ASTRO 2022: Phase 3 clinical results of SBRT combined with sorafenib announced, liver cancer radiotherapy shows better efficacy (NRG/RTOG 1112 study)

The 64th Annual Meeting of the American Society of Radiation Oncology (ASTRO) was held
in San Antonio, USA, October 23-26, 2022.
At a plenary session on the 24th, Laura A.
Dawson, MD, of the Princess Margaret Cancer Center in Toronto, reported on an NRG oncology clinical trial, NRG-RTOG 1112, Phase III NRG/RTOG 1112, designed and led by NRG Oncology and funded
by the National Cancer Institute, part of the National Institutes of Health.

Stereotactic radiation therapy (SBRT) plus sorafenib (Nexavar) improves overall survival (OS), progression-free survival (PFS), and time to progression (TPP)
compared with sorafenib monotherapy in patients with locally advanced hepatocellular carcinoma (HCC).

From April 2013 to March 2021, the Phase III NRG-RTOG 1112 trial enrolled 193 patients from 23 sites, and 177 eligible patients were randomized to sorafenib (n=92) vs.
SBRT + sorafenib (n=85).

Stratify
patients according to macrovascular invasion (MVI), hepatitis B versus C and other, North versus non-North American regions, and presence of HCC/liver volume.
Patients received SBRT of 400 mg or 27.
5 to 50.
0 Gy orally twice daily in 5 divided doses, followed by 200 mg sorafenib for 4 weeks, followed by 400 mg
.

Patients with locally advanced HCC deemed unsuitable for resection, radiofrequency ablation, or transarterial chemoembolization are eligible to participate in the study
.
Other inclusion criteria included Child-Pugh A, Barcelona Clinical Liver Cancer (BCLC) stage B or C disease, HCC combined not exceeding 20 cm, and MVI
of any degree.

The primary endpoint of the study was OS
.
Secondary endpoints included PFS, TTP, and toxicity
based on CTCAE v4.
0 criteria.

Median PFS was 5.
5 months (95% CI, 3.
4-6.
3) in patients receiving sorafenib monotherapy and 9.
2 months (95% CI, 7.
5-11.
9) in patients receiving sorafenib plus SBRT (HR, 0.
55; 95% CI, 0.
40-0.
75); P = .
0001)
。 For the sorafenib monotherapy and sorafenib plus SBRT cohorts, PFS rates at 6 months were 41% (95% CI, 30% to 51%) and 71% (95% CI, 62% to 81%), 20% (95% CI, 12% to 29%) at 12 months, vs 37% (95% CI, 26% to 47%), 11% (95% CI, 5% to 18%) vs 28% (95% CI, %-38% at 18 18 months), respectively, 7% (95% CI, 2% to 12%) vs 17% (95% CI, 9% to 25%)
at 24 months.

In a multivariate OS analysis, sorafenib plus SBRT showed a statistically significant improvement
compared to sorafenib alone, adjusted for certain baseline characteristics.
This benefit was observed in most subgroups, especially in patients with more advanced disease
.
In particular, the estimated 24-month OS rate for patients with inferior vena cava or portal MVI alone when receiving sorafenib was 8.
8% (95% CI, 1.
4% to 16.
2%) and 28.
4% (95% CI, 15.
9% to 41.
0%) when
receiving sorafenib plus SBRT.

The median TTP was 9.
5 months for patients receiving sorafenib alone and 18.
5 months for patients receiving sorafenib plus SBRT (HR, 0.
69; 95% CI, 0.
48-0.
99; P = 0.
034).

。 TTP rates were 44% (95% CI, 33% to 54%) and 23% (95% CI, 14% to 32%) for monotherapy and dual therapy, 57% (95% CI, 46% to 67%) vs 43% (95% CI, 32% to 53%) at 18 months, and 63% (95% CI, 52% to 72%) vs 48% (95% CI, 37% to 58%) at 18 months, respectively, at a 24-month rate 66% (95% CI, 55%-75%) versus 56% (95% CI, 45%-66%)
.

In terms of safety, there is a worrying
lack of increased adverse effects (AEs) of sorafenib plus SBRT compared with sorafenib monotherapy.
Grade 3 or higher AEs
were observed in 74% (n = 65/88) of patients in the sorafenib cohort alone versus 75% (n = 62/83) of patients in the sorafenib plus SBRT cohort.
High-grade gastrointestinal (GI) bleeding
occurred in 6% and 4% of patients in each group, respectively.
Grade 3 or higher treatment-associated AE (TRAE)
was observed in 42% of patients in the sorafenib monotherapy group and 47% of patients in the combination group.
The most common high-grade TRAE in the monotherapy and dual-agent groups were abnormal blood tests (19% versus 27%), gastrointestinal disease (7% versus 10%), and hepatobiliary disease (3% versus 1%)
, respectively.
Grade 5 TRAE occurs in 2% and 1% of patients
, respectively.

Dr.
Laura Ann Dawson, lead author of the NRG-RTOG 1112 abstract, commented: "The early end of the study means a weakening
of the research power.
Nevertheless, the addition of SBRT has improved
significantly both clinically and statistically.
An important question for future clinical trials is to determine what the benefits of using SBRT are in patients receiving immunotherapy, and what is optimal sequencing
.
”

Resources:

Dawson LA, Winter KA, Knox JJ, et al.
NRG/RTOG 1112: Randomized phase II study of sorafenib vs.
stereotactic body radiation therapy (SBRT) followed by sorafenib in hepatocellular carcinoma (HCC) (NCT01730937).
Presented at 2022 American Society for Radiation Oncology Annual Meeting (ASTRO); October 23-26, 2022; San Antonio, TX.
Abstract LBA01.
Accessed October 24, 2022.