BACKGROUND:Transforming Growth Factor Beta (TGFβ) plays a dual role in cancer, acting as a tumor suppressor early in disease but promoting progression and immune evasion when dysregulated. In pancreatic ductal adenocarcinoma (PDAC), TGFβ-driven desmoplasia fosters chemoresistance and immunosuppression, limiting therapeutic efficacy. NIS793, a fully human monoclonal antibody targeting TGFβ, demonstrated anti-fibrotic and immunomodulatory activity in preclinical models and early-phase trials. METHODS:We conducted a randomized, open-label, phase II study in treatment-naïve metastatic PDAC patients to evaluate NIS793 ± spartalizumab (anti-PD-1) combined with nab-paclitaxel/gemcitabine (ABRA/GEM) versus ABRA/GEM alone. Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), safety, pharmacokinetics, and biomarker analyses. Exploratory assessments included paired tumor RNA sequencing, cfDNA profiling, and plasma proteomics. RESULTS:NIS793 demonstrated target engagement and suppression of TGFβ signaling, confirmed by transcriptomic and proteomic analyses. Stromal remodeling was evident, with significant downregulation of CAF markers (ACTA2, FAP) and collagen-related signatures. Despite proof-of-mechanism, clinical efficacy was not observed: median PFS and OS were comparable or numerically worse in NIS793 arm versus control (HR for OS in NIS793+ABRA/GEM vs ABRA/GEM: 1.32; 95% CI: 0.84-2.07). Safety profile was manageable, with no unexpected toxicities. Biomarker data revealed increased expression of neutrophil-related genes post-treatment, suggesting potential induction of tumor-promoting inflammation. CONCLUSIONS:NIS793 effectively inhibited TGFβ signaling and led to stroma remodeling but failed to improve outcomes in metastatic PDAC. These findings highlight the complexity of TGFβ biology and caution against its blockade in combination with chemotherapy for PDAC. Future strategies should consider context-dependent effects of TGFβ inhibition(NCT04390763).

PURPOSE:Mutations or silencing of the von Hippel-Lindau tumor suppressor gene accumulate hypoxia-inducible factors (HIF). HIF-2α is implicated in the oncogenesis of ∼50% of patients with clear-cell renal cell carcinoma (ccRCC) but has been considered "undruggable." DFF332, an orally administered novel allosteric inhibitor of HIF-2α, showed dose-dependent antitumor efficacy in preclinical models of ccRCC. PATIENTS AND METHODS:This first-in-human study evaluated the safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamics of DFF332 in patients with heavily pretreated advanced ccRCC. Preliminary data from the dose escalation of DFF332 monotherapy, administered orally at 50 or 100 mg weekly or 25, 50, 100, or 150 mg once daily in 28-day treatment cycles, are reported. RESULTS:As of January 15, 2024, 40 patients (median age, 62.5 years) received DFF332 for a median duration of 12.1 weeks. Overall, two patients (5%) achieved a partial response, and 19 (48%) achieved stable disease as the best overall response. DFF332 showed a favorable safety profile, with treatment-related adverse events occurring in 25 patients (63%). Only five patients (13%) experienced treatment-related anemia, and no hypoxia was observed. The only serious treatment-related adverse event, hypertension, was reported in one patient. The maximum tolerated dose was not reached. CONCLUSIONS:Although clinical responses were limited in the doses evaluated, dose exploration halted prematurely, making it difficult to draw definitive conclusions about the efficacy of DFF332. Further investigation is required to establish a recommended dose regimen, assess its efficacy and safety, and evaluate its full potential as a partner in combination studies.

Nanrilkefusp alfa (nanril; SOT101) is an interleukin (IL)-15 receptor βγ superagonist that stimulates natural killer (NK) and CD8+ T cells, thereby promoting an innate and adaptive anti-tumor inflammatory microenvironment in mouse tumor models either in monotherapy or combined with an anti-programmed cell death protein 1 (PD-1) antibody. In cynomolgus monkeys, a clinical schedule was identified, which translated into the design of a phase 1/1b clinical trial, AURELIO-03 (NCT04234113). In 51 patients with advanced/metastatic solid tumors, nanril increased the proportions of CD8+ T cells and NK cells in peripheral blood and tumors. It had a favorable safety profile when administered subcutaneously on days 1, 2, 8, and 9 of each 21-day cycle as monotherapy (0.25-15 μg/kg) or combined (1.5-12 μg/kg) with the anti-PD-1 pembrolizumab (200 mg). The most frequent treatment-emergent adverse events were pyrexia, injection site reactions, and chills. Furthermore, early clinical efficacy was observed, including in immune checkpoint blockade-resistant/refractory patients.

Immune checkpoint inhibitors (ICIs), including those targeting PD-1, are currently used in a wide range of tumors, but only 20–40

Breast cancer is a highly heterogeneous disease. Its intrinsic subtype classification for diagnosis and choice of therapy traditionally relies on the presence of characteristic receptors. Unfortunately, this classification is often not sufficient for precise prediction of disease prognosis and treatment efficacy. The N-glycan profiles of 145 tumors and 10 healthy breast tissues were determined using Matrix-Assisted Laser Desorption-Ionization Time-of-Flight Mass Spectrometry. The tumor samples were classified into Mucinous, Lobular, No-Special-Type, Human Epidermal Growth Factor 2 + , and Triple-Negative Breast Cancer subtypes. Statistical analysis was conducted using the reproducibility-optimized test statistic software package in R, and the Wilcoxon rank sum test with continuity correction. In total, 92 N-glycans were detected and quantified, with 59 consistently observed in over half of the samples. Significant variations in N-glycan signals were found among subtypes. Mucinous tumor samples exhibited the most distinct changes, with 28 significantly altered N-glycan signals. Increased levels of tri- and tetra-antennary N-glycans were notably present in this subtype. Triple-Negative Breast Cancer showed more N-glycans with additional mannose units, a factor associated with cancer progression. Individual N-glycans differentiated Human Epidermal Growth Factor 2 + , No-Special-Type, and Lobular cancers, whereas lower fucosylation and branching levels were found in N-glycans significantly increased in Luminal subtypes (Lobular and No-Special-Type tumors). Clinically normal breast tissues featured a higher abundance of signals corresponding to N-glycans with bisecting moiety. This research confirms that histologically distinct breast cancer subtypes have a quantitatively unique set of N-glycans linked to clinical parameters like tumor size, proliferative rate, lymphovascular invasion, and metastases to lymph nodes. The presented results provide novel information that N-glycan profiling could accurately classify human breast cancer samples, offer stratification of patients, and ongoing disease monitoring.

Esophageal and gastric cancer are diseases with a serious prognosis. While the incidence of gastric cancer is decreasing, the incidence of the gastroesophageal junction and esophageal cancer is increasing. Men are affected more often than women. Despite some progress in the last 10 years, cancer-specific mortality is very high, reaching 70%. The prognosis is mainly determined by the stage, histology, general condition and comorbidities. The treatment approach is curative for early and localized stages, requir-ing comprehensive care already during neoadjuvant therapy. Nutritional support is an essential part of preoperative preparation, and centres specializing in esophagogastric surgery are increasingly adopting the concept of prehabilitation. The main treatment modalities are endoscopy, surgery, systemic therapy and radiotherapy. In locally ad-vanced squamous cell carcinoma, neoadjuvant chemoradiotherapy followed by post-operative immunotherapy is the standard of care, if pathological complete remission has not been achieved. Definitive chemoradiotherapy is an alternative in patients with comorbidities. For adenocarcinoma, perioperative FLOT chemotherapy is the first choice and has shown better results than chemoradiotherapy. Chemoradiotherapy has its place in patients who would not tolerate FLOT or when trying to achieve a higher response rate. According to phase II studies, patients with MSI-high tumours could be treated with neoadjuvant immunotherapy, alone or in combination with chemotherapy; this approach has led to a pathological complete remission rate of approximately 60% and is a promising organ-preserving approach. For HER2-positive tumours, preoperative systemic therapy with trastuzumab may be considered as it demonstrates a significantly higher number of pathological complete remissions and offers the possibility of achiev-ing a higher R0 resection rate. In oligometastatic disease, surgical management of the primary tumour and metastases may be considered in individual cases in patients who respond to systemic therapy. However, an impact on overall survival has only been documented in patients with retroperitoneal involvement and no peritoneal metastases.

197 Background: Trifluridine/tipiracil (T/T) is effective in patients with pretreated metastatic colorectal cancer (mCRC). RAS mutational status could predict magnitude of T/T effect (van de Haar et al, Nat Med. 2023), but the data are conflicting. Methods: We retrospectively reviewed the clinical data of 402 patients consecutively treated with T/T in two institutions in the Czech Republic and analysed the potential predictive value of different RAS mutations. Results: Baseline characteristics: median age 65 (range 28-84), female 32.8%, ECOG PS 0 in 32.8% and 1 in 64.9%, primary tumor location left colon in 76.3%. The median line in which T/T was administered was 3 (range 2-8). Median number of T/T cycles administered was 3 (range 2-27). Median follow-up was 32.4 months, 358 patients died (89.1%). Overall survival (OS) was 9.3 months (95% CI 8.7 to 10.3) and progression-free survival (PFS) 3.5 months (3.2 to 3.6). RAS mutation was detected in 54.2% patients. KRAS G12 mutation was found in 117 patients (29.1%), KRAS G13 in 19 (4.7%), other RAS mutation in 25 (6.2%), non-specified RAS mutation in 57 (14.2%), and BRAF mutation in 14 (4.8%). No difference in OS in RAS wildtype (wt) vs mutated group (P=.50) was observed. OS in the defined groups was found: wtRAS group (9.1 months), KRAS G12 (9.1 m), KRAS G13 (5.6 m), and other RAS mutations (10.6 m, P=.180). Patients with KRAS G13 had worse OS vs all other patients (P=.029; HR 1.97), vs wt (P=.02; HR 2.08), vs other mutated (P=0.067; HR 1.75), vs KRAS G12 mutated patients (P=.069; HR 1.75). Patients with KRAS G12 had no OS difference vs other groups of patients. In KRAS G12 group we found that specific gene variants have different OS (for G12C, 7 patients, OS was 6.0 months; for G12D, 41 patients, 9.0 m; for G12V, 45 patients, 10.5 m; for G12S, 7 patients, 16.1 m; for G12A, 11 patients, 7.6; other G12 variants, 5 patients, 10.0 months, P=.028). BRAF mutation was associated with worse OS (6.6 vs 9.1 months, P=.02, HR 2.46). Conclusions: We did not confirm the negative predictive value of KRAS G12 mutation in patients treated with T/T, however, OS depends on the specific G12 mutation. In contrast, patients with KRAS G13 mutation had worse survival.

Immune checkpoint inhibitors (ICI) are the main therapy currently used in advanced malignant melanoma (MM) and non-small cell lung cancer (NSCLC). Despite the wide variety of uses, the possibility of predicting ICI efficacy in these tumor types is scarce. The aim of our study was to find new predictive biomarkers for ICI treatment. We analyzed, by immunohistochemistry, various cell subsets, including CD3+, CD8+, CD68+, CD20+, and FoxP3+ cells, and molecules such as LAG-3, IDO1, and TGFβ. Comprehensive genomic profiles were analyzed. We evaluated 46 patients with advanced MM (31) and NSCLC (15) treated with ICI monotherapy. When analyzing the malignant melanoma group, shorter median progression-free survival (PFS) was found in tumors positive for nuclear FoxP3 in tumor-infiltrating lymphocytes (TILs) (p = 0.048, HR 3.04) and for CD68 expression (p = 0.034, HR 3.2). Longer PFS was achieved in patients with tumors with PD-L1 TPS ≥ 1 (p = 0.005, HR 0.26). In the NSCLC group, only FoxP3 positivity was associated with shorter PFS and OS. We found that FoxP3 negativity was linked with a better response to ICI in both histological groups.

Importance There remains an unmet need to improve clinical outcomes in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Objective To evaluate clinical benefit of first-line nivolumab plus ipilimumab vs nivolumab alone in patients with R/M SCCHN. Design, Setting, and Participants The CheckMate 714, double-blind, phase 2 randomized clinical trial was conducted at 83 sites in 21 countries between October 20, 2016, and January 23, 2019. Eligible participants were aged 18 years or older and had platinum-refractory or platinum-eligible R/M SCCHN and no prior systemic therapy for R/M disease. Data were analyzed from October 20, 2016 (first patient, first visit), to March 8, 2019 (primary database lock), and April 6, 2020 (overall survival database lock). Interventions Patients were randomized 2:1 to receive nivolumab (3 mg/kg intravenously [IV] every 2 weeks) plus ipilimumab (1 mg/kg IV every 6 weeks) or nivolumab (3 mg/kg IV every 2 weeks) plus placebo for up to 2 years or until disease progression, unacceptable toxic effects, or consent withdrawal. Main Outcomes and Measures The primary end points were objective response rate (ORR) and duration of response between treatment arms by blinded independent central review in the population with platinum-refractory R/M SCCHN. Exploratory end points included safety. Results Of 425 included patients, 241 (56.7%; median age, 59 [range, 24-82] years; 194 males [80.5%]) had platinum-refractory disease (nivolumab plus ipilimumab, n = 159; nivolumab, n = 82) and 184 (43.3%; median age, 62 [range, 33-88] years; 152 males [82.6%]) had platinum-eligible disease (nivolumab plus ipilimumab, n = 123; nivolumab, n = 61). At primary database lock, the ORR in the population with platinum-refractory disease was 13.2% (95% CI, 8.4%-19.5%) with nivolumab plus ipilimumab vs 18.3% (95% CI, 10.6%-28.4%) with nivolumab (odds ratio [OR], 0.68; 95.5% CI, 0.33-1.43; P = .29). Median duration of response for nivolumab plus ipilimumab was not reached (NR) (95% CI, 11.0 months to NR) vs 11.1 months (95% CI, 4.1 months to NR) for nivolumab. In the population with platinum-eligible disease, the ORR was 20.3% (95% CI, 13.6%-28.5%) with nivolumab plus ipilimumab vs 29.5% (95% CI, 18.5%-42.6%) with nivolumab. The rates of grade 3 or 4 treatment-related adverse events with nivolumab plus ipilimumab vs nivolumab were 15.8% (25 of 158) vs 14.6% (12 of 82) in the population with platinum-refractory disease and 24.6% (30 of 122) vs 13.1% (8 of 61) in the population with platinum-eligible disease. Conclusions and Relevance The CheckMate 714 randomized clinical trial did not meet its primary end point of ORR benefit with first-line nivolumab plus ipilimumab vs nivolumab alone in platinum-refractory R/M SCCHN. Nivolumab plus ipilimumab was associated with an acceptable safety profile. Research to identify patient subpopulations in R/M SCCHN that would benefit from nivolumab plus ipilimumab over nivolumab monotherapy is warranted. Trial Registration ClinicalTrials.gov Identifier: NCT02823574

Immune checkpoint inhibitors (ICI) are currently use in a wide range of tumors, but only 20-40% of patients achieve clinical benefit. Aim of our study was to find predictive biomarkers of ICI treatment. We analyzed by immunohistochemistry various cell subsets, including CD3+ cells, CD8+ cells, CD68+ cells, CD20+ cells, FoxP3+ cells, and molecules as LAG-3, IDO1, TGfβ. Comprehensive genomic profiles were analyzed. Correlation of various biomarkers with efficacy of ICI treatment in patients with advanced solid tumors was evaluated. We evaluated 56 patients treated with ICI monotherapy. Longer median progression-free survival (PFS) was found in tumors negative for nuclear FoxP3 (P = 0.002, HR 0.14) and in TMB-high tumors (P = 0.024, HR 0.38). Longer overall survival (OS) was found in patient with intraepithelial CD8 negativity (P = 0.045, HR 0.47). In malignant melanoma CD68 negativity, FoxP3 negativity and PDL TPS ≥ 1 was associated with longer PFS. In NSCLC FoxP3 was associated with longer PFS and OS. We found that absence of expression of several biomarkers such as CD68 and FoxP3 is associated with better survival. TMB-high and PD-L1 expression not universally but in certain disease could predict response.

Anti–PD-(L)1 agents have limited activity in relapsed/refractory (r/r) TNBC. Blockade of immune suppression by antagonism of the adenosine pathway may increase the antitumor activity of PD-1 inhibitors in r/r TNBC. Here, we present data on the A2AR antagonist TAM + the anti–PD-1 antibody spartalizumab in TNBC.

TPS761 Background: Overall survival remains short for pts with mPDAC despite approved therapies, highlighting the need for more effective treatment options. While TGF-β can act as a tumor suppressor in normal tissue and early-stage PDAC, it is associated with tumorigenic processes (such as enhanced genomic instability, neoangiogenesis, epithelial-to-mesenchymal transition, and metastasis) observed in late-stage PDAC. Within the pancreatic tumor microenvironment (TME), TGF-β activates stellate cells and cancer-associated fibroblasts, thereby promoting fibrotic network development and immune exclusion, maintaining an immunosuppressive TME. Preclinical data in murine models have shown that addition of TGF-β blockade to anti-PD-1 therapy or NG augmented the antitumor activity of those agents, leading to tumor regression. These data provide the rationale for combining TGF-β-targeting agents with chemotherapy and/or immunotherapy. This study investigates NIS793, a human IgG2 mAb that binds TGF-β1 and 2, with and without spartalizumab (PD-1 antagonist) combined with NG in treatment-naïve mPDAC. Methods: This is a phase II open-label, randomized study (NCT04390763) with a safety run-in period followed by randomization. Eligible pts are adults with previously untreated mPDAC with measurable disease as per RECIST 1.1 and ECOG performance status score ≤1. Pts are excluded if they have a microsatellite-unstable tumor. The safety run-in was completed and confirmed a dose of NIS793 (intravenously [IV] 2100 mg Q2W) + spartalizumab (IV 400 mg Q4W) + nab-paclitaxel (IV 125 mg/m2 on Days 1, 8, and 15) + gemcitabine (IV 1000 mg/m2 on Days 1, 8, and 15). In the randomized part, pts will be randomized 1:1:1 to NIS793 + spartalizumab + NG (n = 50) or NIS793 + NG (n = 50) or NG (n = 50). Treatment will continue until disease progression, unacceptable toxicity, discontinuation by investigator’s/pt’s choice, or withdrawal of consent. The primary objective is to evaluate the progression-free survival per RECIST v1.1 of NIS793 + NG with or without spartalizumab, versus NG alone. Secondary objectives include safety and tolerability, antitumor activity, overall survival, change in tumoral CD8 and PD-L1 status, and characterization of immunogenicity and pharmacokinetics. Efficacy will be assessed by investigator per RECIST v1.1 and iRECIST at screening, every 8 weeks for 1 year and then every 12 weeks until disease progression. The study is ongoing and has an estimated enrollment of 161 pts. There are currently 31 sites participating across 14 countries. The study is funded by Novartis. Clinical trial information: NCT04390763 .

2502 Background: SOT101 (previously SO-C101) is a fusion protein of IL-15 and the IL-15 receptor α sushi+ domain. Synergistic effects of SOT101 and an anti-programmed cell death protein 1 antibody have been validated in various tumor mouse models inducing a protective memory response. Methods: In this phase 1 study, safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of increasing doses of SOT101 administered subcutaneously were investigated in patients (pts) with advanced solid tumors as monotherapy (Part A) and in combination with pembrolizumab every 3-week cycle (Part B). Dose escalation followed a standard 3+3 design. Data cut-off was 26 January 2022. Results: Overall, 51 pts were treated: 30 in Part A monotherapy at 0.25 to 15 μg/kg SOT101 and 21 in Part B combination therapy (Tx) at 1.5 to 12 μg/kg SOT101. The median (range) number of previous lines of Tx was 3 (1-9) in Part A and 2 (1-6) in Part B. In Part A, 19 (63.3%) pts had previous check-point inhibitor (CPI) Tx, of whom 9 (30 %) were refractory, 5 (16.7%) relapsed. In Part B, 11 pts (52.4%) had previous CPI Tx, and the outcome was 9 (42.9%) pts relapsed, 1 (4.8%) refractory. The most common treatment-emergent adverse events (TEAEs) were transient, and included pyrexia, chills, lymphopenia, anemia, transaminase elevation and vomiting. Most TEAEs were ≤ Grade 2. No treatment-related death was reported. For both monotherapy and combination Tx, the recommended phase 2 dose of SOT101 was determined to be 12 μg/kg. In Part A, in 13 pts at 6 to 12 μg/kg SOT101, the observed clinical benefit rate was 38%. A partial response (PR) was confirmed in 1 pt with skin squamous cell carcinoma, CPI refractory, PR duration 46 days (d), on treatment 154 d. Four pts (all CPI pretreated) had stable disease (SD), range 33-183 d. Final median duration on treatment was 84 d, range 43-183 d. The median duration of clinical benefit was 190 d. In Part B, the observed clinical benefit rate across all SOT101 doses was 63%. A complete response (CR) was confirmed in 1 pt with mesothelioma, CPI naïve, starting at the first tumor assessment, and the pt is ongoing in cycle 5. Three pts, 2 CPI pretreated, had a PR, range 51-232 d, 2 ongoing with PR, and 1 Tx discontinuation while still on PR. Five pts, 3 CPI pretreated, had SD, range 92-340 d, 2 ongoing with SD. The 3 CPI pretreated pts had SD range 41-340 d, 1 pt ongoing. The preliminary median duration on combination Tx was 113 d, range 7-429 d. The preliminary median duration of clinical benefit was 131 d. Conclusions: SOT101 as monotherapy and in combination with pembrolizumab showed a favorable safety profile. Highly promising efficacy signals with one ongoing CR and several long-lasting PRs were reported in CPI-naïve and CPI pretreated pts, including CPI-resistant tumors. Clinical trial information: NCT04234113.

Background SOT101 (INN: nanrilkefusp alfa), a fusion protein of IL-15 and the IL-15 receptor α sushi+ domain, was investigated in AURELIO-03 (NCT04234113), a phase 1 dose-escalation study, as monotherapy and in combination with pembrolizumab. In that trial, combination had a favorable safety profile and MTD was not reached up to the recommended phase 2 dose (RP2D) for monotherapy. Maximum activation of natural killer cells was observed already at low dose levels, maximum CD8+ T cell activation was reached from 9 to 12 µg/kg, no relevant effect on T regulatory cells was observed. Therefore, 12 µg/kg SOT101 was selected as combination RP2D. Encouraging efficacy signals were observed, even in immune checkpoint inhibitor (CPI)-relapsed patients. For combination therapy, the majority of patients had clinical benefit.1,2 Study AURELIO-04 (NCT05256381) aims to further evaluate the efficacy of SOT101 in combination with pembrolizumab in selected solid tumor indications. Methods AURELIO-04 is a phase 2 single-arm study in: Non-small cell lung cancer after a CPI and/or platinum regimen, with no EGFR or ALK aberration Unresectable or metastatic MSI-H/dMMR colorectal cancer First-line cutaneous squamous cell carcinoma not curable by surgery or radiation and second-line after a CPI regimen Hepatocellular carcinoma after a CPI regimen Metastatic castrate-resistant prostate cancer (mCRPC) after docetaxel Ovarian cancer after a platinum regimen Main inclusion criteria are measurable disease as per RECIST 1.1, accessible tumor tissue, ECOG PS 0-1, adequate organ function, no prior IL-2 or IL-15 therapy. For mCRPC, a defined number of patients with non-measurable disease is allowed. Patients will receive 12 µg/kg SOT101 s.c. on days 1, 2, 8, and 9 in combination with 200 mg pembrolizumab i.v. on day 1 every 3 weeks until disease progression or unacceptable toxicity. Primary endpoint is overall response rate (ORR) per RECIST 1.1. Key secondary endpoints include efficacy parameters such as progression-free survival, frequency and severity of treatment-emergent adverse events, pharmacokinetics (PK) including population PK, pharmacodynamics, and immunogenicity parameters. Approximately 55 patients per indication will be enrolled. No formal testing of statistical hypotheses is planned, analyses will be descriptive. Considering benchmark ORRs, a futility analysis is planned for each indication separately. Exploratory analyses include immune and molecular biomarkers. Recruitment started in June 2022. References Champiat S, Marabelle A, Galvao V, et al. SOT101, an IL-2/IL-15 Rβγ superagonist, in combination with pembrolizumab in patients with advanced solid tumors: Interim safety and efficacy results from the AURELIO-03 dose escalation trial. Presented at: American Association for Cancer Research Annual Meeting 2022; April 8-13, 2022; New Orleans, LA. Garralda E, Naing A, Galvao V, et al. Interim safety and efficacy results from AURELIO-03, a phase 1 dose escalation study of the IL-2/IL-15R βγ receptor superagonist SOT101 as a single agent and in combination with pembrolizumab in patients with advanced solid tumors. Presented at: American Society of Clinical Oncology Annual Meeting 2022; June 3-7, 2022; Chicago, IL. Ethics Approval The study was approved by Advarra Institutional Review Board approval number Pro00062123. Participants give informed consent before taking part

Introduction: SOT101 (previously SO-C101), a fusion protein of IL-15 and the IL-15 receptor α sushi+ domain, was investigated in an open-label, multicenter, dose-escalation study as monotherapy and in combination with pembrolizumab in patients with selected advanced tumors (NCT04234113). Here we report an update on the safety and efficacy of the combination treatment. Methods Dose escalation followed a standard 3+3 design. Objectives were to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). The evaluation period for dose-limiting toxicities in each dose step was 21 days. The RP2D was defined as the MTD or a dose below, considering pharmacokinetic and pharmacodynamic parameters. The study is ongoing (data cut-off 26 January 2022). Results: Twenty-one patients with a median of 2 (range 1-6) lines of previous systemic therapies were treated with 1.5, 3.0, 6.0, 9.0, and 12.0 μg/kg of SOT101 subcutaneously in combination with pembrolizumab. The MTD was not yet reached at the ongoing dose level 12.0 µg/kg, which is the RP2D in SOT101 monotherapy. The most common treatment-emergent adverse events were transient and included pyrexia, chills, injection site reaction, anemia, transaminase elevation, vomiting, and lymphopenia. One dose-limiting toxicity with rash, hypotension, and oliguria was reported at 6.0 µg/kg. The event resolved within 2 days and the patient continued with SOT101 at a lower dose. No treatment-related death was reported. One patient achieved a confirmed complete response (CR): mesothelioma at 9.0 µg/kg, on treatment 20 weeks with CR. This patient was immune checkpoint blocker (ICB)-naïve. Four patients achieved a partial response (PR): thyroid gland carcinoma at 3.0 µg/kg, ICB-naïve, on treatment 61 weeks with PR; skin squamous cell carcinoma at 6.0 µg/kg, ICB-relapsed, with PR and disappearance of target lesions, then fluctuating lesions, and on treatment 46 weeks with significant clinical benefit; skin melanoma at 6.0 µg/kg, ICB-relapsed, on treatment 41 weeks with PR; cervical melanoma at 9.0 µg/kg, ICB-pretreated, discontinued treatment after 8 weeks while still on PR. Five patients had confirmed stable disease (SD): anal squamous cell carcinoma (anal SCC) at 1.5 µg/kg, gastric cancer at 3.0 µg/kg, cervical cancer at 6.0 µg/kg, liver cancer at 6.0 µg/kg, and colorectal cancer at 9.0 µg/kg, with 1 patient (anal SCC) having a long-lasting SD over 40 weeks. In this heavily pretreated population, the observed preliminary clinical benefit rate was 63%. Conclusions: SOT101 in combination with pembrolizumab showed a favorable safety profile. Highly promising efficacy signals were reported in ICB-naïve and ICB pre-treated patients, including ICB-resistant tumors. Citation Format: Stephane Champiat, Aurelien Marabelle, Vladimir Galvao, Patricia LoRusso, Peter Grell, Philippe Cassier, Carlos Gomez-Roca, Iphigenie Korakis, Aung Naing, Lenka Palova Jelinkova, Irena Adkins, Ulrich Moebius, Richard Sachse, Sascha Tillmanns, David Bechard, Joachim Kiemle-Kallee, Elena Garralda. SOT101, an IL-2/IL-15 Rβγ superagonist, in combination with pembrolizumab in patients with advanced solid tumors: Interim safety and efficacy results from the AURELIO-03 dose escalation trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT040.

Adenosine A2a receptor (A2AR) blockade in combination with anti-programmed death-1 (PD-1) antibody (Ab) may alleviate immune-suppression, reduce tumor growth, and increase antitumor activity of anti-PD-1 Ab. Taminadenant (A2AR antagonist) +/- spartalizumab (anti-PD-1 Ab) has preliminary antitumor activity in a Ph Ib study in non-small cell lung carcinoma. We present results of taminadenant + spartalizumab in a Ph II study in MSS CRC (NCT03207867). In Part I of the study, pts with MSS CRC were treated with 160 mg oral taminadenant twice daily continuously + 400 mg intravenous spartalizumab every 4 weeks. The primary objective was to evaluate efficacy, using overall response rate (ORR by RECIST v1.1). Disease control rate (DCR) is the proportion of complete response, partial response (PR), or stable disease (SD). Following an interim analysis after the initial 14 evaluable pts with MSS CRC, 40 additional pts were enrolled in two groups: RAS-wildtype (WT) and RAS-mutant (Mt). Tumor biopsies were taken pre- and on-treatment. As of 20 Nov 2020, 58 pts with MSS CRC were enrolled (RAS-WT: n=27; RAS-Mt: n=29; RAS-Unknown [Uk]: n=2); demographics were similar across cohorts. The majority (69%) of pts had received ≥3 lines of prior therapy. Of 58 pts, 1 (2%) had a PR (Mt: n=1), 11 (19%) SD (WT: n=7; Mt: n=4), 34 (59%) progressive disease (WT: n=16; Mt: n=16; Uk: n=2), and 12 (21%) response unknown (WT: n=4; Mt: n=8). Of the pts with SD, 5 showed tumor shrinkage (WT: n=4; Mt: n=1); 4 had response for >6 months and 1 discontinued treatment due to an adverse event (AE). ORR was 2% (95% CI: 0.0–9.2), and DCR was 21% (95% CI: 11.2–33.4). Of 58 pts, common all-grade (G) treatment-related AEs ([TRAEs]; ≥15% pts) were fatigue (21%) and decreased appetite (16%); ≥G3 TRAEs (≥5% pts) were aspartate/alanine aminotransferase (5/9%) or lipase (5%) increase. Pharmacokinetics and biomarker data will be presented. Efficacy results of taminadenant + spartalizumab showed 5 pts obtained clinical benefit (1 PR and 4 sustained SD with tumor shrinkage), with no difference in response between RAS-WT and RAS-Mt. Taminadenant + spartalizumab was well tolerated in pts with MSS CRC.

BackgroundSO-C101 (IL 15/IL-15Rα sushi + domain fusion protein) was investigated in a multicenter, open-label, dose escalation study as monotherapy and in combination with pembrolizumab in patients with selected advanced/metastatic tumors (NCT04234113). Synergistic effects of SO-C101 and an anti-programmed cell death protein 1 (PD-1) antibody have been validated in various tumor mouse models inducing a protective memory response.MethodsThe combination part of the study follows a classical 3+3 dose escalation design. Study objectives are to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). The evaluation period for dose-limiting toxicities in each dose step is 21 days. The RP2D is defined as MTD or a dose below, taking into consideration pharmacokinetic and pharmacodynamic parameters.The study is ongoing (data cut-off 21 June 2021).ResultsA total of 12 patients with a median of 2 (range 1–6) lines of previous systemic therapies were treated at SO-C101 dose levels 1.5 µg/kg (3 patients), 3.0 µg/kg (3 patients), and 6.0 µg/kg (6 patients) together with 200 mg of pembrolizumab. One dose-limiting toxicity of grade (G) 3 cytokine release syndrome (CRS) was observed in one patient at 6.0 µg/kg. The MTD has not yet been reached.Of the treated patients, 2 had long-term stable disease (anal squamous cell carcinoma patient at 1.5 µg/kg, duration 25 weeks; gastric carcinoma patient at 3.0 µg/kg, duration 14 weeks) and 3 achieved a partial response (thyroid gland cancer patient at 3.0 µg/kg, target lesion decrease by 36%; skin squamous cell carcinoma patient at 6.0 µg/kg, target lesion decrease by 40%; and melanoma patient at 6.0 µg/kg, target lesion decrease by 58%). The patients with skin squamous cell carcinoma and melanoma had previously progressed on anti-PD-1 therapy, while the patient with thyroid cancer was anti-PD-1 naïve.The most common study drug-related adverse events were lymphopenia, local injection site reactions, transaminase increase, fever, chills as well as CRS-related symptoms (all mainly G1 or G2 and resolved). The only study drug-related adverse event >G2 that occurred in more than one patient was lymphopenia. No treatment-related death was reported.ConclusionsAlthough the MTD of SO-C101 in combination with pembrolizumab has not been reached yet, clinical efficacy signals were already observed in 5 patients. Available safety data indicate good tolerability. SO-C101 in combination with pembrolizumab has already shown the potential to provide an additional clinical benefit to patients with solid tumors.Trial RegistrationNCT04234113Ethics ApprovalThis study was approved by the FDA (IND 140011) and by the Ethics Boards of participating institutions