1. Samson, Kurt

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CHICAGO-For some patients with metastatic non-small cell lung cancer (NSCLC), carefully targeted and escalated doses of stereotactic body radiotherapy (SBRT) appear to somehow trigger and reinvigorate their immune system and increase progression-free survival, according to new research.

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Findings of the phase II randomized trial were presented in September at the 2019 ASTRO Annual Meeting.


"This study provides one more important piece of data that indicates that, for some patients, the immune system can be a really powerful tool to combat metastatic lung cancer," said lead author of the paper Allison M. Campbell, MD, PhD, a resident in at Yale New Haven Hospital. "It points us in the direction of places to look for biomarkers that might predict which patients would best respond to this type of therapy."


Because nearly 60 percent of NSCLC patients have reached stage IV cancer by the time they are diagnosed, they are especially difficult to treat, Campbell noted. Current treatment options include radiation, immunotherapy, surgery, chemotherapy, or and/or targeted drug therapy.


In the phase II prospective trial, investigators tested treating one cancerous lesion with SBRT in a patient where their disease had spread after treatment with the immunotherapy agent pembrolizumab. The researchers wanted to see whether or not tumors beyond the SBRT-treated area might also shrink. They also wondered how long patients might live before their disease progressed and what occurred in the immune systems of patients who responded well to SBRT and immunotherapy.


A total of 56 patients with NSCLC were included, all with two or more tumors at enrollment. Among them, six had, and 16 already received immunotherapy and were immediately treated with SBRT. The others had yet to receive immunotherapy and, of these, 16 received SBRT when their disease had progressed after being treated with pembrolizumab.


In all, 21 patients finished both treatments and lived, on average, 5 months longer without disease progression. In two patients, tumors outside the treated area shrank by 30 percent or more, and stayed that way 1 year and more. In addition, disease stabilization was recorded in 10 patients, or 47.6 percent, where their tumors neither grew nor shrank after SBRT.


Campbell said the research team really wanted to learn more about what was happening in the immune systems of those patients. "There's been a lot of interest in how radiation can stimulate the immune system, and we naturally wanted to learn all we could from our very best responders."


They examined peripheral blood cells in patients whose tumors shrank, and those where this did not occur, and discovered specific activities that T cells played in the immune system response, Campbell noted.


"We found that there were two things that correlated with patients living longer without their disease progressing," she said. "Those two things were T cells infiltrating the tumor before immunotherapy was given, and the presence of immune-related side effects at any time during the course of treatment, such as inflammation of the lung or inflammation of the GI tract. Patients who experienced these side effects lived a longer period of time before the disease progressed."


The investigators identified two different types of T cells that played an important role in fighting the tumors. In patients who responded well to the combination therapy, both CD8 T cells, which can kill cancer cells directly, and CD4 T cells, which help the immune system marshal its forces against threats like as cancer, were key.


"We saw different proportions of these cells in our good responders versus our bad responders, as well as different activation statuses," she said. "In people who responded well to the combination therapy, we saw a population of CD8 T cells that looked more excited, and in those with poor responses, we saw a population of CD4 T cells with inhibitory markers. The bigger picture here is that there are signatures in the peripheral blood that are promising avenues for future identification of people who will respond well to SBRT combined with immunotherapy."


The next step, Campbell noted, will be to validate these findings in a larger study group.


"We are starting to see that the combination of immunotherapy and radiation is safe and there are some hints that, for certain patients, radiation might be an important option when immunotherapy no longer curbs disease progression," she said. "Our study lays the groundwork for a phase III randomized trial, which is the gold standard for changing guidelines and clinical practice."


Kurt Samson is a contributing writer.