Nivolumab/SBRT Data Leave Role of Radiation Unclear in RCC

Stereotactic body radiotherapy (SBRT) combined with nivolumab (Opdivo) was associated with “high” disease control and overall survival (OS) rates in a phase II study of pretreated patients with metastatic renal cell carcinoma (RCC); however, the combination did not meet the primary endpoint of overall response rate (ORR).¹

Data presented at the 2020 Genitourinary Cancers Symposium showed that in the single-arm, multicenter NIVES study, the objective response rate (ORR) of the SRBT/nivolumab combination was 17.4% in the intent-to-treat (ITT) analysis and 19.0% in the per protocol analysis,¹ which fell short of the hypothesized rate of 40% on ITT analysis. Among the 69 patients enrolled, there was 1 complete response and 11 partial responses. Stable disease was the best response in 28 patients, for a disease control rate of 58.0% (40 of 69) on ITT analysis.

The median duration of response was 9.7 months, with 9 of the 12 responses ongoing. Six patients have ongoing stable disease.

The median progression-free survival (PFS) was 4.1 months (95% CI, 2.8-7.1), with a 12-month PFS rate of 32.6% (95% CI, 21.0%-44.6%). Median OS was 22.07 months (95% CI, 18.1-not reached), with a 12-month OS rate of 73.4% (95% CI, 60.6%-82.6%).

The investigators were looking to improve upon the dismal prognosis of metastatic RCC, which carries a 5-year survival rate of only about 10%. SBRT is a focused radiation therapy thought to effectively kill tumor cells while minimizing damage to adjacent healthy tissue and enhancing antitumor immune responses, said lead investigator Cristina Masini, MD, from the Medical Oncology unit, Clinical Cancer Centre, Azienda Unit Sanitaria Locale di Reggio Emilia—Instituto di Ricovero e Cura Carattere Scientifico, Reggio Emilia, Italy. “Several preclinical studies have documented an increase in peripheral antitumor immunity with an increased tumor antigen release, improved antigen presentation, and T-cell infiltration in the irradiated tumor,” she said.

Tumor PD-L1 expression can also be induced by radiation; inhibition of the PD-1/PD-L1 axis with nivolumab has been shown to improve antitumor immunity by blocking tumor-mediated suppression of cytotoxic T cells. In addition, radiation may have an abscopal effect on metastases.

On the trial, eligible patients had progressive disease after ≤2 prior antiangiogenic therapies and measurable metastatic sites with at least 1 suitable for SBRT.

Patients received hypofractionated radiation in 1 tumor at a dose of 10 Gy × 3 fractions, started 7 days after the first infusion of nivolumab. Nivolumab was given as a fixed dose of 240 mg on day 1 of every 14 days for 6 months. In responding patients, the nivolumab dosage was then increased to 480 mg every 4 weeks until progressive disease or unacceptable toxicity.

A total of 69 patients were treated with at least 1 dose of nivolumab, 2 of whom didn’t receive SBRT and 4 of whom did not complete the first cycle of treatment. Twelve centers in Italy participated in the study.

Histology was clear cell in 79.7% of patients and non—clear cell in 14.5%, with unknown histology in 5.8%. Some 82.6% of patients enrolled were male. Median age at therapy initiation was 67 years (range, 43-85). The International Metastatic RCC Database Consortium risk score was intermediate in 68.1%, good in 20.3%, and poor in 11.6%. More than half of patients (50.7%) had ≥3 metastatic sites and 33.4% had 2 metastatic sites. In total, 56 patients (81.2%) received nivolumab as second-line therapy and 13 (18.8%) received it in the third line. The most common first-line therapy was sunitinib (65.2%). About three-fourths of those included on the study (76.9%) had prior nephrectomy.

The most frequent sites of SBRT were lung (37.7%), lymph nodes (11.6%), and bone (11.6%). At the time of this analysis and with a median follow-up of 15 months (range, 0-25.6), the median number of nivolumab doses received was 12 (range, 1-32). Fifty-four patients (78.3%) discontinued treatment, most often due to disease progression (55.2%).

When sites of metastases were stratified by whether they received SRBT, the ORR was 26.9% in irradiated sites and 17.4% in nonirradiated sites. Masini said what was “interesting was the very high disease control rate in the irradiated metastases, 82%, whereas in the past, metastatic kidney cancer has been considered resistant to therapy,” said Masini. The disease control rate in nonirradiated sites was 59.4%.

The ORR was significantly higher in patients with clear cell versus non—clear cell histology (20.4% vs 0%; P = .01).

Grade 3/4 toxicities related to nivolumab were experienced by 17 patients (24.6%), with the most frequent events being diarrhea (5.8%), an increase in amylase/lipase (4.3%), and fatigue (4.3%). Six patients (8.7%) were hospitalized due to treatment-related serious adverse events.

Analysis of the correlation between efficacy with PD-L1 expression and molecular alterations in tumor tissue samples as well as in circulating tumor DNA is ongoing, she said.

Randomized perioperative trials of radiation therapy for kidney cancer have been negative, but SBRT is a different approach that “has established a footprint in renal cancer,” although the data to support it are weak, said discussant Thomas Powles, MD, director of Barts Cancer Center in London, United Kingdom. “If this was a drug, we probably wouldn’t be using SBRT the same way as we are now. The robustness of the data in renal cancer is not there.”

The median PFS in NIVES is not much different from the 4.6-month median PFS in the CheckMate-025 study with nivolumab alone, he pointed out.²

The immunogenic effect of SBRT may be different in kidney cancer and other tumor types in which it has shown efficacy, such as in lung and bladder cancer, said Powles.

“We are in an era where I think we are keen to believe that this [the effect of radiotherapy on the immune cycle] exists, but that doesn’t mean that we should be adopting it just because we can give radiation therapy and SBRT,” he said. “Just because we can do it, doesn’t mean we should be doing it without robust data.”

References

1. Masini C, Iotti C, De Giorgi U, et al. Nivolumab (NIVO) in combination with stereotactic body radiotherapy (SBRT) in pretreated patients (pts) with metastatic renal cell carcinoma (mRCC): First results of phase II NIVES study. J Clin Oncol. 2020;38(suppl 6;abstr 613). doi: 10.1200/JCO.2020.38.suppl_6.613.
2. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813. doi: 10.1056/NEJMoa1510665.