NRG/RTOG 1112 Trial Highlights Benefit of Adding SBRT to Sorafenib in Locally Advanced HCC

The addition of stereotactic body radiation therapy (SBRT) to sorafenib (Nexavar) provided a significant survival benefit vs sorafenib alone in patients with locally advanced hepatocellular carcinoma (HCC), including those with macrovascular invasion (MVI). These data are “practice changing” and bring SBRT to the arsenal for this population, according to Laura Dawson, MD, FRCPC, who added that next steps for research will focus on better understanding the benefits of SBRT in the era of immunotherapy.

Data from the phase 3 NRG/RTOG 1112 trial (NCT01730937) presented at the 2023 Gastrointestinal Cancers Symposium showed that patients treated with SBRT/sorafenib experienced a median overall survival (OS) of 15.8 months (90% CI, 11.4-19.2) 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). Notably, 75% and 73% of patients in the SBRT/sorafenib and sorafenib monotherapy arms had macrovascular invasions, respectively.

Additionally, those given SBRT/sorafenib achieved a median progression-free survival (PFS) of 9.2 months (95% CI, 7.5-11.9) vs 5.5 months (95% CI, 3.4-6.3) in those treated with sorafenib alone (HR, 0.55; 95% CI, 0.40-0.75; P = .0001). The median time to progression in the investigative and control arms was 18.5 months and 9.5 months, respectively (HR, 0.69; 95% CI, 0.48-0.99; P = .034).

“External beam radiotherapy and SBRT are effective therapies to treat [patients with] liver cancer, especially for patients who have MVI and those who would be considered to be treated with a TKI,” Dawson said in an interview with OncLive^®. “It’s a very useful therapy and hopefully [these data] will allow guidelines committees and thought leaders around the world to consider radiation as one of the tools that can help patients [with HCC]. Hopefully, [they will] highlight [this approach] in international guidelines.”

In the interview, Dawson, lead study author and a clinician scientist at the Princess Margaret Cancer Centre in Toronto, Ontario, Canada, discussed data from the NRG/RTOG 1112 trial examining the addition of SBRT to sorafenib, the implications of the data for the paradigm, and next steps for research.

OncLive^®: What inspired the launch of the NRG/RTOG 1112 trial evaluating the addition of SBRT to sorafenib in patients with locally advanced HCC?

Dawson: [For many years], patients with HCC did not have many treatment options. Now, there are many options and a lot of promise, which is exciting. However, patients who have macrovascular invasion have a worse prognosis, regardless of the treatment that is used; [these patients have] been traditionally challenging to [treat].

There has been experience around the world using external beam radiation to treat these patients. Mostly single-arm studies, [with] a few small comparative studies, have shown that external beam radiation can help patients [with HCC]. However, there have not been large phase 3 studies studying radiation, [even though] we know it can help with vascular invasion.

When there is vascular invasion, it means there’s a high likelihood of microscopic cancer even beyond what you can see on imaging, so the standard of care has been systemic therapy. When we opened the study and designed it, sorafenib, which is a TKI, was the standard-of-care [SOC] therapy. These patients are not suitable for surgery, transplants, local ablation, or regional therapies, and their SOC would be systemic therapy.

The rationale was that if radiation can help their macrovascular invasion and their local control, then sorafenib would be more effective at treating the microscopic disease, [thus] leading to improved survival, time to progression, and [improvement in] other end points.

We launched the randomized study with that in mind, with the hypothesis that radiotherapy [plus sorafenib] would improve all outcomes for patients compared with sorafenib alone.

How did the investigation of the immunotherapy-based combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) in the phase 3 IMbrave150 trial (NCT03434379) affect the NRG/RTOG 1112 trial?

[The NRG/RTOG 1112 study] was a randomized phase 3 trial with a 1-sided alpha of 0.05, looking at improvement in survival based on prior data of sorafenib.

[NRG/RTOG 1112] did close earlier than expected because the SOC systemic therapy changed from TKI-based [therapy] to immunotherapy-based [therapy] with the phase 3 IMbrave150 study. With that closure, we had 196 patients accrued to the study.

There was an amendment in [statistics for NRG/RTOG 1112] looking for the same effect size, with the same alpha, and the power was reduced from [80%] to 65%. With a lower power, we still wanted to report the outcomes. As of July [2022], we looked at the outcomes and reported it.

The hypothesis was that radiation therapy would improve OS, PFS, and other end points. [NRG/RTOG 1112] was a multicenter trial and had many centers around North America with a few from around the world.

What was the design of the NRG/RTOG 1112 trial? What were the key objectives of the research?

Patients who were treated in this study had locally advanced cancer, so they could have tumors up to 20 cm in size with any degree of invasion into the vasculature and a very small amount of extrahepatic disease, up to 3 cm. The [median] tumor size, excluding the vascular invasion, was [7.8 cm] in diameter, and [tumors ranged] up to 19.1 cm, so these were very large tumors.

Any degree of vascular vision was permitted, and 74% of all patients accrued to the study had invasion into their vasculature. These numbers are higher than any other randomized study to date [that has looked] at systemic therapy for [patients with] liver cancer. Of those with vascular invasion, the great majority have invasion into the main portal vein, which is associated with worse prognosis, so they were tough-to-treat patients.

Radiotherapy, which was personalized, ranged from 27.5 Gy and 50 Gy in 5 fractions [and this was] followed by sorafenib.

What were the efficacy data reported with this approach?

We did find that OS was improved from a median of 12.3 months with sorafenib alone to 15.8 months with the addition of SBRT, [translating to] a hazard ratio [HR] of 0.77.

On a preplanned multivariable analysis of all important factors, the addition of SBRT was statistically significantly associated with improved survival, with a HR of [0.72] and P value of .042.

Not surprisingly, the time to progression and PFS were also clinically and statistically significant improved with [the addition of] radiation. There was an almost doubling of PFS, from a median of 5.5 months [with sorafenib alone] to 9.2 months with radiotherapy. This was similar for time to progression, with a median of 9.5 months [for sorafenib alone] to 18.5 months with the addition of radiotherapy.

What was found regarding safety?

There was no concerning increase in adverse effects [AEs] in the patients [who also received the radiation]. Transient grade 2 bloodwork and gastrointestinal toxicity was increased in those patients, but grade 3 and higher [AEs] were similar in both arms. Most of the time, the AEs are due to cancer. Very locally advanced cancer can cause liver failure, bleeding, and other [toxicities]. With better control of the tumor, there should be less grade 3 to 5 AEs, which we did see.

What was found in terms of quality of life (QOL)?

We did look at QOL in these patients. Not all patients consented, [and the QOL data did not have] statistical significance. However, when we looked at our end point for QOL, using the FACT-Hep tool, we found that a higher proportion of patients who were treated with radiotherapy reported clinically significant improved QOL 6 months following therapy, at 33% [for those] receiving radiotherapy vs 10% [for those who] had sorafenib alone. That was also complementary to the survival data that I showed and consistent with no observed increased AEs in patients who were treated with radiotherapy.

What are the clinical implications of these findings? How else should SBRT be investigated in this patient population?

Presently, the SOC in most parts of the world is an immunotherapy-based systemic therapy for patients who were eligible for this study. That does beg the question: What is the additional value of external beam radiotherapy with immunotherapy?

I do believe this trial is practice changing, as patients who are eligible for or offered a TKI such as sorafenib should be offered radiotherapy to improve outcomes. In some parts of the world, [sorafenib] still is the first option, or immunotherapy may not be affordable. Here, in North America, that is a minority of patients.

So, how do we treat patients with local therapy with external beam and immunotherapy? It’s hard to know for sure, but the best way to know that is to launch another randomized study, which would be similar in design to NRG/RTOG 1112, but with an immunotherapy-based backbone. The NRG Cooperative Group is working on that, so hopefully that will be the next phase 3 study where we can learn about the benefits [of SBRT] in the era of immunotherapy.

I would hypothesize that there may be larger benefits, as the systemic therapy is more effective at controlling the microscopic disease. Hopefully, that study will be launched and will accrue well, because we will be interested in it, and we will learn with certainty how radiation fits with present-day systemic therapy.

What other questions would you like to see addressed with future research efforts?

We also need to know better who benefits the most [from these kinds of approaches], how to select patients, and what biomarkers tell us how to best treat patients. We would look at the details of the study in terms of dose [of SBRT], because there is personalized dosing. The doses that were used were not ablative doses. The median dose was 35 Gy in 5 fractions. That’s a modest dose of radiation and still was associated with benefits.

Looking more deeply into [the dosing of radiation] will hopefully help us know what the right doses are for these patients. We want to make sure we don’t cause toxicity. Fortunately, we didn’t [in the NRG/RTOG 1112 trial], but it is often a fine balance of [identifying] the right dose to control the tumor [but] not to increase toxicities, so we will look into that more.

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