546 Results from Phase Ib study of tebentafusp (tebe) in combination with durvalumab (durva) and/or tremelimumab (treme) in metastatic cutaneous melanoma (mCM)

BackgroundTebe, a T cell receptor fused to an anti-CD3 effector, can redirect T cells to target gp100+ cells and in Ph3, demonstrated overall survival (OS) benefit as monotherapy in metastatic uveal melanoma. In Ph2, any tumor shrinkage (44% of patients) was a better predictor of OS than response rate. In Ph1, Tebe had monotherapy activity in mCM, also a gp100+ tumor, with 1-year OS ~74% in PD-1 naïve mCM. A Ph1 dose escalation of tebe with durva (anti-PD-L1) and/or treme (anti-CTLA4) was conducted in pre-treated mCM [NCT02535078], with nearly all patients having prior PD1-treatment, and where recently reported therapies have 1-yr OS of ~55%.MethodsHeavily pre-treated HLA-A2+ mCM patients received weekly IV tebe alone (Arm 4) or with increasing doses of durva and/or treme (Arm 1–3) administered IV monthly starting day 15 of each cycle. Primary objective was to identify RP2D of combination therapy. Secondary objectives included adverse events (AE) and efficacy.Results112 pts received ≥1 tebe dose. Median age was 59, 77% were ECOG 0, and 37% were BRAFm (of which 71% received prior BRAFi/MEKi). 91% of pts were 2L+, while 74% were 3L+. 103 (92%) received prior PD-1 inhibitor, of which 87% also received prior ipilimumab. 43 pts received tebe + durva (Arm 1), 13 received tebe + treme (Arm 2), 29 received triplet therapy (Arm 3), and 27 received tebe alone (Arm 4). Maximum target doses of tebe (68 mcg) + durva (20 mg/kg) and treme (1 mg/kg) were tolerated. MTD was not formally identified for any arm. Two DLTs occurred: prolonged grade 3 rash (Arm 1) and grade 2 diarrhea leading to treatment delay (Arm 2). Related AEs that were Grade ≥3 or led to discontinuations were: 44%/0% (Arm 1), 23%/0% (Arm2), 38%/7% (Arm3), 26%/4% (Arm 4). There were no treatment-related deaths.In prior PD-1 pts, tumor shrinkage occurred in 36% and 1-yr OS was 68%. Of 51 evaluable PD-1 resistant pts (best response CR/PR/SD to prior PD1), tumor shrinkage occurred in 28% and 1-yr OS was 73% (figure 1). In 35 evaluable PD-1 refractory pts (prior best response PD), tumor shrinkage occurred in 49% and 1-yr OS was 61%. For 38 prior PD-1 pts who received ≥10mg/kg durva, 1-yr OS was 81%.Abstract 546 Figure 1% tumor change from baseline in evaluable patients with known response to prior PD1 exposureConclusionsTebe with anti-PD-L1 and/or anti-CTLA4 had an acceptable safety profile. Tebe + durva demonstrated durable tumor shrinkage and promising 1-yr OS rates in prior-PD1 treated mCM relative to recent reports.Trial RegistrationNCT02535078Ethics ApprovalThe institutional review board or independent ethics committee at each center approved the trial. The trial was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines

Tebentafusp in Combination With Durvalumab And/or Tremelimumab in Patients With Metastatic Cutaneous Melanoma: A Phase 1 Study

BACKGROUND: Immune checkpoint inhibitors have significantly improved outcomes in first line cutaneous melanoma. However, there is a high unmet need for patients who progress on these therapies and combination therapies are being explored to improve outcomes. Tebentafusp is a first-in-class gp100×CD3 ImmTAC bispecific that demonstrated overall survival (OS) benefit (HR 0.51) in metastatic uveal melanoma despite a modest overall response rate of 9%. This phase 1b trial evaluated the safety and initial efficacy of tebentafusp in combination with durvalumab (anti-programmed death ligand 1 (PDL1)) and/or tremelimumab (anti-cytotoxic T lymphocyte-associated antigen 4) in patients with metastatic cutaneous melanoma (mCM), the majority of whom progressed on prior checkpoint inhibitors. METHODS: In this open-label, multicenter, phase 1b, dose-escalation trial, HLA-A*02:01-positive patients with mCM received weekly intravenous tebentafusp with increasing monthly doses of durvalumab and/or tremelimumab starting day 15 of each cycle. The primary objective was to identify the maximum tolerated dose (MTD) or recommended phase 2 dose for each combination. Efficacy analyses were performed in all tebentafusp with durvalumab±tremelimumab treated patients with a sensitivity analysis in those who progressed on prior anti-PD(L)1 therapy. RESULTS: 85 patients were assigned to receive tebentafusp in combination with durvalumab (n=43), tremelimumab (n=13), or durvalumab and tremelimumab (n=29). Patients were heavily pretreated with a median of 3 prior lines of therapy, including 76 (89%) who received prior anti-PD(L)1. Maximum target doses of tebentafusp (68 mcg) alone or in combination with durvalumab (20 mg/kg) and tremelimumab (1 mg/kg) were tolerated; MTD was not formally identified for any arm. Adverse event profile was consistent with each individual therapy and there were no new safety signals nor treatment-related deaths. In the efficacy subset (n=72), the response rate was 14%, tumor shrinkage rate was 41% and 1-year OS rate was 76% (95% CI: 70% to 81%). The 1-year OS for triplet combination (79%; 95% CI: 71% to 86%) was similar to tebentafusp plus durvalumab (74%; 95% CI: 67% to 80%). CONCLUSION: At maximum target doses, the safety of tebentafusp with checkpoint inhibitors was consistent with safety of each individual therapy. Tebentafusp with durvalumab demonstrated promising efficacy in heavily pretreated patients with mCM, including those who progressed on prior anti-PD(L)1. TRIAL REGISTRATION NUMBER: NCT02535078

Tebentafusp in combination with durvalumab and/or tremelimumab in patients with metastatic cutaneous melanoma: a phase 1 study

Background: Immune checkpoint inhibitors have significantly improved outcomes in first line cutaneous melanoma. However, there is a high unmet need for patients who progress on these therapies and combination therapies are being explored to improve outcomes. Tebentafusp is a first-in-class gp100×CD3 ImmTAC bispecific that demonstrated overall survival (OS) benefit (HR 0.51) in metastatic uveal melanoma despite a modest overall response rate of 9%. This phase 1b trial evaluated the safety and initial efficacy of tebentafusp in combination with durvalumab (anti-programmed death ligand 1 (PDL1)) and/or tremelimumab (anti-cytotoxic T lymphocyte-associated antigen 4) in patients with metastatic cutaneous melanoma (mCM), the majority of whom progressed on prior checkpoint inhibitors. Methods: In this open-label, multicenter, phase 1b, dose-escalation trial, HLA-A*02:01-positive patients with mCM received weekly intravenous tebentafusp with increasing monthly doses of durvalumab and/or tremelimumab starting day 15 of each cycle. The primary objective was to identify the maximum tolerated dose (MTD) or recommended phase 2 dose for each combination. Efficacy analyses were performed in all tebentafusp with durvalumab±tremelimumab treated patients with a sensitivity analysis in those who progressed on prior anti-PD(L)1 therapy. Results: 85 patients were assigned to receive tebentafusp in combination with durvalumab (n=43), tremelimumab (n=13), or durvalumab and tremelimumab (n=29). Patients were heavily pretreated with a median of 3 prior lines of therapy, including 76 (89%) who received prior anti-PD(L)1. Maximum target doses of tebentafusp (68 mcg) alone or in combination with durvalumab (20 mg/kg) and tremelimumab (1 mg/kg) were tolerated; MTD was not formally identified for any arm. Adverse event profile was consistent with each individual therapy and there were no new safety signals nor treatment-related deaths. In the efficacy subset (n=72), the response rate was 14%, tumor shrinkage rate was 41% and 1-year OS rate was 76% (95% CI: 70% to 81%). The 1-year OS for triplet combination (79%; 95% CI: 71% to 86%) was similar to tebentafusp plus durvalumab (74%; 95% CI: 67% to 80%). Conclusion: At maximum target doses, the safety of tebentafusp with checkpoint inhibitors was consistent with safety of each individual therapy. Tebentafusp with durvalumab demonstrated promising efficacy in heavily pretreated patients with mCM, including those who progressed on prior anti-PD(L)1. Trial registration number: NCT02535078

Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma

Background: Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells. Methods: In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival. Results: A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported. Conclusions: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.). Copyright © 2021 Massachusetts Medical Society

Characterizing metastatic uveal melanoma patients who develop symptomatic brain metastases.

Metastatic uveal melanoma (mUM) is an advanced ocular malignancy characterized by a hepatotropic pattern of spread. As the incidence of brain metastases (BM) in mUM patients has been thought to be low, routine CNS surveillance has not been recommended. Notably, no formal assessment of BM incidence in mUM has to date been published to support this clinical practice. We aimed to determine the true rate of BM in mUM and to clarify the clinical and genomic risk factors associated with BM patients through a collaborative multicenter, retrospective research effort. Data collected from 1,845 mUM patients in databases across four NCI-designated comprehensive cancer centers from 2006-2021 were retrospectively analyzed to identify patients with BM. Brain imaging in most cases were performed due to onset of neurological symptoms and not for routine surveillance. An analysis of demographics, therapies, gene expression profile, tumor next generation sequencing (NGS) data, time to metastasis (brain or other), and survival in the BM cohort was completed. 116/1,845 (6.3%) mUM patients were identified with BM. The median age at time of UM diagnosis was 54 years old (range: 18-77). The median time to any metastasis was 4.2 years (range: 0-30.8). The most common initial metastatic site was the liver (75.9%). 15/116 (12.9%) BM patients presented with BM at the time of initial metastatic diagnosis. Median survival after a diagnosis of BM was 7.6 months (range: 0.4-73.9). The median number of organs involved at time of BM diagnosis was 3 (range: 1-9). DecisionDX-UM profiling was completed on 13 patients: 10-Class 2, 2-Class 1B, and 1-Class 1A. NGS and cytogenetic data were available for 34 and 21 patients, respectively. BM was identified in 6.3% of mUM cases and was associated with high disease burden and a median survival of under 8 months once diagnosed. Since most patients in this cohort were symptomatic, the incidence of asymptomatic BM remains unknown. These data suggest the use of routine brain imaging in all mUM patients at risk for developing BM for early detection

Three-Year Overall Survival with Tebentafusp in Metastatic Uveal Melanoma.

BackgroundTebentafusp, a T-cell receptor-bispecific molecule that targets glycoprotein 100 and CD3, is approved for adult patients who are positive for HLA-A*02:01 and have unresectable or metastatic uveal melanoma. The primary analysis in the present phase 3 trial supported a long-term survival benefit associated with the drug.MethodsWe report the 3-year efficacy and safety results from our open-label, phase 3 trial in which HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma were randomly assigned in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with pembrolizumab, ipilimumab, or dacarbazine (control group), with randomization stratified according to the lactate dehydrogenase level. The primary end point was overall survival.ResultsAt a minimum follow-up of 36 months, median overall survival was 21.6 months in the tebentafusp group and 16.9 months in the control group (hazard ratio for death, 0.68; 95% confidence interval, 0.54 to 0.87). The estimated percentage of patients surviving at 3 years was 27% in the tebentafusp group and 18% in the control group. The most common treatment-related adverse events of any grade in the tebentafusp group were rash (83%), pyrexia (76%), pruritus (70%), and hypotension (38%). Most tebentafusp-related adverse events occurred early during treatment, and no new adverse events were observed with long-term administration. The percentage of patients who discontinued treatment because of adverse events continued to be low in both treatment groups (2% in the tebentafusp group and 5% in the control group). No treatment-related deaths occurred.ConclusionsThis 3-year analysis supported a continued long-term benefit of tebentafusp for overall survival among adult HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma. (Funded by Immunocore; IMCgp100-202 ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.)

Detection of Circulating Tumor Cells in Uveal Melanoma by the Photoacoustic Method

Abstract Circulating tumor cells (CTCs) have been shown to be a prognostic marker in breast cancer1. We hypothesize that circulating melanoma cell (CMC) detection could be utilized in the management of uveal melanoma, including early intervention. Prior methodologies for circulating uveal melanoma cell (CUMC) detection have been fraught with poor sensitivity, limiting their clinical utility2. Development of an improved method is necessary to establish the clinical utility of CUMC monitoring. Photoacoustics, also referred to as laser-induced ultrasound, is a novel platform for the detection and capture of CMCs. Photoacoustics uses short duration pulsed light to create ultrasonic acoustic waves in an optically absorbing medium, in this case melanin within melanoma3. As light is absorbed by irradiated chromophores, the optical energy gets converted into kinetic thermal energy trapped within the chromophore and subsequent thermal expansion ensues. Transient thermoelastic expansion of the absorbent cell results in the propagation of ultrasonic acoustic waves which can be detected and analyzed using a piezoelectric response mechanism. In addition, detected CMCs can be isolated by a two-phase flow cell separation technique4. Due to the low cost and melanoma specific capabilities of photoacoustics, we evaluated this technology for the purpose of CUMC detection. Methods: Cells from uveal melanoma cell line UM002B, established at Thomas Jefferson, were titrated to various cell concentrations and analyzed in a neutral density solution utilizing the photoacoustic method. Uveal melanoma cells of differing concentrations were spiked into isolated healthy donor peripheral blood mononuclear cells (PBMCs) and healthy whole blood samples. PBMC isolates were analyzed for CUMCs. Results: CUMCs were successfully quantified by the photoacoustic method including single cell detection. Recovery rates of cultured cells in a neutral density solution approached 25%. Recovery rates for CUMCs in whole blood averaged 10% of expected cell yield (56/540 cells detected) with a higher detection rate at lower cell concentrations. Photoacoustics offers a viable method for the detection of CUMCs with an accuracy that meets or exceeds previously reported CUMC yields. Studies analyzing CUMCs from patients with metastatic disease are ongoing.https://jdc.jefferson.edu/medoncposters/1002/thumbnail.jp