In the phase III HIMALAYA study (NCT03298451), STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) vs. sorafenib in unresectable HCC and demonstrated long-term survival benefits. We report an updated exploratory analysis of OS after 5 years of follow-up, including survival by multiple tumour response measures. Participants were randomised to STRIDE (tremelimumab plus durvalumab), durvalumab or sorafenib. OS, depth of response and serious adverse events were assessed. Extended long-term survivors (≥48 months beyond randomisation) were described. The updated data cut-off was 01 March 2024. Median (95% CI) follow-up durations were 62.49 (59.47-64.79) months (STRIDE) and 59.86 (58.32-61.54) months (sorafenib). The OS hazard ratio (95% CI) for STRIDE vs. sorafenib was 0.76 (0.65-0.89). OS rates at 60 months for STRIDE vs. sorafenib were 19.6% vs. 9.4% overall, 28.7% vs. 12.7% in participants achieving disease control per RECIST v1.1, and 50.7% vs. 26.3% in participants achieving >25% tumour shrinkage. No late-onset treatment-related serious adverse events were reported for STRIDE. There were more extended long-term survivors with STRIDE (83/393, 21.1%) than sorafenib (45/389, 11.6%), and extended long-term survival occurred across all clinically relevant subgroups. At 5 years, STRIDE sustained an OS benefit vs. sorafenib and maintained a manageable safety profile. OS benefit with STRIDE was improved in participants with disease control. Data suggest that any degree of tumour shrinkage with STRIDE can be associated with improved OS, indicating that conventional response measures may not fully capture the benefits of STRIDE. Nevertheless, participants experiencing deep responses appear to have the greatest benefit. STRIDE continues to set new benchmarks in unresectable HCC with 1 in 5 patients alive at 5 years. NCT03298451. The phase III HIMALAYA study showed that STRIDE (Single Tremelimumab Regular Interval Durvalumab) improved overall survival (OS) vs. sorafenib in participants with unresectable HCC, including after 4 years of follow-up. Understanding the efficacy and safety of STRIDE over the longer term is important for healthcare providers; here, we demonstrate that STRIDE sustained an OS benefit vs. sorafenib and maintained a manageable safety profile after 5 years of follow-up. OS benefit with STRIDE was improved in participants with disease control and any degree of tumour shrinkage, indicating that conventional response measures may not fully capture the benefits of STRIDE. These findings are important as they set new benchmarks in unresectable HCC and may help guide clinical decisions in the future.

Background and Aims: In the global, Phase 3 HIMALAYA study in unresectable hepatocellular carcinoma (HCC), STRIDE significantly improved overall survival (OS) versus sorafenib; durvalumab was noninferior to sorafenib. Immune checkpoint inhibitor studies have shown an association between the occurrence of immune-mediated adverse events (imAEs) and improved OS. We assessed potential associations between the occurrence of imAEs and OS, and temporal patterns of imAEs, in HIMALAYA. Approach and Results: OS in participants who did and did not experience imAEs and the frequency and timing of imAEs were assessed for STRIDE and durvalumab in the safety analysis set of HIMALAYA. imAEs occurred in 139/388 (35.8%) and 64/388 (16.5%) participants with STRIDE and durvalumab, respectively; most were low grade. OS hazard ratios (95% CI) in participants who experienced imAEs versus those who did not were 0.73 (0.56-0.95) for STRIDE and 1.14 (0.82-1.57) for durvalumab. The 36-month OS rate (95% CI) for STRIDE was 36.2% (28.1-46.7) and 27.7% (22.4-34.2) in participants who did and did not experience imAEs, respectively. The most common imAE category with STRIDE was endocrine events (16.5%). Most imAEs occurred ≤3 months after treatment initiation. Conclusions: Participants who experienced imAEs with STRIDE had a numerical improvement in OS versus those who did not, which was not observed for durvalumab. Long-term OS with STRIDE was observed regardless of imAEs. Most imAEs were low grade, manageable, and occurred in the first 3 months after treatment initiation. Results continue to support the benefits of STRIDE in a diverse population that reflects unresectable HCC globally. Export

Purpose: Devimistat (CPI-613) is a novel inhibitor of tumoral mitochondrial metabolism. We investigated the effect of devimistat in vitro and in a phase Ib clinical trial in patients with advanced biliary tract cancer (BTC). Patients and Methods: Cell viability assays of devimistat ± gemcitabine and cisplatin (GC) were performed and the effect of devimistat on mitochondrial respiration via oxygen consumption rate (OCR) was evaluated. A phase Ib/II trial was initiated in patients with untreated advanced BTC. In phase Ib, devimistat was infused over 2 hours in combination with GC on days 1 and 8 every 21 days with a primary objective to determine the recommended phase II dose (RP2D). Secondary objectives included safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: In vitro, devimistat with GC had a synergistic effect on two cell lines. Devimistat significantly decreased OCR at higher doses and in arms with divided dosing. In the phase Ib trial, 20 patients received a median of nine cycles (range, 3–19). One DLT was observed, and the RP2D of devimistat was determined to be 2,000 mg/m2 in combination with GC. Most common grade 3 toxicities included neutropenia (n = 11, 55%), anemia (n = 4, 20%), and infection (n = 3, 15%). There were no grade 4 toxicities. After a median follow-up of 15.6 months, ORR was 45% and median PFS was 10 months (95% confidence interval, 7.1–14.9). Median OS is not yet estimable. Conclusions: Devimistat in combination with GC is well tolerated and has an acceptable safety profile in patients with untreated advanced BTC.

Purpose: TPST-1120 is a first-in-class oral inhibitor of peroxisome proliferator-activated receptor α (PPARα), a fatty acid ligand-activated transcription factor that regulates genes involved in fatty acid oxidation, angiogenesis, and inflammation, and is a novel target for cancer therapy. TPST-1120 displayed antitumor activity in xenograft models and synergistic tumor reduction in syngeneic tumor models when combined with anti-PD-1 agents. Experimental Design: This phase I, open-label, dose-escalation study (NCT03829436) evaluated TPST-1120 as monotherapy in patients with advanced solid tumors and in combination with nivolumab in patients with renal cell carcinoma (RCC), cholangiocarcinoma (CCA), or hepatocellular carcinoma. Objectives included evaluation of safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity (RECIST v1.1). Results: A total of 39 patients enrolled with 38 treated (20 monotherapy, 18 combination; median 3 prior lines of therapy). The most common treatment-related adverse events (TRAE) were grade 1–2 nausea, fatigue, and diarrhea. No grade 4–5 TRAEs or dose-limiting toxicities were reported. In the monotherapy group, 53% (10/19) of evaluable patients had a best objective response of stable disease. In the combination group, 3 patients had partial responses, for an objective response rate of 20% (3/15) across all doses and 30% (3/10) at TPST-1120 ≥400 mg twice daily. Responses occurred in 2 patients with RCC, both of whom had previously progressed on anti-PD-1 therapy, and 1 patient with late-line CCA. Conclusions: TPST-1120 was well tolerated as monotherapy and in combination with nivolumab and the combination showed preliminary evidence of clinical activity in PD-1 inhibitor refractory and immune compromised cancers. Significance: TPST-1120 is a first-in-class oral inhibitor of PPARα, whose roles in metabolic and immune regulation are implicated in tumor proliferation/survival and inhibition of anticancer immunity. This first-in-human study of TPST-1120 alone and in combination with nivolumab supports proof-of-concept of PPARα inhibition as a target of therapeutic intervention in solid tumors.

438 Background: Patients (pts) with advanced biliary tract cancers (BTC) have poor prognosis despite systemic chemotherapy and treatment beyond first-line platinum doublet remains largely investigational. The immunomodulatory properties of conventional cytotoxic therapy, particularly in regard to the upregulation of PD-L1 expression rendering tumor cells less sensitive to T cell-mediated lysis, rapid emergence of chemotherapy resistance, and known modest efficacy of single agent anti-PD-1 antibody in BTC provide a rationale for combination chemoimmunotherapy. We conducted a multi-center, phase Ib/II, single-arm study to investigate the role of liposomal-irinotecan, 5FU and LV in combination with nivolumab as second-line therapy in pts with advanced BTC. Methods: Key eligibility criteria include histologically confirmed unresectable or metastatic BTC after progression or intolerance of first-line systemic therapy, measurable disease per RECISTv1.1, ECOG PS 0-1, and absence of autoimmune disease or chronic steroid use. The limited phase Ib portion evaluated 10 pts to determine the recommended phase 2 dose (RP2D) based on the probability of dose-limiting toxicity (DLT) rate <30% during days 1-29. Study treatment included 5FU 2400 mg/m² over 46 hrs, LV 400 mg/m², liposomal-irinotecan 70 mg/m² at dose level 0 along with nivolumab 240 mg every 2 wks for up to 2 yrs in absence of disease progression or unacceptable toxicity. The primary endpoint was median progression-free survival (PFS) rate with an alternative and null hypothesis of 5.0 mo and 2.9 mo (two-sided alpha 0.05, power 80%), respectively. Secondary endpoints included best overall response rate (ORR) per immune related (ir)RECIST, median overall survival (OS), 75^th percentile estimates of PFS and OS, and safety. Exploratory objectives include biomarker analysis using include targeted panel exome/transcriptome and immune cell subsets in tissue. Results: 30 eligible pts (60% men, 83% Caucasian) including 10 pts in phase Ib and 20 pts in phase II with a median age of 63.5 yrs (range 36-75) were enrolled across 4 US sites between June 2019 and July 2021. In phase Ib, one pt experienced DLT (grade 3 enterocolitis); RP2D was confirmed at dose level 0. All 30 pts were included in study reported outcomes with a median follow-up time of 10.7 mo. Median PFS was 4.2 mo (95% CI, 1.9-10.2) and failed to reject the null hypothesis. Median OS was 7.5 mo (95% CI, 5.8-21.4). The 75^th percentile estimates for PFS and OS are 10.2 mo (95% CI, 5.4-NE) and 21.4 mo (95% CI, 7.8-21.4). ORR estimates and toxicity data are pending and will be presented at the meeting. Conclusions: The observed median PFS is insufficient to reject the null hypothesis. The 75^th percentile estimates for PFS and OS are suggestive of prolonged benefit with chemoimmunotherapy in a small fraction of patients with BTC. Clinical trial information: NCT03785873.