Combination Radiotherapy and Immunotherapy Appears Safe and Clinically Active in Advanced Solid Tumors


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Results from the first and largest prospective trial to determine the safety of multisite ablative stereotactic body radiotherapy (SBRT) in combination with anti–programmed cell death protein 1 (anti–PD-1) immunotherapy pembrolizumab (Keytruda) suggest the combination regimen may improve outcomes in patients with advanced solid tumors and multiple metastatic sites.1 According to data presented at the 2018 ASCO-SITC Clinical Immuno-Oncology Symposium, SBRT prior to pembrolizumab treatment was well tolerated, with no radiation dose reductions, and the


There was some intriguing clinical activity with both the irradiated and nonirradiated treatment sites, and we feel this justifies further randomized studies.
— Jeffrey M. Lemons, MD

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overall objective response rate was 13.2% in the 68 patients with imaging follow-up. Moreover, when defined as a 30.0% reduction in any single nonirradiated measurable lesion, the abscopal response was present in 26.9% of patients, the authors noted.

“There was some intriguing clinical activity with both the irradiated and nonirradiated treatment sites, and we feel this justifies further randomized studies,” said Jeffrey M. Lemons, MD, of the Department of Radiation Oncology at the University of Chicago.

As Dr. Lemons reported, previous studies have shown that SBRT can stimulate innate and adaptive immunity to potentially augment immunotherapy.2 Research has also shown that anti–PD-1 treatment outcomes are improved with a lower disease burden, he added, so utilizing ablative radiation to lower that disease burden is an attractive modality.3

“Multisite radiation, which focuses radiation beams to deliver high radiation doses while minimizing radiation exposure to surrounding organs at risk, is an emerging paradigm for eradicating metastatic disease,” said Dr. Lemons. “However, SBRT requires a lot more planning to make sure this approach is safe for patients.”

Study Design

For this phase I study with a radiation dose reduction design, Dr. Lemons and colleagues enrolled patients with metastatic solid tumors whose disease had progressed on standard treatment. All patients had measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) and metastases amenable to SBRT, with 0.25 cc to 65 cc of viable tumor. Metastases greater than 65 cc were partially targeted. Radiation doses were adapted from recently completed National Cancer Institute (NCI) trials, and pembrolizumab (200 mg given intravenously every 3 weeks) was initiated within 7 days after the final SBRT treatment.

As Dr. Lemons reported, 76 patients were treated with SBRT for a total of 151 metastases, and 73 patients went on to receive at least 1 cycle of pembrolizumab. Of these patients, 62 were evaluable for toxicity at 3 months, and 68 patients had at least 1 imaging follow-up.

“This was a heavily pretreated patient population,” said Dr. Lemons, who noted the median number of prior therapies was five.

COMBINATION THERAPY IN SOLID TUMORS

  • In a phase I study, multiorgan site SBRT followed by pembrolizumab was well tolerated, with no radiation dose reductions.
  • The overall objective response rate was 13.2% in heavily pretreated patients with 27 tumor types unselected for PD-L1 expression.
  • Results showed superior control of irradiated lesions, but abscopal (out-of-field) responses were seen in 26.9% of patients.

Primary cancers included ovarian/fallopian tube (12.3%), non–small cell lung (9.6%), breast (8.2%), cholangiocarcinoma (8.2%), and endometrial (8.2%).

Not all sites of disease were targeted, said Dr. Lemons, who noted that 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 in the abdomen/pelvis, 24 were in the liver, with other sites treated less frequently (16 in the bone, 15 in the mediastinal/thoracic region, and 15 in the spine).

Combination Therapy Well Tolerated

After a median-follow up 5.5 months, researchers identified six dose-limiting toxicities, which were defined as grade 3 or higher, related to treatment (excluding asymptomatic biochemical abnormalities) and were determined by the location of metastasis. All six dose-limiting toxicities were grade 3 and included pneumonitis (n = 3), hepatic failure (n = 1), and colitis (n = 2). It is important to note, said Dr. Lemons, there were no SBRT dose reductions.

After determining the treatment was safe, investigators looked at preliminary clinical activity. In the 68 patients with imaging follow-up, the RECIST overall objective response rate was 13.2%. The data also demonstrated superior control of irradiated lesions in the 52 patients with paired data. The mean tumor diameter change was –21.7% for irradiated lesions, compared with 1.7% for nonirradiated lesions (P = .0008).

Although tumor diameter decreased significantly more in irradiated than in nonirradiated lesions, researchers did observe some abscopal effects. When defined as a 30.0% reduction in the aggregate sum of nonirradiated lesions, 13.5% of patients had an abscopal response. A reduction of at least 30.0% in any single nonirradiated lesion, however, was seen in 26.9% of patients. Based on these data, the combination of multiorgan site SBRT followed by pembrolizumab is safe and justifies further randomized studies, the authors concluded. ■

DISCLOSURE: Dr. Lemons reported no conflicts of interest.

REFERENCES

1. Lemons J, Luke JJ, Karrison T, et al: Safety and clinical activity of pembrolizumab and multi-organ site ablative stereotactic body radiotherapy in patients with advanced solid tumors. 2018 ASCO-SITC Clinical Immuno-Oncology Symposium. Abstract 20. Presented January 25, 2018.

2. Weichselbaum RR, Liang H, Deng L, et al: Radiotherapy and immunotherapy: A beneficial liaison? Nat Rev Clin Oncol 14:365-379, 2017.

3. Joseph RW, Elassaiss-Schaap J, Wolchok JD, et al: Baseline tumor size as an independent prognostic factor for overall survival in patients with metastatic melanoma treated with the anti-PD-1 monoclonal antibody MK-3475. 2014 ASCO Annual Meeting. Abstract 3015.


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