SBRT Could Augment Anti–PD-1 Therapy in Patients With Metastatic Disease

SBRT Could Augment Anti–PD-1 Therapy in Patients With Metastatic Disease

Treatment with multisite stereotactic body radiotherapy (SBRT) prior to pembrolizumab treatment may help improve outcomes in patients with advanced solid tumors and multiple metastatic sites, according to a phase I study (Abstract 20). The treatment was generally well tolerated, and abscopal (out of field) responses were seen, suggesting further study is warranted for this treatment paradigm.

Dr. Jeffrey Lemons presents Abstract 20 during General Session 3.
Previous work has shown that SBRT can stimulate both innate and adaptive immunity to potentially augment immunotherapy, Jeffrey M. Lemons, MD, BS, of the University of Chicago, said during General Session 3, “Integrating Immunotherapy Into the Management of Head and Neck Cancers,” on January 25. Response to anti–PD-1 therapy seems to correspond with interferon-gamma, and anti–PD-1 treatment outcomes are improved with lower disease burden, he said.

With SBRT, “we can focus radiation beams to deliver high radiation doses while minimizing [exposure] to surrounding organs at risk,” Dr. Lemons said. He also noted that there is “great interest” in abscopal effects, meaning the effects of radiation on lesions not targeted by the treatment.

The new study included patients with metastatic solid tumors who progressed on standard treatment. All patients had metastases amenable to SBRT, with 0.25 to 65 cc of viable tumor, although patients with larger tumors could be targeted but received only partial targeting with SBRT; two to four metastatic sites were targeted with SBRT, which did not include all sites of disease. SBRT doses varied based on metastatic locations, ranging from 30 Gy in three fractions to 50 Gy in five fractions. Pembrolizumab therapy was initiated 7 days after the final SBRT treatment.

A total of 79 patients enrolled, 76 of whom with 151 total metastases were treated with SBRT; of those, 73 went on to receive pembrolizumab therapy and were considered for this analysis. A total of 68 patients underwent at least one imaging follow-up; most patients were female (60.3%), and the mean age was 62 years. Primary cancers included ovarian/fallopian tube (12.3%), non–small cell lung (9.6%), breast (8.2%), cholangiocarcinoma (8.2%), endometrial (8.2%), and others with fewer patients.

Most patients (94.5%) received SBRT at two sites, whereas three patients (4.1%) had three treated sites and one patient (1.3%) had four treated sites. Of the 151 total treated lesions, 30 were in the peripheral lung, 23 were in the central lung, 28 were abdominal/pelvic, 24 were in the liver, with other sites treated less frequently.

After a median follow-up for toxicity of 5.5 months, six dose-limiting toxicities were seen. All six dose-limiting toxicities were grade 3 adverse events, including three cases of pneumonitis, two of colitis, and one case of hepatic failure. No SBRT dose reductions were required.

Dr. Ravindra Uppaluri discusses Abstract 20 during General Session 3.
The overall objective response rate was 13.5% in the 68 patients who had imaging follow-up. The study showed superior control of irradiated lesions in the 52 patients with paired data; in 36 patients, neither irradiated nor nonirradiated lesions progressed. In one patient, the irradiated lesions progressed but nonirradiated lesions did not, and in 15 patients the opposite was true, with progression seen in the nonirradiated lesions but not in irradiated lesions (p = 0.0005). The mean tumor diameter change was -21.7% for irradiated lesions, compared with 1.7% for nonirradiated lesions (p = 0.0008).

Some abscopal responses were seen, meaning a reduction in lesion size even among nonirradiated sites. A reduction of at least 30.0% in any single nonirradiated lesion was seen in 26.9% of patients, whereas an aggregate sum of nonirradiated lesions showed at least a 30.0% reduction in 13.5% of patients.

“Multiorgan site SBRT followed by pembrolizumab was safe with no radiation dose reductions,” Dr. Lemons said. “This is the first and largest prospective trial to determine the safety of this combination.”

Dr. Lemons noted a few possibilities for the mechanism that may underlie SBRT’s potential augmentation of checkpoint immunotherapy. These included increased tumor antigen release, increased T-cell infiltration, improved antigen presentation or T-cell function, and the modulation of immunosuppressive cell populations such as T-regulatory cells and myeloid-derived suppressor cells. He added that the “intriguing” clinical activity justifies further randomized studies of the combination.

“This is a large, well-done study,” Ravindra Uppaluri, MD, PhD, of the Brigham and Women’s Hospital and Dana-Farber Cancer Institute, who was the discussant for the abstract, said. “I think this is a very exciting area, combining SBRT with immunotherapies.”

He did note that it is difficult from these data to separate out whether the effects seen were because of the combination or from SBRT alone.

In an Evening Highlights session on January 25, Katy K. Tsai, MD, of the University of California, agreed that there is an open question on how much of the effect was because of SBRT, and also said the overall survival curve in the study was promising. With a median overall survival approaching 8 months, she said, this was an important study. She categorized it as “practice-motivating data, or what I call ‘food for thought.’”

–Dave Levitan