Faculty Bibliography

BACKGROUNDMEK inhibitors have limited activity in biliary tract cancers (BTCs) as monotherapy but are hypothesized to enhance responses to programmed death ligand 1 (PD-L1) inhibition.METHODSThis open-label phase II study randomized patients with BTC to atezolizumab (anti-PD-L1) as monotherapy or in combination with cobimetinib (MEK inhibitor). Eligible patients had unresectable BTC with 1 to 2 lines of prior therapy in the metastatic setting, measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1. The primary endpoint was progression-free survival (PFS).RESULTSSeventy-seven patients were randomized and received study therapy. The trial met its primary endpoint, with a median PFS of 3.65 months in the combination arm versus 1.87 months in the monotherapy arm (HR 0.58, 90% CI 0.35-0.93, 1-tail P = 0.027). One patient in the combination arm (3.3%) and 1 patient in the monotherapy arm (2.8%) had a partial response. Combination therapy was associated with more rash, gastrointestinal events, CPK elevations, and thrombocytopenia. Exploratory analysis of tumor biopsies revealed enhanced expression of antigen processing and presentation genes and an increase in CD8/FoxP3 ratios with combination treatment. Patients with higher baseline or lower fold changes in expression of certain inhibitory ligands (LAG3, BTLA, VISTA) on circulating T cells had evidence of greater clinical benefit from the combination.CONCLUSIONThe combination of atezolizumab plus cobimetinib prolonged PFS as compared with atezolizumab monotherapy, but the low response rate in both arms highlights the immune-resistant nature of BTCs.TRIAL REGISTRATIONClinicalTrials.gov NCT03201458.FUNDINGNational Cancer Institute (NCI) Experimental Therapeutics Clinical Trials Network (ETCTN); F. Hoffmann-La Roche, Ltd.; NCI, NIH (R01 CA228414-01 and UM1CA186691); NCI's Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers (P50 CA062924); NIH Center Core Grant (P30 CA006973); and the Passano Foundation.

Background/UNASSIGNED:gemcitabine (GEM)-based 3-week chemoradiation (3WCRT) with 36 Gy in 15 fractions. This study aimed to compare the odds of achieving surgical resection, time to progression (TTP), and overall survival (OS) of patients treated with 3WCRT with concurrent CAPE versus GEM. Methods/UNASSIGNED:A retrospective cohort study was conducted, examining medical records from a single center for patients with (B)RPC treated with 3WCRT between 1/2009-12/2020. Odd ratios (OR) of achieving surgical resection were estimated using logistic regression for univariable and multivariable analyses. Median TTP (mTTP) and median OS (mOS) were estimated using the Kaplan-Meier method. Cox proportional hazards analysis was conducted to estimate hazard ratios (HR) of progression and survival in univariable and multivariable analyses. Results/UNASSIGNED:4.0 months, 95% CI: 0.4-14.5; P=0.01), corresponding to a hazard ratio of 0.33 (95% CI: 0.14-0.81). Adjusting for covariates this effect persisted; the adjusted hazard ratio (AHR) for progression was 0.24 (95% CI: 0.08-0.77). Cox proportional hazards analysis also demonstrated that the CAPE group had superior OS compared to the GEM group in unadjusted (HR =0.13; 95% CI: 0.04-0.40) and adjusted models (HR =0.13, 95% CI: 0.03-0.52). Conclusions/UNASSIGNED:For neoadjuvant 3WCRT, this hypothesis-generating study suggests concurrent CAPE may be a more effective radiosensitizer than GEM for patients with (B)RPC.

Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and a leading cause of cancer deaths worldwide. HCC is a male-dominant cancer with a male:female ratio of up to 7:1. The androgen receptor (AR) is the male hormone receptor known as a major oncogenic driver of prostate cancer. Although AR has been linked to the sexual dimorphism of HCC, clinical trials with AR-targeted agents failed to generate survival benefits. Recent studies provide new insights into the role of AR in liver tumorigenesis and therapeutic responses. Herein, we review current understanding of AR signaling in HCC and feedback mechanisms that limit response to AR blockade. New AR-targeting strategies that might improve outcomes in HCC therapies are also discussed.

INTRODUCTION/BACKGROUND:Hepatic artery infusion pump (HAIP) chemotherapy is a specialized therapy for patients with unresectable colorectal liver metastases (uCRLM). Its effectiveness was demonstrated from a high volume center, with uncertainty regarding the feasibility and safety at other centers. Therefore, we sought to assess the safety and feasibility of HAIP for the management of uCRLM at other centers. METHODS:We conducted a multicenter retrospective cohort study of patients with uCRLM treated with HAIP from January 2003 to December 2017 at six North American centers initiating the HAIP program. Outcomes included the safety and feasibility of HAIP chemotherapy. RESULTS:We identified 154 patients with HAIP insertion and the median age of 54 (48-61) years. The burden of disease was >10 intra-hepatic metastatic foci in 59 (38.3%) patients. Patients received at least one cycle of systemic chemotherapy before HAIP insertion. Major complications occurred in 7 (4.6%) patients during their hospitalization and 13 (8.4%) patients developed biliary sclerosis during follow-up. A total of 148 patients (96.1%) received at least one-dose of HAIP chemotherapy with a median of 5 (4-7) cycles. 78 patients (56.5%) had a complete or partial response and 12 (7.8%) received a curative liver resection. CONCLUSION/CONCLUSIONS:HAIP programs can be safely and effectively initiated in previously inexperienced centers with good response.

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).