Sorafenib in Combination with SBRT Extends Survival in Locally Advanced HCC

In patients with locally advanced, hepatocellular carcinoma (HCC), stereotactic body radiation therapy (SBRT) added to sorafenib (Nexavar) improved overall survival (OS), progression-free survival (PFS), and time to disease progression compared with sorafenib alone according to findings from the phase 3 NRG/RTOG 1112 trial (NCT01730937) that were presented at the 2023 Gastrointestinal Cancers Symposium.¹

The results demonstrated a median OS of 15.8 months (90% CI, 11.4-19.2) with sorafenib/SBRT vs 12.3 months (90% CI, 10.6-14.3) with sorafenib alone (HR, 0.77; 90% CI, 0.59-1.01; 1-sided P = .55). The median PFS was 9.2 months (95% CI, 7.5-11.9) with SBRT/sorafenib vs 5.5 months (95% CI, 3.4-6.3) with sorafenib alone (HR, 0.55; 95% CI, 0.40-0.75; P = .0001). Time to progression with sorafenib/SBRT and sorafenib alone was 18.5 months and 9.5 months, respectively (HR, 0.69; 95% CI, 0.48-0.99; P = .034).

“This adds to the body of evidence for the role of external beam radiation, bringing SBRT to the armamentarium of treatment options for patients—particularly those with locally advanced HCC and macrovascular invasion, especially if they are treated with TKIs,” lead study author Laura Dawson, MD, FRCPC, clinician scientist at Princess Margaret Cancer Centre in Toronto, Ontario, Canada, said in a presentation of the data.

Prior to the readout of the phase 3 IMbrave150 trial (NCT03434379), which evaluated atezolizumab (Tecentriq) plus bevacizumab (Avastin) as frontline therapy for locally advanced or metastatic HCC, sorafenib was the standard therapy for patients unfit for surgery, ablation, and/or transarterial chemoembolization (TACE). This, coupled with interest in radiation therapy for HCC management, led to the inception of the NRG/RTOG 1112 trial.

To be eligible for enrollment, patients had to have locally advanced HCC unsuitable for, or relapsed/refractory to radiofrequency ablation or TACE post resection. Additional criteria included Child-Pugh A status, platelet level above 60 bil/L, BCLC stage B or C, no greater than 20 cm sum of tumor mass, 5 or fewer HCC foci, and no more than 3 cm of extrahepatic spread. Any degree of vascular invasion was allowed.

Patients were randomly assigned to 400 mg of oral sorafenib twice daily, or between 27.5 and 50 Gy of SBRT in 5 fractions, followed by 200 mg of oral sorafenib twice daily for 4 weeks, which was escalated to 400 mg twice daily thereafter if tolerated.

The primary end point was OS. Secondary end points included PFS, time to progression, toxicity, and quality of life (QOL), which was defined as the proportion of patients with an improvement of at least 5 points in the FACT-Hep score from baseline to 6 months.

Early accrual closure to the study due to the change in standard systemic therapy for HCC forced investigators to reduce the statistical power for OS from 80% to 65%.

Baseline demographics reflected a median patient age of 66 years (range, 27-84), and the median sum of the diameter of disease was 7.8 cm (range, 1-19.1). The median HCC volume was 180 cc (interquartile range, 72-409).

Most patients (94%) in the combination arm received SBRT as intended; 12 patients received SBRT without sorafenib. In the sorafenib arm, 3 patients did not receive the TKI and 21% proceeded to SBRT after sorafenib discontinuation.

The median treatment duration was 2.7 months in the sorafenib arm and 5.1 months in the combination arm. The median daily dose of sorafenib was higher in the monotherapy arm at 500 mg vs 371 mg in the combination arm; 63% and 46% of patients received the maximum dose of 800 mg daily, respectively.

Additional findings demonstrated early and sustained separation of the curves for OS, PFS, and time to progression. The 6-, 12-, 18-, and 24-month OS rates for SBRT/sorafenib were 88%, 59%, 43%, and 33%, respectively, vs 71%, 53%, 35%, and 23%, respectively, with sorafenib.

The 6- and 12-month PFS rates with SBRT/sorafenib were 71% (95% CI, 62%-81%) and 37% (95% CI, 26%-47%), respectively, vs 41% (95% CI, 30%-51%) and 20% (95% CI, 12%-29%), respectively, with sorafenib alone. The 6- and 12-month time to progression rates were 23% (95% CI, 14%-32%) and 43% (95% CI, 32%-53%), respectively, with SBRT/sorafenib vs 44% (95% CI, 33%-54%) and 57% (95% CI, 46%-67%), respectively, with sorafenib alone.

Regarding safety, gastrointestinal (GI) bleeds occurred in 4% (n = 3) of patients in the combination arm vs 6% (n = 5) of those in the monotherapy arm. In the combination and monotherapy arms, respectively, patients experienced GI disorders (10% vs 7%), bloodwork abnormalities (27% vs 19%), and hepatobiliary disorders (1% vs 3%).

In terms of QOL, approximately half of patients consented to data collection, but only 21% (n = 37) completed baseline and 6-month surveys, rendering the analysis without statistical power.

Despite this, investigators noted an improvement in the FACT-Hep score from 35% of patients in the combination arm vs only 10% in the monotherapy arm.

Dawson concluded by stating, “SBRT is a standard treatment option for patients with locally advanced HCC, especially with macrovascular invasion.”

Discussant Laura Goff, MD, MSCI, MMHC, of Vanderbilt University Medical Center, added that “sorafenib plus SBRT represents an intriguing first-line option for patients who cannot be treated with immunotherapy, and other settings in which to use radiation for HCC should be actively explored.”

Editor’s Note: Dr Dawson has received research grants from Bayer and Merck.

_Reference

_{Dawson L, Winter K, Knox J, et al. NRG/RTOG 1112: randomized phase III study of sorafenib vs. stereotactic body radiation therapy (SBRT) followed by sorafenib in hepatocellular carcinoma (HCC). J Clin Oncol. 2023;41(suppl 4):489. doi:10.1200/JCO.2023.41.3_suppl.489}