctDNA at baseline and wk 9, 126 (62%) received TBP (80 <16 wks, 46 ≥ 16 wks). Undetectable ctDNA at baseline was associated with improved OS regardless of TBP, while TBP was associated with improved OS in those with baseline detectable ctDNA (hazard ratio, HR, 0.59, 95% confidence interval, CI, 0.4-0.88). Subgroup analysis of those with baseline detectable ctDNA demonstrated improved OS in only those who received TBP for ≥ 16 wks (HR 0.33; 95% CI 0.21-0.51). Clearance of ctDNA at wk 9 was associated with better OS than in those who did not have clearance. TBP was associated with better OS in pts who did not have clearance (HR 0.48, 95% CI 0.30-0.79), but not in those with clearance (HR 0.87, 95% CI 0.43-1.78). Finally, TBP was associated with improved outcomes in pts with ≥50% and ≥68% reduction, compared to those without reduction, HR 0.63 (95% CI 0.4-0.97) and 0.62 (95% CI 0.39-0.99), respectively. Conclusions: Baseline and wk 9 ctDNA detection predicts OS in mUM pts treated with first line tebe. The utility of ctDNA predicting pts most likely to benefit from TBP is less clear, although TBP seems to be more beneficial in those with reduction of ctDNA at wk 9. Optimization of time points, assay, and integration of ctDNA data with radiomics are necessary to understand the true utility of ctDNA in helping select which pts should receive TBP. Clinical trial information: NCT03070392 .

Лечение метастатической увеальной меланомы. Опыт ведущего референсного центра

Uveal melanoma (UM) is the most common primary intraocular tumor. Despite successful treatment of the primary tumor, 50% of patients develop distant metastases. To date, there are no clear standards for choosing the first line of therapy for metastatic UM. The article presents a retrospective analysis of the effectiveness and safety of first-line therapy in 125 patients with metastatic UM who applied to the N.N. Blokhin National Medical Research Center of Oncology in the period from 2020 to 2023.

Tebentafusp in the treatment of metastatic uveal melanoma - the first patient treated in the Czech Republic.

Uveal melanoma is a rare cancer, in which metastases occur in approximately one half of cases. In metastatic disease, the prognosis is unfavorable and the median of survival does not exceed 6 months. Effective treatment options were very limited up to date. Tebentafusp is a bispecific fusion protein, which as the first drug proved efficacy in uveal melanoma. The patient was referred for suspected uveal melanoma of the left eye. She was treated for Hodgkin's disease in the past. Primarily, the tumor was treated by radiosurgery with radiotherapy of a small lesion of the vertebral body. However, later the patient had to undergo bulbus enucleation with confirmation of a large tumor category pT4b. PET/CT revealed metastases of the bones and the liver; simultaneously, haplotype A*02: 01 was confirmed. The patient underwent radiotherapy of the sternum and later, after confirmation of payment from the health insurance company, she started treatment with tebentafusp. The first three doses were administered during admission to the hospital, with a need to treat cytokine release syndrome by corticosteroids. Later, the administration was performed in an out-patient regimen, without complications, except for a transient elevation of transaminases. The first CT restaging confirmed stable disease; however, the second restaging confirmed a new osteolytic lesion in the processus of Th11. Because of progression, the treatment with tebentafusp was withdrawn after 6 months. Unfortunately, the lesion could not be treated by radiotherapy. Two months later, the patient was urgently admitted to the hospital because of right-sided hemiplegia; MRI revealed bleeding metastatic lesion in the brain stem. In this case report, we present the case of the first patient treated with this drug in the Czech Republic.

Immune checkpoint inhibitors for metastatic uveal melanoma: a meta-analysis

Several studies have evaluated immune checkpoint inhibitors (ICIs) for metastatic uveal melanoma; however, the efficacy of ICIs in the previous studies varied greatly. In this systematic review, we searched for prospective or retrospective studies on single or dual-ICIs for metastatic uveal melanoma treatment. A random-effect model meta-analysis with generic inverse-variance was conducted, and 36 articles representing 41 cohorts of 1414 patients with metastatic uveal melanoma were included. The pooled outcomes were as follows: objective response rate (ORR) was 5.6% (95% confidence interval [95%CI] 3.7–7.5%; I2, 36%), disease control rate (DCR) was 32.5% (95% CI 27.2–37.7%; I2, 73%), median progression-free survival was 2.8 months (95% CI 2.7–2.9 months; I2, 26%), and median overall survival (OS) was 11.2 months (95% CI 9.6–13.2 months; I2, 74%). Compared to single-agent ICI, dual ICI led to better ORR (single-agent: 3.4% [95% CI 1.8–5.1]; dual-agent: 12.4% [95% CI 8.0–16.9]; P < 0.001), DCR (single-agent: 29.3%, [95% CI 23.4–35.2]; dual-agent: 44.3% [95% CI 31.7–56.8]; P = 0.03), and OS (single-agent: 9.8 months [95% CI 8.0–12.2]; dual-agent: 16.3 months [95% CI 13.5–19.7]; P < 0.001). Our analysis provided treatment outcomes as described above. Dual-ICIs appear better than single-agent ICIs for the treatment of metastatic uveal melanoma.

Abstract 1529: Development of lymphoid aggregates in metastatic uveal melanoma tumors treated with tebentafusp

Abstract Tebentafusp (tebe), targeting gp100, is the first TCR-CD3 bispecific to demonstrate overall survival (OS) benefit and is approved for the treatment of metastatic uveal melanoma (mUM). We have previously shown B cell recruitment into the tumor associates with OS on tebe [1]. We explored further the formation of lymphoid aggregates (LA) within the tumor microenvironment in response to tebe. HLA-A*02:01+ 2L+ adult patients (pts) with mUM were treated with tebe (NCT02570308). Paired tumor biopsies were collected at baseline (n=70), after 3 doses of tebe (n=48), and at radiographical progression (n=17). Presence of B cells, T cells and macrophages was assessed by immunohistochemistry, using antibodies against CD20, CD3 and CD163 respectively, and digitally quantified. Using digital density analysis, aggregates of ≥10 CD20+ B cells within CD3+ T cell area in a 100µm radius were defined as LA. At progression pts were categorized by OS ≥12 or &amp;lt;12 months. Mean fold change (FC) was used. At baseline, B cells were detected in 90% of pts (median 5 B cells/mm2) with those pts having no more than 2 LA/mm2 (17% pts with 1 LA/mm2 and 3% pts with 2 LA/mm2). The median number of B cells in the biggest LA per sample was 24.B cells were recruited into the tumor after 3 doses of tebe (median 32 B cells/mm2, FC 3, p=6.5e-05). The LA density increased up to 6 LA/mm2 (23% pts with 1 LA/mm2, 8% pts with 2 LA/mm2, 6% pts with 3 LA/mm2 and 2% pts with 6 LA/mm2) with a trend for an increase in LA size (median B cell number in biggest LA = 30, p = 0.67). Tumors with a low baseline CD163+ macrophage to CD3+ T cell ratio, which was previously associated with longer OS on tebe, tended to have more LA/mm2 at baseline and on-treatment than those with a high ratio. At progression, pts with long OS had more B cells in the tumor compared to short OS (median 20 vs 2 B cells/mm2; FC 5, p=0.05). Additionally, more pts with long OS had LA than pts with short OS (6/12 pts vs 1/5 pts respectively) with a density not exceeding 1 LA/mm2. LA size was larger in pts with long OS compared to short OS (median B cell number in biggest LA 30 vs 10 respectively). LA in the short OS patient was found in the normal adjacent tissue compared to the LA in long OS patients which were located in the tumor and invasive margin. Tebe enhanced the formation of LA in the tumor microenvironment, notably in the low immunosuppressed tumors, which is consistent with the hypothesis that it results in epitope spread. These observations provide deeper insight into the mechanism of action of tebe and helps to explain prolonged survival of mUM pts beyond radiographical progression. [1] Greenshields-Watson A. et al., 619, SITC 2022 Citation Format: Takami Sato, Camille Britton-Rivet, Sophie Khakoo, Alistair Easton, Anastasiya Kazachenka, Laura Collins, Emma Leach, Adel Benlarech, Sarah Stanhope, Marcus O. Butler. Development of lymphoid aggregates in metastatic uveal melanoma tumors treated with tebentafusp [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1529.

Immunoembolization for the Treatment of Uveal Melanoma Hepatic Metastases.

Uveal melanoma is the most common primary intraocular tumor in adults. Approximately 50% of patients develop metastatic disease despite successful treatment of the primary eye tumor. The liver is the most common site of metastatic disease occurring in more than 90% of patients. Clinical prognosis is dependent on the ability to control the growth of liver tumors. Locoregional therapies play an important role in stabilizing liver metastases, prolonging survival for patients with metastatic uveal melanoma. As overall survival is prolonged, the development of extrahepatic disease becomes more common. Immunoembolization, a form of liver-directed therapy, not only focuses on treating hepatic metastases by stimulating the local immune system to suppress the growth of liver tumors, but it potentially generates a systemic immune response delaying the growth of extrahepatic metastases as well. The following article discusses immunoembolization for the treatment of metastatic uveal melanoma including the rationale, mechanism of action, indications, contraindications, outcomes, and associated toxicities.

Cutaneous type IV hypersensitivity reaction following tebentafusp treatment for uveal melanoma.

Tebentafusp is a bispecific protein that recently underwent FDA approval for the treatment of metastatic uveal melanoma that functions by redirecting cytotoxic T cells to glycoprotein-100, a protein highly expressed in melanoma. Although clinical trials have demonstrated that rashes are common in the first few days of treatment, little is known about skin reactions that develop later in the treatment course. Herein, we describe a type IV hypersensitivity reaction and vitiligo-like depigmentation that developed six weeks into treatment and discuss the possible mechanisms underlying these reactions. The type IV hypersensitivity reaction resolved without intervention within seven weeks of onset, suggesting that tebentafusp can be safely continued in select patients who develop this cutaneous reaction.

1128P A phase I dose escalation and expansion study of FHD-286, a novel BRG1/BRM (SMARCA4/SMARCA2) inhibitor, for the treatment of metastatic uveal melanoma

1128P A phase I dose escalation and expansion study of FHD-286, a novel BRG1/BRM (SMARCA4/SMARCA2) inhibitor, for the treatment of metastatic uveal melanoma

Darovasertib, a novel treatment for metastatic uveal melanoma.

The FDA granted orphan drug designation to darovasertib, a first-in-class oral, small molecular inhibitor of protein kinase C (PKC), for the treatment of uveal melanoma, on 2 May 2022. Primary uveal melanoma has a high risk of progressing to metastatic uveal melanoma, with a poor prognosis. The activation of the PKC and mitogen-activated protein kinase pathways play an essential role in the pathogenesis of uveal melanoma, and mutations in the G protein subunit alpha q (GNAQ), and G protein subunit alpha11 (GNA11) genes are considered early events in the development of uveal melanoma. Compared to other PKC inhibitors, such as sotrastaurin and enzastaurin, darovasertib is significantly more potent in inhibiting conventional (α, β) and novel (δ, ϵ, η, θ) PKC proteins and has a better tolerability and safety profile. Current Phase I/II clinical trials indicated that darovasertib, combined with the Mitogen-activated protein kinase/Extracellular (MEK) inhibitors, binimetinib or crizotinib, produced a synergistic effect of uveal melanoma. In this article, we summarize the development of drugs for treating uveal melanomas and discuss problems associated with current treatments. We also discuss the mechanism of action, pharmacokinetic profile, adverse effects, and clinical trial for darovasertib, and future research directions for treating uveal melanoma.

Combined Mcl-1 and YAP1/TAZ inhibition for treatment of metastatic uveal melanoma.

Uveal melanoma is the most common intraocular tumor in adults, representing approximately 5% of all melanoma cases. Up to 50% of uveal melanoma patients develop metastases that are resistant to most of the commonly used antineoplastic treatments. Virtually all uveal melanoma tumors harbor activating mutations in GNAQ or GNA11 , encoding Gαq and Gα11, respectively. Constant activity of these proteins causes deregulation of multiple downstream signaling pathways including PKC, MAPK and YAP1/TAZ. While the importance of YAP1 signaling for the proliferation of uveal melanoma has recently been demonstrated, much less is known about the paralog of YAP1 transcriptional coactivator, named TAZ; however, similar to YAP1, TAZ is expected to be a therapeutic target in uveal melanoma. We performed a small-scale drug screen to discover a compound synergistically inhibiting uveal melanoma proliferation/survival in combination with YAP1/TAZ inhibition. We found that the combination of genetic depletion of YAP1/TAZ together with Mcl-1 inhibition demonstrates a synergistic inhibitory effect on the viability of uveal melanoma cell lines. Similarly, indirect attenuation of the YAP1/TAZ signaling pathway with an inhibitor of the mevalonate pathway, that is, the geranyl-geranyl transferase inhibitor GGTI-298, synergizes with Mcl-1 inhibition. This combination could be potentially used as a treatment for metastatic uveal melanoma.

Tebentafusp in Patients with Metastatic Uveal Melanoma: A Real-Life Retrospective Multicenter Study.

Tebentafusp has recently been approved for the treatment of metastatic uveal melanoma (mUM) after proving to have survival benefits in a first-line setting. This retrospective, multicenter study analyzed the outcomes and safety of tebentafusp therapy in 78 patients with mUM. Patients treated with tebentafusp had a median PFS of 3 months (95% CI 2.7 to 3.3) and a median OS of 22 months (95% CI 10.6 to 33.4). In contrast to a published Phase 3 study, our cohort had a higher rate of patients with elevated LDH (65.4% vs. 35.7%) and included patients with prior systemic and local ablative therapies. In patients treated with tebentafusp following ICI, there was a trend for a longer median OS (28 months, 95% CI 26.9 to 29.1) compared to the inverse treatment sequence (24 months, 95% CI 13.0 to 35.0, p = 0.257). The most common treatment-related adverse events were cytokine release syndrome in 71.2% and skin toxicity in 53.8% of patients. Tumor lysis syndrome occurred in one patient. Data from this real-life cohort showed a median PFS/OS similar to published Phase 3 trial data. Treatment with ICI followed by tebentafusp may result in longer PFS/OS compared to the inverse treatment sequence.

Tebentafusp in the Treatment of Metastatic Uveal Melanoma: Patient Selection and Special Considerations.

Uveal melanoma (UM) is a rare type of melanoma with distinct features from cutaneous melanoma, low response rates to immune checkpoint inhibition, and poor survival rates. Tebentafusp, a bispecific antibody engaging T cells with gp 100 on HLA-A*02:01, was recently approved by the FDA as the first drug of its class and the first treatment approved by the FDA to treat UM. In this review, we summarize the preclinical and clinical data on tebentafusp for UM. We additionally discuss patient selection and the relevant challenges. For the literature search, PubMed search and relevant articles presented at international conferences were used.

Hepatic Radiotherapy in Addition to Anti-PD-1 for the Treatment of Metastatic Uveal Melanoma Patients.

Uveal melanoma is the most common ocular tumor with frequent metastatic spread to the liver. Immune checkpoint inhibitors have demonstrated poor results in this disease. The addition of hepatic radiotherapy to anti-PD-1 could enhance the sensitivity to immunotherapy. In this study, patients treated with pembrolizumab and who have undergone hepatic radiotherapy have been retrospectively evaluated. Twenty-two patients have been considered. Six patients (27.3%) achieved a partial response and 3 (13.6%) a stable disease. Disease control rate was 40.9%. Thirteen patients (59.1%) had progression as best response. The median PFS was 4.8 months and 6 months PFS rate 45.4%. The median OS was 21.2 months, while 1 year OS rate was 72.7%. Longer survival was observed in patients who achieved a partial response on irradiated metastases (HR 0.23, 95% CI 0.06-0.83) or progressed after 6 months (HR 0.12-95% CI 0.03-0.44). No radiotherapy-related or grade 3-4 adverse events were reported. This study demonstrates that the addition of hepatic radiotherapy to anti-PD-1 treatment can be a valid option for the treatment of metastatic uveal melanoma, particularly for HLA A 02:01 negative patients. Prospective studies should be conducted to confirm these data.

Preclinical Evaluation of Trabectedin in Combination With Targeted Inhibitors for Treatment of Metastatic Uveal Melanoma.

Uveal melanoma (UM) is considered a rare disease; yet, it is the most common intraocular malignancy in adults. Although the primary tumor may be efficiently managed, more than 50% of patients with UM develop distant metastases. The mortality at the first year after diagnosis of metastatic UM has been estimated at 81%, and the poor prognosis has not improved in the past years due to the lack of effective therapies. In order to search for novel therapeutic possibilities for metastatic UM, we performed a small-scale screen of targeted drug combinations. We verified the targets of the tested compounds by western blotting and PCR and clarified the mechanism of action of the selected combinations by caspase 3 and 7 activity assay and flow cytometry. The best two combinations were tested in a mouse patient-derived xenograft (PDX) UM model as putative therapeutics for metastatic UM. Combinations of the multitarget drug trabectedin with either the CK2/CLK double-inhibitor CX-4945 (silmitasertib) or the c-MET/TAM (TYRO3, Axl, MERTK) receptor inhibitors foretinib and cabozantinib demonstrated synergistic effects and induced apoptosis (relative caspase 3 and 7 activity increased up to 20.5-fold in UM cell lines). In the case of the combination of foretinib and cabozantinib, inhibition of the TAM receptors, but not c-Met, was essential to inhibit the growth of UM cells. Monotreatment with trabectedin inhibited tumor growth by 42%, 49%, and 35% in the MM26, MM309, and MM339 PDX mouse models, respectively. Trabectedin alone or in combination with cabozantinib inhibited tumor growth in PDX UM mouse models. Blocking of MERTK, rather than TYRO3, activity inhibited UM cell growth and synergized with trabectedin.

Prognostic Hematologic Biomarkers Following Immune Checkpoint Inhibition in Metastatic Uveal Melanoma.

Background: There is no standardized treatment for metastatic uveal melanoma (MUM) but immune checkpoint inhibitors (ICI) are increasingly used. While ICI has transformed the survival of metastatic cutaneous melanoma, MUM patients do not equally benefit. Factors known to affect ICI response include the hematologic markers, lactate dehydrogenase (LDH) and neutrophil:lymphocyte ratio (NLR). We evaluated the prognostic value of LDH and NLR at the start of ICI and on treatment in MUM. Methods: MUM patients were treated between August 2006 and May 2022 with combination ipilimumab/nivolumab or ipilimumab/nivolumab/pembrolizumab single-agent therapy. Univariable (UVA) and multivariable (MVA) analyses were used to assess the prognostic value of predefined baseline factors on progression-free (PFS) and overall survival (OS). Results: In forty-six patients with MUM treated with ICI, elevated baseline and on-treatment LDH was prognostic for OS (start of ICI, HR (95% CI): 3.6 (1.9−7.0), p < 0.01; on-treatment, HR (95% CI): 3.7 (1.6−8.8), p < 0.01) and PFS (start of ICI, (HR (95% CI): 2.8 (1.5−5.4), p < 0.0001); on-treatment LDH (HR (95% CI): 2.2 (1.1−4.3), p < 0.01). On-treatment NLR was prognostic for PFS (HR (95% CI): 1.9 (1.0−3.9), p < 0.01). On-treatment LDH remained an important contributor to survival on MVA (OS: HR (95% CI): 1.001 (1.00−1.002), p < 0.05); PFS: HR (95% CI): 1.001 (1.00−1.002), p < 0.01). Conclusions: This study demonstrates that LDH and NLR could be useful in the prognostication of MUM patients treated with ICI. Additional studies are needed to confirm the importance of these and other prognostic biomarkers.

Intermittent MEK inhibition for the treatment of metastatic uveal melanoma.

IntroductionUveal melanoma (UM) is associated with poor outcomes in the metastatic setting and harbors activating mutations resulting in upregulation of MAPK signaling in almost all cases. The efficacy of selumetinib, an oral allosteric inhibitor of MEK1/2, was limited when administered at a continual dosing schedule of 75 mg BID. Preclinical studies demonstrate that intermittent MEK inhibition reduces compensatory pathway activation and promotes T cell activation. We hypothesized that intermittent dosing of selumetinib would reduce toxicity, allow for the administration of increased doses, and achieve more complete pathway inhibition, thus resulting in improved antitumor activity.MethodsWe conducted a phase Ib trial of selumetinib using an intermittent dosing schedule in patients with metastatic UM. The primary objective was to estimate the maximum tolerated dose (MTD) and assess safety and tolerability. Secondary objectives included assessment of the overall response rate (RR), progression-free survival (PFS) and overall survival (OS). Tumor biopsies were collected at baseline, on day 3 (on treatment), and between days 11-14 (off treatment) from 9 patients for pharmacodynamic (PD) assessments.Results29 patients were enrolled and received at least one dose of selumetinib across 4 dose levels (DL; DL1: 100 mg BID; DL2: 125 mg BID; DL3: 150 mg BID; DL4: 175 mg BID). All patients experienced a treatment-related adverse event (TRAE), with 5/29 (17%) developing a grade 3 or higher TRAE. Five dose limiting toxicities (DLT) were observed: 2/20 in DL2, 2/5 in DL3, 1/1 in DL4. The estimated MTD was 150 mg BID (DL3), with an estimated probability of toxicity of 29% (90% probability interval 16%-44%). No responses were observed; 11/29 patients achieved a best response of stable disease (SD). The median PFS and OS were 1.8 months (95% CI 1.7, 4.5) and 7.1 months (95% CI 5.3, 11.5). PD analysis demonstrated at least partial pathway inhibition in all samples at day 3, with reactivation between days 11-14 in 7 of those cases.ConclusionsWe identified 150 mg BID as the MTD of intermittent selumetinib, representing a 100% increase over the continuous dose MTD (75 mg BID). However, no significant clinical efficacy was observed using this dosing schedule.

Treatment of metastatic uveal melanoma in 2022: improved treatment regimens and improved prognosis.

Until recently, metastatic uveal melanoma was associated with essentially uniform fatality within months. However, recent developments in screening, improved understanding of the genetic underpinnings of metastatic disease, and pivotal medication approvals have improved the disease's rate of fatality. Routine implementation of genetic testing at the time of primary tumor treatment via gene expression profiling or chromosomal analysis has identified patients who are at high risk for metastatic disease. Enhanced screening with imaging directed at the liver and lungs has allowed for identification of early disease and lower tumor burden. Significant work on improved liver directed therapy along with systemic chemotherapy and immunotherapy has improved life expectancy. The first systemic immunotherapy specifically for metastatic uveal melanoma was approved this year. This medication, tebentafusp, is likely to improve life expectancy for all patients with metastatic melanoma assuming they have appropriate human leukocyte antigen (HLA) markers. Multiple clinical trials with novel immunotherapeutic agents are promising as well. The prognosis for patients with uveal melanoma is far better than ever before because of recent developments in the understanding and treatment of metastatic disease.

Combination strategies to durably suppress HIV-1: Soluble T cell receptors

Immunotherapeutic interventions to enhance natural HIV-specific CD8+ T cell responses, such as vaccination or adoptive T cell transfer, have been a major focus of HIV cure efforts. However, these approaches have not been effective in overcoming viral immune evasion mechanisms. Soluble T cell receptor (TCR) bispecifics are a new class of ‘off-the-shelf’ therapeutic designed to address these limitations. These biologics are built on the Immune mobilising monoclonal TCRs against X disease (ImmTAX) platform, which was pioneered in oncology and recently validated by the FDA's approval of tebentafusp for treatment of metastatic uveal melanoma. ImmTAV® are an application of this technology undergoing clinical development for the elimination of chronic viral infections. ImmTAV molecules comprise an affinity-enhanced virus-specific TCR fused to an anti-CD3 effector domain. Engineering of the TCR confers extraordinary specificity and affinity for cognate viral antigen and the anti-CD3 enables retargeting of non-exhausted cytolytic T cells, irrespective of their specificity. These features enable ImmTAV molecules to detect and kill infected cells, even when expressing very low levels of antigen, bypassing ineffective host immune responses. Furthermore, the modularity of the platform allows for engineering of TCRs that effectively target viral variants. In this review, we discuss the progress made in the development of ImmTAV molecules as therapeutics for functional cure of chronic hepatitis B and HIV, from concept to the clinic.