ACIS at the European Society for Medical Oncology (ESMO) Annual Congress
| ACIS’s Research Coordinator (Kevin) collected clinical data from uveal melanoma sessions at ESMO (reported below), and met with Patient Advocates from Germany, Slovenia, Ireland, the UK and pictured here colleagues from “Stichting Melanoom” in the Netherlands. We all attended four excellent Patient Advocacy sessions, with speakers from ESMO, EU cancer centers, European Union government agencies, the European Medicines Agency and the World Health Organization. |  |
UVEAL MELANOMA PRESENTATIONS:
Non-cutaneous melanoma and non-melanoma skin cancers: There is much more we can do
Chair: Caroline Robert (Institut Gustav Roussy, Villejuif, Cedex, France
Uveal Melanoma Speaker: Josep Maria Piulats Rodriguez (Hospitalet de Llobregat, Barcelona, Spain)
Dr. Josep Piulats actually walked ‘all the way’ from his hospital in the same neighborhood as the ESMO Fira Congress Center! He impressed the ESMO attendees with a very thorough overview of the key biologic mechanisms which make uveal melanoma genomically distinct, more prone to transform to metastases, and unusually resistant to immune-therapies which are effective in treating metastatic -cutaneous- melanoma. Specifically, uveal melanoma metastatic disease is known to have ‘exhausted’ CD8+ T-cells and few cytotoxic T-cells, low infiltration of PD-1 positive lymphocytes, and low levels of PDL-1, resulting in very few clinical responses to immune agents such as ipilimumab, nivolumab and pembrolizumab. He went on to describe the initiating genetic events in uveal melanoma in the primary eye tumor,
as starting with GNAQ and GNA11 which activate three key pathways which drive tumor cell growth. Secondary post-translation modifications then occur through genes SF3B1, SRFS2, EIF1AX and BAP1, which we now know are able to predict prognosis and risk of metastasis through the highly-validated pioneering work of Dr. William Harbour and the Castle Biosciences’ Decision DX UM Gene Expression Panel/PRAME/NGS testing.
Dr. Piulats then summarized ongoing clinical trials of various experimental therapies for patients with metastatic uveal melanoma: Systemic TIL therapy (lifleucel, NCT05607095), TILs delivered by Intra-Arterial Hepatic Infusion for UM
liver mets (NCT04812470), Anti-angiogenic drugs affecting tumor blood supply (sitravatinib, lenvatinib), relatlimab (human LAG-3 antibody), and immune-stimulating roginolisib (the first highly selective PI3Kδ modulator).
Mini oral session: Melanoma and other skin tumours
Chairs Jessica C. Hassel (Heidelberg, Germany) Bart Neyns (Brussels, Belgium)
Abstract # 1080MO – Sitravatinib (Mirati/BMS) Plus Tislelizumab (BeiGene) for Metastatic Uveal Melanoma with Liver Metastasis: The Open-Label, Multicenter, Phase II GEM-2101 Trial,
Luis Paul De Carpio Huerta (Barcelona, Spain)
Luis P. Del Carpio Huerta (Hospitalet de Llobregat, Barcelona, Spain) Enrique Espinosa (Madrid, Spain)
Luis De la Cruz Merino (Seville, Spain) Alfonso Berrocal-Jaime (Valencia, Spain) Josep Maria Piulats (L`Hospitalet
de Llobregat, Spain)
Background: Immune checkpoint inhibitors have limited activity in metastatic uveal melanoma (MUM). Modulation of the tumor vasculature and immune microenvironment could increase patient survival, especially in patients with liver metastasis (LM). This study aims to assess the efficacy of the combination of sitravatinib (sitra), a pan-TKI inhibitor (targeting RET, the TAM family (TYRO3, AXL and MER-TK), VEGFR2, and KIT), and tislelizumab (tisle), an anti-PD1 antibody designed to minimize the binding to Fcγ receptors, in patients with MUM and LM.
Methods: This was a single-arm, phase II trial testing sitra and tisle (sitra+tisle) for systemic treatment-naïve patients or after failure to 1st line tebentafusp if HLA-A02:01. Eligible patients had confirmed diagnosis of Liver Metastasis for MUM that is considered adequate for correlative biopsies. Sitra (100 mg p.o. q.d.) and tisle (200 mg q.3-w) were administered until progressive disease (PD), toxicity, or withdrawal. The primary endpoint was ORR according to RECIST 1.1. Image evaluations were performed q.6-w.
Results: From Nov 2022 to Jul 2023, 16 patients were enrolled. Median age was 63 years (range: 49-86).
Update from Slides- 37.5% of the patients had prior tebentafusp, and two-thirds had no prior therapy for metastatic UM. Extrahepatic disease was present in 43.8%, high LDH in 56.2% and high ALP in 31.2%. Median duration of treatment was 6.6 months (95% CI: 3.5-12.2). Overall Response Rate was 18.8%, with 3 confirmed partial responses. Stable disease was the most common outcome (81.2%), achieving a disease control rate of 100% with a median follow-up of 6.9 months (range: 2.8-13.4). Median Progression-Free Survival was 8.3 months (95% CI: 7.2-NR). The projected 1-year OS rate was 79.6% (95% CI: 61.1-100). Grade 3-4 treatment-related adverse events were reported in 8 (50%) patients, the most common being hypertension (25%) and diarrhea (18.5%). Treatment was discontinued due to toxicity in
3 (18.8%) patients.
Conclusions: Sitra+tisle showed promising activity with a manageable toxicity profile in patients with MUM and LM.
The PFS observed is the longest PFS ever reported for systemic treatment in MUM. An update on translational research to understand synergy between both drugs using correlative liver biopsies is underway.
Clinical trial identification EudraCT: 2021-002474-99; NCT05542342
UVEAL MELANOMA POSTERS:
https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal_2/presentation/list?q=melanoma
Abstract # 626P – Roginolisib (IOA-244, iOnctura), a first oral allosteric modulator of phosphoinositide 3-kinase inhibitor delta (PI3Kδ) in patients with metastatic uveal melanoma. Anna Marie Giacomo, Univ. Siena, Italy
Matteo Simonelli (Pieve Emanuele, Italy) Federica Santangelo (Siena, Italy) Giovanni Amato (Siena, Italy) Elena Simonetti (Siena, Italy) Jill Graham (Glasgow, United Kingdom) Michael Lahn (Geneva, Switzerland) Giusy Di Conza (Geneva, Switzerland) Tracey Hammett (Geneva, Switzerland) Rebeca Zorrilla (Geneva, Switzerland) Paramjit Kaur (Geneva, Switzerland) Tan Ziyang (Stockholm, Sweden) Tadepally Lakshmikanth (Stockholm, Sweden) Petter Brodin (Stockholm, Sweden) Mariaelena Occhipinti (Liège, Belgium) Carmelo Carlo-Stella (Milan, Italy) Armando Santoro (Rozzano, Italy, (MI)) Pavlina Spiliopoulou (Glasgow, United Kingdom) T.R. Jeffry Evans (Glasgow, United Kingdom) Michele Maio (Siena, Italy)
Background: Roginolisib, a highly selective (oral) modulator of PI3Kδ, reinvigorates antitumor immunity in patients with metastatic uveal melanoma (mUM).
Methods: Roginolisib was investigated in a First-in-human (FIH) dose escalation (Part A) and in a dose expansion (Part B) study at the biologically effective dose (BED) of 80 mg QD in mUM pts. Primary objective: Safety. Secondary objectives: PK; PD (e.g., CD63 expression on basophils, changes in immune cell subsets in peripheral blood); radiographic responses
(RECIST v1.1); PFS and OS. Exploratory: changes in circulating immune cells by mass cytometry; response assessments
by radiomics and blood-based proteins.
Results: Update from Poster- Among the 44 patients with various tumors enrolled and treated in this Phase I study,
43 patients had one or more prior therapies for metastatic disease.
At the BED of 80 mg QD, no treatment-related dose modifications or dose-limiting toxicity (DLT) were seen.
Twenty-nine patients had metastatic Uveal Melanoma (Part A: 9 pts; Part B: 20 pts). Mean time on treatment: 10.9 mo (range: 1.5-42.6 mo). Overall Response Rate (RECIST v1.1): PR: 1/29 (3%); SD: 20/29 (69%). Median OS for Part A: 20.8 mo; Part B: ongoing; Part A+B: ongoing. Update from Poster- Among the 29 met. UM patients, 85% had prior therapy with a median of 2 prior lines (range 0-8, and 86% hepatic+extrahepatic mets) median Overall Survival was 15.9 mo compared to historic median OS of 7.2 mo (published meta-analysis control study, Rantala et al 2019).
Roginolisib decreased circulating regulatory T cells and concomitantly increased CD8T and NK cells. This pattern of immune cell balances was accompanied by a decrease in soluble CTLA4 and an increase of IL15. Volumetric reduction in spleen was observed in most of the mUM patients. Based on RECIST v1.1, two distinct groups were recognized at Week 16 (3.8 mo): pts with SD (median OS: 20 mo; 13/29; 45%) and pts with PD (median OS: 10 mo). Pts with SD had slow volumetric increases by radiomic evaluation of all tumour lesions. Both patient groups had similar tumour genetic backgrounds. The main differences between SD and PD pts at Week 16 were increased activated CD8T cells and IFNγ signaling for SD pts. Furthermore, PI3K-associated signaling molecules and immune-exhaustion markers were significantly higher at baseline in the SD compared to PD pts and decreased only in the SD pts.
Update from Poster- The safety profile of oral roginolisib in this Phase I study demonstrated only two grade 3 toxicities among the previously-treated uveal melanoma patients: 5% diarrhea and 2% abdominal pain.
Conclusions: Uninterrupted administration of roginolisib in mUM patients with advanced malignancies is well tolerated, exhibits immuno-modulatory effects, and in a subset of patients with mUM, shows immune cell activation with associated survival benefit.
Clinical trial identification NCT04328844.
Abstract # 1126P – A Phase 2 study of Nivolumab/Relatlimab (BMS) in Metastatic Uveal Melanoma
Jose Lutzky, Univ. Miami Leonel Hernandez-Aya (Miami, United States of America) Lynn Feun (Miami, United States of America) Zelia Correa (Miami, United States of America) Jeanelle King (Miami, United States of America) Christina Estevez (Miami, United States of America) Christina Decatur (Miami, United States of America) James J. Dollar (Miami, United States of America) Isildinha Reis (Miami, United States of America) J William Harbour (Dallas, United States of America)
Background: Metastatic uveal melanoma (UM) is a difficult to treat rare malignancy. Lymphocyte activation gene 3(LAG-3) is an immune checkpoint receptor associated with T cell exhaustion highly expressed in uveal melanoma CD8+ T cells (Durante et al.). Relatlimab is a human LAG-3 specific blocking antibody currently approved in combination with PD-1 blocking antibody nivolumab in metastatic cutaneous melanoma. Here we report the results of a phase 2 study in patients with metastatic uveal melanoma (MUM).
Methods: A Simon two-stage minimax design was used. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), median duration of response (mDOR), and safety (AEs). The null hypothesis (ORR=5%) is rejected if 4 or more responses are observed in 27 patients.
Results: As of 1/31/2024, 27 metastatic uveal melanoma patients were enrolled and treated. No prior PD-1, CTLA-4 and/or LAG-3 blocking antibody treatment was allowed. Patients were treated with nivolumab 480 mg/relatlimab 160 mg IV q4wks to progression or intolerable toxicity. At a median follow -up of 11.2 months, the Overall Response Rate
in the 26 evaluable patients was 7.7% (Partial Response in 2/26 patients). SD and PD were 42.3% (6/18) and 50% (10/18) respectively. 92.6% of patients experienced treatment related adverse events (TRAE). Of 173 TRAE, 88.9%,66.7% and 25.9% were grade 1, 2 and 3, respectively. There were no grade 4/5 AEs. The most common TRAEs were fatigue (55.6%), ALT elevation (40.7%), AST elevation (29.6%) arthralgias (25.9%) and hypothyroidism (25.9%). There were 10 grade 3 TRAE in 7 patients. Six serious adverse reactions (SAE) were seen in 3 patients; one was considered treatment related (Update from poster– pleural effusion) and 5 were due to PD. Additional results of secondary outcomes will be presented. Results of extensive correlative studies will be submitted as a separate abstract.
Conclusions: Nivolumab + relatlimab is safe but is associated with a -low response rate-
in MUM. Clinical trial identification NCT04552223.
Abstract # 1127P – Subgroup Analysis of FOCUS Phase 3 Trial Efficacy Results.
Matthew Wheater, University Hospital, Southampton, UK
Marlana Orloff (Philadelphia, United States of America) Pier Francesco Ferrucci (Milan, Italy) Junsung Choi (Tampa, United States of America) David Eschelman (Philadelphia, United States of America) Evan Glazer (Memphis, United States of America) Aslam Ejaz (Columbus, United States of America) Erika Richtig (Graz, Austria) Sebastian Ochsenreither (Berlin, Germany) Sunil A. Reddy (Stanford, United States of America) Michael Lowe (Atlanta, United States of America) Georgia M. Beasley (Durham, United States of America) Anja Gesierich (Würzburg, Germany) Martin Gschnell (Marburg, Germany) Reinhard Dummer (Zurich, Switzerland) Ana Maria Arance (Barcelona, Spain) Stephen Fenwick (Liverpool, United Kingdom) Johnny John (New York, United States of America) Christian H. Ottensmeier (Liverpool, United Kingdom) Jonathan S. Zager (Tampa, United States of America, FL)
Background: The majority of metastatic uveal melanoma (mUM) patients require liver-directed therapy at some point in the course of their disease. Melphalan/Hepatic Delivery System (melphalan/HDS, DELCATH CHEMOSAT/HEPZATO) is a drug/medical device combination that was recently approved by FDA for liver-directed treatment of unresectable mUM patients. The phase III FOCUS study demonstrated efficacy and safety of melphalan/HDS in a heterogenous patient population with unresectable mUM. Here we present efficacy analyses in clinically important subgroups.
Methods: Eligible patients with unresectable liver metastases from mUM, with or without extrahepatic disease, received treatment with percutaneous hepatic perfusion (PHP) of melphalan (3.0 mg/kg ideal body weight) once every 6-8 weeks for a maximum of 6 cycles. Efficacy endpoints including objective response rate (ORR), progression-free survival (PFS), overall survival (OS), were assessed among subgroups of patients with and without extrahepatic disease, previously treated and treatment-naive patients, and those with low (1-25%) and high (26-50%) liver tumor burden. Onset of ORR, serious adverse events (SAEs) and Grade 3/4 adverse events (AE) were assessed by treatment cycle.
Results: 102 patients with mUM were enrolled; treatment was attempted in 95 patients, and 91 patients received treatment. Across the 6 subgroups, Overall Response Rate ranged from 31.6% to 37.5%, median Progression Free Survival ranged from 6.2 to 9.3 months, and median Overall Survival ranged from 16.9 to 22.4 months.
57.6% of tumor responses were observed in the first two treatment cycles. The percentages of patients who experienced SAEs in treatment cycles 1-6 were 22%, 15.5%, 13.6%, 5.5%, 7.5% and 17.6%, respectively, of the patients treated in each cycle; by-cycle percentages for Grade 3/4 AEs were 53.8%, 57.1%, 53%, 45.5%, 50% and 47.1%, respectively. Update from Poster– In a subset analysis of patients who had prior treatment for metastatic UM,
the following efficacy rates were observed: Complete Response 4/40 (10%), Partial Response 11/40 (27.5%) and
Stable Disease 11/40 (27.5%), for a combined Disease Control Rate of 65% from Melphalan/Hepatic Delivery System.
Conclusions: Treatment with melphalan/HDS provides clinically meaningful efficacy across the evaluated subgroups. Objective tumor responses occurred throughout all 6 treatment cycles, without evidence of cumulative toxicity.
Clinical trial identification NCT02678572; EudraCT 2015-000417-44.
Abstract # 1128P – Preliminary Results of First-in-Human Study of 225-Actinium MTI-201 (225Ac-MTI-201)
in Metastatic Uveal Melanoma.
Nikhil Khushalani, H. Lee Moffitt Cancer Center, Tampa, FL
Ghassan El-Haddad (Tampa, United States of America) Kenneth Gage (Tampa, United States of America) Mikalai Budzevich (Tampa, United States of America) Michael Schell (Tampa, United States of America) Eduardo G. Moros (Tampa, United States of America) Christopher Tichacek (Tampa, United States of America) Will Gibbons (Tampa, United States of America) Rebecca Rogers (Tampa, United States of America) Michael Nickels (St. Louis, United States of America) Leticia Tetteh (Tampa, United States of America) Zeynep Eroglu (Tampa, United States of America) Lilit Karapetyan (Tampa, United States of America) Andrew S. Brohl (Tampa, United States of America) Joseph Markowitz (Tampa, United States of America) Ahmad Tarhini (Tampa, United States of America, PA) Karen Hayes (Morgantown, United States of America) Lori Hazlehurst (Morgantown, United States of America) Mark McLaughlin (Morgantown, United States of America) David Morse (Tampa, United States of America)
Background: Metastatic UM (mUM) has a poor prognosis with limited therapy options. The melanocortin-1 receptor (MC1R) receptor is highly expressed in UM. Actinium-225 (225Ac) is an alpha particle emitting radionuclide with high linear energy transfer & limited free path in tissue. We developed a novel MC1R targeted radiopharmaceutical, 225Ac-MTI-201 with high biostability, affinity, MC1R-specific cytotoxicity & defined dosimetry/pharmacokinetics (PK) in preclinical studies. Murine studies in UM showed significant tumor growth delay & improved survival with 225Ac-MTI-201. NCT05496686 is a first-in-human trial of 225Ac-MTI-201 in mUM.
Methods: Eligibility includes mUM patients (pts) with progressive disease after at least 1 prior systemic or liver-directed therapy. Patients receive 1 dose of intravenous 225Ac-MTI-201 with PK sampling. The one-compartment model was used to calculate blood and urine PK. There are 12 escalating dose levels (DL) from 4.7 μCi (0.17 MBq) to 1327 μCi (49.1 MBq). This follows a modified continual re-assessment method with cohort size of 1-2 based on dose limiting toxicity (DLT). Primary endpoint (EP) is safety with secondary EPs of PK, response rate & survival.
Results: Updates from Poster in { } – Seven patients {8} (3 female), median age 65 years (46-83), with median 2 (0-3) prior lines of systemic therapy, & three {4} with prior liver directed therapy have been enrolled; six patients {8} have received 225Ac-MTI-201 up to dose level 5 (76μCi). There has been no DLT or G4 toxicity so far. Toxicities include leucopenia (1 G3; 1 G2, {2 G4}), lymphopenia (1 G3, 1G2, {1G4}), neutropenia (1 G3, {2 G4}), ↓ platelets (1 G2, {1 G4}), anemia ({2} G1) & high AST (1 G1). Best response has been stable disease (n= {3}), both at DL 4 and 5; one response is ongoing at 16 {32} weeks post-dose. Blood half-life ranged from 28 to 99 minutes with an elimination rate constant (k1) of 0.007 to 0.025 min-1, and a urinary excretion rate constant (ke) of 1.1 to 4.2 min-1.
Conclusions: In early assessment, 225Ac-MTI-201 single dose administration appears safe up to 76μCi with PK parameters as anticipated. The observation of disease stability is encouraging.
Accrual & dose-escalation is ongoing & a multi-dose study of 225Ac-MTI-201 in mUM is planned.
Supported by NIH/NCI SBIR Phase II Contract HHSN261201700035C & Modulation Therapeutics.
Clinical trial identification NCT05496686.
Abstract # 1129P – Clinical outcomes from a Tebentafusp UK expanded access program in patients with metastatic uveal melanoma (mUM)
Paul Nathan, Mt. Vernon Cancer Centre, Northwood, Middlesex, UK
Jacob N. Tharakan (Northwood, United Kingdom) Joseph J. Sacco (Wirral, United Kingdom) Jemma Proudfoot-Jones (Metropolitan Borough of Wirral, United Kingdom) Andrew Furness (London, United Kingdom, London) David J. McMahon (Dublin, Ireland) Lalit Pallan (Birmingham, United Kingdom, West Midlands) Leila T. Khoja (Birmingham, United Kingdom, Hertfordshire) Patricio Serra-Bellver (Manchester, United Kingdom) Dulani Ranatunge (Cottingham, United Kingdom) Olabode Oladipo (Belfast, United Kingdom) Gemma Clements (Belfast, United Kingdom) Lavanya Mariappan (Newcastle-upon-Tyne, United Kingdom, Tyne and Wear) Toby Talbot (Truro, United Kingdom, Cornwall) Jenny Nobes (Norwich, United Kingdom) Thomas J. Carter (Northwood, United Kingdom) Heather Shaw (London, United Kingdom)
Background: Tebentafusp (T), a T Cell Receptor (TCR) bispecific therapeutic (gp100 x CD3) is licensed for the treatment of mUM in HLA A2.01 patients. Between July 2021 and June 2023, T was made available to HLA A2.01 positive patients with mUM in 17 treating centres in the UK.
Methods: Treating centres were asked to complete an audit database of anonymised outcomes. Submitting centres ensured local data transfer regulations were satisfied. At the time of abstract submission, survival data had been received on 92 patients and additional clinical data on 75.
Results: The audited population (n=75) had a median age of 62 years (range 18-82), 47% female, 53% male. 58% were ECOG PS 0, 39% PS1, 3% PS2. 66% had no previous systemic treatment. 25% had previous hepatic local treatment. 47% had hepatic only disease, 47% both hepatic + extra-hepatic, 6% extra-hepatic only. LDH was normal in 47%, 33% > 1x ULN, 20% > 2x ULNi.v. fluid support was required in 43% patients on wk 1, 37% wk 2, 29% wk 3, 13% wk 4, 4% week 5. G3-4 rash was seen in 17% of patients on wk 1, 16% wk 2, 14% wk 3, 4% wk 4. Corticosteroids were administered to 24% of patients wk1, 20% wk 2, 9% wk 3, 1% wk 4. Response data is currently available for 66 patients. Responses were investigator assessed: CR 3%, PR 12%, SD 51.5%, PD 33.5%. ORR 15%. Median PFS was 2.53 months (95% CI 2.3-2.76) (n=66) Median OS was 19 months (n=92).
Conclusions: This real-world dataset of patients with mUM receiving tebentafusp demonstrates clinically meaningful survival benefit compared with historical datasets. The proportion of patients requiring fluid or corticosteroid is of interest for resource planning. Updated data and additional clinical outcomes will be presented.
Abstract # 1139 Trial in Progress – IDE196 (Darovasertib) in Combination with Crizotinib Versus Investigator’s Choice of Treatment as First-line Therapy in HLA-A2 Negative Metastatic Uveal Melanoma
Marcus Butler, University of Toronto, Ryan Weight (Denver, United States of America) Rizwan Haq (Boston, United States of America) Asad Javed (Iowa City, United States of America) Sreenivasa Chandana (Grand Rapids, United States of America) Bartosz Chmielowski (Los Angeles, United States of America) Reinhard Dummer (Zurich, Switzerland) Matteo S. Carlino (Westmead, Australia, NSW) Meredith Mckean (Nashville, United States of America) Justin Moser (Scottsdale, United States of America) Sanjay Chandrasekaran (Dallas, United States of America) Shaheer Khan (Lake Success, United States of America) Kevin B. Kim (San Francisco, United States of America, TX) Jose Lutzky (Miami, United States of America, FL) Mark Shackleton (Melbourne, Australia) Victoria G. Atkinson (Woolloongabba, Australia) Darrin Beaupre (South San Francisco, United States of America, CA) George W. Cole Jr (South San Francisco, United States of America) Hetal Patel (South San Francisco, United States of America) Marlana Orloff (Philadelphia, United States of America)
Background: Activating mutations in GNAQ & GNA11 (GNAQ/11), the Gα subunits of certain G protein-coupled receptors, have been observed in >90% of patients (pts) with uveal melanoma (UM) and are considered genetic disease drivers. These mutations are present in other solid tumors, including cutaneous and mucosal melanoma, and are recorded in The Cancer Genome Atlas (TCGA) and FoundationOne databases. IDE196 (Darovasertib, previously known as LXS196) is a selective protein kinase C inhibitor which has demonstrated preliminary anti-tumor activity in patients with metastatic UM (MUM). In a phase I/II study the combination of IDE196+ crizotinib (a MET inhibitor) demonstrated an objective response rate (ORR) of 45% in treatment-naïve patients with MUM. The purpose of this study is to determine clinical and safety outcomes of IDE196 in combination with crizotinib in adult participants with HLA-A2 negative MUM.
Trial design: Study IDE196-002 (NCT05987332) is a phase II/3, multi-arm, multi-stage, multicenter, global, open-label study for first-line therapy for HLA-A*02:01 negative patients with MUM who will be randomized to receive either IDE196 + crizotinib or investigator’s choice of treatment (ipilimumab + nivolumab, pembrolizumab or dacarbazine). Approximately 260 and 120 MUM pts will be enrolled in phase II (phase IIa and 2b) and phase III portions of the study, respectively. The primary endpoints of the phase IIa portion are to determine the recommended phase II dose of IDE196 + crizotinib for expansion in the phase IIb portion of the trial and to compare the Progression Free Survival (PFS) of IDE196 + crizotinib vs the investigator’s choice per RECIST 1.1, as assessed by the Blinded Independent Central Review (BICR) committee. Secondary endpoints include ORR, disease control rate (DCR), safety and pharmacokinetics parameters. The primary endpoint of the phase III portion is to compare IDE196 + crizotinib to investigator’s choice of treatment with respect to overall survival (OS).
Clinical trial identification NCT05987332.
Abstract # 1954P – 5-Methylthioadenosine phosphorylase (MTAP) loss in Clinically Advanced Uveal Melanoma (CAUM): A Comprehensive Genomic Profiling (CGP) Study
Nimisha Shrivastava, SUNY Upstate New York, Dean C. Pavlick (Cambridge, United States of America) Sanchit Panda (Syracuse, United States of America) Jeffrey S. Ross and ALINA BASNET (Syracuse, United States of America, NY)
Background: Uveal melanoma is the most prevalent intra-ocular tumor among adults, with nearly half of the patients developing metastatic disease. Treatment options are limited to Tebentafusp in patients with HLA-A*02:01 mutation with immunotherapy and chemotherapy yielding poor results. 5-Methylthioadenosine phosphorylase (MTAP), a key enzyme in the methionine salvage pathway, has emerged as a biomarker for synthetic lethality-based trials featuring Protein Arginine Methyltransferase 5 (PRMT5). In a recent phase I trial of a PRMT5 inhibitor, PRT811, clinical activity was described in cases of CAUM.
Methods: 676 CAUM and 9666 CASM patients underwent hybrid capture based CGP to evaluate genomic alterations (GA). Microsatellite instability high status (MSIH), tumor mutation burden (TMB), homologous recombination defect (HRD) score, genomic ancestry and genomic signature were determined from the sequencing data. PD-L1 was determined by immunohistochemistry (Dako 22C3).
Results: CAUM patients when compared to clinically advanced skin melanoma (CASM) patients were more often female (53.7% vs 36.7%), and younger (median age 64 vs 66). CAUM had lower frequency of UV-light exposure signature (2.5% vs 55.9%), GA/tumor frequency (3 vs 6), and TMB>10mutations/Mb (4.1% vs 58%). CAUM had lower frequency of BRAF GA (13.3% vs 44.4%), MTAP loss associated with 9p chromosomal loss and CDKN2A/B (4% vs 15.5%). CAUM associated GA in GNA11 (44.1%) and GNAQ (46.2%) were rarely identified in CASM (1.0% or less). GA more frequent in CAUM included BAP1 (53.1% vs 1.7%), MYC (33.6% vs 4.0%), while in CASM included KIT (5.4% vs 0.7%), NF1 (21.0% vs 2.1%), and TERT (24.6% vs 4.0%). These differences were statistically significant (p<0.0001). Any level of PD-L1 expression was higher in CASM (43.8% vs 26.1%; p=0.0007). Both groups were noted to have 93% European ancestry and neither group had MSIH cases.
Conclusions: ESMO recap ocular melanoma – Although MTAP loss is less frequent in CAUM than in CASM, the recent evidence that this genomic alteration predicts responsiveness to PRMT5 inhibition is noteworthy. This highlights the importance of further investigating this biomarker for patients with this rare and clinically aggressive type of cancer.
–end– ESMO 2024 report compiled by Kevin (ACIS Research Coordinator) ESMO recap ocular melanoma