Showing papers by "Richard D. Carvajal published in 2023"

A phase I trial of LXS196, a protein kinase C (PKC) inhibitor, for metastatic uveal melanoma

Abstract: Up to 50% of patients with uveal melanoma develop metastases (MUM) with a poor prognosis and median overall survival of approximately 1 year.This phase I study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of the oral protein kinase C inhibitor LXS196 in 68 patients with MUM (NCT02601378). Patients received LXS196 doses ranging from 100-1000 mg once daily (QD; n = 38) and 200-400 mg twice daily (BID; n = 30).First cycle dose-limiting toxicities (DLTs) were observed in 7/38 (18.4%) QD and 2/17 (11.8%) BID patients. Hypotension was the most common DLT, occurring at doses ≥500 mg/day, and manageable with LXS196 interruption and dose reduction. Median duration of exposure to LXS196 was 3.71 months (range: 1.81-15.28) for QD and 4.6 months (range: 0.33-58.32) for BID dosing. Clinical activity was observed in 6/66 (9.1%) evaluable patients achieving response (CR/PR), with a median duration of response of 10.15 months (range: 2.99-41.95); 45/66 had stable disease (SD) per RECIST v1.1. At 300 mg BID, the recommended dose for expansion, 2/18 (11.1%) evaluable patients achieved PR and 12/18 (66.7%) had SD.These results suggest manageable toxicity and encouraging clinical activity of single-agent LXS196 in patients with MUM.

A transcriptome-based precision oncology platform for patient-therapy alignment in a diverse set of treatment resistant malignancies.

Abstract: Predicting in vivo response to antineoplastics remains an elusive challenge. We performed first-of-kind evaluation of two transcriptome-based precision cancer medicine methodologies to predict tumor sensitivity to a comprehensive repertoire of clinically relevant oncology drugs, whose mechanism-of-action we experimentally assessed in cognate cell lines. We enrolled patients with histologically distinct, poor prognosis malignancies who had progressed on multiple therapies, and developed low-passage, patient-derived xenograft models that were used to validate 35 patient-specific drug predictions. Both OncoTarget, which identifies high-affinity inhibitors of individual Master Regulator (MR) proteins, and OncoTreat, which identifies drugs that invert the transcriptional activity of hyper-connected MR modules, produced highly significant 30-day disease control rates (68% and 91%, respectively). Moreover, of 18 OncoTreat-predicted drugs, 15 induced the predicted MR-module activity inversion in vivo. Predicted drugs significantly outperformed antineoplastic drugs selected as unpredicted controls, suggesting these methods may substantively complement existing PCM approaches, as also illustrated by a case study.

A phase Ib trial of combined PKC and MEK inhibition with sotrastaurin and binimetinib in patients with metastatic uveal melanoma

Abstract: Background Uveal melanoma is a disease characterized by constitutive activation of the G alpha pathway and downstream signaling of protein kinase C (PKC) and the mitogen-activated protein kinase (MAPK) pathway. While limited clinical activity has been observed in patients with metastatic disease with inhibition of PKC or MEK alone, preclinical data has demonstrated synergistic antitumor effects with concurrent inhibition of PKC and MEK. Method We conducted a phase Ib study of the PKC inhibitor sotrastaurin in combination with the MEK inhibitor binimetinib in patients with metastatic uveal melanoma using a Bayesian logistic regression model guided by the escalation with overdose control principle (NCT01801358). Serial blood samples and paired tumor samples were collected for pharmacokinetic (PK) and pharmacodynamic analysis. Results Thirty-eight patients were treated across six dose levels. Eleven patients experienced DLTs across the five highest dose levels tested, most commonly including vomiting (n=3), diarrhea (n=3), nausea (n=2), fatigue (n=2) and rash (n=2). Common treatment related adverse events included diarrhea (94.7%), nausea (78.9%), vomiting (71.1%), fatigue (52.6%), rash (39.5%), and elevated blood creating phosphokinase (36.8%). Two dose combinations satisfying criteria for the maximum tolerated dose (MTD) were identified: (1) sotrastaurin 300 mg and binimetinib 30 mg; and, (2) sotrastaurin 200 mg and binimetinib 45 mg. Exposure to both drugs in combination was consistent with single-agent data for either drug, indicating no PK interaction between sotrastaurin and binimetinib. Stable disease was observed in 60.5% of patients treated. No patient achieved a radiographic response per RECIST v1.1. Conclusions Concurrent administration of sotrastaurin and binimetinib is feasible but associated with substantial gastrointestinal toxicity. Given the limited clinical activity achieved with this regimen, accrual to the phase II portion of the trial was not initiated.

Abstract 5881: PERIO-01: Initial safety experience and immunologic effects of a Class C TLR9 agonist using pressure- enabled drug delivery in a phase 1 trial of hepatic arterial infusion of SD-101 +/- checkpoint inhibition in metastatic uveal melanoma

Abstract: Immune checkpoint inhibitors (ICI) have demonstrated limited success in patients with metastatic uveal melanoma (MUM) with liver involvement due to an immunosuppressive tumor microenvironment (TME) driven in part by myeloid-derived suppressor cells (MDSCs). Toll-like receptor-9 agonists (TLR-9A) have improved ICI response rates in cutaneous melanoma, but delivery challenges have limited their application for MUM. Hepatic arterial infusion (HAI) of TLR-9A using a pressure-enabled drug deliveryTM (PEDDTM) device has the potential to enhance responsiveness to ICI by optimizing delivery to intrahepatic tumors and reprogramming the TME, including elimination of MDSCs.PERIO-01 is an open-label first-in-human Phase 1 trial of SD-101 given by HAI using a PEDDTM in MUM (NCT04935229). The study consists of dose-escalation cohorts of single agent SD-101 alone and with ICI. SD-101 is delivered over 2 cycles, with 3 weekly doses per cycle. Research blood, tumor and normal liver biopsies are collected serially for correlative studies. At data cutoff, a total of 20 patients were enrolled, with 13 in the single agent dose escalation cohort (2, 4, and 8 mg) and 7 patients with SD-101 (2 mg) + nivolumab. The median age was 65.5 years with an equal gender distribution. Only 2 patients were treatment-naïve and the median number of liver metastases was 5.1. The average number of SD-101 infusions was 5.2. One patient in the combination cohort experienced a serious adverse event related to treatment - asymptomatic Grade 3 increase in liver enzymes. PEDDTM resulted in high drug levels in the liver (up to 2,340 ng/ml at 8mg) with only transient exposure in the periphery (<4 hours) with one Grade 2 cytokine related syndrome adverse event. Dose-dependent increases in canonical TLR9-associated cytokines (IL-18, IFNγ, IP-10, and soluble CD25) was observed across the 2mg, 4mg, and 8mg single-agent dose levels. Concordant with predicted mechanism of action, PEDDTM HAI administered SD-101 resulted in decreases in liver monocytic MDSCs in 4 of 4 patients with available multiplex immunofluorescence data. NanoString analysis from three patients revealed increases in ISG15, IL-9, IFNα, and IL-2 transcripts and decreases in ARG1 and IDO transcripts, with increased scores for macrophages, activated CD8 T cells, Th1 cells, and Th1 activation. For patients who received 2mg SD-101 + ICI with available liquid biopsy data, 4 of 7 demonstrated decreases in circulating tumor cells and 3 of 5 showing ctDNA decreases after the first cycle. In this first-in-human experience, HAI of SD-101 via PEDDTM was well tolerated and associated with encouraging immunologic activity. Evidence of biologic activity with 2 mg of SD-101 with nivolumab is encouraging and patients are currently enrolling at higher SD-101 dose levels + ICI. Citation Format: Sapna P. Patel, Cara Haymaker, Rahul A. Sheth, Joshua D. Kuban, Joshua Weintraub, Eric Wehrenberg-Klee, Paula Novelli, Carin Gonsalves, Robert Adamo, Virgina Honaker, Laura Timciuc, Tarin Hennegan, Juan C. Amador Molina, Dzifa Duose, Edwin R. Parras Cuenta, Anthony Lucci, Salyna Meas, Vanessa Sarli, Victor G. Prieto, Jason LaPorte, Ann-Marie Hulstine, Ashley Moody, Bryan Cox, David Geller, Diwakar Davar, Kamaneh Montazeri, Marlana Orloff, Steven C. Katz, Richard Carvajal. PERIO-01: Initial safety experience and immunologic effects of a Class C TLR9 agonist using pressure- enabled drug delivery in a phase 1 trial of hepatic arterial infusion of SD-101 +/- checkpoint inhibition in metastatic uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5881.

Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab

Abstract: Purpose Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued. Patients and Methods Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation. Results Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative. Conclusion Overall survival following nivolumab treatment in patients with advanced treatment–refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.

Abstract CT253: Phase 1/2 study of the safety, pharmacokinetics, and preliminary clinical activity of BT7480 in patients with nectin-4 associated advanced malignancies

Abstract: Background: Bicycles are a novel class of synthetic molecules formed by using a central scaffold to constrain short linear peptides into a stabilized bi-cyclic structure, which can then be readily conjugated to other molecules. BT7480 is a trimeric first-in-class Bicycle tumor-targeted immune cell agonist (Bicycle TICA) comprised of two unique bicyclic peptides: one that binds to Nectin-4 and two identical Bicycles that bind and agonize CD137. The resulting multi-specific molecule stimulates an immune response in the presence of both Nectin-4-expressing tumor cells as well as CD137-expressing immune cells. Nectin-4, a cell adhesion molecule overexpressed on the surface of tumor cells and CD137, a costimulatory receptor expressed on immune cells, are co-expressed in a variety of solid tumors including lung, head and neck, breast, ovarian, and bladder. Co-ligation of Nectin-4 and CD137 by BT7480 is hypothesized to induce oligomerization and activation of CD137, resulting in a tumor-localized costimulatory signal. A favorable preclinical profile supported the initiation of this first-in-human study to investigate the safety and efficacy of BT7480 in patients with solid tumors associated with Nectin-4 expression (NCT05163041). Methods: This is a phase 1/2, open-label, multicenter study to assess safety, clinical activity, and pharmacokinetics (PK) and pharmacodynamics (PD) of BT7480. Patients must have an advanced malignancy associated with Nectin-4 expression that is not eligible for standard therapy. Additional key criteria include ≥18 years of age, ECOG of 0 or 1, adequate organ function, and no prior therapy with a CD137-targeted agent. Patients are treated at one of the escalating doses (3+3 design) by weekly IV infusion in a 4-week cycle. Primary objectives are to assess safety (phase 1) and clinical activity per RECIST v1.1 (phase 2). Secondary objectives include assessment of PK parameters, measurement of anti-drug antibodies, and evaluation of CD137 target engagement in blood. Key exploratory objectives include evaluating pharmacogenomics, ctDNA, and biomarkers in blood and tumors associated with pharmacological activity, including signals of immune activations and target expression. PK and PD analyses will be performed to support dose escalation decisions and to further the understanding of safety and clinical activity signals as a result of treatment with BT7480. This study is actively recruiting. Citation Format: Thomas R. Evans, Afshin Dowlati, Juanita S. Lopez, Mohammed M. Milhem, Jordi Rodón Ahnert, Alexander Spira, Richard D. Carvajal, Matthew Zibelman, Sebastien J. Hazard, Amy Dickson, Lei Xu, Heather Cohen, Justin Bader, Kristen Hurov, Rajiv Sharma, Dominic Smethurst, Kyriakos P. Papadopoulos. Phase 1/2 study of the safety, pharmacokinetics, and preliminary clinical activity of BT7480 in patients with nectin-4 associated advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT253.

Abstract 3876: Kinetics of RTK activation determine ERK signaling dynamics and resistance to BRAF and MEK inhibitors

Abstract: Combination treatment of BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) produces remarkable response rates and is expected to prevent ERK activation in BRAF-mutant melanoma. However, sporadic ERK reactivation occurs in melanoma models, and efficacy is severely limited by the emergence of drug resistance. The underlying molecular mechanisms that drive ERK reactivation and adaptation to BRAFi/MEKi remain elusive. Here, using single-cell imaging and optogenetic approaches, we show that the strength and duration of receptor tyrosine kinase (RTK) activation determines ERK reactivation and the development of BRAFi/MEKi-resistant cells. Single-cell data reveal that despite global RTK activation by the same external stimuli, only small subsets of melanoma cells induce effective RTK and ERK activation to develop BRAFi/MEKi resistance. Furthermore, by directly controlling RTK activity, we demonstrate that the kinetics of RTK activation determine ERK signaling dynamics and the percentage of drug-resistant cells. While these drug-resistant cells are rare during early stages of drug treatment, they eventually become the dominant population through sustained RTK-mediated ERK activation that drives cell proliferation. Thus, RTK activation in established drug-resistant cells causes effective ERK activation and cell proliferation. Importantly, limiting RTK signaling activation reverses the BRAFi/MEKi-resistant state. We show that targeting SHP2, a mediator of RTK signaling, effectively suppresses RTK-mediated ERK activation and cell proliferation in BRAFi/MEKi-resistant cells. Our results provide mechanistic insights into the contribution of heterogeneity in RTK activation kinetics to ERK reactivation and BRAFi/MEKi resistance, also highlighting SHP2 activity as a promising target to overcome drug resistance in BRAF-mutant melanoma. Citation Format: Sungsoo Kim, Richard Carvajal, Minah Kim, Hee Won Yang. Kinetics of RTK activation determine ERK signaling dynamics and resistance to BRAF and MEK inhibitors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3876.

Safety and early biologic effects of phase 1 PERIO-01 trial of pressure-enabled drug delivery (PEDD) of TLR9 agonist SD-101 and immune checkpoint inhibition (ICI) in uveal melanoma metastatic to the liver (MUM).

Abstract: 2521 Background: Delivery barriers due to intratumoral pressure and immunosuppression related to myeloid-derived suppressor cells (MDSC) in liver tumors have created challenges for immunotherapy. TLR9 agonists seem to improve response to ICI. PERIO-01 is a first-in-man trial of PEDD of SD-101 using hepatic arterial infusion (HAI) with ICI in MUM. Methods: PERIO-01 is an open-label phase 1 trial of SD-101 given by HAI in MUM (NCT04935229). The study consists of dose-escalation cohorts of SD-101 alone (Cohort A), with nivolumab (Cohort B), or nivolumab + ipilimumab (Cohort C). SD-101 is delivered over 2 cycles, with 3 weekly doses per cycle. Blood, liver metastasis (LM) and normal liver biopsies are collected for correlative studies. Results: At data cutoff, 33 patients were enrolled, 30 of whom received at least one dose of SD-101, 13 in Cohort A (2, 4, and 8 mg), 15 patients in Cohort B (2 mg and 4 mg) and 2 patients in Cohort C (2 mg). The median age was 63 years of equal gender. Only 3 patients were treatment-naïve and 2 were HLA-A*-02:01+ who received prior tebentafusp. Nine subjects had 4-7 LM and 4 had > 10. The median index LM size was 4.7 cm. Only one patient experienced a grade ≥3 adverse event (AE) related to SD-101, which was increased liver enzymes. All AEs related to cytokine release syndrome have been low-grade with the most common being fever (9), chills (5), and dizziness (4). Treatment resulted in high liver drug levels (median at 2 mg = 1540 ng/g and 8 mg = 2325 ng/g, p = 0.035), with only transient exposure in the periphery ( < 4 hours) and a maximum peak serum level of 554 mg/ml 30 minutes post-infusion. Increases in serum IL-18 and IFNγ were noted, with highest levels at 8 mg. Expansion of natural killer cells were detected in 9 of 10 patients from flow cytometry data peripherally. Monocytic MDSC levels were decreased in 5 of 5 patients on immunofluorescence, and NanoString analysis revealed decreases in ARG-1 and IDO-1 gene levels up to 100 days from initial treatment. Broad immunostimulatory gene expression changes were noted in tumor and normal liver following SD-101, including increases in IFNB1 and IL-9. Using the available samples from 13 patients, 7 of 10 had decrease in ctDNA, with complete clearance in 3, along with circulating tumor cell decreases in 6 of 13. In cohort B at 2 mg, 5 of 6 with available response data have stable disease with a median duration of disease control of 12 weeks (range = 7.5-24) at data cutoff. Conclusions: HAI of SD-101 has been well tolerated and associated with encouraging immunologic activity. Evidence of biologic effects at the lower doses of SD-101 with nivolumab is encouraging and enrollment with escalation continues in Cohorts B and C. Clinical trial information: NCT04935229 .

Survival outcomes associated with liver-directed therapies in patients with metastatic uveal melanoma.

Abstract: 9590 Background: Metastatic uveal melanoma (mUM) is characterized by a hepatotropic pattern of spread and poor outcomes. Tebentafusp, the only FDA approved therapy, is restricted to patients (pts) with the HLA-A*02:01 genotype. As a result, a variety of liver-directed therapies (LDT) are commonly used for management of hepatic metastases. Methods: Pts with mUM with hepatic metastases who underwent LDT, including radiofrequency ablation, microwave ablation, hepatic metastatectomy, Yttrium-90 radioembolization (SIRT), transarterial chemoembolization (TACE), bland embolization, and immunoembolization (IE), were identified from an institutional database. Data collected included: age, gender, tumor location and size, baseline liver function tests (LFT) and lactate dehydrogenase (LDH), molecular tumor characteristics (where available), type(s) of LDT received, systemic therapies received, and vital status. Time from onset of hepatic metastasis until death (Liver-OS), as well as time from initial diagnosis of primary uveal melanoma until death (Ocular-OS) were calculated. Results: A total of 119 pts were identified. The median age at diagnosis was 53.8 years (range 26-83), 47% were female. At the time of LDT initiation, 33% had bilobar disease and 16% had extrahepatic metastasis. 18% pts had elevated LFTs and 55% had elevated LDH. 72% of pts had M1a disease, 24% had M1b and 4% had M1c disease. 45% of pts received more than one form of LDT. SIRT (31%) was the commonly administered initial LDT, followed closely by IE (26%) and TACE (9%). 86% of pts received systemic therapy including 42% who received immune checkpoint blockade overlapping with LDT. Molecular profiling in 26 pts revealed recurrent mutations in BAP1 (n = 18) and SF3B1 (n = 8). The median ocular-OS across all pts was 71.0 months (95% confidence intervals (CI), 62.8-99.4). The median liver-OS across all pts was 31.8 months (95% CI 25.2-35.3). In pts who received TACE, IE, or SIRT exclusively (n = 44), the median Liver-OS was 15.2 months (95% CI 12.8-NA) for TACE (n = 8), 23.3 months (95% CI 15.8-NA) for SIRT (n = 28), and 28.2 months (95% CI 22.6-NA) for IE (n = 8). Conclusions: Our results provide additional support for the utilization of LDT in pts with mUM, as demonstrated by improved OS compared to historical survival data.

A phase 1 study of AGEN2373, a novel CD137 agonist antibody designed to avoid hepatoxicity, in patients with advanced solid tumors.

Abstract: 2524 Background: We present results from the completely enrolled monotherapy arm of the first-in-human dose escalation study of AGEN2373, a novel CD137 agonist antibody engineered to maximize efficacy by circumventing the dose-limiting hepatotoxicity reported for prior CD137 agonists (NCT04121676). AGEN2373 binds to a unique epitope of CD137 on effector T and NK cells in the tumor and tumor-draining lymph nodes, promoting co-engagement of activating Fcγ receptors. CD137 (4-1BB) is a tumor necrosis factor receptor superfamily protein and co-stimulatory receptor that promotes anti-tumor activity of adaptive and innate immune cells, making it an attractive target for immunotherapy. Methods: 46 patients (pts) received AGEN2373 IV every 2 weeks (Q2W), Q3W, or Q4W at doses between 0.03 and 10 mg/kg in a 3+3 design. Key endpoints included safety, tolerability, PK, preliminary efficacy, and PD markers. Imaging was Q8W. Results: Pts were enrolled between Oct 2019 and May 2022 with a median follow-up of 7.2 months. The median age was 64 (range 33-82). The most common tumor types were colorectal cancer, 13 pts (28%) and sarcoma, 8 (17%). Median prior therapies were 4 (range 1-14) including 48% with prior immunotherapy. There were no dose-limiting toxicities (DLTs) and no treatment-related hepatitis. 37% of pts had treatment-related AEs (TRAEs). TRAEs >10% were limited to fatigue (17%) and nausea (15%). There were no G3, 4 or 5 TRAEs. Pharmacokinetic parameters including half-life, clearance, and volume of distribution were consistent with a human IgG1 Fc backbone. Induction of soluble CD137 was dose dependent with 2 mg/kg as the lowest saturating dose and minimum predicted efficacious dose. In 19 pts treated at 2 mg/kg or higher who had at least one post-baseline scan, the overall response rate (ORR) was 11% (n=2); 37% had SD (n=7) resulting in a disease control rate (DCR) (CR, PR or SD) of 47%. Notable responses include: a pt with vulvar SCC who had progressed rapidly on pembrolizumab and had a confirmed partial response (cPR) while remaining on AGEN2373 x 2 mg/kg q2w for ~40 wks, and a pt with ampullary carcinoma with 4 prior regimens had a cPR on AGEN2373 x 6 mg/kg q3w with complete resolution of the pancreatic lesion. A pt with CRPC had a 38% tumor reduction in liver target lesions (confirmed) on AGEN2373 x 10mg/kg q3w but was non-evaluable due to palliative radiation to bone metastases. Conclusions: AGEN2373 showed objective responses as monotherapy in heavily pretreated pts with solid tumors and was well-tolerated with no evidence of hepatotoxicity. This distinguishes AGEN2373 from previous CD137-targeted agents that reported dose-limiting hepatotoxicity. Combination therapy with botensilimab, a novel Fc-enhanced CTLA-4 antagonist, is being studied in pts with PD(L)-1 pretreated melanoma. Clinical trial information: NCT04121676 .

Abstract CT223: Long-term survival follow-up of tebentafusp in previously treated metastatic uveal melanoma (mUM)

Abstract: Background: Tebentafusp, a bispecific (gp100 x CD3) ImmTAC, is approved for adult HLA-A*02:01+ patients with unresectable or metastatic uveal melanoma (mUM). In the Ph2 IMCgp100-102 study of pts with previously treated mUM (NCT02570308), tebentafusp demonstrated a median OS of 16.8 months and 1-year OS of 61% after a minimum 2 yrs of follow-up, nearly double the historical observed rates.12, Here we present the final analysis of OS of the Ph2 IMCgp100-102 study. Methods: 127 HLA-A*02:01+ 2L+ pts with mUM were dosed weekly with intravenous tebentafusp following intra-patient dose escalation of 20mcg dose 1, 30mcg dose 2 and 68mcg dose 3+. Primary objective was overall response rate and secondary objectives included safety and OS. OS was estimated by Kaplan-Meier method. Survival for ctDNA evaluable patients was assessed. Analyses are based on a 17 Oct 2022 database lock. Results: With a median follow-up of 46 months, median OS was 16.8 (95% CI: 12.3-21.3) months, consistent with previous reports. Estimated 1-yr, 2-yr, 3-yr and 4-yr OS rates were 61%, 36%, 21% and 11%, respectively. ctDNA clearance by week 9 (n=12) was associated with 100% 1-yr, 73% 2-yr, 45% 3-yr and 23% 4-yr survival. OS for patients with poor prognostic factors compared favorably relative to historical benchmarks (Table 1). Mean and median duration of treatment was 9.9 and 5.6 months. Majority of pts who received a subsequent line of therapy received immunotherapy (48/72; 67%) followed by liver-directed therapy (14/72; 19%). No new safety signals were identified. Conclusions: This study provides the longest follow-up of OS for a soluble TCR therapeutic to date. Tebentafusp continued to show unprecedented survival benefit for 2L+ mUM pts, including the poorest prognostic groups, with estimated OS rates that remain nearly double the historical rates observed in this population at a median follow-up of ~4 years. Early ctDNA clearance was associated with indication of survival benefit. 1. Carvajal et al. Nat Med 2022 2. Sacco et al. J Immunother Canc 2021 Table 1. OS in Ph2 IMCgp100-102 versus historical benchmarks Ph2 IMCgp100-102 Historical benchmarks*,† Population 1-yr 2-yr 3-yr 1-yr 2-yr 3-yr Overall 2L+ 61% 36% 21% 37% 15% 9% Subgroups Age ≥ 65 yrs 51% 31% 25% 38% 12% 6% LDH > ULN 44% 22% 11% 23% 8% 3% Baseline largest liver lesion ≥ 3cm 52% 26% 14% 32% 11% 4% *OS benchmark for 2L+ patients calculated from Rantala et al 2019 †OS benchmarks for pt subgroups (all lines of therapy) estimated from digitized OS curves presented in Khoja et al. 2019 Citation Format: Joseph J. Sacco, Richard D. Carvajal, Marcus O. Butler, Alexander N. Shoushtari, Jessica C. Hassel, Alexandra Ikeguchi, Leonel Hernandez-Aya, Paul Nathan, Omid Hamid, Josep M. Piulats, Matthew Rioth, Douglas B. Johnson, Jason J. Luke, Erique Espinosa, Serge Leyvraz, Laura Collins, Chris Holland, Michelle L. McCully, Takami Sato. Long-term survival follow-up of tebentafusp in previously treated metastatic uveal melanoma (mUM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT223.

Precision Dose-finding Cancer Clinical Trials in the Setting of Broadened Eligibility

Abstract: Broadening eligibility criteria in cancer trials has been advocated to rep-resent the true patient population more accurately. While the advantages are clear in terms of generalizability and recruitment, novel dose-finding designs are needed to ensure patient safety. These designs should be able to recommend precise doses for subpopulations if such subpopulations with different toxicity profiles exist. While dose-finding designs accounting for patient heterogeneity have been proposed, all existing methods assume the source of heterogeneity is known and thus pre-specify the subpopulations or only allow inclusion of a few patient characteristics. We propose a precision dose-finding design to address the setting of unknown patient heterogeneity in phase I cancer clinical trials where eligibility is expanded, and multiple eligibility criteria could potentially lead to different optimal doses for patient subgroups. The design offers a two-in-one approach to dose-finding by simultaneously selecting patient criteria that differentiate the maximum tolerated dose (MTD) and recommending the subpopulation-specific MTD if needed, using marginal models to sequentially incorporate patient covariates. Our simulation study compares the proposed design to the naive approach of assuming patient homogeneity and our design recommends multiple doses when heterogeneity exists and a single dose when no heterogeneity exists. The proposed dose-finding design addresses the challenges of broadening eligibility criteria in cancer trials and the desire for a more precise dose in the context of early phase clinical trials.