At the 2023 ASCO Gastrointestinal Cancers Symposium, Laura Dawson, MD, Princess Margaret Cancer Center, Toronto, Ontario, Canada, presented updated results from the NRG RTOG 1112 trial evaluating the use of stereotactic body radiotherapy plus sorafenib, compared with sorafenib alone, for patients with hepatocellular carcinoma.

Dr Dawson stated she considers these results, which found that stereotactic body radiotherapy plus sorafenib improved overall survival, progression-free survival, and time to progression, to be practice-changing.

Transcript:

Hello, I'm Laura Dawson. I am professor and chair of the Department of Radiation Oncology at the University of Toronto, and I'm a practicing radiation oncologist at the Radiation Medicine Program at the Princess Margaret Cancer Center at UNH in Toronto. My main area of clinical and research interest is in the treatment of patients with liver cancer, both primary liver cancer and metastases.

It is my pleasure to speak to you about the results of NRG/RTOG 1112, a cooperative group study investigating the use of stereotactic body radiotherapy (SBRT) in patients with hepatocellular carcinoma. This is a randomized phase 3 study of sorafenib vs SBRT followed by sorafenib. And the presentation at ASCO GI is an update of our primary end points and some of the secondary end points. This was a 1-to-1 randomized study that was focusing on investigating the benefits of radiation in patients who are challenging to treat. Those patients had locally advanced hepatocellular carcinoma that was unsuitable for or refractory to standard treatments. At the time of the study initiation, the systemic standard of care was sorafenib, a tyrosine kinase inhibitor and patients could not be suitable for transcatheter arterial chemoembolization (TACE), radioablation, surgery, or transplant. So standard of care for these patients was systemic therapy. The majority of these patients were hypothesized to have macrovascular invasion, which does make treatment more challenging and is associated with worse overall survival.

The hypothesis was that stereotactic body radiotherapy would improve outcomes with a primary end point being overall survival compared to sorafenib alone. Secondary end points include progression-free survival, toxicity, time to progression, and quality of life. Stratification factors include a degree of vascular invasion, underlying liver disease, whether patients were treated in North America or not. And just to point out, this study allowed patients with very locally advanced cancer to be treated, with tumors up to 20 centimeters in max diameter permitted, up to 5 lesions, and any degree of macrovascular invasion was permitted including main portal vein and IVC.

The standard arm was sorafenib as per standard of care and the experimental arm was personalized stereotactic body radiotherapy varying in dose from 27.5 to 50 Gray in 5 fractions followed by half-dose sorafenib for 1 month that was escalated up to standard of care, as tolerated. This study did close earlier than planned due to a change in the standard of care that came up with the IMbrave150 study showing a survival benefit to immunotherapy-based treatment compared to sorafenib and thus there was an amendment to the protocol with the same expected improvement over survival, the same effect size with the hypothesis hazard ratio of 0.72, but it was a time-driven analysis as opposed to event-driven.

We had a sample size of 193 when the study was closed. As mentioned, we had the same alpha and same effect size, but with the reduction in number of patients, the statistical power was reduced from 80% to 65%. Patients and tumor characteristics were similar in both arms. Just to point out, there was a high percentage of patients who had macrovascular invasion, 74% of patients had invasion into the large veins and the majority of those patients had invasion into the main portal vein or main right or left portal vein. That is somewhat higher than most other randomized studies for patients with hepatocellular carcinoma. The median radiation dose delivered in experimental arm was 35 Gray in 5 fractions with a spectrum of 27.5 to 50 Gray in those patients who received all the treatment as planned.

There were 4 that had incomplete stereotactic body radiotherapy due to side effects, the lowest dose delivered was 20 Gray in 2 fractions. Of note, 3 patients in the sorafenib arm did not receive sorafenib, and 12 patients in the SBRT arm did not go on to receive sorafenib. 21% of patients who received SBRT who received sorafenib went on to receive radiotherapy at the time of sorafenib discontinuation.

In this patient population, there was a clinically significant improvement in overall survival. The median survival of patients randomized to SBRT was 15.8 months improved from 12.3 months in those patients who received sorafenib alone. And on a pre-planned, multi-variable analysis accounting for important factors, there was an improvement in survival with the addition of SBRT with a hazard ratio of 0.075 and a P-value of 0.042. Similarly, there was statistically significantly and clinically important improvements in progression-free survival and time to progression with the addition of radiotherapy.

Adverse events were similar in both arms, specifically, adverse events of grade 3 or higher were seen in about 75% of patients in both arms. Many of these adverse events are probably attributed to the locally advanced cancer that can cause liver toxicity, liver failure itself. There was an increase in blood work adverse events that were grade 3 or higher in those patients receiving SBRT, 27% of patients versus 19% in those who received sorafenib, but again, grade 4/5 events were similar in both arms with no increase in those patients who received radiotherapy.

At the ASCO meeting, we are presenting quality of life. However, there was a lower number of patients who consented to quality-of-life testing than anticipated. Therefore, a statistical analysis was not done on the quality of life hypothesis. The hypothesis was that patients treated with SBRT would have improved quality of life 6 months following their treatment. And we used the (Functional Assessment of Cancer Therapy) FACT-Hepatobiliary tool to measure patient-reported quality of life. And as mentioned, there were fewer patients than we anticipated who completed at baseline and six-month tools.

There were 41 patients who did that but looking at those 41 patients qualitatively, the patients who received sorafenib and SBRT at 6 months, 35% had a clinically significant improvement in the FACT-Hepatobiliary Score at baseline to 6 months versus 10% in the sorafenib alone. And similarly, there were fewer patients who had a decline in patients received radiotherapy. So there is a strong suggestion of improvement of quality of life with the addition of radiotherapy in addition to the improvement in survival, progression-free survival seen with SBRT.

Overall, I believe this study is practice-changing and hopefully will bring radiotherapy to the standard armamentarium of effective treatments for patients, with potentially the largest benefits in patients who are challenging to treat with macrovascular invasion. Clearly, this is most applicable to patients who are treated with sorafenib or another tyrosine kinase inhibitor such as lenvatinib. And next steps will be to determine what the magnitude of benefit is in patients treated with now standard-of-care, immunotherapy-based systemic therapy. And clinical trials looking at radiotherapy in this setting with modern treatment including immunotherapy, are in development and hopefully will open soon. Thank you.

Source:

Dawson L, Winter K, Knox J. NRG/RTOG 1112: Randomized phase III study of sorafenib vs. stereotactic body radiation therapy (SBRT) followed by sorafenib in hepatocellular carcinoma (HCC). Presented at 2023 ASCO Gastrointestinal Symposium; January 19 – 21, 2023; San Francisco, California. Abstract 489