4002 Background: Several immuno-oncology therapies are available for 1L HCC, but data are limited after progression. IMbrave251 (NCT04770896) is the first global randomized Phase 3 trial to assess atezo + lenva or sora (TKIs) vs lenva or sora alone in patients (pts) with LA/mHCC that progressed after atezo + bev treatment (tx). This is the final analysis. Methods: Eligible pts had LA/mHCC that was responsive to atezo + bev tx but then progressed (atezo + bev was given for ≥4 cycles and ≥2 tumor assessments, of which ≥1 showed stable disease or complete/partial response). In the atezo + TKI arm, pts received atezo (1200 mg Q3W) + lenva (8 mg for pts < 60 kg or 12 mg for pts ≥60 kg QW) or sora (800 mg QW). Pts in the TKI-only arm received lenva or sora alone. The primary endpoint was OS. Secondary endpoints included PFS, ORR by RECIST 1.1, DOR, time to tumor progression (TTP), quality of life, and safety. Stratification factors were disease etiology (hepatitis B/C infection vs non-viral), ALBI score (1 vs 2/3), AFP ( < 400 vs ≥400 ng/mL), and TKI therapy (lenva vs sora). Results: IMbrave251 enrolled 557 pts (full analysis population). Median duration of follow-up was 12 mo. Pts were assigned to receive atezo + TKI (n = 279) or TKI-only (n = 278). Most pts in both arms received lenva (92.1%) vs sora (7.9%). At clinical cutoff (Oct 10, 2025), median (m)OS with atezo + TKI vs TKI-only was 14.6 vs 12.5 mo (stratified HR 0.88; P = 0.2115) and mPFS was 4.3 vs 4.8 mo (stratified HR 1.05), respectively. Confirmed ORR was 7.5% vs 5.8% with atezo + TKI vs TKI-only. DOR was 10.2 vs 6.9 mo, respectively (stratified HR 0.47) (Table). Additional subgroup analyses and complete duration of systemic therapy will be shown. In the atezo + TKI vs TKI-only arm, the median tx duration was 5.6 vs 4.7 mo for lenva and 2.9 vs 2.3 mo for sora. No new or unexpected safety signals were seen (safety analysis n = 554; Table). Conclusions: IMbrave251 did not meet its primary OS endpoint but showed that the addition of atezo to TKIs had a manageable safety profile. This study provides clinically relevant Phase 3 evidence addressing an important, unanswered clinical question regarding 2L tx sequencing after immunotherapy and establishes a new OS benchmark for 2L tx in LA/mHCC. Clinical trial information: NCT04770896 . Efficacy (95% CI) Atezo + lenva or sora(n=279) Lenva or sora(n=278) Stratified HR (95% CI) mOS, mo 14.6 (12.6, 16.8) 12.5 (10.7, 15.5) 0.88 (0.72, 1.08) P =0.2115 mPFS, mo 4.3 (4.1, 5.4) 4.8 (4.2, 5.6) 1.05 (0.88, 1.25) ORR, % 7.5 (4.7, 11.3) 5.8 (3.3, 9.2) Δ1.77 (−2.72, 6.26) a mDOR, mo 10.2 (5.6, 13.0) 6.9 (5.5, 11.7) 0.47 (0.18, 1.23) mTTP, mo 4.4 (4.2, 5.5) 5.4 (4.2, 5.6) 1.06 (0.87. 1.28) Safety, n (%) n=279 n=275 Grade 3/4 | 5 AE 207 (74.2) | 15 (5.4) 182 (66.2) | 16 (5.8) - Serious AE | AE leading to withdrawal from any study drugs 112 (40.1) |33 (11.8 101 (36.7) |19 (6.9) - a Difference in confirmed ORR (95% CI).

Table S1. Representativeness of study participants.

Supplementary Figure S1. Kaplan-Meier estimates of (A) DOR, (B) PFS, and (C) TTP per RECIST v1.1 by BICR

e16380 Background: With a 5-year overall survival (OS) rate <5%, PDAC is a major cause of cancer-related mortality. OPTIMIZE-1 is an open-label, single-arm, multicenter phase 1b/2 study to evaluate efficacy and safety of mitazalimab, a human CD40 agonistic IgG1 antibody, in combination with mFFX in untreated patients with mPDAC. The study met its primary endpoint with promising clinical efficacy vs. historical controls resulting in an overall response rate (ORR) of 54.4 % (unconfirmed; 42.1% confirmed) (Van Laethem 2024). We report the final efficacy analysis for patients treated with 450 and 900 µg/kg mitazalimab. Methods: Patients received mitazalimab on day 1 (priming dose), followed by a 2-week regimen starting with mFFX on day 8 and mitazalimab on day 10. The primary endpoint was ORR compared to 30% ORR for FFX alone. Secondary and exploratory endpoints include Duration of Response (DoR), Progression Free Survival (PFS), OS, safety, PK and PD biomarker assessments. Results: Between 2021 and 2025 94 patients with mPDAC were treated with mFFX + mitazalimab (29 at 450 µg/kg and 65 at 900 µg/kg). 22 patients at 450 µg/kg and 57 at 900 µg/kg received ≥2 treatment cycles and were efficacy evaluable. Efficacy outcomes for both dose levels are summarized in Table 1. The 900 µg/kg dose presented higher ORR, DoR, mPFS and mOS and has been selected for Phase 3 development. The primary efficacy analysis comprised 57 evaluable patients treated with 900 µg/kg mitazalimab + mFFX. Median follow up was 36 months and median exposure to treatment was 7 months. Eighteen patients remained treatment for more than 12 months, including seven who continued beyond 24 months. One patient remains on treatment. ORR was 54.4% (42.1% confirmed) and 22 patients achieved stable disease, for a disease control rate of 78.9%. Three patients achieved complete responses (CR) in target lesions, including one with CR in target and non-target lesions. Median DoR was 12.6 months, mPFS was 7.7 months and mOS was 14.9 months (12, 18, 24 and 30-mo OS rates of 58%, 37%, 26% and 21% respectively). Conclusions: Mitazalimab (900 µg/kg) in combination with mFFX continues to demonstrate clinically meaningful survival benefits compared with historical controls. The robust duration of response and encouraging long-term survival—six patients surviving >36 months—support continued development of mitazalimab in a confirmatory Phase 3 study. Clinical trial information: NCT04888312 . 450 µg/kg(N=22) 900 µg/kg(N=57) Median follow up (95% CI) 13.1 (12.1 - 13.9) 36.2 (30.9 - 36.7) ORR n % (90% CI) 5 (22.7) 24 (42.1) DoR (95% CI) NE (3.7 - NE) 12.6 (7.5 - 22.0) mPFS (95% CI) 5.3 (2.0 - 9.2) 7.8 (5.8 - 11.5) mOS (95% CI) 9.7 (5.9 - NE) 14.9 (10.0 - 17.3) 12-month OS, % (95% CI) 42.9 (21.9 - 62.3) 57.8 (43.9 - 69.4) 18-month OS, % (95% CI) 32.1 (11.1 – 55.7) 37.3 (24.8 - 49.9) 24-month OS, % (95% CI) - 26.1 (15.4 - 38.2) 30-month OS, % (95% CI) - 20.5 (11.0 - 32.1)

AbstractPurpose: In the phase II KEYNOTE-224 study, pembrolizumab showed durable antitumor activity and manageable safety in participants with sorafenib-treated (cohort 1) or treatment-naïve (cohort 2) advanced hepatocellular carcinoma (HCC). We present data after a median follow-up of ∼7 years for cohort 1 and ∼5 years for cohort 2. Patients and Methods: Adults with advanced HCC received pembrolizumab 200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity for ≤35 cycles. The primary endpoint was objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Results: Overall, 155 participants received ≥1 dose of pembrolizumab (cohort 1, n = 104; cohort 2, n = 51). The median follow-up was 83 months (range, 79.3–87.3) for cohort 1 and 58.8 months (range, 55.3–60.8) for cohort 2. The median OS was 13.2 months [95% confidence interval (CI), 9.7–15.3] and 16.9 months (95% CI, 8.3–23.1), respectively; 24- and 48-month OS rates were 31%/17% and 34%/20%, respectively. The median PFS was 4.9 months (95% CI, 3.5–7) and 4.3 months (95% CI, 2.1–7.8), respectively. Treatment-related adverse events occurred in 76 participants [73.1%; grade 3–5, 27 (26%)] in cohort 1 and 28 participants [54.9%; grade 3–5, 8 (15.7%)] in cohort 2. Conclusions: Pembrolizumab continued to show durable response and manageable safety in participants with advanced HCC with or without prior systemic therapy, with long-term effects on OS lasting beyond 48 months in some participants despite receiving study treatment for ≤2 years.

INTRODUCTION:High-grade pancreatic neuroendocrine tumors are rare, and most of them are well differentiated. Management of this type of tumor is not yet well established. METHODS:A 28-year-old woman was referred to our hospital for a well-differentiated grade-3 pancreatic neuroendocrine tumor with multiple liver metastases. The patient received neoadjuvant therapy consisting of combination of Capecitabine/Temozolomide chemotherapy and somatostatin analogue. RESULTS:An excellent regression was observed on both pancreatic and hepatic lesions, and therefore, an aggressive surgical management could be performed with a two-step scheme. Adjuvant hormono-chemotherapy was administered between the two surgeries. The patient achieved six years of disease-free survival following the last therapy. DISCUSSION AND CONCLUSION:We highlight the difference between well and poorly differentiated high-grade neuroendocrine neoplasia and report that aggressive surgery is a valid option even in metastatic presentation at diagnosis.

Background and study aims:Selective internal radiation therapy (SIRT) has shown good results in unresectable liver metastases from neuroendocrine neoplasms (NELM) with a high disease control rate (DCR) reported. The aims of the study is to assess retrospectively the efficacy and safety of 10y of SIRT for NELM. Patients and methods:Primary endpoint was objective response rate (ORR) and DCR by RECIST 1.1 at 2, 4 and 12 months (m). Secondary endpoints were overall survival (OS), liver progressionfree survival (liver-PFS), clinical response (NEN-related symptoms improvement) and safety. Results:50 consecutive patients with NELM who got SIRT from 2011 to 2021 in one center. The two major NEN primary sites were pancreas (46%) and small intestine (36%). Histological NEN grades were 10%, 46% and 44% for grades 1, 2 and 3 respectively. ORR and DCR were 16% and 80% at 2m, 22% and 92% at 4m and 32% and 82% at 12m. Survival rates at 1 and 2 y were 76% and 72% respectively. Prognostic factors for OS and liver-PFS were NEN histological grade (3 vs 1+2) (hazard ratio (HR) for OS: 4.33 [1.8-10.6], for liver-PFS: 3.91 [1.3-11.4]), and early (2m) DCR (HR for OS: 0.14 [0.1-0.4], for liver-PFS: 0.016 [0.003-0.08]). Clinical response occurred in 7 of the 10 symptomatic patients. One patient died from radioembolization-induced liver disease. Conclusion:SIRT showed efficacy in NELM pts, with a high DCR and an good safety profile. G1-2 grade and early DCR were associated with a better OS and liver-PFS.

Background/purpose Immune checkpoint inhibitor-induced arthritis (ICI-IA) is the most common rheumatic immune-related adverse event (irAEs). Its pathogenesis remains unknown. Ultrasound (US)-guided synovial biopsy (USGSB) has been proven to be a safe and reliable procedure in rheumatoid arthritis (RA), enlarging the understanding of synovitis in RA. To the best of our knowledge, no studies have analyzed the histology of ICI-induced arthritis. This study aimed to describe ICI-IA from clinical presentation to histology.Materials and methods Patients who developed inflammatory arthritis while under treatment by ICIs were enrolled. A US assessment of 38 joints [shoulders, elbows, knees, wrists, metacarpophalangeal joints (MCPs), proximal interphalangeal joints (PIPs), and metatarsophalangeal joints (MTPs)] was systematically performed for inflammatory assessment and joint selection before synovial biopsy. Histopathological analyses consisted of semiquantitative scores for histological parameters (synovial hyperplasia, fibrinoid necrosis, hypervascularization, and inflammatory infiltrate) and immunohistochemistry staining (CD3, CD20, CD138, and CD68). As a control group, we enrolled age- and sex-matched untreated early RA (ERA) patients with synovial tissue available.Results A total of 13 patients were included [men/women (10/3), with a median age of 65 years (interquartile range: IQR: 14.5)]. Overall, seven patients suffered from polyarthritis (53.8%), and five (38.4%) suffered from oligoarthritis. The US pre-biopsy evaluation detected synovitis in 23.4% of joints; the most involved was the knee, followed by wrist, elbow, MCP2, MCP3, and MTP 2-5. Samples for synovial tissue analysis were primarily obtained from the knee (69.2%). The histology of ICI-induced arthritis demonstrated a synovial inflammation similar to that found in ERA. ICI-IA and ERA show similar clinical and histological characteristics.Conclusion Clinically, ICI-IA manifested as oligoarthritis and polyarthritis, similar to RA. Synovial histology in ICI-induced arthritis is indistinguishable from RA, suggesting common pathogenic mechanisms. Further transcriptomics analyses are ongoing to better describe this new arthritis condition.

Response determinants to immunotherapy in metastatic pancreatic ductal adenocarcinoma (mPDAC) remain unclear, limiting treatment advancements. We report a single-arm phase 1b/2 study (OPTIMIZE-1) evaluating the safety and efficacy of the cluster of differentiation 40 (CD40) agonist mitazalimab combined with modified FOLFIRINOX (mFOLFIRINOX), in chemotherapy-naive patients with mPDAC. Patients receive an initial dose of mitazalimab one week before starting biweekly cycles of mFOLFIRINOX plus mitazalimab. The study meets its pre-specified primary endpoint, achieving a confirmed objective response rate (ORR) of 42.1%. Median duration of response, progression-free survival, and overall survival was 12.6 months, 7.7 months, and 14.9 months, respectively. Multi-omic analyses of tumor and blood specimens identify a baseline tumor-intrinsic gene signature related to fibrosis associated with improved survival. Additionally, mitazalimab-induced increases in activated circulating myeloid, B cell, and T cell frequencies correlate with better outcomes. These results may inform future patient stratification strategies supporting a planned randomized confirmatory trial of mitazalimab with mFOLFIRINOX in mPDAC. This study was registered at ClinicalTrials.gov (NCT04888312).

723 Background: Mitazalimab, a human CD40 agonistic IgG1antibody has demonstrated encouraging results in combination with mFOLFIRINOX (mFFX) in the phase 2 single arm trial OPTIMIZE-1 in patients with mPDAC. We conducted unanchored ITCs to assess the relative efficacy of mitazalimab + mFFX vs FOLFIRINOX (FFX) / mFFX and NALIRIFOX (NFX), the most effective therapies to date. Methods: Using data from OPTIMIZE-1 and published data from five RCTs identified via a literature review, matching-adjusted indirect comparisons (MAIC) and simulated treatment comparisons (STC), two commonly used ITC methods for health technology assessment (1) were conducted to balance effect modifiers and prognostic factors between trials. Analysis outcomes were overall survival (OS), objective response rate (ORR), and progression free survival (PFS). Reconstructed survival data from FFX, mFFX, and NFX studies were pooled together for the comparison with FFX/mFFX (Pool #1) and FFX/mFFX/NFX (Pool #2) pooled studies. Results: In the STC analysis mitazalimab + mFFX showed a significantly higher OS versus Pool #1 [hazard ratio (HR): 0.64; 95% CI: 0.46 – 0.87] and #2 [HR: 0.65; 95% CI: 0.47 – 0.87], corresponding to an improvement in median OS by 3.4 and 3.3 months respectively. The OS HRs of study-level pairwise comparisons ranged from 0.57 (95% CI: 0.39 – 0.80) to 0.85 (95% CI: 0.53 – 1.39) with only one non-significant comparison. MAICs showed similar trends, although the comparison with Pool #1 was close to statistical significance (HR: 0.68; 95% CI: 0.45 – 1.02). Results of the PFS and ORR comparisons are shown in the table below. Conclusions: Literature based ITCs show a significantly better efficacy of mitazalimab + mFFX versus the current available therapies in patients with mPDAC. These trends will have to be confirmed in a randomized Phase 3 study. 1. Phillippo DM et al, 2019. Clinical trial information: NCT02829099 . ITC results – HR (for OS and PFS) and odds ratios (for ORR) and their 95% CIs. STC MAIC Comparator study OS PFS ORR OS PFS ORR PRODIGE 4 (FFX) 0.57 (0.39 – 0.80) 0.63 (0.44 – 0.88) 1.62(0.87 – 2.99) 0.60 (0.40 – 0.89) 0.56 (0.37 – 0.82) 1.55(0.84 – 2.87) PANOPTIMOX (FFX) 0.58 (0.39 – 0.84) 0.68 (0.47 – 0.98) 1.17(0.59 – 2.30) 0.60 (0.38 – 0.94) 0.67(0.44 – 1.02) 1.04(0.52 – 2.05) AVENGER500 (FFX) 0.71 (0.50 – 0.98) 1.15(0.82 – 1.60) 1.35(0.75 – 2.42) 0.69(0.46 – 1.03) 1.11(0.76 – 1.62) 1.30(0.72 – 2.34) SWOGS1313 (mFFX) 0.85(0.53 – 1.39) 0.89(0.57 – 1.36) 0.90(0.43 – 1.89) 0.91(0.55 – 1.50) 0.86(0.55 – 1.33) 0.88(0.42 – 1.86) Pool #1 0.64 (0.46 – 0.87) 0.81(0.59 – 1.10) 1.33(0.77 – 2.32) 0.68(0.45 – 1.02) 0.81(0.56 – 1.18) 1.20(0.69 – 2.09) NAPOLI-3 (NFX) 0.68 (0.49 – 0.93) 0.85(0.61 – 1.17) 0.97(0.55 – 1.71) 0.67 (0.46 - 0.97) 0.83(0.58 – 1.20) 0.92(0.52 – 1.62) Pool #2 0.65 (0.47 – 0.87) 0.82(0.60 – 1.11) 1.17(0.68 – 2.02) 0.68 (0.47 – 0.99) 0.84(0.59 – 1.19) 1.11(0.64 – 1.91)

INTRODUCTION:Gastroenteropancreatic neuroendocrine tumours (GEP NET) are malignant neoplasms that impact survival. Somatostatin analogues (SSA) are used for treating hormonal symptoms caused by GEP NET and have antiproliferative effects. They are used as first-line therapy in patients with advanced GEP NET, but disease control is limited to a median progression-free survival (mPFS) of 14-32 months. Second-line treatment options include targeted therapy (everolimus or sunitinib), or peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE. In patients suffering from a NET-related hormonal syndrome, SSA is generally continued life-long. However, there is no consensus on whether it is beneficial to continue SSA in non-functional NET upon disease progression. Due to the ongoing activity of the somatostatin receptor pathway in GEP NET progressing on first-line SSA, we hypothesise that SSA have an added efficacy in second-line therapy. METHODS AND ANALYSIS:The SAUNA trial is an international, multicentre, open-label, randomised, controlled, pragmatic clinical trial. 270 patients with advanced, non-functional GEP NET and progression under first-line SSA will be included in substudy 1 (PRRT; n=142) or substudy 2 (targeted therapy (everolimus/sunitinib); n=128) per investigator's choice of second-line therapy and will be randomised (1:1) per substudy between SSA continuation or SSA withdrawal arms. Co-primary endpoints are the difference in progression-free survival (PFS) according to the RECIST (Response Evaluation Criteria In Solid Tumours) V.1.1 criteria and difference in time to deterioration (TTD) in quality of life (QoL) per substudy after initiating second-line therapy with or without SSA. Secondary endpoints include the PFS rate at 18 months, the difference in pooled PFS and TTD combining both substudies, overall survival, response rates, QoL, costs, cost-effectiveness and toxicity. The study design was developed in cooperation with the Belgium and Dutch patient organisations. ETHICS AND DISSEMINATION:The study has been approved on 31 May 2023 by the Ethical Committees and Regulatory Authorities of the concerned member states (EU CT number 2022-502703-30-00). Both the trial management group and the steering committee will oversee good governance of this trial. Results of the study will be published in peer-reviewed international journals and presented at international conferences. TRIAL REGISTRATION NUMBER:NCT05701241.

Gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) exhibit substantial biological heterogeneity, impacting clinical management and outcomes. In 2019, the WHO subdivided the grade 3 (G3) neuroendocrine neoplasms (NEN) characterised by Ki-67 > 20% into the well-differentiated G3 neuroendocrine tumour (NET) and G3 poorly differentiated neuroendocrine carcinoma (NEC) subgroups. Since this update, questions about the prognostic implications and best treatment strategies for NET G3 and NEC remain. Therefore, we initiated a real-world retrospective observational cohort study using data from 225 NEC and 58 NET G3 patients treated in Belgium. Analysis of patient and tumour characteristics and the effect of survival was conducted. Most frequent primary locations were pancreatic (32.9%) and colorectal (21.5%), and 71.8% was diagnosed with stage IV disease. Median overall survival (mOS) was higher in NET G3 (41.3 months (m)) compared to NEC (13.2m). Of those who underwent functional imaging, fluorodeoxyglucose–positron emission tomography (18F-FDG-PET) imaging was positive in 90.6 and 95.6% of the NET G3 and NEC patients, respectively, and somatostatin receptor (SSTR) expression was seen in 97.4 and 66.0%, respectively. The latter was linked to better mOS, suggesting the added value of performing both SSTR imaging and 18F-FDG-PET for high-grade (HG) NEN to provide prognostic information and to possibly expand therapeutic options, which are currently reserved for lower-grade NEN patients. Moreover, while debated, in our population, primary surgery was performed in 92 and 73.5% of locoregional NET G3 and NEC cases, respectively, indicating that surgery can be considered in locoregional setting. Finally, platinum–etoposide was the predominant first-line treatment in metastatic NEC, with no significant survival difference between carboplatin and cisplatin.

4133 Background: With a 5 year overall survival (OS) rate <5%, PDAC is a leading cause of cancer related mortality. Currently available systemic therapies are not curative and new therapeutic options are needed. Mitazalimab is a human CD40 agonistic IgG1antibody that reduces immune suppression, sensitizes the tumor to chemotherapy, and induces long lasting anti-tumor T cell responses. OPTIMIZE-1 (NCT04888312) is a Phase 1b/2, open label, multicenter study assessing mitazalimab's safety and efficacy combined with mFOLFIRINOX (mFFX) in chemotherapy naïve mPDAC patients (pts). Methods: In the first 21 day cycle, mitazalimab was administered on day 1 and 10 and mFFX infusion started on day 8. In subsequent cycles, treatment followed a 14 day cycle with mitazalimab given 2 days after mFFX. The primary endpoint is objective response rate (ORR) compared to 30% ORR for FFX (Conroy, 2011) (80% power; α (1-sided) =0.10). Secondary and exploratory endpoints include Duration of Response (DoR), progression free survival (PFS), OS, safety, PK and PD biomarker assessments. Results: Seventy pts with mPDAC were treated with mFFX + mitazalimab (safety set: 5 at 450 µg/kg and 65 at 900 µg/kg). 57 patients at 900 µg/kg received ≥2 treatment cycles and were efficacy evaluable. The most common grade ≥3 AEs were neutropenia (25.7%), anemia (11.4%), hypokalemia (15.7%) and thrombocytopenia (11.4%), consistent with FFX safety profile. Two pts discontinued treatment due to AEs. Confirmed ORs were observed in 23 pts (40.4%), including 1 complete responder (CR). Median OS, PFS and duration of Response (DoR) were 14.3 months (mo), 7.4 mo and 12.5 mo respectively, with a median follow up of 12.7 mo. 29 pts (51%) remain in the study (32% on treatment, 19% in survival follow up). Efficacy results including correlation with detected KRAS G12 mutations are summarized (Table). Conclusions: Mitazalimab in combination with mFFX is a feasible regimen with a manageable safety profile. The primary endpoint was met; KRAS G12 V and R mutations were associated with better efficacy. Given the promising DoR linked with survival benefit in previously untreated mPDAC, these results merit continued development of mitazalimab in a confirmatory phase 3 study. Clinical trial information: NCT04888312 . [Table: see text]

4100 Background: Based on the results of the open-label, phase 2 KEYNOTE-224 study (NCT02702414), pembro received US FDA and the Center for Drug Evaluation of the China National Medical Products Administration approval for pts with sorafenib-treated aHCC (cohort 1). Durable activity and manageable safety were also observed for pts with tx-naive aHCC in cohort 2 of KEYNOTE-224. We report updated efficacy and safety from both cohorts of KEYNOTE-224 after approximately 7 and 5 years of median follow-up, respectively. Methods: Adults with pathology-confirmed aHCC whose disease progressed after or who were intolerant to sorafenib tx (cohort 1) and adults with histologically, cytologically, or radiologically confirmed aHCC with no prior systemic tx (cohort 2) were eligible. Pts in both cohorts had BCLC stage C or B not amenable or refractory to locoregional therapy and not amenable to curative tx, Child-Pugh A liver function, measurable disease per RECIST v1.1, and ECOG PS 0 or 1. Pts received pembro 200 mg IV Q3W for ≤35 cycles (~2 y). Primary end point was ORR per RECIST v1.1 by BICR. Secondary end points included DOR, DCR, TTP, and PFS (all per RECIST v1.1 by BICR), OS, and safety/tolerability. Results: A total of 155 pts enrolled in cohorts 1 (n = 104) and 2 (n = 51) received ≥1 dose of pembro. Median follow-up, defined as time from first dose to data cutoff (Sept 29, 2023), was 83.0 mo (range, 79.3-87.3) for cohort 1 and 58.8 mo (range, 55.3-60.8) for cohort 2. In each cohort, 90% of pts discontinued, mostly due to progressive disease (59%); 10% of pts in each cohort completed 2 y of tx. ORR was 18.3% (95% CI, 11.4-27.1) for cohort 1 (5 CRs [4.8%] and 14 PRs [13.5%]) and 17.6% (95% CI, 8.4-30.9) for cohort 2 (2 CRs [3.9%] and 7 PRs [13.7%]). Median DOR was 21.0 mo (range, 3.1 to 75.8+) for cohort 1 and 24.7 mo (range, 3.1 to 53.4+) for cohort 2; 77%/43% and 76%/64% of responders, respectively, had a response duration of ≥12 mo/≥24 mo per the Kaplan-Meier method for censored data. Data for PFS, TTP, and OS are shown in the Table. Tx-related AEs were reported in 76 pts (73.1%; grade 3-5, 27 [26.0%]) in cohort 1 and 28 pts (54.9%; grade 3-5, 8 [15.7%]) in cohort 2. Conclusions: Pembro continued to provide durable responses in pts with aHCC with or without prior systemic therapy, with some lasting beyond 20 mo; long-term effects on OS beyond 24 mo and manageable safety were also observed. Together with data from KEYNOTE-394 and KEYNOTE-240, these data support the efficacy and safety of pembro as a tx option for aHCC. Clinical trial information: NCT02702414 . [Table: see text]

SAR439459, a 'second-generation' human anti-transforming growth factor-beta (TGF beta) monoclonal antibody, inhibits all TGF beta isoforms and improves the antitumor activity of anti-programmed cell death protein-1 therapeutics. This study reports the pharmacodynamics (PD) and biomarker results from phase I/Ib first-in-human study of SAR439459 +/- cemiplimab in patients with advanced solid tumors (NCT03192345). In dose-escalation phase (Part 1), SAR439459 was administered intravenously at increasing doses either every 2 weeks (Q2W) or every 3 weeks (Q3W) with cemiplimab IV at 3 mg/kg Q2W or 350 mg Q3W, respectively, in patients with advanced solid tumors. In dose-expansion phase (Part 2), patients with melanoma received SAR439459 IV Q3W at preliminary recommended phase II dose (pRP2D) of 22.5/7.5 mg/kg or at 22.5 mg/kg with cemiplimab 350 mg IV Q3W. Tumor biopsy and peripheral blood samples were collected for exploratory biomarker analyses to assess target engagement and PD, and results were correlated with patients' clinical parameters. SAR439459 +/- cemiplimab showed decreased plasma and tissue TGF beta, downregulation of TGF beta-pathway activation signature, modulation of peripheral natural killer (NK) and T cell expansion, proliferation, and increased secretion of CXCL10. Conversion of tumor tissue samples from 'immune-excluded' to 'immune-infiltrated' phenotype in a representative patient with melanoma SAR439459 22.5 mg/kg with cemiplimab was observed. In paired tumor and plasma, active and total TGF beta 1 was more consistently elevated followed by TGF beta 2, whereas TGF beta 3 was only measurable (lower limit of quantitation >= 2.68 pg/mg) in tumors. SAR439459 +/- cemiplimab showed expected peripheral PD effects and TGF beta alteration. However, further studies are needed to identify biomarkers of response.

Background & Aims: We aimed to explore patient expectations regarding their treatments and prognosis in comparison physicians' assessments in patients with advanced hepatocellular carcinoma (HCC) receiving systemic treatments. Methods: We prospectively enrolled 205 patients in France and Belgium with Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC receiving systemic treatment (NCT04823754). Patients completed a 28-question survey and the hospital anxiety and depression scale (HADS), while physicians filled a 17-question survey after the initial consultation. Univariate and multivariate models were used to assess factors associated with concordant patient-physician responses, HADS, as well as predicted (by physicians) and observed overall survival. Results: Patients had a median age of 68 years with 75% having BCLC C HCC; 86.3% received atezolizumab/bevacizumab. 60% of patients did not discuss life expectancy with the physician. 63% of the patients believed they had a life expectancy >5 years. Among shared questions between patients and physicians, 36.4% concordance was observed; major differences centered on life expectancy with patients more optimistic than physicians. A lower patient-physician concordance was seen with shorter consultations (p = 0.003), female physicians (p = 0.02), BCLC C (p = 0.03) and >100 HCC patients/year per physician (p 0.008). Compared to France, patients from Belgium were more likely to be satisfied with the consultation (p <0.001) but were less optimistic about life expectancy. Using HADS, 52% of the patients had anxiety/depression that was correlated with alphafetoprotein level (p = 0.03). The predicted median overall survival by physicians was 18 months vs. 13 months for the observed overall survival (weak correlation, q = 0.31). Conclusion: Expectations regarding systemic treatments for advanced HCC differ significantly between patients and physicians, showing notable variations across countries.

Background The aim of the COSMIC-312 trial was to evaluate cabozantinib plus atezolizumab versus sorafenib in patients with previously untreated advanced hepatocellular carcinoma. In the initial analysis, cabozantinib plus atezolizumab significantly prolonged progression-free survival versus sorafenib. Here, we report the pre-planned final overall survival analysis and updated safety and efficacy results following longer follow-up. Methods COSMIC-312 was an open-label, randomised, phase 3 study done across 178 centres in 32 countries. Patients aged 18 years or older with previously untreated advanced hepatocellular carcinoma were eligible. Patients must have had measurable disease per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1), and adequate marrow and organ function, including Child-Pugh class A liver function; those with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were ineligible. Patients were randomly assigned (2:1:1) using a web-based interactive response system to a combination of oral cabozantinib 40 mg once daily plus intravenous atezolizumab 1200 mg every 3 weeks, oral sorafenib 400 mg twice daily, or oral single-agent cabozantinib 60 mg once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were for cabozantinib plus atezolizumab versus sorafenib: progression-free survival per RECIST 1.1, as assessed by a blinded independent radiology committee, in the first 372 randomly assigned patients (previously reported) and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib. The secondary endpoint was progression-free survival in all patients randomly assigned to cabozantinib versus sorafenib. Outcomes in all randomly assigned patients, including final overall survival, are presented. Safety was assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03755791. Findings Between Dec 7, 2018, and Aug 27, 2020, 432 patients were randomly assigned to combination treatment, 217 to sorafenib, and 188 to single-agent cabozantinib, and included in all efficacy analyses. 704 (84%) patients were male and 133 (16%) were female. 824 of these patients received at least one dose of study treatment and were included in the safety population. Median follow-up was 22 center dot 1 months (IQR 19 center dot 3-24 center dot 8). Median overall survival was 16 center dot 5 months (96% CI 14 center dot 5-18 center dot 7) for the combination treatment group and 15 center dot 5 months (12 center dot 2-20 center dot 0) for the sorafenib group (hazard ratio [HR] 0 center dot 98 [0 center dot 78-1 center dot 24]; stratified log-rank p=0 center dot 87). Median progression-free survival was 6 center dot 9 months (99% CI 5 center dot 7-8 center dot 2) for the combination treatment group, 4 center dot 3 months (2 center dot 9-6 center dot 1) for the sorafenib group, and 5 center dot 8 months (99% CI 5 center dot 4-8 center dot 2) for the single-agent cabozantinib group (HR 0 center dot 74 [0 center dot 56-0 center dot 97] for combination treatment vs sorafenib; HR 0 center dot 78 [99% CI 0 center dot 56-1 center dot 09], p=0 center dot 05, for single-agent cabozantinib vs sorafenib). Grade 3 or 4 adverse events occurred in 281 (66%) of 429 patients in the combination treatment group, 100 (48%) of 207 patients in the sorafenib group, and 108 (57%) of 188 patients in the single-agent cabozantinib group; the most common were hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), palmar-plantar erythrodysaesthesia (36 [8%] vs 18 [9%] vs 16 [9%]), aspartate aminotransferase increased (42 [10%] vs eight [4%] vs 17 [9%]), and alanine aminotransferase increased (40 [9%] vs six [3%] vs 13 [7%]). Serious adverse events occurred in 223 (52%) patients in the combination treatment group, 84 (41%) patients in the sorafenib group, and 87 (46%) patients in the single agent cabozantinib group. Treatment-related deaths occurred in six (1%) patients in the combination treatment group (encephalopathy, hepatic failure, drug-induced liver injury, oesophageal varices haemorrhage, multiple organ dysfunction syndrome, and tumour lysis syndrome), one (<1%) in the sorafenib group (general physical health deterioration), and four (2%) in the single-agent cabozantinib group (asthenia, gastrointestinal haemorrhage, sepsis, and gastric perforation). Interpretation First-line cabozantinib plus atezolizumab did not improve overall survival versus sorafenib in patients with advanced hepatocellular carcinoma. The progression-free survival benefit of the combination versus sorafenib was maintained, with no new safety signals. Copyright (c) 2024 Elsevier Ltd. All rights reserved.