Sessions, Posters and Abstracts in Uveal MelanomaThis year at ASCO 2024 was a bit more special, as it marks the 5-year anniversary of Kevin’s first contact with Loren and Melody at the ACIS Patient Advocacy Booth! In June 2019, Kevin was facing biopsy a few weeks later, and he didn’t know anything about the Castle DecisionDx-UM® Gene Expression Panel and Next Gen. Sequencing. Melody and Loren told him to obtain the forms from Castle at their booth. He flew home to Philadelphia to have his ocular oncologist sign and order the testing kit in time for the biopsy. Now 5 years later, he is living proof of the real predictive value of these very unique prospectively-validated analytical tests. We convey our thanks to Dr. Harbour and the Castle Team for their incredible gift of high-tech medical science to patients living with UM.
A. Key Uveal Melanoma Abstracts Presentations
Abstract# 9511 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 (REPLIMUNE) Joseph Sacco, Kevin Harrington, Anna Olsson-Brown, Tze Chan, Pablo Nenclares, Isla Leslie, Praveen Bommareddy, Alireza Kalbasi, Ben Xie, Moran Mishal, David Cohan, Aglaia Skolariki, Mark Middleton
A total of 17 patients with Metastatic UM 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 Overall Response Rate was 29.4% (5/17; all PRs;
RP2 monotherapy, 1/3; RP2 + nivo, 4/14). The Disease Control Rate (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. NOTES FROM SLIDES: Three patients with PR still responding 500+ days. Patient responses by HLA -A02:01 status: positive (1 PR and 2 SD) and negative
4 PR and 3 SD). One Patient with liver mets who had failure of their prior nivo+ipi had durable SD/PR at
9 months. The most common overall grade 1–2 treatment-related Adverse Events (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.
Replimune reports preparations are underway for pivotal registration study.
Abstract# 9509 Phase II multi-center study of adjuvant nivolumab in combination with ipilimumab in patients with high-risk uveal melanoma (HCRN MEL17-309) (BMS) Suthee Rapisuwon, Richard D. Carvajal, George Ansstas, Katy K. Tsai, Leonel Fernando Hernandez-Aya, Shaheer Khan, Sunandana Chandra, J. William Harbour, Jeffrey A. Sosman, Adil Daud, Deniz Ozisik, Ming Tony Tan, Michael B. Atkins, Sapna Pradyuman Patel, Christina Decatur
Fifty-two UM patients (not yet metastatic, and defined as high risk- matched for tumor characteristics: GEP class 2, LBD≧12mm) were enrolled and 50 were treated from 12/18/2018-9/29/2021. As of 11/6/2023, with a median follow-up of 36 months, the 3-year median distant metastatic-free survival (DMFS) rate vs. COOG control, was 69.1% vs 45.1% (two-sided p = 0.012) without any adjustment; and 70.4% vs 43.4% (two-sided p = 0.018) with the propensity score method. The median DMFS was not reached (NR) in the tx cohort vs 33.8 months. There was a reduction in the risk of distant recurrence with Nivo/Ipi vs control cohort (RR 0.52, 95%CI, 0.309-0.888). Median OS has not been reached with only 7 deaths from UM in the Tx cohort so far. Grade ≥3 any-cause AE occurred in 27 pts (54%) . Grade ≥3 treatment-related (TR) AE occurred in 48% (colitis, diarrhea, ALT increase, adrenal insufficiency) .
22 pts (44%) discontinued the treatment due to toxicity (myocarditis, pneumonitis, colitis, hepatitis). One patient died due to immune-related myocarditis.
Abstract# 9510 A Phase 2 safety and efficacy study (NADOM) of neoadjuvant/adjuvant darovasertib (IDE-196) for localized ocular melanoma (Ideaya) Anthony M. Joshua, Roderick O’day, William Glasson, David Sia, Lindsay McGrath, Malaka Ameratunga, Rasha Cosman, Svetlana Cherepanoff, Michael O’Quigley, Darrin M. Beaupre, Max Conway, Li-Anne Lim, John McKenzie, Daniel McKay, Mark J. Shackleton, Adrian Fung, Timothy Isaacs, Jacob Yousif, Christine Brooks, Trifon Psaroulis
Patients planned for enucleation with localized UM were treated in an initial safety cohort with darovasertib 300mg BID for 1 month (n=3 patients), and then following DSMB agreement in an expansion cohort for up to 6 months (n=12 patients) as neoadjuvant treatment prior to definitive management (enucleation, plaque brachytherapy or EBRT). 15 patients (male n=7, female n=8; median age 62 years (range, 33-76 years)) were enrolled. At baseline, AJCC tumor stages were T3a (n=5), T3b (n=4), T4a (n=4), T4b (n=2), and the median tumor size (maximum thickness/diameter/volume) was 9.7mm/ 15.6 mm/ 2463 mm3. At datalock; 11/15 patients had completed primary treatment, 4/15 remained on neoadjuvant treatment, 6 patients received adjuvant darovasertib after primary treatment of their UM with 3 patients completing the planned 6-months. Median tumor shrinkage (maximum height/base/volume change) was 11.2%/ 7.6%/ 22.7% after 1 month of treatment and 31.7%/ 11.9% /45.3% after 6 months. At datalock, 6/9 (66%) currently completed neoadjuvant patients were converted to plaque brachytherapy (n=5) or EBRT (n=1) with 3 ongoing. One patient with high-risk cytogenetic features had relapsed with metastatic disease despite receiving 6-months of neoadjuvant darovasertib and another 6-months of adjuvant treatment. Treatment emergent adverse events included postural hypotension (Gr1/2 – 5/33%), syncope (Gr3 – 2/13%), rash (Gr1/2/3 – 10/67%), pruritis (Gr1 – 13%), dizziness (Gr1 – 6/40%), fatigue (Gr1/2 – 60%), nausea (Gr1/2 – 13/87%), vomiting (Gr1/2 – 7/47%), and diarrhea (Gr1 – 11/73%). The investigators discussed implications of this study and darovasertib adjuvant/neo-adjuvant therapy for primary UM patients as possibly offering 2-3 fold lower risk of loss
of sight from substantially lower radiation doses reaching and damaging the optic nerve and fovea.
Ideaya is now conducting anew Phase 2 study in patients diagnosed with primary localized uveal melanoma requiring enucleation or plaque radiotherapy: https://classic.clinicaltrials.gov/ct2/show/NCT05907954
Kevin attended an ASCO Patient-Advocate meeting with the staff from the FDA’s Oncology Center of Excellence. Topics we addressed with FDA OCE Director Dr. Pazdur and
his Physicians included: Durable Stable Disease vs. Progressive Disease as a clinical endpoint for studies in rare cancers, and “too-stringent exclusion criteria” in early- and late- stage clinical trials (which may exclude cancer patients with common co-existing diseases such as hypertension, diabetes and impaired renal function). FDA OCE staff doctors also related that Project Optimus (dose optimization for oncology trials) continues to be reconsidered for such limitations, and currently cardiovascular disease parameters are being re-evaluated.
Kevin also attended an ASCO-FDA Special Session on the critical drug/chemotherapy shortage. The FDA Commissioner Dr. Robert Califf, and Dr. Pazdur, were welcomed by
Dr. Julie Gralow, ASCO’s Chief Medical Officer. FDA and ASCO reviewd their recent joint initiatives which expedited importation of generic chemotherapies (ie. cisplatin) into the
USA from Chinese sources via Canada (which had not been previously approved by FDA). Kevin suggested a novel regulatory opportunity, which Dr. Califf noted would require
an act of Congress to become law, prior to enactment and easing of the drug shortage crisis.
B. Posters and Published Abstracts in Uveal Melanoma
Abstract TPS9612: First-in-human study of 225actinium mti-201 (225Ac-MTI-201) in metastatic uveal melanoma (UM) (Modulation Therapeutics) Podcast with Dr. Khushalani on ACIS website.
Nikhil Khushalani, Ghassan El-Haddad, Kenneth Gage, Mikalai Budzevich, Michael Schell, Eduardo Moros, Christopher Tichacek, William Gibbons, Rebecca Rogers, Michael Nickels, Leticia Tetteh, Zeynep Eroglu, Lilit Karapetyan, Andrew Brohl, Joseph Markowitz, Ahmad Tarhini, Karen Hayes, Lori Hazlehurst, Mark McLaughlin, David Morse
This is a single institution (Moffitt Ca. Ctr., Tampa) first-in-human Phase I study (NCT05496686) of
225Ac-MTI-201 in metastatic UM. The primary objective is to determine the safety of a single intravenous dose of 225Ac-MTI-201 relative to radioactivity dose. Secondary endpoints include 1) pharmacokinetics (PK) and clearance of 225Ac-MTI-201, 2) objective response rate and duration, progression-free survival, and overall survival in metastatic UM. Salient eligibility criteria include: 1) age ≥18 years; 2) histologically confirmed metastatic UM with progression after at least 1 prior line of therapy; 3) measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1; 4) Eastern Cooperative Oncology Group performance status of ≤1; 5) adequate marrow, renal and hepatic function; 6) no more than 25% of bone marrow treated with prior radiotherapy. Patients will receive a single dose of 225Ac-MTI-201 under appropriate guidelines and precautions for administration of radiopharmaceuticals. Pre-injection and post-injection PK sampling at defined intervals are undertaken. There are 12 dose levels for 225Ac-MTI-201 being investigated ranging from 4.7 microcurie (µCi) to 1327 µCi. Dose escalation is done using a modified continual re-assessment method with a cohort size of one based on dose limiting toxicity (DLT) assessment within 28 days of drug administration using CTCAE v5.0. Definitions of DLT include G4 neutropenia or febrile neutropenia, G4 thrombocytopenia or G3 thrombocytopenia with clinically significant bleeding, > G3 non-hematological toxicity with selected exceptions, laboratory abnormalities that satisfy Hy’s law, or any death not related to underlying disease or extraneous cause. Response assessments are undertaken with cross-sectional imaging every 8 weeks in year 1, and every 12 weeks in year 2. This study is currently open for enrollment. Dose levels 1-4 have been completed without Dose Limiting Toxicity. Clinicaltrials.gov
link to ongoing Phase I study: https://classic.clinicaltrials.gov/ct2/show/NCT05496686
Abstract# 9556: Melphalan/hepatic delivery system versus best available care in patients with unresectable metastatic uveal melanoma: Randomized FOCUS trial results. (Delcath, Hepzato®) Jonathan Zager, Marlana Orloff, Pier Francesco Ferrucci, Junsung Choi, David Eschelman, Evan Glazer, Aslam Ejaz, Erika Richtig, Sebastian Ochsenreither, Sunil Reddy, Michael Lowe, Georgia Beasley, Anja Gesierich, Martin Gschnell, Reinhard Dummer, Ana Arance, Stephen Fenwick, Johnny John, Matthew Wheater, Christian Ottensmeier
Pivotal Phase III trial of Hepzato (Melphalan/Hepatic Delivery System) in patienst with unresectable metastatic UM. From February 2016 to October 2018 a total of 129 patients were screened and 85 patients were enrolled at 22 centers in the US and Europe; eligible patients were randomized to receive melphalan/HDS (N=43) or Best Alternative Care (N=42) and 72 patients received study treatment. Exploratory analyses of efficacy endpoints showed numerical differences consistently favoring the melphalan/HDS arm vs. BAC (median Overall Survival: 18.5 vs 14.5 months; median progression free survival: 9.1 vs 3.3 months; objective response rate: 27.5% vs 9.4%; and disease control rate: 80.0% vs 46.9%). Serious adverse events (SAEs) occurred in 51.2% of melphalan/HDS and in 21.9% of BAC patients. Most common (>5%) SAEs included thrombocytopenia (19.5%), and neutropenia (9.8%), leukopenia (9.8%) and febrile neutropenia (7.3%) in melphalan/HDS patients and cholecystitis, nausea and vomiting (6.3% each) in BAC patients. No treatment-related deaths were observed.
Abstract # 9598: The 15-gene expression profile test is independent from PRAME and
7-gene next-generation sequencing: Results from 3,267 clinically tested uveal melanomas.
(Castle Biosciences, Decision DX-UM®) Robert Cook, Katherina Alsina, Jennifer Siegel, Kristen Oelschlager, Sherri Borman Podcast with Dr. Alsina on ACIS website.
The 15-gene expression profile (15-GEP) test is the gold standard in the US for metastatic risk prediction in uveal melanoma (UM). Studies have shown that the 15-GEP is superior to and independent of other clinicopathologic and molecular risk factors, including PRAME expression status and BAP1 mutation status. Supplemental tests for PRAME and the 7-gene NGS panel (BAP1, SF3B1, EIF1AX, GNA11, GNAQ, CYSLTR2, PLCB4)are validated and can now be run clinically from the same biopsy specimen. However, the discordance between 15-GEP, PRAME and NGS in clinical specimens is unknown. This study aimed to determine whether PRAME status or DNA mutation status could be used to predict the 15-GEP result. Data from fine-needle aspiration biopsy or formalin-fixed paraffin-embedded UM specimens submitted for routine comprehensive clinical testing with all three commercial tests (15-GEP, PRAME, and NGS) between February 2018 and December 2023 were collected through an Institutional Review Board-approved protocol.
Overall, 3267 tumors with comprehensive molecular testing were analyzed. 15-GEP testing yielded 65.9% (n=2152/3267) Class 1 and 34.1% (n=1115) Class 2 tumors. While Class 2 tumors were more than twice as likely to be PRAME(+) vs Class 1, 54.3% (606/1115) of Class 2 cases were PRAME(–), and 20.9% (450/2152) of Class 1 cases were PRAME(+) resulting in a PRAME/15-GEP discordance rate of 32.3% (10-56/3267). Mutations in genes associated with increasing metastatic risk (EIF1AX, SF3B1, and BAP1, respectively) were identified in 58.7% (1918/3267) of cases.
Most EIF1AX mutations (569/623, 91.3%) occurred in Class 1 tumors that were PRAME(–), while most SF3B1mutations were found in Class 1, PRAME(+) tumors (244/404, 60.4%). Most BAP1 mutations (863/976, 88.4%) occurred in Class 2 (high risk) tumors, of which 53.9% (465/863) were PRAME(–). Importantly, 56.0% (1205/2152) of Class 1 tumors did not harbor detectable EIF1AX or SF3B1 mutations, and 22.6% (252/1115) of Class 2 tumors did not harbor a detectable BAP1 mutation, yielding an NGS/15-GEP discordance rate of 44.6% (1457/3267).
Given that the 15-GEP has been shown to be superior to both PRAME and NGS in predicting metastatic outcomes, it is recommended that these supplemental tests only be considered in the context of a 15-GEP test result to prevent potentially over or under identifying high-risk biology. An ongoing prospective study with long term outcomes for over 1700 UM patients led by the Collaborative Ocular Oncology Group (COOG2) will provide insight into how best to effectively integrate these supplementary biomarkers with the 15-GEP class result.
Abstract# 9597: Roginolisib, an oral, highly selective and allosteric modulator of phosphoinositide 3-kinase inhibitor delta (PI3Kδ) in patients with uveal melanoma and advanced cancers. (iOnctura SA)
Anna Maria Di Giacomo, Matteo Simonelli, Federica Santangelo, Giovanni Amato, Elena Simonetti, Jill Graham, Michael M. F. Lahn, Giusy Di Conza, Tracey Hammett, Rebeca Zorrilla, Marco Durini, Ziyang Tan, Lakshmikanth Tadepally, Petter Brodin, Mariaelena Occhipinti, Carmelo Carlo-Stella, Armando Santoro, Pavlina Spiliopoulou, T.R. Jeffry Evans, Michele Maio
Continuous daily dosing of roginolisib at 10, 20, 40 and 80 mg in patients with pretreated solid tumours and Follicular Lymphoma (FL) were evaluated (Part A). Part B consists of a dose confirmation cohort in uveal melanoma (UM) patients of 2 parts: B.1 and B.2.
Results: Part A Solid Tumour (completed): Sixteen pts were treated in 4 cohorts of 4 pts each. Pts characteristics: uveal melanoma (9/16; 56%), cutaneous melanoma (5/16; 31%) and pleural mesothelioma (2/16; 13%). Only Grade 1 and 2 Adverse Events by CTCAE v.5 were observed, including
2 cases of transient (lasting < 24 hrs) diarrhea and 2 of AST/ALT elevation. Treatment-emergent adverse events (TEAEs) did not result in study drug discontinuation, immune-related toxicity, or dose-limiting toxicity in either the solid tumor or hematological patients. UM pts (Part A and Part B)>: 29 pts (Part A:
9 pts; Part B.1: 7 pts, Part B.2: 13 pts), of which 23 were treated at 80 mg QD (RP2D). Mean time on treatment: 10.7 mo (range: 1.5-39.6 mo). Objective Response Rate (RECIST 1.1): PR: 1/29 (3%); SD: 21/29 (72%). Median Overall Survival for Part A: 20.8 months (5/9 with 4 pts alive); Part B.1 20.1 months (4/7 with 3 pts alive); Part B.2 not determined; 1-year OS rate: Part A 66.7%; Part B.1 71%; Part B.2 immature. Exploratory Investigations: At 3.7 mo (Cycle 5), there were 2 groups: one with Stable Disease (13/29; 45%) and the other with Progressive Disease (16/29; 55%). At 6 mo, this split continued with 38% (11/29) showing SD and 62% having PD (18/29). Volumetric changes matched durable SDs while having higher sensitivity in the 15 analyzed patients. Interestingly, tumor burden reduction in mediastinal lymph nodes was indicative of SD and 70% of pts had volumetric spleen size reduction. Volumetric and radiomic changes were matched with peripheral changes in plasma proteins and immune cell changes. Notes from data on Poster: Patients with Stable Disease at Week 16 (13/29) had median OS 28.5 months and patients with Progressive Disease at 16 weeks (16/29) had median OS 10.9 months.
Roginolisib is well tolerated at 80 mg, demonstrates efficacy, and induces phenotypic changes in circulating immune cells. At the RP2D, the most robust anti-tumour activity was observed in FL (50% PR) and UM pts (3% PR; 72% SD). Link to clinical trial in Europe: https://clinicaltrials.gov/study/NCT04328844?intr=ioa-244&rank=1
Abstract# 9533: Overall survival after isolated hepatic perfusion in combination with ipilimumab and nivolumab in patients with uveal melanoma metastases (the SCANDIUM II trial) (Sahlgrenska University Hospital, Gothenburg, Sweden and BMS)
Axel Nelson, Amir Shafazand, Christian Cahlin, Ana Carneiro, Hildur Helgadottir, Max Levin, Magnus Rizell, Gustav J. Ullenhag, Sara Wirén, Per Lindner, Jonas A Nilsson, Lars Ny, Roger Olofsson Bagge
In this multicenter open, randomized, controlled, Phase Ib trial, patients with liver dominant metastatic uveal melanoma were randomized to receive either: IHP followed by combination immunotherapy (four cycles IPI3/NIVO1) (Arm A), or one cycle of IPI3/NIVO1 before IHP followed by three cycles IPI3/NIVO1 (Arm B). Thereafter, patients in both Arm A and B received monotherapy with nivolumab (480 mg q4w) for up to 1 year. Isolated hepatic perfusion was performed using melphalan 1mg/kg perfused through the liver for 60 minutes under hyperthermia (40°C). The primary endpoint was incidence and severity of adverse events.
In total, 18 patients were included in the trial, 9 randomized to Arm A and 9 to Arm B. 78% were treatment naïve; 28% had both hepatic and extra-hepatic metastases. Three patients did not undergo IHP as planned, one in arm A and two in arm B. Patients received a mean of 2.4 cycles of IPI/NIVO in Arm A and 3.0 cycles in Arm B. There were more IPI/NIVO related adverse events (grade I-IV) in arm B (48 vs. 86). The overall response rate was 38%, 57% in arm A and 22% in arm B, and the median duration of response was 11.9 months (95% CI, 8.2-NE, n = 6). At a minimum follow-up of 18 months, the overall survival rate was 50% (95% CI, 31.5-79.4%) in the whole study population, 56% (95% CI, 31-99%) in arm A and 44% (95% CI, 21-92%) in arm B. The median OS in arm A was 18.2 months (95% CI, 13.2-NA months) and 17.2 months (95% CI, 14.0-NA months) in arm B. In patients with liver dominant metastatic uveal melanoma, combining IHP with IPI3/NIVO1 is a feasible treatment. One dose of IPI3/NIVO1 before IHP had no obvious benefit in response or OS, but was associated with higher rates of toxicity. There was no apparent survival advantage compared to patients in the SCANDIUM trial with IHP only, however, sample size and non-overlapping patient characteristics severely hamper comparison between the trials. The numerically higher response rate in Arm A warrants a larger randomized study that is designed to detect a difference between IPI/NIVO with or without IHP.
Abstract# 9532: Long-term overall survival after isolated liver perfusion (IHP) with melphalan in patients with isolated liver metastases of uveal melanoma (SCANDIUM trial). (Sahlgrenska University Hospital, Gothenburg, Sweden) Axel Nelson, Amir Shafazand, Charlotta All-Eriksson, Christian Cahlin, Nils Elander, Hildur Helgadottir, Jens Folke Kiilgaard, Sara Kinhult, Ingrid Ljuslinder, Jan Erik Mattsson, Magnus Rizell, Malin Sternby Eilard, Gustav J. Ullenhag, Jonas A Nilsson, Lars Ny, Per Lindner, Roger Olofsson Bagge
A total of 87 patients were randomized and assigned to either IHP (43 patients) or control (44 patients).
In the IHP group, 41 (89%) patients received IHP. In the control group, the first-line treatment was chemotherapy (49%), immunotherapy (39%) or localized treatment interventions (9%). The overall response rate was 40% in the IHP group, with a median duration of response of 13.7 months (95% CI, 11.6-18.3, n=17). At a minimum follow-up of 36 months, the 3-year Overall Survival rate was 18.6% (95% CI, 10.0-34.8%)
in the IHP group compared to 9.1% (95% CI, 3.6-23.1%) in the control group (p=0.23, fisher exact test),
and the 5-year OS rate was 16.3% (95% CI, 8.3-32.1%) compared to 6.8% (95% CI, 2.3-20.3%). The median OS in the IHP group was 21.4 months (95% CI, 19.0-30.4 months) compared to 17.3 months (95% CI, 13.8-22.3 months) in the control group (p=0.11, log-rank test). This extended analysis from the SCANDIUM trial supports long-term efficacy of a one-time treatment with IHP compared to best alternative care in patients with isolated liver metastases of uveal melanoma.
Abstract# 9529: Comparison of clinical outcomes of stable disease with confirmed tumor reduction and RECIST partial response for tebentafusp in metastatic uveal melanoma (mUM).
(Immunocore, KIMMTRAK®) Alexandra Ikeguchi, Takami Sato, Marcus O. Butler, Richard D. Carvajal, Joseph J Sacco, Alexander Noor Shoushtari, Jessica Cecile Hassel, Paul D. Nathan, Josep M. Piulats, Douglas Buckner Johnson, Jason J. Luke, Enrique Espinosa, Serge Leyvraz, Laura Collins, Ramakrishna Edukulla, Piruntha Thiyagarajah, Omid Hamid
127 HLA-A*02:01+ pts with previously treated mUM received weekly intravenous tebentafusp following
intra-patient dose escalation of 20mcg Week 1, 30mcg Week 2 and 68mcg Week 3+ (NCT02570308; Carvajal 2022). Radiologic assessments were performed every 8 weeks until week 40, then q12 weeks. Tumor assessment was evaluated by a blinded independent review committee per RECISTv1.1. MR was prospectively defined as RECISTv1.1 best response of SD with reduction in sum of target lesions of -10% to -29% and which was confirmed ≥ 4 weeks later. ctDNA levels were assessed using a targeted mPCR-NGS assay for mutations in 15 genes including mUM oncogenes GNAQ, GNA11, SF3B1, CYSLTR2, PLCB4 and EIF1AX (Natera). Molecular response was defined as ≥ 0.5 log [68%] ctDNA reduction by week 9. Data cut off: Oct 2022. Median duration of follow-up was 46 months.
Of 127 pts, the clinical benefit rate of PR + SD was 50% (64/127). 25% (32/127) had any tumor reduction that was confirmed on ≥ 1 subsequent scan, including 6 PR (ORR 5%) and 26 SD (20%). 8/26 SD (6% of 127) met the pre-defined threshold for MR, most (5/8) had >20% reduction. The median duration of response for PR and MR were 8.7 months and 10.6 months, respectively. The estimated percent of pts with PR and MR remaining in response at Month 20 were 20% and 33%, respectively. 3/6 PR pts were alive ≥ 3 years vs 3/8. 58% of PR + SD pts with evaluable ctDNA had a molecular response (26/45), including 2/4 PRs and 5/5 MRs.
This Phase 2 UM study prospectively confirmed that a subset of SD patients had tumor reduction over multiple scans. The frequency of minor response was similar to that of PR and had similar durability,
OS and ctDNA molecular response. SD with confirmed tumor reduction is an emerging endpoint for the ImmTAC platform and will be studied in other trials (NCT05549297, NCT04262466). Clinical trial information: NCT02570308.
Abstract# 9536: 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. (Immunocore, KIMMTRAK®) Ryan J. Sullivan, Laura Collins, Joseph J Sacco,
Piruntha Thiyagarajah, Paul D. Nathan, Richard D. Carvajal
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).
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. 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.
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.
Abstract# 9537: Association between clinical and disease characteristics and detectable or undetectable baseline ctDNA in patients with metastatic uveal melanoma. (Immunocore, KIMMTRAK®) Paul D. Nathan, Laura Collins, Richard D. Carvajal, Piruntha Thiyagarajah, Ryan J. Sullivan, Joseph J Sacco
Disease characteristics of Study IMCgp100-202 1st Line (Study 202) and IMCgp100-117 2nd Line+ (Study 102) patients 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.
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.
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.
C. Publication Only:
Abstract# e-21572: Real world experience of molecular landscape of uveal melanomas: Implications for personalized medicine strategies. (Datar Cancer Genetics (UK) and HCA Healthcare-UK) Tim Crook, Vineet Datta, Eisa Velicaria, Poornima Vijayan, Rahul Gosavi, Darshana Patil, Ramin Ajami
In this study, we conducted a comprehensive genomic analysis of tissue samples from 7 UM cases to identify key genetic alterations and molecular features, elucidating the heterogeneity of this ocular malignancy. Consistent with other studies, 57% (4/7 patients) of our cohort harbored a driver mutation in either the GNAQ or GNA11 genes. GNAQ Q209 codon mutations (Q209L or Q209P), were the most frequent variants identified. GNAQ/GNA11 mutations are known to activate the MAPK/ERK signaling pathway, contributing to uncontrolled cell proliferation; its presence qualifies for entry into clinical trial testing DYP688 in metastatic UM. Concurrent mutations were identified in EIF1AX (n = 1), SF3B1 genes (n = 1) and BAP1 (n = 1), highlighting the molecular diversity. EIF1AX, SF3B1, and BAP1 inactivating mutations indicate varying risks for distant metastasis, categorized as low, medium, and high risk, respectively. Notably, homologous recombination repair (HRR) pathway gene mutations were identified in 28% (2/7) of cases. Additionally, SF3B1 mutations have been proposed to induce a BRCA-like phenotype, resulting in synthetic lethality to PARP inhibitors (PARPi). These findings provide opportunities to explore additional targeted therapy (off label) options with PARPi. In a case where gene expression profiling (GEP) was performed, an upregulation in PRAME gene expression (PRAME+) was observed. This finding potentially indicates an increased metastatic risk and a shorter time to metastasis, given that PRAME+ status has been established as an independent risk modifier for metastasis, regardless of the GEP-derived UM class (Class 1 or 2). TMB ranged from 2 to 21 muts/mb, with 5 out of 7 specimens showing low TMB ( < 10 mutations/Mb) and two sample with high TMB (15 and 21muts/mb). This case with TMB of 21 muts/mb showed Deficient Mismatch Repair (dMMR) status. All samples evaluated for PD-L1 expression (n = 4) in our cohort showed < 1% PD-L1 expression in tumor cells, including the dMMR tumor.
Abstract # e21566 Geospatial analysis of the distribution of uveal melanoma patients at a referral center in the United States. (Thomas Jefferson University) Rino Seedor, Daniel Vader, Renee Moore, Alexandre Motta, Sara Lally, Carol Shields, Takami Sato, Marlana Orloff
We previously identified three unique geospatial accumulations of UM in North Carolina, Alabama, and New York based on our clinical experience. Such unexpected findings prompted us to conduct a more systematic evaluation of geospatial accumulations of UM patients at our institution.
Through the electronic medical record system, we identified patients seen at our institution with a diagnosis of UM. Identified living patients and family of deceased patients were either sent an e-mail or paper letter with an internet link to a survey. The survey asked for the patient’s name, date of birth, sex, date of primary UM diagnosis, address at time of UM diagnosis and number of years at that address, and all previous addresses and dates of residence prior to the UM diagnosis. Using these addresses, ArcGIS and R software was used to analyze the geospatial distribution of our UM patients. The data was supplemented with 2020 American Community Survey census estimates at the state, county, and census tract level to estimate population-based rates of UM.
We identified 2718 UM patients in our clinical database, and a total of 726 participants completed the survey with a total of 2939 US addresses. The majority of addresses were precise to the street address level (77.9%). At the time of UM diagnosis, patients had lived at their current address for a median of 16 years. Pennsylvania and the neighboring states expectedly made up the majority (63.6%) of our patients, but about 1/3 of our patients resided in other states at the time of their UM diagnosis (total of 42 different states). Several counties presented elevated rates of UM with ≥5 case per 100,000 persons. We observed a group of counties in central Pennsylvania, at the border of Pennsylvania and New York, and in upper New York by the Finger Lakes with notably elevated rates of UM, which was consistent with our clinical observations at our institution. Several neighboring counties in Kentucky and Virginia also presented elevated rates.
Through this pilot project, we have demonstrated that it is possible to collect lifetime residency information from UM patients in order to map their geospatial distribution in the US. Furthermore, although institutional bias toward referring physicians should be considered, our geospatial analysis identified accumulations of UM in areas similar to our clinical concerns. The results of our study warrant further investigations into environmental influences on UM development. Our future goal is to extend our approach through national and international collaborations to increase the number of participants in the analysis and to minimize institutional bias.