Tebe, 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%.
Methods
Heavily 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.
Results
112 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%.
Conclusions
Tebe 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 Registration
NCT02535078
Ethics Approval
The 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.
e20054 Background: Uveal melanoma is the most common primary intraocular tumor in adults, median age at diagnosis of 60 years. Despite a growing understanding of the molecular characteristics of uveal melanoma, the etiology remains unknown. We identified 2 clusters of uveal melanoma in young females with median ages 24 and 31 respectively. Information gained from this cluster evaluation would guide our investigation of potential risk factors for this rare disease. Methods: Descriptive data from medical records and patient questionnaires were obtained on 8 cases involving young females who previously resided in Huntersville, North Carolina (NC) and Auburn, Alabama (AL). Reports on standard incidence ratio (SIR) calculations were provided by the respective states’ departments of health. Results: In NC, 5 females who were identified as living in Huntersville, NC during the year of 2005, were diagnosed with uveal melanoma at ages 20, 22, 24, 30, and 31 in years 2013, 2009, 2008, 2014, and 2011, respectively. Three of these females attended the same high school. In AL, 3 females who were identified as living in the same dormitory while in college from 1989-1993, were diagnosed with uveal melanoma at ages 31, 31, and 42 in years 2000, 2001, and 2012 respectively. These patients were not blood-related relatives and none had a family history of melanoma. The SIR calculations considering the observed and expected incidence of uveal melanoma was 0.7 (95% CI 0.5-0.9), in Mecklenberg County, NC, and 1.15 (95% CI 0.989-1.328) in white females in AL, respectively, and did not show increased incidence of uveal melanoma patients in these regions. Conclusions: Considering the age distribution of uveal melanoma patients, the clustering of this disease in young females is unusual. No increased incidence of uveal melanoma in their communities might indicate existence of distinct causative agents in their shared living environments or lifestyle that might have contributed to the eventual development of uveal melanoma in this unique population. Further investigation into these cases considering infectious etiology, biomarkers for carcinogenesis, environmental exposures, and genetic predisposition to cancer is ongoing.
Abstract Background: Metastatic uveal melanoma (mUM) has a poor prognosis with a 1-yr OS rate of 52%. No systemic treatment has proven an OS benefit in randomized trials. Tebentafusp (tebe), a bispecific consisting of an affinity-enhanced T cell receptor (TCR) fused to an anti-CD3 effector that can redirect T cells to target gp100+ cells, has shown promising activity in previously treated mUM pts. Here, we report the primary analysis of overall survival (OS) in the intention-to-treat population (ITT) of a Ph3 trial of tebe vs. investigator's choice (IC) as first line (1L) therapy in pts with mUM [NCT03070392]. Materials and Methods: In this randomized, open-label, Ph3 trial, 1L HLA-A*02:01+ pts with mUM were randomized 2:1 to receive tebe or IC of pembrolizumab, ipilimumab or dacarbazine, stratified by LDH. The primary endpoint was OS, defined as the time from randomization to death from any cause. Dual primary objectives were to evaluate 1) OS in the ITT population by comparing all tebe-randomized pts to all IC-randomized pts; and 2) OS in tebentafusp-treated patients with rash during week 1 versus all IC-treated patients. Secondary endpoints included safety and RECIST-defined overall response rate (ORR), progression free survival (PFS) and disease control rate (DCR). Here we present the OS in the ITT population. The study was unblinded by an independent data monitoring committee at the first pre-specified interim analysis. Investigator-reported radiographic-based endpoints were not mature at the first interim analysis. This analysis was conducted on the first interim analysis (data extracted Nov 2020). Results: 378 pts were randomized to tebe (252) or IC, including pembrolizumab (103), ipilimumab (15) or dacarbazine (7). Tebe significantly prolonged OS compared to IC (HR 0.51; 95% CI 0.36-0.71; P<0.0001) in the ITT population, with estimated 1-yr OS rate of 73.2% (95% CI 66.3-78.9) vs 57.5% (95% CI 47.0-66.6), respectively. The OS benefit of tebe was observed in pre-specified subgroups, including by stratification variable of LDH>ULN and versus pembrolizumab IC. Most common TRAEs were skin-related (gp100+ melanocytes) or cytokine-mediated (T cell activation) and included pyrexia, pruritus, and rash. These AEs decreased in frequency and severity after the first 3-4 doses and were generally manageable with standard interventions. In the tebe arm, the rate of treatment discontinuation due to TRAEs was low (<4%), and there were no treatment-related deaths. Conclusions: In 1L treatment of mUM pts, tebe monotherapy significantly improved OS compared to IC; the first investigational therapy to improve OS in pts with mUM. Tebe had a predictable and manageable AE profile with a low rate of related discontinuation. Tebe is the first TCR therapeutic to demonstrate an OS benefit. Citation Format: Sophie Piperno-Neumann, Jessica C. Hassel, Piotr Rutkowski, Jean-Francois Baurain, Marcus O. Butler, Max Schlaak, Ryan J. Sullivan, Sebastian Ochsenreither, Reinhard Dummer, John M. Kirkwood, Anthony M. Joshua, Joseph J. Sacco, Alexander N. Shoushtari, Marlana Orloff, Richard D. Carvajal, Omid Hamid, Shaad E. Abdullah, Chris Holland, Howard Goodall, Paul Nathan. Phase 3 randomized trial comparing tebentafusp with investigator's choice in first line metastatic uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT002.
Aim: To compare PD-L1 expression between metastatic uveal melanoma (MUM) and metastatic cutaneous melanoma (MCM). Materials & methods: A total of 295 MCM and 78 MUM specimens were analyzed for tumor cell PD-L1 expression. Additionally, 91 MCM and 45 MUM specimens were analyzed for PD-1 expression on tumor-infiltrating lymphocytes. Results: A total of 77/295 (26.1%) MCM specimens expressed PD-L1 as compared to 4/78 (5.1%) MUM specimens (p < 0.0001). PD-1 expression on tumor-infiltrating lymphocytes was greater in MCM (73.6%; 67/91) than in MUM (51.1%; 23/45), respectively (p = 0.009). Conclusion: Significant differences exist in PD-L1 expression between MCM and MUM. The lower PD-L1 expression in MUM may provide a rationale for failure of PD-1 inhibitor therapy and suggests that immune evasion in this disease may occur via alternative mechanisms.
<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.
e15095 Background: Immune checkpoint blockade is being used with increasing frequency across a variety of tumor types. Corticosteroids are used in diverse clinical scenarios and can have immune-modulatory effects. The administration of steroids with immune checkpoint blockade in combination with cytotoxic chemotherapy has not diminished treatment efficacy in select patient populations1. However, the effect of steroids on the development of immune-related adverse events (irAEs) across tumor types is unknown. We hypothesized that pretreatment with corticosteroids reduces treatment-limiting irAEs. Methods: A single institution registry of patients (n = 163) receiving immune checkpoint blockade, including anti-CTLA-4 antibody (n = 51) or anti-PD-1 antibody (n = 112), was reviewed. Various primary tumor types were included (33% melanoma, 31% non-small cell lung, 36% other). Patients were determined to have discontinued treatment because of irAEs versus any other cause (disease progression, infection, comorbidity, or death). Results: None of the 17 patients (0%) who were receiving corticosteroids prior to starting immunotherapy experienced treatment-limiting irAEs (average dose 34mg/day prednisone or equivalent, only one patient taking < 10mg/day prednisone). This is compared to 29 of 146 patients (19.9%) who were not taking steroids at the start of treatment (p = 0.045). Interestingly, pretreatment steroids were not associated with an increase in disease progression or death. Conclusions: Incidence of treatment-limiting immune-related adverse events was significantly decreased, regardless of tumor type, in patients receiving corticosteroids prior to initiation of immunotherapy. An associated decrease in treatment efficacy was not seen. Table: Incidence of treatment-limiting adverse events in patients undergoing immunotherapy Treatment-Limiting Adverse Events - n (%) Immune Infection or Comorbidity Disease Progression or Death Ongoing Treatment Total On Steroids When Immunotherapy Initiated? Yes 0 (0) 7 (41.1) 8 (47.1) 2 (11.8) 17 (100) No 29 (19.9) 19 (13.0) 71 (48.6) 27 (18.5) 146 (100) Total 29 (17.8) 26 (16.0) 79 (48.4) 29 (17.8) 163 (100)
Patients with advanced melanoma have limited treatment options after progression on immune checkpoint inhibitors (ICI). Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, demonstrated an investigator-assessed objective response rate (ORR) of 36% in 66 patients who progressed after ICI and targeted therapy. Herein, we report independent review committee (IRC)-assessed outcomes of 153 patients treated with lifileucel in a large multicenter Phase 2 cell therapy trial in melanoma.Eligible patients had advanced melanoma that progressed after ICI and targeted therapy, where appropriate. Melanoma lesions were resected (resected tumor diameter ≥1.5 cm) and shipped to a central good manufacturing practice facility for 22-day lifileucel manufacturing. Patients received a non-myeloablative lymphodepletion regimen, a single lifileucel infusion, and up to six doses of high-dose interleukin-2. The primary endpoint was IRC-assessed ORR (Response Evaluation Criteria in Solid Tumors V.1.1).The Full Analysis Set consisted of 153 patients treated with lifileucel, including longer-term follow-up on the 66 patients previously reported. Patients had received a median of 3.0 lines of prior therapy (81.7% received both anti-programmed cell death protein 1 and anti-cytotoxic lymphocyte-associated protein 4) and had high disease burden at baseline (median target lesion sum of diameters (SOD): 97.8 mm; lactate dehydrogenase (LDH) >upper limit of normal: 54.2%). ORR was 31.4% (95% CI: 24.1% to 39.4%), with 8 complete responses and 40 partial responses. Median duration of response was not reached at a median study follow-up of 27.6 months, with 41.7% of the responses maintained for ≥18 months. Median overall survival and progression-free survival were 13.9 and 4.1 months, respectively. Multivariable analyses adjusted for Eastern Cooperative Oncology Group performance status demonstrated that elevated LDH and target lesion SOD >median were independently correlated with ORR (p=0.008); patients with normal LDH and SOD
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.
