Radiation May Boost Immunotherapy in Metastatic Lung Cancer

Roxanne Nelson, RN, BSN

September 17, 2019

CHICAGO — Adding stereotactic body radiotherapy (SBRT) to the treatment regimen increased progression-free survival (PFS) in some patients with metastatic non-small cell lung cancer (NSCLC) in what may be the result of synergistic effect with immunotherapy, according to researchers.

Among 21 patients who had progressed on antiPD-1 therapy and subsequently were treated with SBRT, three patients achieved either a partial response or stable disease that lasted for 1 year or longer.

Overall, the addition of SBRT to pembrolizumab (Keytruda, Merck) resulted in a mean PFS of 151 days for the cohort.

Lead author Allison M. Campbell, MD, PhD, a resident in the Department of Therapeutic Radiology at Yale Cancer Center in New Haven, Connecticut, pointed out that all of the patients who achieved a durable response had already progressed on immunotherapy when SBRT was initiated.

"These patients had many sites of disease, but only got radiation at a single site," she explained. "Some responses were abscopal, meaning that they occurred outside the radiation field."

Of note, certain subsets of T cells in the tumor biopsy were associated with longer PFS, as were any immune-related adverse event prior to disease progression.

"Patients who responded well to SBRT had more CD8+ killer T cells in their blood," Campbell said, "And those who responded poorly to SBRT had more CD4+ regulatory T cells in their blood," she said.

The study results were presented here at the 61st Annual Meeting of the American Society for Radiation Oncology (ASTRO).

Abscopal Effect?

Historically, radiation therapy has been considered a localized treatment, but a growing body of evidence suggests that it may induce a regression of tumor cells that are beyond the field of irradiation. This phenomenon is known as the abscopal effect.

While the abscopal effect remains relatively rare, combining immunotherapy with radiation therapy appears to be a promising approach for inducing this response. "Immunotherapy activates the immune system to attack cancer," said Campbell. "Adding radiation to immunotherapy has been shown to result in therapeutic synergy."

She explained that in this study, she and her colleagues sought to answer the following question: "Can the addition of high-dose radiation given in a few fractions to a single site of disease reinvigorate an immune response in patients who have progressed on anti-PD-1 therapy?"

The study cohort included 56 patients with NSCLC, all of whom had two or more measurable tumors at enrollment. Histologic analysis of biopsy samples was performed at enrollment, with the number of tumor-infiltrating lymphocytes (TILs) given a qualitative score between 0 to 3.

If patients had progressed on prior anti-PD-1 therapy at the time of enrollment (n = 6) they received SBRT upfront and continued on pembrolizumab. For the remaining 50 patients who were immunotherapy naïve, they received pembrolizumab once every 3 weeks until disease progression, at which point SBRT was initiated and they continued on pembrolizumab.

"Only one site of disease was treated with radiation therapy," Campbell explained. "Other tumor sites of were measured and tracked over time."

A total of 21 patients completed both treatments and achieved a PFS of about 5 months. Two patients (9.5%) had tumor shrinkage of 30% or greater, all outside of the area treated with radiation therapy, and the response was sustained for more than a year.

In addition, 10 patients (47.6%) achieved disease stabilization, and the overall disease control rate of the cohort was 57%.

"These responses are all distant so they are abscopal," said Campbell. "It is important to keep in mind that these patients had already progressed on immunotherapy at the time of radiation."

Patients with elevated TIL scores (2 - 3) showed improved PFS as compared with patients with lower scores (0 - 1), with a mean of 215 vs 59 days respectively.

Additionally, patients with any immune-related adverse event prior to disease progression had a longer median PFS as compared with those who didn't; median of 6.5 months vs a median of 2.2 months.

Campbell explained that they also looked at T cells in the peripheral blood to see if any of the T cell subsets were enriched in excellent responders vs poor responders. Mass cytometry by time-of-flight (CyTOF) was performed using peripheral blood, and the analysis showed that patients with a systemic partial response following SBRT had a population of CD8+ CD127- Ki-67+ CD45RO+ T cells that correlated with response.

While PD-L1+ status trended toward increased PFS (6.5 vs 2.4 months) it did not achieve statistical significance. The median overall survival after SBRT was 7.6 months.

The next step will be to validate these findings in a larger population, Campbell explained, and these findings lay the groundwork for a phase 3 randomized trial.

Key Findings

Weighing in on the data, Terence T. Sio, MD, MS, radiation oncologist and assistant professor of radiation oncology at the Mayo Clinic, Phoenix, Arizona, noted that this is very detailed prospective data and that there are several key findings.

"The first is that adding radiotherapy to a group of patients that are progressing on immunotherapy clearly has benefits," he said. "And this study provides a nice baseline for a phase 3 randomized trial."

"The second is that we know now that tumors with infiltrating lymphocytes seem to have a better response in the context of radiotherapy and immunotherapy," Sio continued. "We now see the correlate and this is hypothesis generating and we can take it forward."

Finally, the third key finding is that the authors also confirmed that with CyTOF, there are immunogenic markers that may be present. "The study showed that these were associated with better response, so it is nice to have laboratory data that confirm the findings clinically," Sio told Medscape Medical News. "This is very exciting phase 2 data and we look forward to the full manuscript and publication."

Radiation as Systemic Therapy

Another expert feels that this study adds to the current evidence that suggests radiation therapy can have a systemic effect. "There remains a paucity of prospective data on how we integrate immunotherapy with radiation therapy in lung cancer, so this study is an addition," said Henning Willers, MD, director of the Thoracic Radiation Oncology Program at Massachusetts General Hospital, Boston. "But I think the key value is that it is looking at the systemic effects of radiation therapy, which we still do not understand very well."

He pointed out that in principle, the abscopal effect "sounds amazing and it has been well documented that it can happen in case studies, but in larger cohorts, we really don't know how frequently it happens."

"The response rate they are reporting is 10%, and they are only counting the sites that were not radiated — so they have to be abscopal," he said.

Willers referenced a 2018 study in which radiotherapy was added to ipilimumab (Yervoy, Bristol Myers Squibb) for patients with metastatic NSCLC. One metastatic tumor was irradiated during ipilimumab therapy, and there was an objective response in 18% of the enrolled patients.

The studies were different, but the findings were similar and in the same ballpark, he explained. "And that's the key point, so it does add to the evidence that you can use radiation not only for treating local disease but you can also use it as a systemic tool."

Willers added that in a way, using radiation therapy in this manner is no different than using a single drug in second-, third-, or fourth-line treatment — because often that single drug has a 10% response rate. "The ballpark rate is the same, but we've never thought of radiation like that," he said." And that is the main take-home point from this study."

Campbell, Willers, and Sio have disclosed no relevant financial relationships.

61st Annual Meeting of the American Society for Radiation Oncology (ASTRO): Abstract 74. Presented September 17, 2019.

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