Despite recent enthusiasm for combining stereotactic body radiation therapy with immunotherapy in renal cell carcinoma, two preliminary studies presented at the 2020 Genitourinary Cancers Symposium suggest that it may not be the best path forward.

In one study, the combination of nivolumab plus stereotactic body radiation therapy did not meet the overall primary endpoint of objective response, although it led to a high rate of disease control and a median overall survival of almost 2 years.¹ A second study using two different checkpoint inhibitors—nivolumab and ipilimumab—plus stereotactic body radiation therapy led to objective responses in a majority of patients, but the study was small (25 patients).²

Thomas Powles, MD, PhD

Neither study demonstrated that adding stereotactic body radiation therapy improved outcomes compared with immunotherapy alone, and hard evidence of an “abscopal” effect of radiation therapy was lacking, according to the formal discussant of these trials, Thomas Powles, MD, PhD, of Barts Cancer Institute, London.

“The abscopal effects remain controversial,” Dr. Powles told listeners. “In this work, the null hypothesis has not been rejected. That’s an English way of saying it didn’t work very well,” he added.

NIVES Study Details

The NIVES study sought to study the effects of combining nivolumab with stereotactic body radiation therapy in advanced renal cell carcinoma, based on preclinical studies and clinical studies suggesting that radiation may help to activate the immune response when added to immunotherapy. The hypothesis was that the combination of stereotactic body radiation therapy plus a checkpoint inhibitor (in this case, nivolumab) could enhance antitumor activity and improve responses.

“Two published studies suggested synergy with radiation plus immunotherapy. The safety, efficacy, and ideal timing of concurrent radiotherapy with immune checkpoint inhibitors represent an unmet clinical need,” stated lead author Cristina Masini, MD, of the Clinical Cancer Center, Reggio Emilia, Italy.

NIVES is a phase II multicenter trial that enrolled patients with metastatic renal cell carcinoma that progressed on up to two prior systemic therapies. Nivolumab was given in a flat dose every 2 weeks for 6 months. Stereotactic body radiation therapy was given at 10 Gy x 3 fractions 7 days after the first infusion of nivolumab. Responding patients, including those with stable disease, continued on nivolumab at 480 mg every 4 weeks until progressive disease or unacceptable toxicity.

Cristina Masini, MD

A total of 79 patients were enrolled at 12 centers in Italy, and 68 were evaluable for response. A total of 19 patients received at least a single dose of nivolumab, and 67 patients received the full dose of stereotactic body radiation therapy. At baseline, the median age of study patients was 67 years; 15% did not have clear cell histology; 80% had intermediate/poor-risk disease, and 50% had three or more metastatic sites; 76% had undergone nephrectomy.

Primary Endpoint Not Met

At a median follow-up of 15 months, the primary endpoint of improving response rate to 40% was not met. The objective response rate in an intent-to-treat analysis was 17.4% (12 of 68 patients) and included one complete response. An additional 28
patients (40.6%) had stable disease, for a disease control rate of 58%. At this early time point, the estimated median overall survival was 22 months, and the 12-month survival rate was 73.4%.

Tolerability was generally acceptable. The most common grade 3 or 4 adverse events were diarrhea (5.8%), elevated amylase/lipase levels (4.3%), fatigue (4.3%), rash (2.9%), and hematologic toxicity (2.9%).

“This is the first prospective trial of nivolumab plus stereotactic body radiation therapy in metastatic renal cell carcinoma. The study showed acceptable safety but did not reach the primary endpoint. Correlative studies will give us more information,” Dr. Masini said. “It may be that different timing of stereotactic body radiation therapy would work better.”

RADVAX Trial Details

RADVAX was a small, single-center study designed to evaluate dual checkpoint inhibition with stereotactic body radiation therapy in advanced renal cell carcinoma.

“There is a romance with the thought of combining radiotherapy and immunotherapy, but so far, the romance has been elusive in humans. The most pronounced effects have been in mouse models,” said lead author Hans J. Hammers, MD, PhD, of UT Southwestern Medical Center, Dallas.

“There is a romance with the thought of combining radiotherapy and immunotherapy, but so far, the romance has been elusive in humans.”

— Hans J. Hammers, MD, PhD

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“We designed a small stringent exploratory trial. Radiation induces antigen release but can also stimulate the immune response through the STING pathway. The way we radiate may play a role in induction of this pathway,” he told the audience.

Patients (n = 25) received a total dose of 50 Gy in five fractions. During the induction phase, patients received dual checkpoint blockade with nivolumab/ipilimumab, and radiation was delivered after the first dose. In the maintenance phase, patients received nivolumab monotherapy. Treatment beyond disease progression was allowed if patients obtained a benefit. Imaging was performed at 6-week intervals to assess response. Importantly, irradiated lesions that typically shrank and did not progress were not allowed as target lesions.

All enrolled patients had clear cell histology and at least two metastatic lesions. All patients completed at least one dose of checkpoint inhibitor therapy and stereotactic body radiation therapy as planned. Prior treatment with tyrosine kinase inhibitor was allowed.

Patients were predominantly male, 92% had intermediate/poor-risk disease, 68% had prior nephrectomy, and 44% had three or more metastatic sites of disease. The vast majority (56%) had received radiation therapy to the lungs, followed by lymph nodes (50%), bone/soft tissue (12%), and kidneys (12%).

Key Findings

The objective response rate was 56% (14 of 25 patients, all partial responses), and 6 additional patients had stable disease, for a disease control rate of 68%.

The most common adverse events were fatigue (100%) and diarrhea (56%). The most common grade 3 or 4 adverse events were increased amylase and lipase levels (six patients each), elevated liver enzyme levels (four patients), and diarrhea and colitis (one patient each). Immune-related adverse events requiring high-dose prednisone were reported in 10 patients (3 cases of colitis/diarrhea, 4 cases of pneumonitis, 2 cases of arthritis, and 1 each of hepatitis, pancreatitis, nephritis, and hypophysitis). Seven of these patients required additional immunosuppressive therapy.

“Our observed response rate was higher than the expected response rate, which is around 40%. This particular combination warrants further investigation,” Dr. Hammers said. He acknowledged that a small, single-site study has limitations, but the treatment template should be used for future prospective trials. He suggested a future trial design that determines programmed cell death ligand 1 (PD-L1) expression levels using ImmunoPET and then targets radiation to the coldest, least inflamed tumors. 

Expert Point of View

Although Dr. Powles, formal discussant of the NIVES and RADVAX trials, applauded the effort to do these clinical trials, he was basically unconvinced that further studies exploring the abscopal effects of radiation and immunotherapy should be done in renal cell carcinoma. “Investigator-initiated trials are difficult to do,” he told the audience. “We have gone as far as we could with in vitro studies. These [clinical] trials are timely. Weighing all the evidence, the abscopal effect of radiation remains controversial alone and in combination with immune therapy. Kidney cancer is different from other cancers, and you can’t extrapolate from studies in other cancers, such as melanoma.”

Dr. Powles did acknowledge the rationale for combining these therapies. “In animal studies, when you radiate one cancer site, the other cancer sites improve in some of the experiments,” he noted. “However, renal cell carcinoma cell lines are more resistant to radiation than some other cancers. Clinically, radiotherapy at standard doses are not effective in kidney cancer. The immunogenic effects of stereotactic body radiation therapy will be different in kidney cancer from melanoma, where the data are more promising for the abscopal effect. We need to do the kidney cancer trials, and that’s why I’m glad to see these two abstracts.”

Dr. Powles’ take-away message from these two clinical trials follows: “If the combination of stereotactic body radiation therapy and checkpoint inhibitor were a new drug combination, would we keep going with development? I suspect the answer is probably no. The robustness of evidence is not there.”

He added, “Regarding future trials, I suggest that those dependent on the abscopal effect require careful consideration before proceeding, as neither of these studies met their efficacy endpoints.

DISCLOSURE: The NIVES trial was funded by the Gruppo Oncologico Italiano di Ricerca Clinica, Pharmaceutical/Biotech Company. Bristol-Myers Squibb provided the drugs for RADVAX, and the study was funded by KidneyCAN. Dr. Powles has received honoraria from AstraZeneca, Bristol-Myers Squibb, Ferring, GLG Group, Janssen Research & Development, Merck, Novartis, Pfizer, Roche/Genentech, and Seattle Genetics/Astellas; has served as a consultant or advisor to AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Incyte, Ipsen, Merck, Novartis, Pfizer, and Seattle Genetics; has received research funding from AstraZeneca/MedImmune and Roche/Genentech; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca, Bristol-Myers Squibb, Ferring MSD, Novartis/Ipsen, Pfizer, Research to Practice, and Roche/Genentech. Dr. Masini reported no conflicts of interest. Dr. Hammers has received honoraria from Bristol-Myers Squibb; has served as a consultant or advisor to Armo BioSciences, Bayer, Bristol-Myers Squibb, Corvus Pharmaceuticals, Exelixis, Merck, Novartis, and Pfizer; has received institutional research funding from ­Bristol-Myers Squibb and Merck; and has been reimbursed for travel, accommodations, or other expenses by Bristol-Myers Squibb, Lilly, Merck, Novartis, and Pfizer.

REFERENCES

1. Masini C, Iotti C, De Giorgi U, et al: Nivolumab in combination with stereotactic body radiotherapy in pretreated patients with metastatic renal cell carcinoma: First results of the phase II NIVES study. 2020 Genitourinary Cancers Symposium. Abstract 613. Presented February 15, 2020.

2. Hammers HJ, Vonmerveldt D, Ahn C, et al: Combination of dual immune checkpoint inhibition with stereotactic radiation in metastatic renal cell carcinoma. 2020 Genitourinary Cancers Symposium. Abstract 614. Presented February 15, 2020.