NRG / RTOG 1112 Phase 3 Trial: ASTRO [2022]
Nrg/RTOG 1112 A Randomized Phase III Study
The NRG/RTOG 1112 (NRG Oncology RTOG 112) clinical trial focuses on patients with hepatocellular carcinoma, a group of patients who are understudied and in need of better treatments.
At the start of this study, sorafenib was the standard of care for patients treated with locally advanced hepatocellular carcinoma that could not be removed and did not respond well to standard local ablation therapies or hepatic arterial regional therapies like TACE. And so that is why sorafenib is the backbone systemic therapy that’s used in this trial.
The trial compares stereotactic body radiation therapy (SBRT), followed by sorafenib, to sorafenib alone. Sorafenib is a tyrosine kinase inhibitor, and it was the first systemic agent in hepatocellular carcinoma patients treated to show a survival benefit compared to placebo in one randomized study in 2008. That showed an improvement in median survival from 7.8 months to 10.7 months.
Another Asian study that showed similar benefits in Asian patients treated with hepatocellular carcinoma who had sorafenib had fewer benefits for advanced cancers that invaded the large vessels of the liver (cancer), the portal vein, or the iVC with macrovascular invasion. So medium survival improved from 6.7 months to 8.9 months.
So, those patients with macrovascular invasion are a particularly challenging patient population to treat. And they were the main focus of this clinical trial. Now there are other tyrosine kinase inhibitors that are available for patients. At the time we designed the study, sorafenib was the primary systemic therapy and, in fact, early in the pandemic, this trial NRG/RTOG 1112 (NRG Oncology RTOG 112) was closed earlier than expected because the systemic therapy for these patients changed from a tyrosine kinase inhibitor to an immunotherapy based regimen. As a result, patients treated are currently offered either an immunotherapy-based regimen or a tyrosine kinase inhibitor. But that led to the early closure of the study.
So that was a background of why systemic therapy. An interesting question is why are we studying SRBT (Stereotactic Body Radiation Therapy). So because patients with macrovascular invasion are challenging to treat, outcomes are poor regardless of the treatment that is used. Radiation therapy has been used to try to eradicate the cancer in the vessels, open up the vessels, and improve outcomes for patients.
And for a few decades now, different types of radiation therapy have been used showing better than expected overall survival rates and. Response within the large vessels, sometimes recanalization, and a complete response much better than what was seen with standard therapies that were available. And so based on those mostly single arm studies, a few comparison studies, but not a large randomized phase III study.
The NRG (NRG Oncology RTOG 112) designed a clinical trial that asked the question, “Does Stereotactic Body Radiation Therapy (SBRT) improve overall survival for these patients?” And in my own and other institutions, we conducted Phase 1 studies looking at the combination of stereotactic body radiation with sorafenib and decided a sequencing rather than a concurrent regimen was safer and better for patients treated, starting with stereotactic body radiation therapy followed by sorafenib. So that’s a little bit of the background of the two therapies that are used in these.
Please Tell Us About The Current Standard Of Care.
The patients treated who are the focus of this clinical trial are patients with locally advanced hepatocellular carcinoma (HCC). So they are not suitable for surgery, not suitable for transplant, not suitable for thermal ablation or interventional radiology approaches that may ablate smaller tumors and not suitable for TACE, which is the standard of care in these patients. The degree of macular vascular invasion that patients may have varies in this patient population as patients who had progressive disease following those therapies were permitted to be treated as well as those who were unsuitable for those therapies upfront.
And so, no patient had received prior lines of systemic therapy, and sorafenib tyrosine kinase inhibitor was the standard of care at the time. So that was why it was used, and systemic therapy was and is a standard of care therapy for these patients with major vascular invasion or who have had progression in recurrence following standard therapies.
And the standard of care has changed from tyrosine kinase-based therapy to immunotherapy-based. So there are many more systemic therapies available now than when we designed the study, when sorafenib was the only systemic therapy available. Nonetheless, at least in North America, patients are offered immunotherapy regimens such as the Alemtuzumab and Bevacizumab combination, which did show superiority over saff.
There are some patients who cannot tolerate that. Furthermore, recurrence is unavoidable, and patients who develop recurrence after that may be offered tyrosine kinase therapy with sorafenib vat, and the results of these studies may be relevant to those patients. Why is SRBT (Stereotactic Body Radiation Therapy) stereo body radiotherapy available and widely available?
Photon-based therapy delivers radiation in fewer than usual treatments. So there are five options for this patient population. So the therapy can be delivered quickly. It is convenient for patients, and they can quickly get their systemic therapy afterward. So those are the reasons for the treatment options in the study.
And it was a randomized phase III study that randomized one to one patient to receive sorafenib. Or stereotactic body radiotherapy, followed by sorafenib. There are other ways to give radiation, but SRBT (Stereotactic Body Radiation Therapy) is the way that I’ve delivered it and have the most outcomes and experience with, and as I said, it is widely available.
Hence, why we choose that as the study treatment to investigate. You asked about outcomes and so, the main goal of the trial was to find out how many people with carcinoma in situ that didn’t respond to BCG had a complete response at any time after the first treatment and whether they had improved outcomes in these patients.
The primary outcome of the study, it was the overall survival and the secondary outcomes were progression free, overall survival, adverse events, time to progression, and some others that won’t be presented. Here at the astro meeting, and I’ll talk about them a little bit more, but the bottom line was that there were improvements in all outcomes with the addition of SPRT compared to systemic therapy.
What Is The Trial Design?
The clinical trial design is a randomized phase III (NRG Oncology RTOG 112) study with one to one randomization for patients treated with sorafenib as per standard of care, or personalized stereotactic body radiate therapy followed by half dose sorafenib that could be escalated up to standard of care dosing, depending on tolerability. And the rationale for that is that many of these patients have very locally advanced cancers that are challenging to treat with systemic therapy alone, for example, with major vascular invasion. And in those patients, the experience with radiation is that, radiation could treat the cancer within the large vessels that then can lead to recanalization and allow patients to do much better when there is cancer in many of the major veins within the liver (cancer), that can lead to increased.
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A portal pressure within the liver and actually precipitate an earlier death. And so treating the vascular invasion has been a very challenging scenario for oncologists for a long time. Hence why we focused our study on these challenging patients hoping that radiation would improve the outcomes, particularly in those patients with macrovascular invasion.
It does take some time for radiation to. To have a response. And so the hope is that with the sorafenib also on board, it could treat the cancers that it can reach while radiation was improving, the response of the harder to treat cancer, for example, on the vessels. That was the background of why the combination. It was based on prior studies, phase 1 studies, phase 2 studies, and looking at potential synergy. But at the end of the day, we chose an additive. Question, does SBRT (Stereotactic Body Radiation Therapy) improve outcomes compared to sorafenib? Starting with SBRT (Stereotactic Body Radiation Therapy) alone, followed by sorafenib as opposed to concurrent treatment? And that was predominantly because we did not wanna increase the toxicity.
And our phase 1 studies suggested that a sequential use of SBRT (Stereotactic Body Radiation Therapy) and sorafenib would be safer than a concurrent.
What Are The Inclusions And Exclusions?
The inclusion criteria for this study included patients with locally advanced hepatocellular carcinoma and patients could have up to 5 HCC (sorafenib in hepatocellular carcinoma) or a conglomerate of hepatocellular carcinoma (HCC) or infiltrative hepatocellular carcinoma just under 20 centimeters.
So quite a large burden of disease any degree of macrovascular invasion was permitted and a small burden of disease outside the liver up to a 3 centimeter diameter was permitted. Patients had good liver function, Child-Pugh A 5 or 6, with platelet counts above 60,000 so that they could tolerate sorafenib, and in general, patients.
I could not be treated if they had two extensive hepatocellular carcinomas or had empiric liver function worse than what the criteria were. So these patients had been permitted to have quite locally advanced cancer, including any degree of macrovascular invasion in up to 20 centimeters.
What Was Your Journey to Studying Liver Cancer?
I am from Toronto and I trained in Toronto. I’ve always had an interest in medicine and also technology. And so, during medical school, when I came across the specialty of radiation oncology, I was very intrigued. I. And, as a result of my training and experience in the radiation oncology training program, I developed a strong interest in the specialty, realizing that radiation therapy is a very effective and powerful treatment that can lead to cure and improve overall survival, reduce recurrence, and sometimes preserve organs rather than having a tumor and organ surgically removed, and can improve outcomes for patients, including quality of life, when (radiation therapy) combined with other therapies. It’s also really effective therapy for the palliation of symptoms that patients may have from primary or metastatic cancer.
So very early, I knew that and I recognized that. Using computers and software to more precisely direct radiation therapy to tumors may allow us to treat cancers that were previously difficult to treat more safely with fewer side effects. And so, after my radiation oncology residency program in Toronto, I went to Ann Arbor, Michigan, the University of Michigan, where I did a fellowship that focused on the use of high precision radiotherapy, computerized radiotherapy imaging, and radiation oncology. ability to control for potential motion And in that fellowship, that is where I was first exposed to the possibility that radiation could be used to treat patients with liver cancer. I was fortunate to have mentors in a team and funding to develop conformal radiotherapy studies at the time, demonstrating that radiation could indeed be delivered safely to patients with liver cancer who were previously thought to be untreatable.
And then, about 5 years after that, I decided to come back to Canada. I really wanted to spend my clinical and research efforts on treating these patients who, at that time, weren’t even candidates for systemic therapy such as sorafenib. So I came back to Canada in 2003 and to Princess Margaret Cancer Center, where, with a lot of collaborators and a team, we built a program here.
Delivering radiation in fewer fractions, so-called SRBT (Stereotactic Body Radiation Therapy). And then we designed studies throughout the years to show how we could do that safely, how we could combine it with other medications, such as AFib. And we had phase 2 studies showing promise, which ultimately led to the design of this trial.
Run through the NRG to ask the question definitively. SRBT (Stereotactic Body Radiation Therapy) has been shown to improve overall survival, progression-free survival, and other outcomes in patients with Psal carcinoma. So I’m very proud to be the PI of the study because it’s something that I feel very strongly about.
I’ve seen over the years how radiation can help patients, and yet it’s been challenging for myself and for others to randomized phase III studies that have shown the benefits of radiation. And I do believe that this is a study that does show that radiation can help these patients and hopefully will open the doors for more trials.
As a physician, it is one of the highlights of my career to be able to present these outcomes in patients who require additional therapies.
Final Thoughts
In summary, I am so pleased to be able to share these results with the community, showing improved statistically significant and clinically significant improvement in outcomes.
And we saw an improvement in median survival from 12 months to 16 months with the addition of SRBT (Stereotactic Body Radiation Therapy) to sorafenib and sorafenib. Since this was before immunotherapy, the fact that the average person lived for 16 months is very good. And it’s clinically meaningful to patients when we considered other prognostic factors such as performance status, whether their patients had metastases, the degree of liver function, and liver disease, the macrovascular invasion, there remained a statistically significant improvement in overall survival with the hazard ratio of 0.72 on a P value of .042. Nice to see that benefit, and there appeared to be, perhaps, bigger benefits in those patients with the macrovascular invasion involving the main portal vein and other main vessels.
So really, I think that’s an important group of patients where radiation can lead to benefits. Not surprisingly, there were important differences in progression-free survival and time to progression as well, with a more than doubling of time to progression from a median of 9.5 months to 18.5 months in a change and a near doubling of progression free survival at 18 months, for example, from 11% with sorafenib alone to 28% with the addition of sorafenib. This was also seen without any increase in adverse events. So, really meaningful results for this important patient population. And I guess in final follow up, I would say this is a really good example of a collaborative clinical trial that really could only be done.
With medical oncologists, radiation oncologists, physicists, therapists, and sites that support a cooperative group clinical trial, So I am thankful to all of those who participated in the study from Thanks to the different countries who made it possible, sorafenib, as well as to NRG and the team at NRG who supported the trial.
And of course, most importantly, I’m very grateful to all the patients and families who presented and participated in this study. Hopefully, this will allow us to have access to radiotherapy for more patients in the future.
Laura Dawson, MD, FASTRO, FRCPC (Practicing Radiation Oncologist) – About The Author, Credentials, and Affiliations
Dr. Dawson is a University of Toronto Professor in the Department of Radiation Oncology and a Practicing Radiation Oncologist at Princess Margaret Hospital/University Health Network. Her research focuses on how to use new radiation technologies, like stereotactic body radiation treatment (SBRT), image guidance, and MRI-guided radiation therapy, to help radiation therapy patients get better results and have fewer side effects. She also looks into new ways to use radiation therapy, like SBRT for treating liver cancer, and new ways to combine therapies, like SBRT and immunotherapy. Also of importance to her are advances that lessen the danger of radiation-related toxicity. She is in charge of two randomized phase III clinical trials that look at the use of radiation therapy in people with primary liver cancer (sorafenib in hepatocellular carcinoma) and/or liver metastases. She is also in charge of other local trials that look at radiation therapy (combined) with or without immunotherapy.