Phase II Trial of Sorafenib in Combination with Capecitabine in Patients with Hepatocellular Carcinoma: INST 08-20.

LESSONS LEARNED: There continues to be a lack of systemic options for advanced hepatocellular carcinoma (HCC); sorafenib and, very recently, regorafenib are the only approved options. There exists a potential to combine sorafenib with chemotherapeutic agents shown to be active in HCC, such as capecitabine, safely.Good tumor response was observed, with objective improvement in a few patients seldom seen by single agent sorafenib; however, because of the limited number of patients, meaningful conclusions on survival cannot be drawn.
BACKGROUND: Sorafenib is the currently approved first-line treatment for hepatocellular carcinoma (HCC). Capecitabine has antitumor activity in hepatobiliary cancers. The combination of the two, if tolerated, could possibly improve antitumor response, and survival.
METHODS: Patients with advanced HCC ineligible for locoregional therapy, Eastern Cooperative Oncology Group performance status of ≤2, Child-Pugh class A or B-7 cirrhosis, hemoglobin ≥8.5 g/dL, platelets ≥50,000/μL, absolute neutrophil count (ANC) ≥1,500 cells/μL, and serum creatinine of ≤2.0 mg/dL were recruited. All subjects received a combination of sorafenib and capecitabine, on a 14-day 7-days on 7-days off schedule. The primary end point was safety and secondary end points were overall survival (OS) and disease control rate.
RESULTS: A total of 15 out of 47 patients met inclusion criteria. Median age was 64 years (56-79) and 77% were male. With a median follow-up of 12 months, median OS was 12.7 months (95% confidence interval [CI], 8.5-23.4). Disease control rate was 77% (complete response 8%, partial response 8%, and stable disease 61%). Common adverse events were as follows: (a) thrombocytopenia (64%); (b) anemia (14%); (c) hypophosphatemia (21%); (d) hypomagnesemia (14%); (e) hyperbilirubinemia (21%); (f) increased aspartate transaminase (AST) (14%); (g) hand-foot syndrome (21%); and (h) deep vein thrombosis (21%).
CONCLUSION: At tolerable doses, the combination of sorafenib and capecitabine seems an active and safe palliative treatment for HCC in class A and B-7 patients with cirrhosis. The small sample size does not allow comparison with single-agent sorafenib. ©AlphaMedPress; the data published online to support this summary is the property of the authors.

Discussion

Sorafenib single agent continues to be the only U.S. Food and Drug Administration‐approved systemic therapy for hepatocellular carcinoma (HCC) in 2017 since its approval almost 10 years ago. This study showed that the combination of sorafenib and capecitabine in patients with advanced HCC is an active and safe palliative regimen. The disease response rate observed in this study was higher than the outcomes reported by other studies using sorafenib as single agent [1], [2]. The small sample size did not allow determining if this observation translated into a better survival outcome as compared with single‐agent sorafenib. Such a determination will require a randomized phase II trial.

Oral capecitabine has been used as single agent in hepato‐biliary cancers, with a median overall survival of 10 months in patients with HCC and well tolerated in cirrhotic patients [3]. Other investigators have explored different combinations with capecitabine, including platinum‐based agents and other biological agents targeting vascular endothelial growth factor (VEGF) [4], [5], [6]. All of these studies have shown comparable results with similar treatment toxicity profile.

Kaplan‐Meier estimate of OS.

Abbreviations: CI, confidence interval; OS, overall survival.

Similar to data reported in previous studies [1], [2], [7], 46% of our patients had been pretreated with locoregional treatments. Transarterial chemoembolization was the most commonly used locoregional modality prior to the beginning of systemic therapy in our population; this observation is consistent with data previously reported by other investigators and the current standard of care guidelines for the management of intermediate‐stage, unresectable, and multifocal HCC [2], [8], [9].

There were two exceptional responders in this study: one patient had a complete response that lasted 14 months, and another patient had a very good partial response for a duration of 11 months; this patient died of complications from cirrhosis while his cancer was still under good control.

The observed rate of serious adverse events was similar to the results from other studies, supporting the published data regarding the safety of sorafenib in Child‐Pugh B patients [7], [10], [11], [12]. Moreover, the addition of capecitabine, with dose adjustment as tolerated, did not seem to increase the rate of serious adverse events; there were no treatment‐related deaths, and dosage adjustments were performed as necessary (Table 1).

Table 1.

Treatment tolerance by dose levels

Trial Information

Hepatocellular carcinoma

Metastatic/advanced

No designated number of regimens

Phase II

Single arm

Safety

Tolerability

Overall response rate

Disease control rate

Active and should be pursued further

Drug Information for Phase II Study

Capecitabine

Xeloda

Genentech

Small molecule

Antimetabolite

500–850 milligrams (mg) per square meter (m2)

Oral (p.o.)

Capecitabine and sorafenib were administered b.i.d., 2 weeks on and 2 weeks off

Sorafenib

Nexavar

Bayer and Onyx Pharmaceuticals

Small molecule

Multi‐targeted kinase inhibitor

200–400 mg per flat dose

Oral (p.o.)

Capecitabine and sorafenib were administered b.i.d., 2 weeks on and 2 weeks off

Patient Characteristics for Phase II Study

65

3

Not collected

Median (range): 65 (58–80)

Median (range): 0 (0–2)

0—7

1—5

2—1

3—

Unknown—

Complete baseline demographic and disease characteristics are presented in Table 2.

Primary Assessment Method for Phase II Study

47

47

15

13

13

Response evaluation criteria in solid tumors (RECIST) 1.0

n = 1 (8%)

n = 1 (8%)

n = 8 (61%)

12.7 months, CI: 8.5–23.4

Adverse Events: Phase II Study

Assessment, Analysis, and Discussion

Study terminated before completion

Did not fully accrue

Active and should be pursued further

This study showed that the combination of sorafenib and capecitabine in patients with advanced hepatocellular carcinoma (HCC) is an active and safe palliative regimen. The disease response rate observed in this study was higher than the outcomes reported by other studies using sorafenib as single agent [1], [2]. The small sample size did not allow determining if this observation translated into a better survival outcome as compared with single‐agent sorafenib. Such a determination will require a randomized phase II trial.

Oral capecitabine has been used as single agent in hepato‐biliary cancers, with a median overall survival of 10 months in patients with HCC and well tolerated in cirrhotic patients [3]. Other investigators have explored different combinations with capecitabine, including platinum‐based agents and other biological agents targeting vascular endothelial growth factor [4], [5], [6]. All of these studies have shown comparable results with similar treatment toxicity profile.

Similar to data reported in previous studies [1], [2], [7], 46% of our patients had been pretreated with locoregional treatments. Trans‐arterial chemoembolization (TACE) was the most commonly used locoregional modality prior to the beginning of systemic therapy in our population; this observation is consistent with data previously reported by other investigators and the current standard of care guidelines for the management of intermediate‐stage, unresectable, and multifocal HCC [2], [8], [9].

One patient had a prolonged complete response (CR) observed during the first 14 months since the beginning of the study regimen. The CR lasted for 11 months before disease progression (Figs. 2A, 2B, 3). Another patient on this trial experienced a good partial response and improvement in tumor markers; however, this patient experienced worsening cirrhosis and died of complications of liver cirrhosis (Figs. 4A, 4B, 5).

Figure 2.

Patient 1. Pre‐treatment (A) and post‐treatment (B) computed tomography scan with a complete response.

Figure 4.

Patient 2. Pre‐treatment (A) and post‐treatment (B) partial response on computed tomography scan.

Of note, this study population had a higher proportion of Child‐Pugh class B; (B‐7) patients compared with other studies (46% vs. 5% and 28% in the SHARP trial and GIDEON study, respectively), and similar prevalence of viral hepatitis infection and alcohol use in the HCC populations from North America analyzed in those same studies. The observed rate of serious adverse events was similar to the results from other studies, supporting the published data regarding the safety of sorafenib in Child‐Pugh B patients [7], [10], [11], [12]. Moreover, the addition of capecitabine, with dose adjustment as tolerated, did not seem to increase the rate of serious adverse events.

Our study represents the first trial combining sorafenib and capecitabine in the management of advanced, unresectable HCC with findings supporting the activity and safety of this regimen. The small sample size does not allow comparison with single‐agent sorafenib or capecitabine and/or in combination with other systemic treatments. Additional phase III data and studies of a larger scale will be necessary to determine if the combination of these two active agents might result in better survival outcomes when compared with the current standard of care.

Corresponding alphafeto‐protein (AFP) curve for patient 1. Corresponding to pre‐treatment (Fig. 2A) and post‐treatment (Fig. 2B) computed tomography scan with a complete response.

Abbreviation: AFP, alphafeto‐protein.

Corresponding AFP curve for patient 2. Corresponding to pre‐treatment (Fig. 4A) and post‐treatment (Fig. 4B) partial response on computed tomography scan.

Abbreviation: AFP, alphafeto‐protein.

Adverse events grade >3 at all dose levels, all cycles.

Abbreviation: NC/NA, no change from baseline/no adverse event.

Table 2.

Baseline demographic and disease characteristics

Abbreviations: AJCC, American Joint Committee on Cancer; ECOG, Eastern Cooperative Oncology Group; INR, international normalized ratio; TACE, trans‐areterial chemoembolization; TNM, TNM classification of malignant tumors.