Treatment (Tx) with fianlimab (anti-LAG-3) + cemiplimab (anti-PD-1) resulted in a 57% ORR by BICR in pts with adv Mel, with an acceptable risk-benefit profile. Here, we present an efficacy analysis by BICR in subgroups of pts with adv Mel (neoadjuvant/adjuvant pretreated [NAP], elevated LDH, BRAF status, adrenal insufficiency [AI], and ctDNA status). Three independent expansion cohorts of pts who were anti-PD-(L)1 Tx-naïve for adv Mel (NCT03005782) received fianlimab 1600 mg + cemiplimab 350 mg IV every 3 weeks (wks) for ≤24 months (mos). Overall, 98 pts were enrolled (median age: 68 years). At the data cutoff (Oct 31, 2023), median follow-up was 23 mos, and median Tx duration was 36 wks. Grade ≥3 TEAEs occurred in 47% of pts, serious TEAEs in 39%, and immune-mediated AEs in 39%. Of the 76 pts (78%) who discontinued Tx, 17 discontinuations (22%) were due to TEAEs. Overall BICR-assessed median PFS (mPFS), median OS (mOS), CR rate, and ORR were 24 mos (95% CI 12-NE), NR (95% CI 42-NE), 25%, and 57% (95% CI 47-67), respectively. Estimated survival probability was 83% at 12 mos and 71% at 24 mos. A total of 31% and 4% of pts completed 1 and 2 years of Tx, respectively. In NAP pts who had received anti-PD-(L)1 Tx (n=13), the mPFS, CR rate, and ORR were NR (95% CI 1-NE), 31%, and 46% (95% CI 19-75), respectively. There were no differences in mOS in NAP pts (NR [95% CI 26-NE]) versus NAP-naïve pts (NR [95% CI 31-NE]). In NAP and NAP-naïve pts, mPFS was NR (95% CI 3-NE) and 24 mos (95% CI 12-NE), respectively. In pts with LDH > ULN (n=31), the mPFS, mOS, CR rate, and ORR were 14 mos (95% CI 4-NE), 42 mos (95% CI 23-NE), 13%, and 55% (95% CI 36-73), respectively. In pts with BRAF mutation (n=48), the mPFS, mOS, CR rate, and ORR were NR (95% CI 39-69), NR (95% CI NE-NE), 31%, and 54% (95% CI 46-70), respectively. In pts with any-grade drug-related AI (n=12), the mPFS, mOS, CR rate, and ORR were NR (95% CI 8-NE), NR (95% CI 21-NE), 58%, and 92% (95% CI 62-100), respectively. The mPFS was NR in pts with PD-L1 expression <1% (95% CI 4-NE) and ≥1% (95% CI 24-NE), and in pts with LAG-3 expression <1% (95% CI 1-NE) and ≥1% (95% CI 19-NE). The mOS was NR in pts with PD-L1 expression <1% (95% CI 23-NE) and ≥1% (95% CI NE-NE), and in pts with LAG-3 expression <1% (95% CI 12-NE) and ≥1% (95% CI NE-NE). The ORR was 50% and 71% in pts with PD-L1 expression <1% and ≥1%, and 50% and 61% in pts with LAG-3 expression <1% and ≥1%, respectively. By Day 1 of Cycle 4, ctDNA was cleared in 15/31 pts. The mOS and mPFS for pts with uncleared ctDNA was 20.8 mos and 2.6 mos, respectively. The mOS and mPFS were NR in pts who were ctDNA-negative at Wk 9. With longer follow-up, fianlimab + cemiplimab continued to demonstrate high clinical activity and a generally acceptable safety profile in subgroups of pts with adv Mel. AI was reported in 12% of pts receiving the Tx; efficacy rates were higher in pts who experienced AI than in the overall study population. Meredith McKean, Amy M. Weise, Kyriakos P. Papadopoulos, John Crown, Sajeve S. Thomas, Janice Mehnert, John M. Kaczmar, Kevin B. Kim, Nehal J. Lakhani, Melinda L. Yushak, Jayakumar Mani, Fang Fang, Shuquan Chen, Jingxiao Chen, Laura Brennan, JuAn Wang, Israel Lowy, Mark Salvati, Matthew G. Fury, Karl D. Lewis, Omid Hamid. Fianlimab + cemiplimab in patients (pts) with advanced (adv) melanoma (Mel): Subgroup analyses by blinded independent central review (BICR) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB366.

TPS8659 Background: Tumor-infiltrating lymphocyte (TIL) therapy with lifileucel plus pembrolizumab (pembro) demonstrated durable and deepening responses with an objective response rate (ORR) of 64.3% in patients (pts) with anti–PD-1/PD-L1–naive, EGFR wild-type, locally advanced or metastatic non-small cell lung cancer (mNSCLC) in cohort 3A of the IOV-COM-202 phase 2 open-label study (NCT03645928), with 4 of 5 ongoing responses lasting >20 months from start of therapy and no new safety signals. We added two new cohorts within this basket study, 3D and 3E, which evaluate if adding lifileucel to pembro ± pemetrexed in the maintenance phase of standard-of-care (SOC) therapy (from tumors procured in treatment-naive pts [3D] versus those who had already started receiving SOC chemotherapy [3E]) is feasible and provides added benefit with an acceptable safety profile. Incorporating TIL with current SOC has the potential to address a major unmet need by improving outcomes that are not durable or adequate for many pts with NSCLC. Methods: Pts have tumor resection before cycle 1 (3D) or between cycles 1 and 4 (3E) of frontline platinum-doublet chemotherapy plus pembro. After completion of SOC chemotherapy, a dose of pembrolizumab will be given followed by nonmyeloablative lymphodepletion (NMA-LD) (day −5 to day −3: cyclophosphamide 20 mg/kg/day; day −5 to day −2: fludarabine 25 mg/m2/day). Lifileucel is administered on day 0, followed by IL-2 continuous infusion on days 1–4. Following lifileucel and IL-2, pembro (plus pemetrexed if nonsquamous histology) will be continued for up to 2 years or until disease progression or unacceptable toxicity. Eligible adults have histologically confirmed mNSCLC, no actionable mutations with effective targeted therapy, no prior systemic therapy for metastatic NSCLC, ECOG performance status 0–1, estimated life expectancy ≥6 mo, and ≥1 resectable lesion >1.5 cm in diameter to generate lifileucel. Prior organ allograft or cell transfer therapy, symptomatic brain metastases, current systemic steroid therapy >10 mg/day of prednisone or other steroid equivalent, and active illnesses or autoimmune disorders are not permitted. Endpoints include ORR, complete response rate, disease control rate, and PFS by investigator-assessed RECIST v.1.1, OS, percentage of manufactured lifileucel drug products that meets release specification, and incidence of grade ≥3 treatment-emergent adverse events. Selected exploratory endpoints include in vivo T-cell persistence, correlative biomarkers, and circulating tumor DNA. Enrollment of approximately 20 pts per cohort will take place in Europe and North America. Clinical trial information: NCT03645928 .

9515 Background: Lifileucel is a personalized, one-time tumor-derived autologous T-cell immunotherapy approved for the treatment of adult patients (pts) with advanced (unresectable or metastatic) melanoma previously treated with a programmed cell death-1 (PD-1)–blocking antibody, and, if BRAF V600 mutation–positive, a BRAF inhibitor with or without a MEK inhibitor. In the registrational C-144-01 study (NCT02360579), pts with advanced melanoma who received lifileucel had an objective response rate (ORR) of 31.4%. Follow-up in therapeutic trials targeting refractory patients with refractory melanoma typically span months rather than years due to lack of activity. Reflective of the durability of lifileucel, we nowreport 5-year survival outcomes from the C-144-01 study. Methods: C-144-01 (NCT02360579) is a phase 2, multicenter, multicohort, open-label study of lifileucel. Eligible pts had advanced melanoma that had progressed on or after immune checkpoint inhibitor and targeted therapy, where appropriate. Before lifileucel infusion, pts underwent nonmyeloablative lymphodepletion (NMA-LD; cyclophosphamide, 60 mg/kg × 2 d plus fludarabine 25 mg/m 2 × 5 d). Pts received cryopreserved lifileucel followed by up to 6 doses of interleukin-2 (IL-2; 600,000 IU/kg every 8–12 hours). The primary endpoint was ORR assessed by an independent review committee (IRC) using RECIST v1.1. Key secondary endpoints were duration of response (DOR), overall survival (OS), and safety. Results: Among pts who received lifileucel (n = 153; median age, 56 y; range, 20–79), 54% were male. All pts had an Eastern Cooperative Oncology Group Performance Status of 0 or 1 and previously received anti–PD-1/PD-L1 therapy. Pts had a median of 3 prior lines of therapy (range, 1–9) and 55% were primary refractory to anti–PD-1/PD-L1 therapy. At a median follow-up of 57.8 mo, all pts have completed or discontinued the study, with 28 (18.3%) pts having completed the 5-year study follow-up. The ORR was 31.4% (complete response, 5.9%; partial response, 25.5%). Median DOR was 36.5 mo (95% confidence interval [CI]: 8.3–not reached), with 31.3% of responders completing the 5-year assessment with a sustained response. Median time to best response was 1.5 mo (range, 1.3–30.4). Median OS was 13.9 mo (95% CI: 10.6–17.8); the 5-year OS rate was 19.7% (95% CI: 13.3–27.0). Treatment-emergent adverse events were consistent with known safety profiles of NMA-LD and IL-2. The extended follow-up revealed no new safety signals. Conclusions: This 5-year analysis of the C-144-01 trial is the longest follow-up of the largest group of pts with melanoma treated with tumor-infiltrating lymphocytes in a single study. This study illustrates lifileucel’s continued durability of response and survival benefit up to 5 years after a single administration without any long-term safety concerns. Clinical trial information: NCT02360579 .

Abstract Checkpoint immunotherapies have revolutionized solid tumor treatment yet durably benefit a minority of patients, as they rely on endogenous anti-tumor T cells. A potential solution for patients lacking functional endogenous anti-tumor T cells is engineering their T cells with exogenous T cell receptors (TCRs) to target and kill tumor cells. Initial clinical trials with TCR engineered T cell therapies (TCR-Ts) targeted single tumor antigens on single HLA and produced partial, short-lasting responses. Solid tumors are notoriously heterogenous with highly variable antigen expression. Recent discoveries also identified HLA loss of heterozygosity in up to 40% of solid tumors, allowing tumor cells to evade T cell attack. To overcome this heterogeneity, TScan has developed T-Plex, a multiplexed cell therapy comprising 2-3 different TCR-Ts, chosen from a collection of TCR-Ts called the ImmunoBank, to target different tumor antigens on different HLA types with confirmed tumor expression. To deepen clinical responses, TCR-T cells are engineered to express CD8α/β co-receptors that, in preclinical experiments, enable CD4+ helper T cells to have >100-fold improved cytotoxicity and cytokine secretion over CD4+ cells expressing the TCR alone. Finally, to allow T cell persistence despite immunosuppressive TGF-β in the solid tumor microenvironment, TCR-T cells also express the dominant negative TGF-βreceptor, enabling ~10-fold improved proliferation in the presence of TGF- β compared to T cells expressing the TCR and CD8α/β co-receptors alone. A proprietary transposon vector with larger cargo limit enables the inclusion of these additional genes. The Phase 1 study utilizes a separate screening protocol to pre-identify patients with head and neck, cervical, anogenital cancers, NSCLC, and melanoma, any time during standard clinical care, enabling rapid enrollment into the treatment protocol upon disease progression. Screening comprises germline HLA testing, and archival tumor testing for antigen expression and exclusion of HLA loss. Treatment includes standard non-myeloablative lymphodepletion followed by one or 2 doses of T-Plex infused 28 days apart. Dose escalation under the interval 3+3 design starts with testing single TCR-Ts in dose levels 1 and 2. Thereafter, TCR-Ts are combined and escalated in dose levels 3 and 4. TCR-Ts currently in the master protocol target PRAME, MAGE-A1 or HPV16 on HLA-A*02:01 or MAGE-A1 on HLA-C*07:02. Additional TCR-Ts added to the ImmunoBank and master protocol go through dose levels 1 and 2 as single therapies before becoming available for multiplexed dose levels 3 and 4. Primary endpoints include safety, feasibility and identifying the recommended Phase 2 dose. Secondary endpoints are rates and durations of response and exploratory endpoints measure T cell activation and persistence. Two additional TCR-Ts are on track to be added to the ImmunoBank, which could allow 50-80% of common solid tumor patients to qualify for multiplexed TCR-T therapy. Citation Format: Justin Moser, Brian Pico, Brian Henick, Rom Leidner, Jared Weiss, James Isaacs, Jaspreet Grewal, Michael Hurwitz, Jim Murray, Marlyane Motta, Yun Wang, Shrikanta Chattopadhyay, Debora Barton, Gavin MacBeath, Sajeve Thomas. Trial in progress: A phase 1, first in human clinical trial for T-Plex, a multiplexed, enhanced T cell receptor-engineered T cell therapy (TCR-T) for solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT170.

Abstract Background: MDNA11 is an albumin-fused ‘beta-enhanced not-alpha’ IL-2 agonist engineered to preferentially expand and activate CD8+ T and NK cells with minimal impact on Tregs. The ABILITY-1 (A Beta-only IL-2 ImmunoTherapY) is a global Phase 1/2 study evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of MDNA11, both as single agent and in combination with a PD-1 inhibitor, in pre-treated patients with advanced solid tumors. Method: The ABILITY-1 study (NCT05086692) comprises monotherapy dose escalation/evaluation with a modified 3+3 design (enrollment complete); monotherapy dose expansion (enrolling); combination with pembrolizumab dose escalation (enrolling) followed by combination expansion. Thirty participants were enrolled in the monotherapy cohorts (3, 10, 30, 60, 90, and 120 μg/kg, IV, Q2W): 23 in dose escalation and 7 in dose evaluation. To enhance tolerability, step-up dosing with 2 or 3 priming doses was implemented starting at 60 μg/kg. Primary endpoints were incidence and severity of adverse events (AEs) and secondary endpoints included PK, PD, and tumor response (RECIST 1.1 and iRECIST). Results: As of December 22, 2023, 30 patients were enrolled in dose-escalation/evaluation, comprising 16 melanoma, 3 NSCLC, 3 PDAC, 2 RCC, 2 sarcoma, 2 ovarian cancer, 1 tonsillar squamous cell carcinoma and 1 gastro-esophageal adenocarcinoma. No dose-limiting toxicities (DLTs) were observed. Most common treatment related AEs were infusion-related reactions (53.3%), primarily grade 1-2, encompassing pyrexia (43.3%), nausea (33.3%), chills (33.3%), hypotension (30%), and fatigue (26.6%) that resolved within 48-72 hours. PK analysis showed sustained dose-dependent increase in serum concentration of MDNA11 with repeat doses. PD evaluation showed robust and durable dose-dependent increase in lymphocyte counts without eosinophilia. Immune effector cells, particularly CD8+ T cells, showed durable expansion with evidence of activation markers (CD25, ICOS and OX40) peaking at the 90 μg/kg dose. Single-agent anti-tumor activity was evident among 26 evaluable patients with confirmed partial responses (PRs) in a PDAC (MSI-H) patient (60 μg/kg cohort) and a melanoma patient (90 μg/kg cohort) as well as 8 (30.7%) stable disease (SD) including 3 melanoma patients with durable SD (>6 months, >8 months, >1.5 years). Based on the combined safety, PK, PD and preliminary anti-tumor activity, a recommended dose for expansion (RDE) of 90 μg/kg (preceded by priming doses of 30 and 60 μg/kg; Q2W) was selected for the ongoing monotherapy dose expansion of the ABILITY-1 study. Conclusions: MDNA11 was well-tolerated with no DLTs observed at all dose levels up to 120 μg/kg. With study currently ongoing, single agent clinical activity was evident with an ORR of 7.7% and Clinical Benefit Rate (CBR) of 19.2% (2 PRs + 3 SDs > 6 months) in dose escalation to date. Monotherapy dose expansion at 90 μg/kg and combination dose escalation with pembrolizumab are enrolling. Citation Format: Victoria G. Atkinson, Jesus F. Antras, Philippe Bedard, Warren Brenner, Jacqueline Brown, Charlotte R. Lemech, Peter Lloyd, Kim Margolin, Matthen Mathew, John J. Park, Sajeve Thomas, Przemyslaw Twardowski, Humphrey Gardner, Amy Prawira, Melissa Coello, Walead Ebrahimimizadeh, Minh D. To, Rosemina Merchant, Sudhir Madduri Karanam, Arash Yavari, Lillian L. Siu, Hussein A. Tawbi, Paolo A. Ascierto. Results from monotherapy dose escalation of MDNA11, a long-acting IL-2 superkine, in a phase 1/2 trial show evidence of single-agent activity in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT259.

Abstract Introduction ICI have improved outcomes for pts with melanoma; however, most pts (~60%) do not achieve long-term survival. Unengineered bulk TIL cell therapy has an objective response rate (ORR) of 31-49% in pts with unresectable or metastatic melanoma (Rohaan NEJM 2022, Chesney JITC 2022), but requires co-administration of systemic high-dose IL2, which is associated with safety risks and limits pt eligibility. OBX-115 TIL are engineered to express regulatable membrane-bound IL15 (mbIL15) under dose-dependent regulation using acetazolamide (ACZ), an FDA-approved small-molecule diuretic, avoiding the need for high-dose IL2. A first-in-human single-institution study (NCT05470283) evaluating the safety of OBX-115 in metastatic melanoma is currently enrolling. The current study (NCT06060613) is enrolling at multiple US sites using centralized manufacturing. Methods This phase 1/2, single-arm, open-label, nonrandomized, multicenter study will assess the safety, tolerability, and efficacy of the OBX-115 engineered autologous TIL cell therapy regimen in pts with unresectable or metastatic melanoma resistant to ICI (Table). Primary objectives of Phase 1 are to characterize safety and tolerability and identify a recommended Phase 2 dose of the OBX-115 regimen; Phase 2 will evaluate efficacy (ORR using RECIST v1.1). Cryopreserved OBX-115 is generated from the pt’s own tumor tissue procured by surgical excision or core biopsy, and is infused after standard- or low-dose (based on clinical eligibility) lymphodepletion (cyclophosphamide and fludarabine). ACZ is administered at cohort-defined doses once daily for up to 10 days, with ACZ redosing at Week 6-8 for 10 days if the initial observed tumor response is less than partial response. No systemic high-dose IL2 is administered. Two sites are open and recruiting pts. TABLE 1. NAND Key Eligibility Criteria Key Inclusion Criteria Key Exclusion Criteria Age ≥18 years Uveal melanoma Histologically confirmed diagnosis of unresectable Stage IIIC, IIID, or Stage IV metastatic melanoma Brain metastasis or leptomeningeal disease Documented radiographic disease progression after systemic therapy containing a PD-1- or PD-L1-blocking antibody (if adjuvant setting, progression during or within 12 weeks after the last dose) Active autoimmune disease, including active uveitis or any other medical illness that would pose increased risks for study participation Received a BRAF inhibitor ± MEK inhibitor if BRAF V600 mutation-positive Prior allogeneic organ transplant, allogeneic cell therapy, or genetically engineered cell therapy (not including autologous stem cell or unengineered TIL cell therapy) ≥1 lesion suitable for OBX-115 generation with expected minimum of 1.5-cm diameter; minimally invasive tumor tissue procurement (core biopsy) may be considered on a case-by-case basis after discussion with the Medical Monitor Systemic steroid therapy >10 mg/day of prednisone or equivalent ≥1 RECIST 1.1-measurable lesion remaining after tumor tissue procurement ECOG performance status 0 or 1 Estimated life expectancy >6 months Citation Format: Sajeve S. Thomas, Jason A. Chesney, Omid Hamid, Gino K. In, Alexander N. Shoushtari, Yazan Samhouri, Parameswaran Hari, Giridharan Ramsingh, Prakash Prabhakar, Lauren Mclaughlin, Allison Betof Warner. Trial in progress: A phase 1/2 study to investigate the safety and efficacy of OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy in patients (pts) with immune checkpoint inhibitor (ICI)-resistant advanced or metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT285.

Background Checkpoint inhibitors are standard adjuvant treatment for stage IIB-IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence -free survival and distant metastasis -free survival versus pembrolizumab monotherapy in resected high -risk melanoma. Methods We did an open -label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high -risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB-IV) were assigned 2:1 to receive open -label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3 -week cycles. The primary endpoint was recurrence -free survival in the intention -to -treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881. Findings From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence -free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0 center dot 561 [95% CI 0 center dot 309-1 center dot 017]; two-sided p=0 center dot 053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18 -month recurrence -free survival was 79% (95% CI 69 center dot 0-85 center dot 6) versus 62% (46 center dot 9-74 center dot 3). Most treatment -related adverse events were grade 1-2. Grade >= 3 treatment -related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA4157-related grade 4-5 events. Immune -mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups. Interpretation Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence -free survival versus pembrolizumab monotherapy in patients with resected high -risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting.

TPS9599 Background: Immune checkpoint inhibitors (ICI) have improved outcomes for pts with solid tumor malignancies; however, most pts relapse and treatment options are limited. Unengineered TIL cell therapy has shown promising efficacy in pts with ICI-resistant melanoma (1,2) and non-small cell lung cancer ([NSCLC] 3,4), but requires co-administration of systemic high-dose IL2, which is associated with safety risks and limits pt eligibility. OBX-115 TIL are engineered to express membrane-bound IL15 (mbIL15) under dose-dependent regulation using acetazolamide (ACZ), an FDA-approved small-molecule diuretic, avoiding the need for high-dose IL2. A first-in-human single-institution study (NCT05470283) evaluating the safety of OBX-115 in metastatic melanoma is ongoing. The current study (NCT06060613) is enrolling pts with solid tumors at multiple US sites using centralized manufacturing. Methods: This phase 1/2, single-arm, open-label, nonrandomized, multicenter study will assess the safety, tolerability, and efficacy of the OBX-115 engineered autologous TIL cell therapy regimen in pts with histologically confirmed unresectable Stage IIIC, IIID, or Stage IV metastatic melanoma (excluding uveal) with documented radiographic progression after systemic therapy containing an anti–PD‐1/PD-L1 agent (if adjuvant, progression during or within 12 wks after the last dose) and received a BRAF inhibitor ± MEK inhibitor if BRAF V600 mutation-positive OR metastatic NSCLC previously treated with an approved systemic therapy for metastatic disease (including an ICI-based regimen and/or targeted therapy where applicable) and progressed, no longer deriving benefit, or unable to continue due to treatment intolerance. Pts must have ECOG PS of 0 or 1 and life expectancy >~6 months. Pts must have ≥1 lesion suitable for OBX-115 manufacturing (≥1.5 cm) and ≥1 RECIST v1.1-measurable lesion remaining after tumor tissue procurement. Primary objectives of Phase 1 are to characterize safety and tolerability and identify a recommended Phase 2 dose of OBX-115 + ACZ; Phase 2 will evaluate efficacy of the regimen (ORR using RECIST v1.1 per investigator). Cryopreserved OBX-115 is generated from the pt’s own tumor tissue procured by surgical excision or core needle biopsy, and is infused after standard- (5 days) or low-dose (4 days) lymphodepletion (cyclophosphamide and fludarabine), based on clinical status. ACZ is administered at cohort-defined doses once daily for up to 10 days starting day of OBX-115 infusion, with optional ACZ redosing at Wk 6–8 for up to 10 days in pts with suboptimal radiographic response. No systemic high-dose IL2 is administered. Two sites are open and recruiting, with additional sites being activated. 1. Rohaan NEJM 2022. 2. Chesney JITC 2022. 3. Creelan Nat Med 2021; Schoenfeld SITC 2021. Clinical trial information: NCT06060613 .

2542 Background: Solid tumors are notoriously heterogenous with highly variable antigen expression and an immunosuppressive microenvironment. HLA loss of heterozygosity (LOH) has also been identified in up to 40% of solid tumors, allowing tumor cells to evade T cell attack. To overcome these issues and a lack of potent endogenous antitumor T cells in cancer patients, TScan has developed T-Plex, a multiplexed cell therapy comprising two to three different TCR-Ts, chosen from a collection of TCR-Ts called the ImmunoBank. Product and study design details were presented at ASCO 2023 (Abstract #2554). Methods: A screening protocol (NCT05812027) pre-identifies patients with solid tumors any time during clinical care, enabling rapid enrollment into the treatment protocol (NCT05973487) upon disease progression. TCR-Ts currently in the master protocol target PRAME on HLA-A*02:01; HPV16 on HLA-A*02:01; MAGE-A1 on HLA-A*02:01, HLA-A*01:01, or HLA-C*07:02; or MAGE-C2 on HLA-B*07:02. All TCR-Ts in the ImmunoBank and master protocol are first tested as single therapies in dose levels 1 and 2 before becoming available for multiplexing in dose levels 3 and 4. Results: From September 2023 to the time of abstract submission, 140 participants with a variety of solid tumors were enrolled in the screening protocol and are in different stages of screening. To date, 65% have ≥1 HLA match, and 20% and 6% have 2 and 3 HLA matches, respectively, highlighting the advantage of including TCR-Ts targeting multiple different HLA types within the same master protocol. Of those who have completed target screening, 92% express at least one target and 65% qualify for at least one TCR-T. Intratumoral heterogeneity of target expression was observed even with the most prevalently expressed target, PRAME, supporting the rationale for multiplexed TCR-T treatment. Although HLA-LOH affects only half of HLA genes and the remaining intact HLA alleles in tumors can still be recognized by TCR-Ts, about 13% of participants had LOH of the targeted HLA allele, excluding them from TCR-T treatment. Conclusions: Initial data indicate that the combination of HLAs and targets in the ImmunoBank results in ≥1 TCR-T match for the majority of solid tumor patients evaluated to date, and many patients qualify for multiplexed TCR-T treatment. LOH testing can prevent selection and treatment with a TCR-T that would not confer benefit. The proportion of patients eligible for multiplexing is expected to increase as the ImmunoBank grows. Updated data on screened and treated patients will be presented at the meeting. Clinical trial information: NCT05973487 ; NCT05812027 .

Abstract Introduction: Novel early-line therapies for advanced (unresectable or metastatic) melanoma are needed to improve the rate of deep and durable responses and increase the proportion of patients with long-term benefit. TILVANCE-301 will evaluate the efficacy and safety of lifileucel autologous TIL cell therapy plus pembrolizumab in patients with untreated advanced melanoma. Methods: TILVANCE-301 (NCT05727904) is a phase 3, multicenter, randomized, open-label, parallel group study that will randomize ~670 patients (1:1; Day 0) to Arm A: lifileucel plus pembrolizumab (Day 3: tumor tissue resection for TIL manufacturing; Day 5: pembrolizumab 200 mg; Day 26: pembrolizumab 400 mg; Day 28-29: cyclophosphamide 60 mg/kg; Day 28-32: fludarabine 25 mg/m2; Day 33: lifileucel; Day 34-37: ≤6 doses of high-dose IL-2; Week 10: pembrolizumab 400 mg Q6W) or Arm B: pembrolizumab alone (same pembrolizumab dosing as Arm A). Patients in Arm B with confirmed progressive disease verified by blinded independent review committee (BIRC) have the option to receive lifileucel monotherapy as immediate next treatment and may continue pembrolizumab until start of nonmyeloablative lymphodepletion. Eligible adults have histologically confirmed advanced melanoma, Eastern Cooperative Oncology Group performance status of 0-1, estimated life expectancy >6 months, ≥1 resectable lesion to generate lifileucel, and ≥1 remaining measurable lesion. Prior neoadjuvant or adjuvant treatment including immune checkpoint inhibitors may be allowed. Prior therapy for metastatic disease, symptomatic untreated brain metastases, organ allograft or prior cell therapy, uveal/ocular melanoma, and chronic systemic steroid therapy are not permitted. The dual primary efficacy endpoints are BIRC-assessed (RECIST v1.1) objective response rate (ORR) and progression-free survival (PFS). Key secondary efficacy endpoint is overall survival. Additional secondary efficacy endpoints include BIRC-assessed complete response (CR) rate, duration of response (DOR), and event-free survival (EFS); investigator-assessed ORR, PFS, CR rate, DOR, EFS, and PFS2; and safety as characterized by severity and seriousness of treatment-emergent adverse events and relationship to study drug. Exploratory endpoints include in vivo T-cell persistence (unique CDR3 sequences in peripheral blood mononuclear cell [PBMC] over time) and correlative biomarkers (eg, lifileucel phenotypic and functional characteristics; lifileucel, tumor, and PBMC gene expression profiles; tumor mutational landscape). The study will enroll globally, with initial sites in Europe, North America, and Australia. Trial registration: NCT05727904 Citation Format: Sajeve Thomas, Young Ki Hong, Yazan Samhouri, James Larkin, David J. Olson, Gino K. In, Victoria Atkinson, Philip Lammers, Andrew J. Furness, Juan Martin-Liberal, Patrick Terheyden, Andrew S. Poklepovic, Ryan H. Nguyen, Idit Peretz, Marcus Butler, Adnan Khattak, Lavinia Spain, E.M. Gaughan, Melissa Wilson, John W. Dubay, Anja Williams, Stephanie Goff, Gary C. Doolittle, Jason Chesney, Friedrich Graf Finckenstein, Jeffrey Chou, Xiao Wu, Giri Sulur, Wen Shi, John Haanen. TILVANCE-301, a phase 3 study of lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in combination with pembrolizumab vs pembrolizumab alone in treatment-naive unresectable or metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT286.

Background The use of pro-inflammatory cytokines as systemic therapies has been explored in the oncology field due to their ability to promote the function and proliferation of immune cells. However, high toxicity and limited efficacy have been reported. CLN-617 is a single-chain fusion protein comprised of human cytokines IL2 and IL12, leukocyte-associated immunoglobulin-like receptor 2 (LAIR2), and human serum albumin (HSA), specifically engineered for intratumoral (IT) delivery and retention within the tumor microenvironment via LAIR2-mediated collagen binding. The murine surrogate to CLN-617 has preclinically demonstrated robust tumor growth inhibition in multiple checkpoint inhibitor refractory syngeneic tumor models, a memory response upon tumor rechallenge, an abscopal response when only a single tumor is injected, and synergy with systemic anti-PD1 treatment. Building upon these preclinical findings, we propose this first-in-human trial to explore the safety and efficacy of IT CLN-617 combined with intravenous (IV) pembrolizumab. Methods This Phase-1, open-label, dose-escalation, optimization, and expansion trial will assess the safety, tolerability, and efficacy of IT CLN-617 in combination with pembrolizumab in patients with advanced/metastatic solid tumors that have accessible tumors for injection. The trial consists of 3 parts (figure 1). In Part 1, we will conduct a dose-escalation study of weekly IT CLN-617 monotherapy for the first 21-day cycle, followed by dosing every 3 weeks thereafter in combination with IV pembrolizumab starting in cycle 2. In Part 2, CLN-617 will be administered weekly for the first 21-day cycle in combination with IV pembrolizumab every 3 weeks in cycle 1, followed by CLN-617 and pembrolizumab every 3 weeks thereafter. This part of the trial will focus on patients with specific tumor types, and two dose levels of CLN-617 will be selected to optimize a dose for the expansion part. In Part 3, we will explore an optimized dose of CLN-617 in combination with Pembrolizumab in patients with advanced melanoma and head and neck squamous cell carcinoma (HNSCC). Dose escalation will be guided following the two-parameter logistic continual reassessment model (CRM) to discover an optimized dose. The primary objectives are determining the maximum tolerated dose and the recommended phase 2 dose in Part 1 and evaluating the objective response according to immune Response Evaluation Criteria in Solid Tumors in Parts 2 and 3. Secondary endpoints involve the assessment of pharmacokinetics, pharmacodynamics, and immunogenicity across the 3 parts of the trial. Patients' enrollment is currently ongoing, and updates will be provided at the time of the presentation.

Background: Dual checkpoint inhibition with Anti-PD-1 and anti-CTLA4 checkpoint inhibitors have shown to be efficacious in many malignancies, but its potential role in various rare solid cancers is yet to be established. Small cell ovarian carcinoma, hypercalcemic type (SCCOHT) is a rare tumor characterized by loss of SMARC 2/4 function and so presents a novel paradigm for the treatment of SWI/SNF pathway deficient tumors (Petar Jelinic et al., 2018; Marc Tischkowitz et al., 2020). This study presents the first results of ipilimumab and nivolumab used in the SCCOHT cohort (#49) of the SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial. Methods: DART is a prospective, open-label, multicenter/multi-cohort phase 2 clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks). The primary endpoint includes objective response rate (ORR) (RECIST v1.1) (confirmed complete (CR) and partial responses (PR)). Secondary endpoints include progression-free survival (PFS), overall survival (OS), stable disease (SD) >6 months, and toxicity. Results: Five evaluable patients (median age 30) with SCCOHT were analyzed. Objective response rate was 20% (1 CR with 100% regression). The patient with CR has a duration of response (DoR) and OS of 35+ months. Another patient, showed unconfirmed PR with 81% regression (DoR 4 months), this patient went on to have confirmed iCR (CR confirmed by iRECIST) at around 24 months and has OS of 38+ months. At 12 months, 3 patients remain alive and 1 patient remains progression free; overall median PFS was 1.8 months (1.0-∞); median OS was 24 months (4.5-∞). The most common adverse events were fatigue, nausea, pruritus, dry mouth, maculo-papular rash and aspartate aminotransferase elevation (50%, n=2, respectively). There were two incidents (33.3%) of grade 3-4 adverse events. None of the adverse events led to discontinuation. There were no grade 5 adverse events. Conclusion: Ipilimumab plus nivolumab in five patients with the ultra-rare small cell ovarian carcinoma (hypercalcemic type) resulted in one CR durable at 35+ months and one unconfirmed PR with 81% regression. This is the first prospective study demonstrating efficacy of nivolumab and ipilimumab in this rare disease. Correlative studies to determine response and resistance markers are ongoing. Expanded prospective studies in small cell ovarian histologies are needed. Citation Format: Young Kwang Chae, Megan Othus, Sandip P. Patel, Raid Aljumaily, Khine Z. Win, Tanya Pejovic, Sajeve S. Thomas, William R. Robinson, Liam Il-Young Chung, Christine M. McLeod, Helen X. Chen, Elad Sharon, Howard Streicher, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the small cell carcinoma of the ovary, hypercalcemic type cohort [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 CT163.

Serum concentration of intact sacituzumab govitecan and hRS7 IgG taken 30 min after injection for each of the 4 dose levels tested.

Trop-2 expression in archived tissue specimens from 6 patients enrolled in the clinical trial with sacituzumab govitecan.

Background Novel early-line therapies for advanced (unresectable or metastatic) melanoma are needed to improve the rate of deep and durable responses and increase the proportion of patients with long-term benefit. TILVANCE-301 will evaluate the efficacy and safety of lifileucel autologous TIL cell therapy + pembrolizumab (pembro) in patients with untreated advanced melanoma. Methods TILVANCE-301 (NCT05727904) is a phase 3, multicenter, randomized, open-label, parallel group study that will randomize ~670 patients (1:1; Day 0) to Arm A: lifileucel + pembro (Day 3: tumor tissue resection for TIL manufacturing; Day 5: pembro 200 mg; Day 26: pembro 400 mg; Day 28–29: cyclophosphamide 60 mg/kg; Day 28–32: fludarabine 25 mg/m2; Day 33: lifileucel; Day 34–37: ≤6 doses of high-dose IL-2; Week 10: pembro 400 mg Q6W) or Arm B: pembro alone (same pembro dosing as Arm A). Patients in Arm B with confirmed progressive disease verified by blinded independent review committee (BIRC) have the option to receive lifileucel monotherapy as immediate next treatment and may continue pembro until start of lymphodepleting chemotherapy. Eligible adults have histologically confirmed advanced melanoma, ECOG PS 0–1, estimated life expectancy >6 mo, ≥1 resectable lesion to generate lifileucel, and ≥1 remaining measurable lesion. Prior neoadjuvant or adjuvant treatment including immune checkpoint inhibitors may be allowed. Prior therapy for metastatic disease, symptomatic untreated brain metastases, organ allograft or prior cell therapy, uveal/ocular melanoma, and chronic systemic steroid therapy are not permitted. The dual primary efficacy endpoints are BIRC-assessed (RECIST v1.1) ORR and PFS. Key secondary efficacy endpoint is OS. Additional secondary efficacy endpoints include BIRC-assessed CR rate, DOR, and EFS; investigator-assessed ORR, PFS, CR rate, DOR, EFS, and PFS2; and safety as characterized by severity and seriousness of TEAEs, and relationship to study drug. Exploratory endpoints include in vivo T-cell persistence (unique CDR3 sequences in PBMC over time) and correlative biomarkers (eg, lifileucel phenotypic and functional characteristics; lifileucel, tumor, and PBMC gene expression profiles; tumor mutational landscape). The study will enroll globally, with initial sites in Europe, North America, and Australia. Acknowledgements Medical writing support was provided by Amanda Kelly (Iovance Biotherapeutics, Inc). Trial Registration NCT05727904 Ethics Approval The study was approved by the institutional review board at each site and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines of the International Conference on Harmonization. All patients provided written informed consent.