Cabozantinib plus atezolizumab in previously untreated advanced hepatocellular carcinoma and previously treated gastric cancer and gastroesophageal junction adenocarcinoma: results from two expansion cohorts of a multicentre, open-label, phase 1b trial (COSMIC-021).

Background: Cabozantinib is approved for previously treated advanced hepatocellular carcinoma (aHCC) and has been investigated in gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJ). Atezolizumab plus bevacizumab is approved for unresectable or metastatic HCC untreated with prior systemic therapy. We evaluated efficacy and safety of cabozantinib plus atezolizumab in aHCC previously untreated with systemic anticancer therapy or previously treated GC/GEJ. Methods: COSMIC-021 (ClinicalTrials.gov, NCT03170960) is an open-label, phase 1b study in solid tumours with a dose-escalation stage followed by tumour-specific expansion cohorts, including aHCC (cohort 14) and GC/GEJ (cohort 15). Eligible patients were aged ≥18 years with measurable locally advanced, metastatic, or recurrent disease per RECIST version 1.1. Patients received oral cabozantinib 40 mg daily and intravenous atezolizumab 1200 mg once every 3 weeks until progressive disease or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate per RECIST version 1.1. Findings: Patients were screened between February 14, 2019, and May 7, 2020, and 61 (30 aHCC, 31 GC/GEJ) were enrolled and received at least one dose of study treatment. Median duration of follow-up was 31.2 months (IQR 28.5-32.7) for aHCC and 30.4 months (28.7-31.9) for GC/GEJ. Objective response rate was 13% (4/30, 95% CI 4-31) for aHCC and 0% (95% CI 0-11) for GC/GEJ. Six (20%) aHCC patients and three (10%) GC/GEJ patients had treatment-related adverse events resulting in discontinuation of either study drug. Interpretation: Cabozantinib plus atezolizumab had clinical activity with a manageable safety profile in aHCC previously untreated with systemic anticancer therapy. Clinical activity of cabozantinib plus atezolizumab was minimal in previously treated GC/GEJ. Funding: Exelixis, Inc., Alameda, CA, USA.

NCCN Guidelines® Insights: Biliary Tract Cancers, Version 2.2023.

In 2023, the NCCN Guidelines for Hepatobiliary Cancers were divided into 2 separate guidelines: Hepatocellular Carcinoma and Biliary Tract Cancers. The NCCN Guidelines for Biliary Tract Cancers provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts meets at least on an annual basis to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. These Guidelines Insights focus on some of the recent updates to the NCCN Guidelines for Biliary Tract Cancers as well as the newly published section on principles of molecular testing.

Imaging to Predict Prognosis in Hepatocellular Carcinoma: Current and Future Perspectives.

The focus of hepatocellular carcinoma (HCC) research for many years has been on noninvasive diagnosis. Standardized systematic algorithms composed of combinations of precise features now serve as diagnostic imaging markers of HCC and constitute a major innovation for liver imaging. In clinical practice, the diagnosis of HCC is based primarily on imaging and secondarily on pathologic analysis if the imaging features are not specific. Whereas accurate diagnosis is essential, the next phase of innovation for HCC will likely encompass predictive and prognostic markers. HCC is a biologically heterogeneous malignancy because of complex molecular, pathologic, and patient-level factors that impact the outcomes of treatment. In recent years, there have been many advances in systemic therapy to augment and extend the existing large cache of local and regional options. However, the guideposts for treatment decisions are neither sophisticated nor individualized. This review provides an overview of prognosis in HCC from the patient to the imaging feature level with a focus on future directions toward more individualized treatment guidance.

Profile and Predictors of Blood Tumor Mutational Burden in Advanced Hepatocellular Carcinoma.

Advanced hepatocellular carcinoma (HCC) is responsive to immune checkpoint inhibitors, but there are currently no known biomarkers to predict treatment benefit. Blood TMB (bTMB) estimation via circulating tumor DNA (ctDNA) profiling can provide a convenient means to estimate HCC TMB. Here we provide the first landscape of bTMB in advanced HCC using a commercially available next-generation sequencing assay, show that it is approximately three times as high as matched tissue TMB, and show that bTMB correlates with NAFLD cirrhosis etiology and the presence of genomic alterations in HTERT and TP53. These results lay the foundation for subsequent studies evaluating bTMB as an immune therapy predictive biomarker in HCC.

Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma.

Atezolizumab (anti-programmed death-ligand 1 (PD-L1)) and bevacizumab (anti-vascular endothelial growth factor (VEGF)) combination therapy has become the new standard of care in patients with unresectable hepatocellular carcinoma. However, potential predictive biomarkers and mechanisms of response and resistance remain less well understood. We report integrated molecular analyses of tumor samples from 358 patients with hepatocellular carcinoma (HCC) enrolled in the GO30140 phase 1b or IMbrave150 phase 3 trial and treated with atezolizumab combined with bevacizumab, atezolizumab alone or sorafenib (multikinase inhibitor). Pre-existing immunity (high expression of CD274, T-effector signature and intratumoral CD8+ T cell density) was associated with better clinical outcomes with the combination. Reduced clinical benefit was associated with high regulatory T cell (Treg) to effector T cell (Teff) ratio and expression of oncofetal genes (GPC3, AFP). Improved outcomes from the combination versus atezolizumab alone were associated with high expression of VEGF Receptor 2 (KDR), Tregs and myeloid inflammation signatures. These findings were further validated by analyses of paired pre- and post-treatment biopsies, in situ analyses and in vivo mouse models. Our study identified key molecular correlates of the combination therapy and highlighted that anti-VEGF might synergize with anti-PD-L1 by targeting angiogenesis, Treg proliferation and myeloid cell inflammation.

Establishment of Patient-Derived Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor Models for Predicting Therapeutic Response.

PURPOSE: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract, with mutant succinate dehydrogenase (SDH) subunits (A-D) comprising less than 7.5% (i.e., 150-200/year) of new cases annually in the United States. Contrary to GISTs harboring KIT or PDGFRA mutations, SDH-mutant GISTs affect adolescents/young adults, often metastasize, and are frequently resistant to tyrosine kinase inhibitors (TKI). Lack of human models for any SDH-mutant tumors, including GIST, has limited molecular characterization and drug discovery. EXPERIMENTAL DESIGN: We describe methods for establishing novel patient-derived SDH-mutant (mSDH) GIST models and interrogated the efficacy of temozolomide on these tumor models in vitro and in clinical trials of patients with mSDH GIST. RESULTS: Molecular and metabolic characterization of our patient-derived mSDH GIST models revealed that these models recapitulate the transcriptional and metabolic hallmarks of parent tumors and SDH deficiency. We further demonstrate that temozolomide elicits DNA damage and apoptosis in our mSDH GIST models. Translating our in vitro discovery to the clinic, a cohort of patients with SDH-mutant GIST treated with temozolomide (n = 5) demonstrated a 40% objective response rate and 100% disease control rate, suggesting that temozolomide represents a promising therapy for this subset of GIST. CONCLUSIONS: We report the first methods to establish patient-derived mSDH tumor models, which can be readily employed for understanding patient-specific tumor biology and treatment strategies. We also demonstrate that temozolomide is effective in patients with mSDH GIST who are refractory to existing chemotherapeutic drugs (namely, TKIs) in clinic for GISTs, bringing a promising treatment option for these patients to clinic.See related commentary by Blakely et al., p. 3.

Pathologic, Molecular, and Prognostic Radiologic Features of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a malignancy with variable biologic aggressiveness based on the tumor grade, presence or absence of vascular invasion, and pathologic and molecular classification. Knowledge and understanding of the prognostic implications of different pathologic and molecular phenotypes of HCC are emerging, with therapeutics that promise to provide improved outcomes in what otherwise remains a lethal cancer. Imaging has a central role in diagnosis of HCC. However, to date, the imaging algorithms do not incorporate prognostic features or subclassification of HCC according to its biologic aggressiveness. Emerging data suggest that some imaging features and further radiologic, pathologic, or radiologic-molecular phenotypes may allow prediction of the prognosis of patients with HCC. An invited commentary by Bashir is available online. Online supplemental material is available for this article. ©RSNA, 2021.

Rescue liver re-transplantation after graft loss due to severe rejection in the setting of pre-transplant nivolumab therapy.

Immune checkpoint inhibitors (ICI) have been used to treat hepatocellular carcinoma (HCC) since 2017. The safety of ICIs in the setting of solid organ transplantation remains controversial. When used in the post-transplant setting, ICIs have been associated with high allograft rejection rates, but there are few published reports on the use of ICIs prior to transplant. We present the first reported case of rescue liver re-transplantation after loss of the first allograft due to severe acute rejection with extensive hepatic necrosis in the setting of pre-transplant ICI therapy with the PD-1 inhibitor nivolumab. It is likely that the durable immune response triggered by nivolumab contributes to graft rejection, therefore extreme caution should be taken when using ICIs before transplant until further investigation has been conducted on their safety in the pre-transplant setting.

Location of Gastrointestinal Stromal Tumor (GIST) in the Stomach Predicts Tumor Mutation Profile and Drug Sensitivity.

PURPOSE: Gastrointestinal stromal tumors (GIST) commonly arise in different regions of the stomach and are driven by various mutations (most often in KIT, PDGFRA, and SDHx). We hypothesized that the anatomic location of gastric GIST is associated with unique genomic profiles and distinct driver mutations. EXPERIMENTAL DESIGN: We compared KIT versus non-KIT status with tumor location within the National Cancer Database (NCDB) for 2,418 patients with primary gastric GIST. Additionally, we compiled an international cohort (TransAtlantic GIST Collaborative, TAGC) of 236 patients and reviewed sequencing results, cross-sectional imaging, and operative reports. Subgroup analyses were performed for tumors located proximally versus distally. Risk factors for KIT versus non-KIT tumors were identified using multivariate regression analysis. A random forest machine learning model was then developed to determine feature importance. RESULTS: Within the NCDB cohort, non-KIT mutants dominated distal tumor locations (P < 0.03). Proximal GIST were almost exclusively KIT mutant (96%) in the TAGC cohort, whereas 100% of PDGFRA and SDH-mutant GIST occurred in the distal stomach. On multivariate regression analysis, tumor location was associated with KIT versus non-KIT mutations. Using random forest machine learning analysis, stomach location was the most important feature for predicting mutation status. CONCLUSIONS: We provide the first evidence that the mutational landscape of gastric GIST is related to tumor location. Proximal gastric GIST are overwhelmingly KIT mutant, irrespective of morphology or age, whereas distal tumors display non-KIT genomic diversity. Anatomic location of gastric GIST may therefore provide immediate guidance for clinical treatment decisions and selective confirmatory genomic testing when resources are limited.

Hepatobiliary Cancers, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Hepatobiliary Cancers focus on the screening, diagnosis, staging, treatment, and management of hepatocellular carcinoma (HCC), gallbladder cancer, and cancer of the bile ducts (intrahepatic and extrahepatic cholangiocarcinoma). Due to the multiple modalities that can be used to treat the disease and the complications that can arise from comorbid liver dysfunction, a multidisciplinary evaluation is essential for determining an optimal treatment strategy. A multidisciplinary team should include hepatologists, diagnostic radiologists, interventional radiologists, surgeons, medical oncologists, and pathologists with hepatobiliary cancer expertise. In addition to surgery, transplant, and intra-arterial therapies, there have been great advances in the systemic treatment of HCC. Until recently, sorafenib was the only systemic therapy option for patients with advanced HCC. In 2020, the combination of atezolizumab and bevacizumab became the first regimen to show superior survival to sorafenib, gaining it FDA approval as a new frontline standard regimen for unresectable or metastatic HCC. This article discusses the NCCN Guidelines recommendations for HCC.

Cancer-associated fibroblast secretion of PDGFC promotes gastrointestinal stromal tumor growth and metastasis.

Targeted therapies for gastrointestinal stromal tumor (GIST) are modestly effective, but GIST cannot be cured with single agent tyrosine kinase inhibitors. In this study, we sought to identify new therapeutic targets in GIST by investigating the tumor microenvironment. Here, we identified a paracrine signaling network by which cancer-associated fibroblasts (CAFs) drive GIST growth and metastasis. Specifically, CAFs isolated from human tumors were found to produce high levels of platelet-derived growth factor C (PDGFC), which activated PDGFC-PDGFRA signal transduction in GIST cells that regulated the expression of SLUG, an epithelial-mesenchymal transition (EMT) transcription factor and downstream target of PDGFRA signaling. Together, this paracrine induce signal transduction cascade promoted tumor growth and metastasis in vivo. Moreover, in metastatic GIST patients, SLUG expression positively correlated with tumor size and mitotic index. Given that CAF paracrine signaling modulated GIST biology, we directly targeted CAFs with a dual PI3K/mTOR inhibitor, which synergized with imatinib to increase tumor cell killing and in vivo disease response. Taken together, we identified a previously unappreciated cellular target for GIST therapy in order to improve disease control and cure rates.

Commission on Cancer Facility Type is Associated with Overall Survival in Patients with Gastric Adenocarcinoma in the United States.

BACKGROUND: In the United States, "high-volume" centers for gastric cancer treat significantly fewer cases per year compared with centers in Asia. Factors associated with oncologic outcomes, aside from volume, are poorly understood. METHODS: Patients with gastric adenocarcinoma between 2004 and 2015 were analyzed in the NCDB cohort. Commission on Cancer facility types were classified as either Academic/Research Programs (ARP) or Non-Academic Programs (NAP). Factors associated with treatment at facility type were assessed by logistic regression. Overall survival was compared between facility types by Cox proportional hazard models. RESULTS: Thirty-nine percent of patients were treated at ARPs. In multivariable analysis, patients treated at ARPs were younger, healthier (Charlson-Deyo score), and had lower AJCC stage. Treatment at an ARP was associated with superior median OS compared with treatment at a NAP (17.3 months vs. 11.1 months, respectively, P < 0.001,) and in each stage of disease. Treatment of stages II and III patients at ARPs increased over time. Among patients with stages II and III disease, adherence to therapy guidelines was higher and postoperative mortality was lower at ARPs. CONCLUSION: Although patients at ARPs tend to have favorable characteristics, superior overall survival may also be due to better adherence to therapy guidelines and capacity to rescue after surgical complications.

Comprehensive genomic landscape and precision therapeutic approach in biliary tract cancers.

Biliary tract cancers have dismal prognoses even when cytotoxic chemotherapy is administered. There is an unmet need to develop precision treatment approaches using comprehensive genomic profiling. A total of 121 patients with biliary tract cancers were analyzed for circulating-tumor DNA (ctDNA) and/or tissue-based tumor DNA (tissue-DNA) using clinical-grade next-generation sequencing: 71 patients (59%) had ctDNA; 90 (74%), tissue-DNA; and 40 (33%), both. Efficacy of targeted therapeutic approaches was assessed based upon ctDNA and tissue-DNA. At least one characterized alteration was detected in 76% of patients (54/71) for ctDNA [median, 2 (range, 0-9)] and 100% (90/90) for tissue-DNA [median, 4 (range, 1-9)]. Most common alterations occurred in TP53 (38%), KRAS (28%), and PIK3CA (14%) for ctDNA vs TP53 (44%), CDKN2A/B (33%) and KRAS (29%) for tissue-DNA. In 40 patients who had both ctDNA and tissue-DNA sequencing, overall concordance was higher between ctDNA and metastatic site tissue-DNA than between ctDNA and primary tumor DNA (78% vs 65% for TP53, 100% vs 74% for KRAS and 100% vs 87% for PIK3CA [But not statistical significance]). Among 80 patients who received systemic treatment, the molecularly matched therapeutic regimens based on genomic profiling showed a significantly longer progression-free survival (hazard ratio [95%confidence interval], 0.60 [0.37-0.99]. P = .047 [multivariate]) and higher disease control rate (61% vs 35%, P = .04) than unmatched regimens. Evaluation of ctDNA and tissue-DNA is feasible in biliary tract cancers.

Design of thienopyranone-based BET inhibitors that bind multiple synthetic lethality targets.

Development of small molecule compounds that target several cancer drivers has shown great therapeutic potential. Here, we developed a new generation of highly potent thienopyranone (TP)-based inhibitors for the BET bromodomains (BDs) of the transcriptional regulator BRD4 that have the ability to simultaneously bind to phosphatidylinositol-3 kinase (PI3K) and/or cyclin-dependent kinases 4/6 (CDK4/6). Analysis of the crystal structures of the complexes, NMR titration experiments and IC50 measurements reveal the molecular basis underlying the inhibitory effects and selectivity of these compounds toward BDs of BRD4. The inhibitors show robust cytotoxic effects in multiple cancer cell lines and induce cell-cycle arrest and apoptosis. We further demonstrate that concurrent disruption of the acetyllysine binding function of BRD4 and the kinase activities of PI3K and CDK4/6 by the TP inhibitor improves efficacy in several cancer models. Together, these findings provide further compelling evidence that these multi-action inhibitors are efficacious and more potent than single inhibitory chemotypes.

Current management of succinate dehydrogenase-deficient gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are increasingly recognized as having diverse biology. With the development of tyrosine kinase inhibitors molecularly matched to oncogenic KIT and PDGFRA mutations, GISTs have become a quintessential model for precision oncology. However, about 5-10% of GIST lack these driver mutations and are deficient in succinate dehydrogenase (SDH), an enzyme that converts succinate to fumarate. SDH deficiency leads to accumulation of succinate, an oncometabolite that promotes tumorigenesis. SDH-deficient GISTs are clinically unique in that they generally affect younger patients and are associated with GIST-paraganglioma hereditary syndrome, also known as Carney-Stratakis Syndrome. SDH-deficient GISTs are generally resistant to tyrosine-kinase inhibitors, the standard treatment for advanced or metastatic GIST. Thus, surgical resection is the mainstay of treatment for localized disease, but recurrence is common. Clinical trials are currently underway investigating systemic agents for treatment of advanced SDH-deficient GIST. However, further studies are warranted to improve our understanding of SDH-deficient GIST disease biology, natural history, surgical approaches, and novel therapeutics.

Loss of the PTCH1 tumor suppressor defines a new subset of plexiform fibromyxoma.

BACKGROUND: Plexiform fibromyxoma (PF) is a rare gastric tumor often confused with gastrointestinal stromal tumor. These so-called "benign" tumors often present with upper GI bleeding and gastric outlet obstruction. It was recently demonstrated that approximately one-third of PF have activation of the GLI1 oncogene, a transcription factor in the hedgehog (Hh) pathway, via a MALAT1-GLI1 fusion protein or GLI1 up-regulation. Despite this discovery, the biology of most PFs remains unknown. METHODS: Next generation sequencing (NGS) was performed on formalin-fixed paraffin-embedded (FFPE) samples of PF specimens collected from three institutions (UCSD, NCI and OHSU). Fresh frozen tissue from one tumor was utilized for in vitro assays, including quantitative RT-PCR and cell viability assays following drug treatment. RESULTS: Eight patients with PF were identified and 5 patients' tumors were analyzed by NGS. An index case had a mono-allelic PTCH1 deletion of exons 15-24 and a second case, identified in a validation cohort, also had a PTCH1 gene loss associated with a suspected long-range chromosome 9 deletion. Building on the role of Hh signaling in PF, PTCH1, a tumor suppressor protein, functions upstream of GLI1. Loss of PTCH1 induces GLI1 activation and downstream gene transcription. Utilizing fresh tissue from the index PF case, RT-qPCR analysis demonstrated expression of Hh pathway components, SMO and GLI1, as well as GLI1 transcriptional targets, CCND1 and HHIP. In turn, short-term in vitro treatment with a Hh pathway inhibitor, sonidegib, resulted in dose-dependent cell killing. CONCLUSIONS: For the first time, we report a novel association between PTCH1 inactivation and the development of plexiform fibromyxoma. Hh pathway inhibition with SMO antagonists may represent a target to study for treating a subset of plexiform fibromyxomas.

Frequent rectal gastrointestinal stromal tumor recurrences in the imatinib era: Retrospective analysis of an International Patient Registry.

INTRODUCTION: Rectal gastrointestinal stromal tumor (GIST) is rare and comprises about 3% of GIST. METHODS: Registry data was collected by the Life Raft Group June 1976 to November 2017. All patients had a histologic GIST diagnosis. Demographic, clinicopathologic, and clinical outcome data were patient reported. Recurrence-free survival (RFS) was analyzed using the Kaplan-Meier method and Cox regression analysis. RESULTS: Of 1798 patients in the database, 48 had localized rectal GIST (2.7%). Patients were frequently male (58.3%) and non-Hispanic whites (58.3%). Median age at diagnosis was 52 years. Most patients (77%) were diagnosed in the imatinib era (2001 to current). Over half (54.2%) of the cohort had mutation testing and all profiled tumors possessed KIT mutations (exon 9: 7.7%, exon 11: 88.5%, and exon 13: 3.8%). Most evaluable patients (26/28; 92.9%) had high-risk disease (modified NIH criteria) and nearly all patients (95.8%) received imatinib. Median follow-up was 8.8 years (range, 0.3-30.7) and overall RFS was 8.0 years (95% CI, 2.9-13.1). Thirty-two percent (12/37) of patients in the post-imatinib era developed recurrent disease. Diagnosis in the imatinib era was associated with improved RFS (HR = 0.22, 95% CI, 0.08-0.62; P = .004) in the multivariable model. CONCLUSION: We find that disease recurrence remains prevalent in one-third of patients treated during the imatinib-era.