As the number of patients receiving immune checkpoint blockade grows, the combination of radiation and immunotherapy has become increasingly relevant, particularly in the palliative care setting, where radiation is used to treat painful lesions, brain metastases, or isolated progression. At the 2017 Palliative and Supportive Care in Oncology Symposium, Jonathan Schoenfeld, MD, MPhil, MPH, presented preclinical data that suggest promise for radiotherapy/immunotherapy combinations, discussed toxicities associated with both treatments, and shared ongoing clinical trials evaluating numerous combined treatment approaches to capitalize on potential synergy.
Rationale for Combining Radiation and Immunotherapy
According to Dr Schoenfeld, a radiation oncologist at Brigham and Women’s Hospital and an assistant professor of radiation oncology at Harvard Medical School, evidence that the immune system contributes to the local effects of radiotherapy dates back to the 1970s, when it was demonstrated that radiation was less effective in immunosuppressed models. Driven by greater understanding of antitumor immune response, more recent studies have shown that radiation is less effective locally in melanoma models with depleted CD8-positive T cells. As Dr Schoenfeld reported, however, targeted radiation can also result in immunogenic cell death, leading researchers to hypothesize that radiation may contribute to a systemic antitumor immune response.
“The hope is that under normal circumstances, if you have a tumor that’s not recognized by the immune system, you can cause immunological cell death through ionizing radiation and get tumor antigen release in a stimulatory environment that can then stimulate a broad antitumor immune response,” he said.
According to Dr Schoenfeld, researchers have observed synergy between radiation and immunotherapy in preclinical models, specifically in combination with PD-1 pathway inhibitors. Moreover, this synergy occurs across multiple models, including breast, colorectal, and pancreatic cancers and melanoma.
“There’s a local benefit and potential systemic benefit where radiation is helping immunotherapy, protecting mice from re-challenge and in some cases resulting in this abscopal or out-of-field effect,” he explained, “and these data go beyond PD-1 pathway inhibitors.”
Tolerability of Radiation and Immune Checkpoint Blockade
Although many patients receiving immune checkpoint blockade could potentially benefit from palliative radiation at some point in their care, whether for painful lesions, brain metastases, or oligoprogression, Dr Schoenfeld acknowledged concerns that radiation and immune checkpoint blockade have overlapping toxicities, especially with radiation fields that include the lung or bowel. Data from over 130 patients receiving palliative radiation as standard of care and immune checkpoint blockade at the Palliative Care Radiation Service at Brigham and Women’s Hospital, however, suggest the combination is generally well tolerated.
“Oncologists have become more comfortable giving radiation therapy concurrent with checkpoint blockade,” said Dr Schoenfeld, who noted that more than 40% of patients received radiation within 14 days of checkpoint blockade.
Although researchers observed a nonstatistically significant increase in pneumonitis in patients who received radiation of the lung, no other association between site, dose, and timing of radiation was found, and overall rates of adverse events were similar to historical data. Nevertheless, said Dr Schoenfeld, more prospective data are needed, and clinicians should monitor for associations with rare but potentially severe side effects (eg, myocarditis), delayed side effects (eg, pneumonitis), and also enhanced radiation effects (eg, radionecrosis).
Recent data also suggest that immunotherapy may be particularly effective following radiation. As Dr Schoenfeld reported, subset analysis of the KEYNOTE- 001 trial looking at patients with non–small cell lung cancer who went on to receive pembrolizumab found that those who had previously received radiation seemed to fare better than those who had not previously received radiation prior to starting immune checkpoint blockade. In addition, said Dr Schoenfeld, analysis of patients at Brigham and Women’s Hospital who received radiation prior to immunotherapy showed that over 40% were able to remain on checkpoint blockade for a median of 179 days following palliative radiation.
“As a result of preclinical and clinical data, there are an increasing number of prospective trials studying this combination of therapies,” said Dr Schoenfeld, who noted at least 80 ongoing trials. “These trials are testing the addition of immunotherapy to radiation standard-of-care approach, the addition of radiation to immunotherapy standard of care, or exploring synergy observed in preclinical models.”