SBRT Plus Sorafenib Improves Survival in Locally Advanced HCC

Laura Dawson, MD, FRCPC

The addition of stereotactic body radiation therapy (SBRT) to sorafenib (Nexavar) led to improvements in overall survival (OS), progression-free survival (PFS), and time to disease progression vs sorafenib alone in patients with locally advanced hepatocellular carcinoma (HCC), according to findings from the phase 3 NRG/RTOG 1112 trial (NCT01730937).

According to Laura Dawson, MD, FRCPC, sorafenib was the standard therapy for patients who were unfit for surgery, ablation, and/or transarterial chemoembolization (TACE) prior to the recent readout of the phase 3 IMbrave150 trial (NCT03434379) which evaluated the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) as a frontline therapy for patients with locally advanced or metastatic HCC. With the positive findings from this study which ultimately changed the standard-of-care, as well as the interest in radiation therapy for HCC management, researchers created the NRG/RTOG 1112 trial.

In this study, patients with HCC were randomly assigned to receive sorafenib at a dose of 400 mg orally, or between 27.5-50 Gy of SBRT in 5 fractions. This was followed by 200 mg of oral sorafenib twice a day for 4 weeks and was escalated to 400 mg 2 times a day if tolerated. The primary end point of the study was OS with secondary end points consisting of PFS, time-to-progression, toxicity, and quality-of-life.

Due to the change in standard-of-care therapy for patients with HCC, early accrual for the study was closed. This also led investigators to change the statistical power for OS from 80% to 65% in the trial.

Updated findings from the randomized, phase 3 study were presented at the 2023 Gastrointestinal Cancers Symposium by lead study author Dawson, Princess Margaret Cancer Centre, Toronto, Ontario, and showed 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). Moreover, 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) and time-to-progression was 18.5 months and 9.5 months, respectively (HR, 0.69; 95% CI, 0.48-0.99; P = .034).

Regarding safety, treatment-related grade 3 or greater adverse events were observed in 42% of patients administered the combination of SBRT and sorafenib and 47% of patients given sorafenib alone (P = .52).

In an interview with Targeted Oncology^TM, Dawson discussed the results of the phase 3 NRG/RTOG 1112 study of SBRT followed by sorafenib vs sorafenib alone in locally advanced HCC.

Targeted Oncology: What can you tell me about the background of the NRG/RTOG 1112 trial?

Dawson: Patients with hepatocellular carcinoma have many treatment options. However, the majority of patients present with advanced disease or recur despite intervention such as surgery. Those patients who are not suitable for ablative or curative approaches with surgery transplant, local ablation with the microwave or radiofrequency ablation, and even treatments that are hepatic arterial driven, those patients are generally treated with systemic therapy if they've had progressive disease despite those therapies and are otherwise not candidates. At the time of the study's inception, the standard-of-care was the tyrosine kinase inhibitor sorafenib. For the past few decades, there have been a growing number of reports on the use of external beam radiation therapy for such patients, and many of these patients have invaded the cancer into their major hepatic vessels. Their prognosis is worse regardless of the therapy that is used. They're a tough group of patients to treat. With external beam radiotherapy, there are reports, mostly single centers, a few smaller comparative studies, and a few smaller randomized trials that have suggested benefits with external beam radiation. This trial was designed to evaluate the role of SBRT in these patients, which would predominantly be patients with vascular invasion and tough to treat, locally advanced disease who otherwise would be treated with systemic therapy alone.

What were the methods and design of the study?

The primary end point of the study was overall survival, and there were secondary end points that include progression-free survival, time-to-progression, toxicity, and some of those were presented to the ASTRO 2023 annual meeting. I also [presented] quality-of-life data and more about the adverse events and compliance with different therapies. At the ASCO GI meeting, I presented more of a description of the patients and the primary and secondary outcomes.

These patients were randomized in a 1:1 fashion to sorafenib or SBRT that was personalized, with doses ranging from 27.5 Gy-50 Gy in 5 treatment fractions, followed by half dose sorafenib for 1 month that was escalated up to standard-of-care if tolerable. Patients could have a large burden of disease in the liver, so up to 20 centimeters sum of diameters or an infiltrative conglomerate of tumor with any degree of vascular invasion, including main portal vein or IVC, as long as they met other eligibility criteria and were suitable for treatment with sorafenib.

How did the IMbrave150 study impact this trial?

During the study accrual period, the standard-of-care changed. The IMbrave150 study came out and showed a benefit for survival with atezolizumab and bevacizumab compared with sorafenib. We closed the study at that time and an amendment was made from statistics to account for a lower number of patients accrued with the same hypothesized benefit in overall survival and same effect size, but the power was reduced from 80% to 65%, given a lower number of patients.

One hundred and ninety-three patients were randomized. Of those patients, 177 met all the eligibility criteria, and those are the patients that were the focus of the report. They were similar in terms of prognostic factors. Of note, approximately 3 quarters of the patients had microvascular invasion, and the great majority of those, close to 64%, had invasion into the main portal vein or the main right or left portal vein, so very large vessels and higher than what has been seen in other randomized studies of patients with liver cancer.

What findings have been previously presented for the study?

The bottom line was that overall survival was improved from a median survival of 12.3 months with sorafenib to 15.8 months with SBRT and sorafenib. On a pre-planned multivariable analysis, the hazard ratio was 0.72, and the P value was .042. Similarly, there were improvements in progression-free survival and time-to-progression, a near doubling in both arms with good hazard ratios and statistical significance confirming the benefit. Interestingly, the adverse events were not of concern with the SBRT arm. In fact, grade 3 or higher events were similar in both arms, probably due to the cancer as the cancer was very advanced and can cause [adverse events] related to liver failure itself, so it's seen in about 3 quarters of patients. The grade 4 or 5 events were similar in both arms. There was a slight increase in GI adverse events with increasing enzymes and decreasing platelets that were grade 3 and reversible in patients who received SBRT. [This shows that] expertise in effective therapy should be considered in the armamentarium for patients with locally advanced disease, especially if they're going to be considered treated with a tyrosine kinase inhibitor.

What was shown in the updated results presented at ASCO GI 2023?

The primary end points and secondary end points are progression-free survival and time-to-progression are the same, so we haven't increased the follow-up. I [presented] a bit more about the treatment protocols, and most patients received treatment as planned. In the sorafenib arm, 3 patients never ended up receiving sorafenib, and 21% received SBRT at the time that they had sorafenib discontinuation. They still were deemed eligible and interested in radiotherapy, and there was that little bit of crossover. Twelve patients received SBRT, but didn't go on to receive sorafenib, and 94%, who received sorafenib had it as planned, with 4 patients receiving incomplete treatment due to 1 progression and 4 with an [adverse event] and 1 received no SBRT and no sorafenib. The median dose delivered with 35 Gy and 5 fractions. That's a modest dose but ranging in the whole range of doses from the protocol and lower doses and those who did not receive their full fractions, and they were all included in the outcome analysis.

Interestingly, the sorafenib treatment was different in both arms. Patients who were randomized to sorafenib had a median duration of treatment with sorafenib above 2.7 months vs 5.1 months and those patients who were randomized to SBRT and sorafenib. However, the dose was lower in patients who were randomized to SBRT and sorafenib. The median daily dose was 371 milligrams for the SBRT arm vs 500 milligrams for the sorafenib arm. In both arms, less than the maximal dose for patients on the SBRT arm remained on half dose for longer than the protocol mandated, and delays were similar. Eighty percent of patients didn't have substantial delays, and there were more delays in those patients who had SBRT.

The newest outcome that was reported at ASCO GI was quality-of-life. The quality-of-life FACT-Hep tool was used for patients who consented to complete their quality-of-life at baseline at 6 months and 12 months. Of the 177 patients who are treated in the protocol, there were 83 who consented to the quality-of-life. However, only 37 patients completed the baseline quality-of-life and 6-month quality-of-life, and the primary hypothesis in the quality-of-life portion of the study was that those patients with SBRT would be more likely to have improved quality-of-life at 6 months.

Given the low power to look at statistical testing, the statistics experts on the study recommended that we report results without any statistics. We did report them and looking at the primary end point, there was a higher proportion of patients who received SBRT who had improved quality-of-life. Thirty-five percent of patients had an improvement by 5 or more points. That's a clinically significant interval compared with 10% of patients who were given sorafenib alone. Similarly, there were more patients who had stable disease and less patients who had a decline when looking at those patients who received SBRT compared with sorafenib. It is aligned with what we saw with improved responses, lower time-to-progression, improved survival, and similar or even lower serious adverse events, probably due to tumor. Although the power is low, the trend is strongly favoring the SBRT as well.

What are the key takeaways that you'd recommend community oncologists learn from this research?

It is important to remember that external beam radiation is a treatment option for patients. Not all patients are eligible for immunotherapy or other systemic therapies. There still is a small role in North America for tyrosine kinase inhibitor treatment. Even after first-line therapy with immunotherapy, some patients may be eligible for sorafenib or lenvatinib [Lenvima], or another tyrosine kinase inhibitor. It's important to remember that radiotherapy can have a profound impact and to ask about a referral to radiation oncologists and consider whether it's the right time to treat patients. Especially for patients who are not well suited for any systemic therapy, so who have similar advanced disease to what is presented, but for some reason, a comorbidity or something else makes them not well suited for systemic therapy, remember that external beam radiotherapy can help patients and make those referrals. It's not a new therapy but is a relatively new therapy to be recognized in the armamentarium and to treat patients with liver cancer. Hopefully, community oncologists will work with their radiation oncology teams and refer more patients for radiation therapy.

What unmet needs still remain in the space?

There are many unmet needs for patients with liver cancer. The incidence and mortality rate continues to rise at a less steep rate due to increased screening, better treatments of hepatitis C, vaccination, etc. Non-alcoholic, fatty liver and NASH is on the rise. It is correlated with the obesity epidemic, and that is a risk factor for liver cancer that is continuing to increase. Liver cancer is an important cancer around the world and will continue to rise. It's a big cause of morbidity and mortality for patients. It's underfunded, probably under-recognized as an important cancer, and in terms of using tools like radiation therapy that are widely available around the world, we underutilize external beam radiation to help patients. I hope that there are many more clinical trials that include radiation therapy in the future, combined with systemic therapies or regional or local therapies. We continue to measure the benefits of external beam radiation in these patients. Hopefully this is the start of many future positive trials that will come from right radiation for treatment of liver cancer patients.

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