SAN DIEGO-Stereotactic body radiation therapy (SBRT) combined with the CTLA4 immune checkpoint inhibitor ipilimumab stopped the growth of tumors in as many as 60 percent of patients with late-stage cancer that had metastasized to the lungs or liver, according to data from a phase II study.
The combination halted the spread of cancer in between 30 percent and 60 percent of patients, said lead author James Welsh, MD, Associate Professor of Radiation Oncology at the University of Texas MD Anderson Cancer Center in Houston.
"If you have someone with 10 or 20 sites of metastatic disease, you cannot irradiate them all," he told a September press briefing at the American Society for Radiation Oncology Annual Meeting (Abstract LBA-2).
"This combination of immunotherapy and radiation therapy was safe and well-tolerated by patients with late-stage cancers. We were surprised that a large percentage of patients achieved stable disease several months after treatment-meaning that, while their tumors didn't shrink, they did stop growing. These are heavily pretreated patients, many of whom progressed on prior PD-1 drugs," Welsh noted. "We found that the addition of SBRT for patients who are on immunotherapy to be safe and well-tolerated, meaning that radiation oncologists can feel confident continuing immunotherapy for most patients when adding SBRT to lung or liver metastases.
"In fact, there may be additional benefit from combining the therapies in terms of improved disease control. Follow-up research in larger clinical trials is needed to determine which types of tumors and patients will respond best to this immunotherapy-radiation approach.
"This heightened immune response was able to keep the tumors stable. Longer follow-up is needed to determine if this benefit of stable disease will endure over time," he said. "It appears that the radiation helped turn the tumor into a vaccine to stimulate an immune response," Welsh said.
"A small percentage of patients experienced a potential abscopal effect, where tumors that were not irradiated became smaller after we treated different sites with radiation. For example, one patient with anaplastic thyroid cancer experienced a reduction in the primary tumor after we irradiated a lung metastasis. This patient had controlled disease for more than 13 months."
Methods, Results
Welsh and his colleagues tested several combinations of high-dose SBRT plus ipilimumab in 100 patients with various types of stage IV cancers, divided into five treatment arms. Each received four cycles of ipilimumab (3 mg/kg every 3 weeks) and SBRT to metastases in the liver or lungs. Radiation therapy was given either concurrently with or sequentially to immunotherapy.
All of the subjects had one or more lesions in the liver or lung, and one or more additional metastases not touching the lung or liver lesion. By cancer type, 55 percent were adenocarcinomas, 13 percent were squamous cell carcinomas, and 32 percent were different other types of disease.
Concurrent radiation was provided to a total dose of 50 Gray (Gy) delivered in four fractions. Sequential radiation to a total radiation dose of 50 Gy was also delivered in four fractions, or 60 Gy in 10 fractions for larger lung or liver metastases.
The five treatment groups were as follows: concomitant liver 50 Gy, concomitant lung 50 Gy, sequential liver 50 Gy, sequential lung 50 Gy, and sequential 60 Gy (lung or liver for larger lesions).
Half of the patients in the sequential 50-Gy lung cohort achieved stable disease, as did 35 percent of the concurrent liver group, and 30 percent of the sequential 50-Gy liver group.
The median progression-free survival (PFS) for all patients was 5 months with a range of 3-7 months, and median overall survival (OS) was 12 months. Patients given sequential radiation to lung metastases rather than liver metastases had better PFS and OS, but no differences were observed in the concurrent lung or liver groups for PFS or OS.
No patients achieved complete responses to treatment, but partial response was found in three patients who received SBRT concurrently with ipilimumab. This included two patients in the concurrent lung group and one patient assigned to the concurrent liver arm. No patients in the sequential radiation groups experienced a partial response.
Non-small cell lung cancer (NSCLC) tumors responded most favorably to the combined treatment-two-thirds of these patients had a favorable response, characterized as either partial response or stable disease following SBRT and immunotherapy. Partial response was determined to be a 50 percent or greater decrease in tumor size while progressive disease represented a 25 percent increase. Stable disease responses included those that did not fall into complete, partial, or progressive response categories.
There were no grade 4 or 5 treatment-related side effects; however, 27 patients experienced grade 3 toxicities. These included colitis (eight patients), diarrhea (seven patients), rash (four patients), elevation of liver enzymes (three patients), hypophysitis (three patients), elevation of bilirubin (one patient), and intestinal obstruction (one patient). In addition, two patients suffered grade 3 toxicities related to combination therapy, including one with elevated liver enzymes and one patient with pneumonitis.
The concept that the approach may promote abscopal antitumor activity is an area being intensely investigated. It's estimated that at least 100 ongoing trials of testing various combinations of radiotherapy and immunotherapy against different types of cancer are underway.
Commentary
Brian Czito, MD, Radiation Oncologist at Duke University, in Durham, N.C., commented on the findings. "With a proposed mechanism of the irradiated tumor acting as a vaccine of sorts to stimulate the body's own immune response, this cutting-edge strategy provides support for larger future trials investigating this mechanism of action and novel approach. The integration of local therapy in this otherwise common scenario has the potential to establish a new treatment paradigm."
"We are dealing with a really novel combination that is in its earliest stages of development," stated Phuoc T. Tran, MD, PhD, Associate Professor of Radiation Oncology and Molecular Radiation Sciences at Johns Hopkins Medicine, Baltimore.
"This is one of the largest, if not the largest, single institution prospective trial using combination radiation and immune checkpoint inhibition. That it demonstrated reasonable toxicity and other positive signals, particularly the abscopal response, is highly encouraging and warrants further exploration in randomized prospective trials," he told Oncology Times.
"We have only recently begun to appreciate the potential synergy between radiation and immunotherapy agents for cancer treatment and igniting systemic effects of radiotherapy.
Kurt Samson is a contributing writer.