Purpose This open-label phase III trial evaluated efficacy and tolerability of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC) without prior systemic therapy. Patients and Methods Patients were randomly assigned in a 1:1 ratio to linifanib 17.5 mg once daily or sorafenib 400 mg twice daily. Patients were stratified by region (Outside Asia, Japan, and rest of Asia), Eastern Cooperative Oncology Group performance score (ECOG PS; 0 or 1), vascular invasion or extrahepatic spread (yes or no), and hepatitis B virus (HBV) infection (yes or no). The primary end point of the study was overall survival (OS). Secondary end points were time to progression (TTP) and objective response rate (ORR) per RECIST v1.1. Results We randomly assigned 1,035 patients (median age, 60 years; Asian, 66.6%; ECOG PS 0, 65.2%; HBV, 49.1%; vascular invasion or extrahepatic spread, 70.1%). Median OS was 9.1 months on the linifanib arm (95% CI, 8.1 to 10.2) and 9.8 months on the sorafenib arm (95% CI, 8.3 to 11.0; hazard ratio [HR], 1.046; 95% CI, 0.896 to 1.221). For prespecified stratification subgroups, OS HRs ranged from 0.793 to 1.119 and the 95% CI contained 1.0. Median TTP was 5.4 months on the linifanib arm (95% CI, 4.2 to 5.6) and 4.0 months on the sorafenib arm (95% CI, 2.8 to 4.2; HR, 0.759; 95% CI, 0.643 to 0.895; P = .001). Best response rate was 13.0% on the linifanib arm versus 6.9% on the sorafenib arm. Grade 3/4 adverse events (AEs); serious AEs; and AEs leading to discontinuation, dose interruption, and reduction were more frequent with linifanib (all P < .001). Conclusion Linifanib and sorafenib had similar OS in advanced HCC. Predefined superiority and noninferiority OS boundaries were not met for linifanib and the study failed to meet the primary end point. TTP and ORR favored linifanib; safety results favored sorafenib.

It has been shown that the level of estrogen receptors (ER), and to some extent progesterone receptors (PR), correlate to a high degree to the response to endocrine therapy in advanced breast cancer patients. To evaluate the prognostic value of ER/PR in early breast cancer, 80 patients with stages I and II were studied. They all underwent modified radical mastectomy. Patients with stage I disease (negative LN) received no further treatment, while those with stage II received standard adjuvant chemotherapy. All the patients were followed for 4 years. The ER and PR were measured in each primary tumor by the glycerol density gradient method. Values of 10 fmole/mgm protein or greater were considered positive (+) and less than 10 fmole/mgm were considered negative (-). The results revealed: (1) Fifty-two patients (65%) had ER+, of which 44 (85%) were also PR+; 28 patients had ER-, of which 24 were also PR- (p less than 0.0001). (2) ER/PR correlated with age as 71% of the patients over age 50 had ER+/PR+, compared to 33% of those under age 50 (p less than 0.05). (3) Postmenopausal patients had a higher incidence of ER+/PR+. (4) Primary tumors less than 2 cm in size had higher ER+; 71% in those with stage I and 80% in stage II. (5) Fifty-eight per cent (38) of patients with ductal carcinoma had ER+/PR+, compared to 67% (4) with lobular carcinoma. (6) The disease-free survival of patients with ER+ tumors was significantly longer than those with ER- tumors (p less than 0.005) both in positive and negative LN patients. The same was true for PR+ compared to PR- (p less than 0.005), but only in those with stage II disease. The overall survival rates were similarly significant in favor of ER+ and PR+ patients (p less than 0.025), but only in stage II disease. It seems that the status of steroid hormone receptors has a major prognostic factor second only to the LN status.