Faculty Bibliography

The clinical management of hepatocellular carcinoma (HCC) has evolved significantly over the past decade. Key advances include the introduction of immune-based treatment options, which now serve as the foundation for systemic therapies. Additionally, innovations in surgical techniques, such as robotic surgery, have broadened the scope of resection to include selected patients previously deemed unsuitable due to factors like tumor location or the presence of portal hypertension. HCC downstaging has also gained recognition as a viable strategy in appropriately selected patients, demonstrating outcomes comparable to those achieved under conventional listing criteria. Consequently, the management of HCC has become increasingly complex, underscoring the critical importance of multidisciplinary collaboration and shared decision-making. In this review, we provide a concise overview of practical recommendations for HCC management, encompassing aspects such as risk stratification, early detection, diagnosis, and treatment strategies.

Introduction In this preclinical human immune system patient-derived xenograft (HIS PDX) model and phase II clinical trial, we assessed evorpacept (anti-CD47 engineered fusion protein with inactive Fc), cetuximab, and pembrolizumab (triple therapy) in microsatellite stable colorectal cancer (MSS CRC). Materials, Patients, and Methods HIS BRGS mice with PDXs were treated with triple therapy or its components. Patients with refractory MSS CRC were treated with triple therapy in a safety run-in (Stage 1) followed by expansion (Stage 2, planned N=42). The co-primary objectives were to determine the recommended dose of evorpacept and objective response rate (vs historical control). Results In HIS-PDX mice, triple therapy decreased the growth of MSS CRC tumors and increased tumor-infiltrating CD8+ T cells. Sixteen patients were treated on the clinical trial across two evorpacept dose levels, including N=12 in Stage 1 and N=4 in Stage 2. Trial enrollment was terminated early due to safety concerns (one treatment-related grade 5 event each of hemophagocytic lymphohistiocytosis and cytokine release syndrome). Otherwise, the adverse event profile was as expected. Among all patients, the ORR was 6.3%; formal hypothesis testing was not performed. The disease control rate was 12.5%, the median progression-free survival was 2.3 months, and the median overall survival was 10.9 months. Blood- and tumor-based clinical trial correlative analyses identified innate and adaptive immune system activation. Conclusions While triple therapy demonstrated evidence of efficacy in refractory MSS CRC, safety concerns halted enrollment. Further investigation is necessary to determine the optimal use of CD47-targeted therapies in MSS CRC.

PURPOSE/OBJECTIVE:Givastomig is a bispecific antibody that targets CLDN18.2 and conditionally activates local 4-1BB-expressing T cells. This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of givastomig in advanced solid tumors. PATIENTS AND METHODS/METHODS:75 patients were enrolled. Escalating givastomig doses of 0.1-18 mg/kg were evaluated in 36 patients with metastatic or advanced solid tumors. An additional 6 patients per cohort with CLDN18.2-positive (defined as membrane intensity score of ≥1+ on ≥1% of tumor cells), advanced or metastatic gastroesophageal carcinoma (GEC) were treated with 5-15 mg/kg givastomig across four cohorts. Fifteen patients with CLDN18.2-positive GEC were then enrolled to the 12 mg/kg dose expansion cohort. RESULTS:No dose-limiting toxicities were reported up to 18 mg/kg, and a maximum tolerated dose was not reached. The most common treatment ‑related adverse events (in ≥10% of patients) were nausea, anemia, fatigue, white blood cell count decrease, vomiting, and increased alanine aminotransferase. Givastomig exposure increased dose proportionally, and soluble 4‑1BB approached a plateau above 5 mg/kg. The 12 mg/kg dose was selected for dose expansion. A 16% objective response rate (ORR) was observed in CLDN18.2-positive GEC above 5 mg/kg (N = 43). CLDN18.2 expression in responders ranged from 11% to 100%. CONCLUSIONS:Givastomig demonstrated manageable safety, dose-proportional exposure, and antitumor activity in patients with advanced solid tumors, particularly in CLDN18.2-positive GEC. A givastomig dose range of 5 to 12 mg/kg was chosen to combine with nivolumab and chemotherapy in part 2 of the study in frontline metastatic GEC.

Biliary tract cancers (BTCs) are a heterogeneous group of tumors arising from cells in the bile ducts and gallbladder. The 5-year overall survival rate for all BTC stages combined is ~20%, and treatment options for patients with unresectable disease are limited, leaving an unmet clinical need. In recent years, significant efforts have been made to refine and implement targeted therapeutic approaches for patients with BTC. The adoption of early and comprehensive molecular profiling is crucial to identifying patients who may be candidates for effective targeted therapies. Characterization of the molecular landscape of BTCs led to the identification of murine double minute 2 homolog gene (MDM2) amplification across all BTC subtypes. The MDM2 protein is a critical negative regulator of p53 stabilization and activity that is an emerging actionable biomarker in BTCs. There are multiple therapeutic approaches that aim to target MDM2 activity, thereby restoring the intrinsic tumor suppressor function of p53 and halting oncogenesis. However, these have been limited by our evolving understanding of the role of MDM2 in BTC pathogenesis. Here, we offer a review of the current understanding of the role of MDM2 in BTC biology and its therapeutic implications.

PURPOSE/OBJECTIVE:Circulating tumor DNA (ctDNA) is an emerging tool in the evaluation of GI cancers. Challenges remain in defining its utility and role as a primary end point in therapeutic trials. The National Cancer Institute (NCI) ctDNA GI working group was created to evaluate current data and provide guidance on the inclusion of ctDNA in GI cancer trials. METHODS:The NCI GI steering committee assigned four task force members to serve as co-chairs for the working group. Co-chairs identified experts within each GI disease group to form a panel that convened to review data and provide recommendations. The group focused on ctDNA's role as a potential surrogate for assessing prognosis and guiding treatment decisions that may enhance GI cancer trials. A manuscript was drafted, circulated, revised, and voted on by the panel. The final draft was reviewed by the Cancer Therapy Evaluation Program. RESULTS:Further data are required to support ctDNA as a primary end point for late-phase therapeutic trials, particularly in studies that could change the standard-of-care. However, the group supports ctDNA as a primary efficacy end point for phase II studies and as a noninvasive evaluation strategy for new drug development. Incorporation of ctDNA as a biomarker in trial design must consider the specific context of disease biology of the GI cancer subtypes. ctDNA should be incorporated as an exploratory end point across a variety of disease settings and indications. Several practical considerations were identified to optimize the incorporation of ctDNA in future trial design. CONCLUSION/CONCLUSIONS:Prospective trials are required to clarify the role of ctDNA as a valid surrogate end point for progression-free or overall survival in GI cancers.

Purpose/Objective(s)Radiation therapy (RT) is a critical modality for the treatment of unresectable hepatocellular carcinoma (HCC). Little is known about how the etiology of HCC impacts overall and progression free survival (OS and PFS) in patients treated with definitive RT. We hypothesize that patients treated with definitive RT for HCC secondary to hepatitis B and hepatitis C viruses (viral group) would have favorable OS and PFS when compared to patients with HCC secondary to other etiologies (non-viral group).

TPS4651Background: E/GEJ adenocarcinoma has a high mortality rate despite curative intent treatment. A pathologic complete response (pCR) is associated with better overall survival (OS) but occurs in less than 30% of pts. Immunotherapy is effective in the metastatic setting. Here we aim to evaluate the contribution of immunotherapy in the neoadjuvant and adjuvant settings in pts with locoregional E/GEJ cancer. Methods: This is a multi-center, randomized phase II/III trial. Surgical candidates with locoregional E/GEJ adenocarcinoma receive carboplatin AUC 2 IV and paclitaxel 50 mg/m2 IV, both weekly x 5 during concurrent radiation (50.4 Gy) either with or without nivolumab 240 mg IV during weeks 1 and 3, followed by surgery. Pts with no post-operative disease receive nivolumab 240 mg IV every 2 weeks for 12 cycles either with or without ipilimumab 1 mg/kg IV every 6 weeks for 4 cycles. Eligibility criteria include pts with T1-N1-3M0 or T2-3N0-2M0 disease whom are candidates for surgery, no prior chemotherapy or radiation for this disease, no prior immunotherapy, no significant autoimmune disease. Pts must be disease free for adjuvant treatment. Primary neoadjuvant endpoint is pCR rate; primary adjuvant endpoint is disease free survival (DFS). Secondary endpoints include toxicity, DFS and OS. Pre- and mid-treatment diffusion weighted imaging MRI will be conducted during the neoadjuvant portion of the study. A neoadjuvant safety run in of 30 pts is underway. Overall, 278 pts will be needed to detect an absolute improvement of 15% in pCR rate in pts receiving and not receiving neoadjuvant nivolumab and 236 pts will be needed to detect a HR of 0.65 in favor of adjuvant ipilimumab/nivolumab over nivolumab (90% power, one sided alpha of 0.10). Accrual is expected over 34 months at a rate of 8 patients per month. If favorable at interim analysis. Clinical trial information: NCT03604991.

TPS9092 Background: The incidence of SCCS has increased over the past two decades, including a high risk subset with aggressive behavior. Due to a lack of high-quality clinical trials in this population, there is no standard systemic therapy for advanced SCCS. The epidermal growth factor receptor (EGFR), often highly expressed in SCCS, is implicated in UV-induced skin carcinogenesis and SCCS development. Cetuximab, a monoclonal antibody that competitively inhibits EGFR, improved disease control as first line therapy in unresectable SCCS in a single arm phase II trial. Despite impressive responses with cetuximab in some, most treated SCCS patients do not respond, and there is a need for predictive biomarkers. We hypothesize that the use of cetuximab will improve clinical outcomes in patients with advanced SCCS in the neoadjuvant setting, and that measures of antibody dependent cytotoxicity (ADCC) in tumor and/or specific genomic features of the tumor may predict response to therapy. Methods: In this pilot trial (NCT 02324608), we will enroll 20 patients with relapsed locally advanced SCCS or SCCS unamenable to definitive local therapy. The primary endpoint will measure response rate to cetuximab by RECIST criteria with secondary endpoints of progression free and overall survival, and conversion to resectability. Molecular tumor correlates include analyzing DNA mutations and measuring downstream activation of EGFR signaling and ADCC, correlating these with clinical benefit. Patients will receive cetuximab at 400mg/m2 ? 1 followed by weekly doses of 250mg/m2 for 8 weeks prior to surgery. Patients will be evaluated for subsequent definitive surgical resection, or definitive radiotherapy if surgical resection is not possible. Postoperative adjuvant radiotherapy will be permitted. Patients will undergo pretreatment biopsies, and post-treatment tissue will be harvested at surgery or through a biopsy at the conclusion of cetuximab. Paired skin and tumor samples will be evaluated through partial DNA (FoundationOne??) and RNA sequencing, IHC analysis of EGFR signaling components, and measurement of ADCC. The trial is currently screening eligible subjects. Clinical trial information: 02324608.