James Welsh, MD
THE NOVEL COMBINATION of immunotherapy with ipilimumab (Yervoy) plus radiation achieved a clinical benefit in up to 57% of patients with solid tumors and metastases to the lungs or liver, according to evidence from a phase II trial presented at the 2017 Annual Meeting of the American Society for Radiation Oncology (ASTRO) in San Diego.1 The majority of the benefit was in achieving stable disease, preventing further disease progression in these heavily pretreated patients with advanced disease.
“This approach is different from the conventional use of radiotherapy to treat metastases, where you attempt to radiate individual metastatic sites to achieve local control. With this strategy, we treated patients with multiple sites of metastatic disease with various combinations of stereotactic radiotherapy and immunotherapy and are attempting to achieve responses at sites where we don’t even add radiation,” explained lead author James Welsh, MD, Associate Professor and physician scientist at The University of Texas MD Anderson Cancer Center in Houston.
Dr. Welsh has been studying the mechanisms by which immunotherapy plus radiation potentiates response in patients with metastatic cancer. “The idea is radiation kills the tumor, and the combination with immunotherapy turns the tumor into a vaccine that activates the immune response,” he explained.
THE 5-ARM PHASE II TRIAL enrolled 100 heavily pretreated patients with metastatic disease and looked at several strategies that included concurrent and sequential radiation in combination with immunotherapy (in this study, 4 cycles of ipilimumab), as well as 2 doses of stereotactic ablative radiotherapy (50 and 60 Gy) to treat lung and liver metastases, with the goal of finding the most effective and least toxic strategy. “We wanted to achieve responses outside of the radiation field and to find the right dose sequence and the best site to treat—lung or liver,” Dr. Welsh explained. “We needed five arms to answer these questions.”
“This is the largest study of stereotactic radiotherapy plus immunotherapy. We wanted to make sure that radiation did not worsen the toxicity of immunotherapy, particularly in the lung and the liver. It was a nice surprise to see that these treatments were well tolerated,” he added.
Response and Toxicity
AT A MINIMAL FOLLOW-UP of 3 months for this very early phase of research, median progression-free survival was 5 months, and median overall survival was 12 months.
The best response (tumor shrinkage of more than 50%) was seen in 5% to 14% of patients. The remaining responses were stable disease. Clinical benefit (ie, response or stable disease) was observed in 26% to 57% of patients, depending on the treatment arm and the type of metastasis (lung or liver).
Interestingly, in a small group of patients, tumors that were not irradiated had shrinkage after radiation therapy was delivered to other sites. The ability of localized radiation to trigger systemic antitumor effects is called the abscopal effect. Dr. Welsh added: “Low-dose scatter from radiation may help improve response. The study gives us the signal that low-dose radiation may push the immune response.”
No patient had grade 4 or 5 treatment-related toxicity. Immune-related adverse events occurred in 27%. Two patients experienced toxicity related to the combination: one had elevated liver enzymes and one had pneumonitis.
“Results are intriguing,” Dr. Welsh continued. “We need longer follow-up of these patients to see if the clinical benefit is enduring. We want to determine which types of tumors have the best response to the combination of immunotherapy plus radiation.”
Dr. Welsh said that at least 100 clinical trials are currently looking at different immunotherapies in combination with radiation. At MD Anderson, a separate phase II trial is comparing immunotherapy alone vs immunotherapy plus radiation in patients with non–small cell lung cancer.
Ipilimumab was the immunotherapy evaluated in the trial reported at the ASTRO meeting. “This drug typically doesn’t work in tumors other than melanoma,” he noted. Other immunotherapy drugs may achieve even better results in combination with radiation therapy, he said. ■
DISCLOSURE: Dr. Welsh owns stock or stock options in Healios, MolecularMatch, OncoResponse, Checkmate Pharmaceuticals, Mavu, and RefleXion Medical.
1. Welsh JW, Tang C, de Groot P, et al: Phase II 5-arm trial of ipilimumab plus lung or liver stereotactic radiation for patients with advanced malignancies. 2017 ASTRO Annual Meeting. Abstract LBA-5. Presented September 24, 2017.
Brian G. Czito, MD
“THESE PRELIMINARY STUDY RESULTS suggest that combining these modalities [immunotherapy and radiation therapy] can halt tumor growth in 30% to 57% of patients, with the radiation-induced tumor response acting as a sort of vaccine in combination with immunotherapy. This...!-->!-->