NRG/RTOG 1112: Randomized Phase III Study of Sorafenib vs. Stereotactic Body Radiation Therapy (SBRT) Followed by Sorafenib in Hepatocellular Carcinoma (HCC) (NCT01730937)

Purpose/Objective(s)

The role of SBRT in the treatment of HCC is not well established. The hypothesis of this study was that overall survival (OS) would improve with SBRT followed by sorafenib (SBRT/S) vs. sorafenib alone (S), in patients with advanced HCC.

Materials/Methods

Eligible patients had new or recurrent HCC, unsuitable for resection, transplant, ablation or TACE, with Zubrod performance status (PS) 0-2, Child-Pugh A, intermediate (B) or advanced (C) Barcelona Clinic Liver Cancer Stage (BCLC), ≤ 5 HCCs, sum of hepatic HCCs ≤ 20 cm, and sum of extrahepatic metastases ≤ 3 cm. Patients were randomized 1:1 to S 400 mg BID vs. SBRT (27.5-50Gy in 5 fractions, with dose individualized based on mean liver dose and other dose constraints) followed by S 200 mg BID then increased to 400 mg BID after 28 days if appropriate. Primary endpoint was OS. Reported secondary endpoints were progression-free survival (PFS), time to progression (TTP), and adverse events (AEs - CTCAEv4). Planned sample size was 292 patients (238 OS events, HR=0.72, 80% power, 1-sided alpha=0.05). Accrual closed early, primarily due to a change in HCC standard of care systemic therapy. Statistics were amended to report data as of 7/1/2022, projecting 155 OS events providing 65% power for the original hypothesis, with the same alpha. OS and PFS were estimated by Kaplan-Meier and arms compared using log-rank test. Cox proportional hazards models were used to analyze treatment effect. TTP was estimated with cumulative incidence and arms compared using Gray's test. Secondary endpoints were tested with 2-sided alpha=0.05.

Results

Of 193 patients accrued from April 2013 to March 2021 from 23 sites, 177 eligible patients were randomized to S (n=92) vs. SBRT/S (n=85). Median age was 66 years (27-84); 41% had Hepatitis C and 19% had Hepatitis B or B/C. The majority were stage BCLC C (82%), with macrovascular invasion (74%). 4% had metastases. Median follow-up for all and alive patients was 13.2 and 33.7 months, respectively. With 153 OS events, median OS was improved from 12.3 months (90% CI 10.6, 14.3) with S to 15.8 months (90% CI 11.4-19.2) with SBRT/S (HR=0.77, 1-sided p=0.0554). After adjusting for PS, M stage, Child Pugh A5 vs. 6, and degree of vascular HCC, OS was statistically significantly improved for SBRT/S (HR=0.72, 95% CI 0.52-0.99, 2-sided Cox p=0.042). Median PFS was improved from 5.5 months (95% CI 3.4-6.3) with S to 9.2 months (95% CI 7.5-11.9) with SBRT/S (HR=0.55, 95% CI 0.40-0.75, 2-sided p=0.0001). TTP was also improved with SBRT/S (HR=0.69, 95% CI 0.48-0.998, 2-sided Gray's p=0.034). Treatment-related grade 3+ AEs were not significantly different (S - 42%, SBRT/S - 47%; p=0.52). There was one grade 5 treatment-related AE, in the S arm.

Conclusion

Adding SBRT improved OS, PFS, and TTP in patients with advanced HCC, compared to Sorafenib alone, with no significant increase in AEs.