Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide. HCC tumor development and treatment resistance are impacted by changes in the microenvironment of the hepatic immune system. Immunotherapy has the potential to improve response rates by overcoming immune tolerance mechanisms and strengthening anti-tumor activity in the tumor microenvironment. In this review, we characterize the impact of immunotherapy on outcomes of advanced HCC, as well as the active clinical trials evaluating novel combination immunotherapy strategies. In particular, we discuss the efficacy of atezolizumab and bevacizumab as demonstrated in the IMbrave150 study, which created a new standard of care for the front-line treatment of advanced HCC. However, there are multiple ongoing trials that may present additional front-line treatment options depending on their efficacy/toxicity results. Furthermore, the preliminary data on the application of chimeric antigen receptor (CAR-T) cell therapy for treatment of HCC suggests this may be a promising option for the future of advanced HCC treatment.

Cholangiocarcinoma (CCA) is a heterogenous group of malignancies originating in the biliary tree, and associated with poor prognosis. Until recently, treatment options have been limited to surgical resection, liver-directed therapies, and chemotherapy. Identification of actionable genomic alterations with biomarker testing has revolutionized the treatment paradigm for these patients. However, several challenges exist to the seamless adoption of precision medicine in patients with CCA, relating to a lack of awareness of the importance of biomarker testing, hurdles in tissue acquisition, and ineffective collaboration among the multidisciplinary team (MDT). To identify gaps in standard practices and define best practices, multidisciplinary hepatobiliary teams from the University of California (UC) Davis and UC Irvine were convened; discussions of the meeting, including optimal approaches to tissue acquisition for diagnosis and biomarker testing, communication among academic and community healthcare teams, and physician education regarding biomarker testing, are summarized in this review.

Introduction: Sarcomas are heterogenous tumors of more than 150 different tumor types. Recently, 56 soft tissue (ST-URS) and 21 bone (B-URS) sarcomas were classified as URS based on incidence of less than 1 in a million by the Connective Tissue Oncology Society. There is only one histology-based treatment approved in URS. Methods: AACR GENIE database cBioPortal were accessed. Individual alterations annotated by OncoKB therapeutic evidence level, TCGA PanCancer pathway alterations, and demographic data were gathered. Detailed cancer type was reclassified into genomically distinct diseases as appropriate. Results: From 112, 222 patients, 3,424 soft tissue sarcomas and 832 bone sarcomas were identified. 1,079 of 4,251 (25.4%) sarcomas were URS including 950 ST-URS and 129 B-URS. Patients included were 54.1% (n=584) female and identified race as 66.1% (n=713) white, 8.5% (n=92) black, and 6.8% (n=73) Asian. 39/56 ST-URS and 11/21 B-URS subtypes had cases in database. The median number of alterations was 3.0 (SD 5.94, Range 0-81), 3.0 for B-URS and 4.0 for ST-URS. Oncogenic alterations were present in 63.6% of B-URS versus 74.0% of ST-URS (p=0.01). Genomic sequencing identified Level 1 (L1) (FDA-approved drug) in 4.9% (n=53) of URS; 5.6% (n=53) of ST-URS and 0 B-URS (p=0.006). Level 2 (L2) (Standard of care) alterations were seen in 1.6% (n=15) ST-URS and no B-URS. 19.5% (n=210) of all URS and 19.9% (n=189) of ST-URS versus 16.3% (n=21) of B-URS (p=0.3) had an FDA approved drug for use in a biomarker approved indication or approved drug in another indication (Level 1-3). Level 3A gene mutations included BRAF (n=12), NRAS (n=2), TSC2 (n=8). 100 level 3B gene alterations were observed; NRAS (n=21), PIK3CA (n=16), IDH1 (n=8), IDH2 (n=4), TSC2 (n=9), HRAS (n=8), TSC1 (n=5), ATM (n=7), BRCA1/2 (n=4). All L1 (n=36) fusions involved NTRK alterations and all L2 fusions (n=14) involved ALK fusion products in inflammatory myofibroblastic tumors. 17 L1 SMARCB1 copy number alterations (CNA) were seen in epithelioid sarcomas. 1 L3A TSC2 CNA was observed in PECOMA; 29 L3B CNAs were observed including SMARCB1 del (n=7), FGFR1 amp (N=6), BRCA2 del (n=4), and Met amp (n=2). 62.9% of cases had PanCancer pathways altered; TP53 (32.7%), RTK-RAS (33.5%), and cell cycle (33.2%) pathway alterations were most common. TP53 (40.3% versus 31.7%, p=0.05) and cell cycle (41.1% versus 32.1%, p=0.04) alterations were more common in B-URS, while RTK-RAS (34.5% versus 25.6%, p=0.04) alterations were more common in ST-URS. Conclusions: Genomic sequencing of URS reveals actionable alterations, their co-alterations, and key clinical characteristics using a large multi-institution publicly accessible registry of real-world patient data opening additional treatment options. Sequencing should be routine care in URS. Increased racial diversity in genetic samples and public databases is warranted. Citation Format: Justin Tyler Moyers, Danielle Brazel, Priyanka Kumar, Hung Doan, Jason Roszik, Jennifer B. Valerin, Roberto Carmagnani Pestana, Warren A. Chow, Vivek K. Subbiah. Landscape of genomic alterations of ultra-rare sarcomas (URS) from 1,079 patients in the AACR GENIE real world database: Clinical implications [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 2184.

98 Background: Salvage treatments for refractory mCRC are an unmet need. This study determined the safety and Recommended Phase 2 Dose (RP2D) of the multi-kinase inhibitor Cabo in combination with FDT/TPI in mCRC. Methods: Single institution investigator-initiated phase 1 study using 3+3 design. Patients (pts) with mCRC previously treated with a fluoropyrimidine, oxaliplatin, irinotecan and appropriate biologics were eligible. Cabo was given orally (p.o.) at 20 mg (dose level [DL] 0) or 40 mg (DL 1) daily on days 1-28, and FTD/TPI p.o. at 35 mg/m2 on days 1-5 and 8-12 every 28 days. Prophylactic growth factors were allowed. The primary endpoint was Dose Limiting Toxicity (DLT) at 28 days. Secondary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate and CEA response. Results: 12 pts were enrolled. Median age 57 years (31-80), male (9/12), ECOG 0/1 = 7/5, Caucasian/Hispanic/Asian = 7/4/1. 3 pts were treated at DL 0 with no observed DLT. Another 9 pts (n = 6 pts to determine RPD2 and additional n = 3 pts in expansion) were treated at DL 1, none exhibiting a DLT. The most common any grade (G) treatment related adverse events (TRAE) were diarrhea (50%), nausea (42%), neutropenia (42%), fatigue (33%) and rash (25%). G3-4 TRAE in > 5% of patients were neutropenia (25%) and thrombocytopenia, hypokalemia, weight loss (each 8%). No serious TRAE or G5 were reported. The RP2D was determined to be DL 1. Median PFS and OS were 4.1 (95% CI 1.9-6.8) and 6.7 (95% CI 2.2-not evaluable) months, respectively. The disease control rate was 75%. 5/12 (42%) pts had a CEA decline > 30%. Conclusions: The combination of Cabo and FTD/TPI is feasible and tolerable and showed encouraging clinical activity in refractory mCRC. Additional pts are being enrolled at DL 1 and will be presented at the meeting. Clinical trial information: NCT04868773 .