San Francisco, CA—Although there is a biological rationale that supports the “abscopal” effects of radiation therapy plus checkpoint immunotherapy in fighting cancer, this combination showed mixed results and no robust effects in patients with metastatic renal-cell carcinoma (RCC), according to results of 2 preliminary studies presented at the 2020 Genitourinary Cancers Symposium.
The first study showed that although the combination of nivolumab (Opdivo) plus stereotactic body radiotherapy (SBRT) failed to meet the primary end point of objective response rate (ORR), it led to a high rate of disease control and a median overall survival (OS) of almost 2 years. A second study using 2 checkpoint inhibitors—nivolumab and ipilimumab (Yervoy)—plus SBRT achieved objective responses in most of the patients, but this was a very small study of only 25 patients.
Nivolumab plus SBRT
The NIVES study was a phase 2 multicenter clinical trial that enrolled 79 patients at 12 centers in Italy with metastatic RCC that progressed during 1 or 2 systemic therapies. Nivolumab was given in a flat dose every 2 weeks for 6 months. SBRT was given at 10 Gy × 3 fractions 7 days after the first infusion of nivolumab. Responding patients, including those with stable disease, continued to receive nivolumab 480 mg every 4 weeks until disease progression or unacceptable toxicity. A total of 68 patients were evaluable for response.
“This is the first prospective trial of nivolumab plus SBRT in metastatic RCC. The study showed acceptable safety but did not reach the primary end point. Correlative studies will give us more information. It may be that different timing of SBRT would work better,” stated lead investigator Cristina Masini, MD, Medical Oncology Unit, Clinical Cancer Centre, AUSL-IRCCS di Reggio Emilia, Italy.
At baseline, the median patient age was 67 years; 15% did not have clear-cell histology; 80% had intermediate to poor risk; 50% had ≥3 metastatic sites; and 76% had undergone nephrectomy.
At a median follow-up of 15 months, the primary end point of improved response rate to 40% was not met. Among the 68 patients, the ORR in an intent-to-treat analysis was 17.4% (12), including 1 complete response. An additional 40.6% (28) of patients had stable disease, for a disease control rate of 58%. At this early time point, the estimated median OS was 22 months and the 12-month OS rate was 73.4%.
The safety and tolerability were generally acceptable. The most common grade 3 or 4 adverse events were diarrhea (5.8%), elevated amylase/lipase (4.3%), fatigue (4.3%), rash (2.9%), and hematologic toxicity (2.9%).
Dual Checkpoint Inhibitor plus SBRT
The second study, called RADVAX, was presented by lead investigator of the RADVAX study, Hans J. Hammers, MD, PhD, Co-Leader, Clinical Research, Kidney Cancer Program, UT Southwestern Medical Center, Dallas, TX.
“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,” stated Dr Hammers.
“We designed a small stringent exploratory trial [in metastatic RCC]. We learned later that radiation induces antigen release but can induce the immune response. The way we radiate may play a role in induction of this pathway,” he told the audience.
A total of 25 patients received a total dose of 50 Gy in 5 fractions. During the induction phase, patients received treatment with nivolumab plus ipilimumab, and radiation was delivered after the first dose. In the maintenance phase, patients received nivolumab monotherapy every 2 weeks, which was amended to every 4 weeks. Treatment beyond disease progression was allowed if patients appeared to benefit. Imaging was performed at 6-week intervals to evaluate response.
All enrolled patients had clear-cell histology and at least 2 metastatic lesions. Patients were predominantly male; 92% had intermediate to poor risk; 68% had previous nephrectomy; and 44% had ≥3 metastatic sites of disease.
The primary tumor was not targeted with radiation in this study. The vast majority (56%) of patients had radiation to the lung, followed by lymph nodes (50%), bone or soft tissue (12%), and kidney (12%).
The ORR was 56% (14 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 (6 patients each), elevated liver enzymes (4 patients), and diarrhea and colitis (1 patient each). Immune-related adverse events were reported in 10 patients, 7 of whom required additional immunosuppressive therapy.
According to Dr Hammers, “This combination warrants further investigation.” He acknowledged that a small single-site study has limitations, but noted that the treatment template should be used for future prospective trials, suggesting that future trials target radiation to the whole tumor.
Discussant Opinion Differs
Discussant Thomas Powles, MD, MBBS, MRCP, Director, Barts Cancer Centre, London, England, noted that neither trial provides hard evidence of a benefit for the combination versus immunotherapy alone.
“The abscopal effects remain controversial, and there will be people who disagree with some of the things I’ve said, although it’s hard to disagree with the data which I presented. In this work, the null hypothesis has not been rejected. That’s an English way of saying it didn’t work very well,” Dr Powles told listeners.
“If the combination of SBRT and checkpoint inhibitor were a new drug combination, would we keep going with development? I suspect that the answer is probably ‘no.’ The robustness of evidence is not there,” Dr Powles stated.