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BACKGROUND: Differential responses to tamoxifen may be due to inter-patient variability in tamoxifen metabolism into pharmacologically active Z-endoxifen. Z-endoxifen administration was anticipated to bypass these variations, increasing active drug levels, and potentially benefitting patients responding sub-optimally to tamoxifen. MATERIALS AND METHODS: Patients with treatment-refractory gynecologic malignancies, desmoid tumors, or hormone receptor-positive solid tumors took oral Z-endoxifen daily with a 3+3 phase 1 dose escalation format over 8 dose levels (DLs). Safety, pharmacokinetics/pharmacodynamics, and clinical outcomes were evaluated. RESULTS: Thirty-four of 40 patients were evaluable. No maximum tolerated dose was established. DL8, 360 mg/day, was used for the expansion phase and is higher than doses administered in any previous study; it also yielded higher plasma Z-endoxifen concentrations. Three patients had partial responses and 8 had prolonged stable disease (≥ 6 cycles); 44.4% (8/18) of patients at dose levels 6-8 achieved one of these outcomes. Six patients who progressed after tamoxifen therapy experienced partial response or stable disease for ≥ 6 cycles with Z-endoxifen; one with desmoid tumor remains on study after 62 cycles (nearly 5 years). CONCLUSIONS: Evidence of antitumor activity and prolonged stable disease are achieved with Z-endoxifen despite prior tamoxifen therapy, supporting further study of Z-endoxifen, particularly in patients with desmoid tumors.
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Hepatocellular carcinoma (HCC) has one of highest mortalities globally amongst cancers, but has limited therapeutic options once in the advanced stage. Hepatitis B or C virus infection are the most common drivers for HCC carcinogenesis, triggering chronic liver inflammation and adding to the complexity of the immune microecosystem of HCC. The emergence of immunotherapy has afforded a new avenue of therapeutic options for patients with advanced HCC with a history of hepatitis B or C virus infection. This article reviews the change of immunity elicited by hepatitis B or C virus infection, the immune feature of HCC, and the clinical evidence for immunotherapy in advanced HCC and discusses future directions in this field.
RESUMEN
PURPOSE: The effectiveness of immune checkpoint inhibitors (ICI) is limited in pancreatic ductal adenocarcinoma (PDAC). We conducted a phase I study to evaluate the safety of ICI with stereotactic body radiation therapy (SBRT) in patients with metastatic PDAC. PATIENTS AND METHODS: Patients enrolled must have received at least one line of prior systemic chemotherapy for metastatic disease. Cohorts A1 and A2 received durvalumab every 2 weeks plus either 8 Gy in one fraction of SBRT on day 1 or 25 Gy in five fractions on day -3 to +1. Cohorts B1 and B2 received durvalumab plus tremelimumab every 4 weeks and either 8 Gy in one fraction of SBRT on day 1 or 25 Gy in five fractions on day -3 to +1. ICIs were continued until unacceptable toxicity or disease progression. The primary objective was the safety and feasibility of treatment. Objective response was assessed in lesions not subjected to SBRT. RESULTS: Fifty-nine patients were enrolled and 39 were evaluable for efficacy. No dose-limiting toxicities were seen. The most common adverse event was lymphopenia. Two patients achieved a partial response (one confirmed and the other unconfirmed). The overall response rate was 5.1%. Median PFS and OS was 1.7 months [95% confidence intervals (CI), 0.8-2.0 months] and 3.3 months (95% CI, 1.2-6.6 months) in cohort A1; 2.5 months (95% CI, 0.1-3.7 months) and 9.0 months (95% CI, 0.5-18.4 months) in A2; 0.9 months (95% CI, 0.7-2.1 months) and 2.1 months (95% CI, 1.1-4.3 months) in B1; and 2.3 months (95% CI, 1.9-3.4 months) and 4.2 months (95% CI, 2.9-9.3 months) in B2. CONCLUSIONS: The combination of ICI and SBRT has an acceptable safety profile and demonstrates a modest treatment benefit in patients with metastatic PDAC.