Further investigation of combined immunotherapy, SBRT may be warranted for mRCC
medwireNews: Findings from two phase 2 trials presented at the 2020 Genitourinary Cancers Symposium in San Francisco, California, USA, suggest that combining immune checkpoint inhibition with stereotactic body radiotherapy (SBRT) is feasible in patients with metastatic renal cell carcinoma (mRCC).
The first study, NIVES, included 69 immunotherapy-naïve patients (82.6% male) with clear-cell or non-clear-cell mRCC and progressive disease despite up to two previous lines of anti-angiogenic therapy.
Presenting author Cristina Masini (AUSL-IRCCS di Reggio Emilia, Italy) explained that participants all received nivolumab at a dose of 240 mg every 14 days for 6 months, along with SBRT comprising three fractions of 10 Gy starting 7 days after the first nivolumab infusion, followed by nivolumab 480 mg every 4 weeks in responding patients until progression or unacceptable toxicity. The most common site for SBRT was lung (37.7%), followed by lymph nodes (11.6%) and bone (11.6%).
Over a median follow-up of 15 months, the objective response rate (ORR) in the intention-to-treat analysis was 17.4%, with a complete response rate of 1.4% and a disease control rate (DCR) of 58.0%.
Masini said that this DCR was “high,” particularly for irradiated metastases, with an ORR of 26.9% and a DCR of 82.0%. However, she noted that the primary study endpoint was not met, based on the trial hypothesis “that treatment with nivolumab plus SBRT compared to treatment with nivolumab is able to improve the ORR from 25% to 40%.” The ORR of 25% with nivolumab was reported previously in the CheckMate 025 trial of the PD-1 inhibitor versus everolimus in patients with advanced RCC.
In survival analyses, the median duration of progression-free survival (PFS) was 4.10 months and the median duration of overall survival (OS) was 22.07 months. One-year PFS and OS rates were 32.6% and 73.4%, respectively.
The presenter said that the combination had an “acceptable safety profile,” with 24.6% of participants experiencing grade 3–4 treatment-related adverse events (TRAEs), all of which were outside the irradiated area.
In the second study, RADVAX RCC, Hans Hammers (University of Texas Southwestern Medical Center, Dallas, USA) and co-investigators evaluated the combination of dual immune checkpoint inhibition with nivolumab and ipilimumab plus SBRT in patients with either clear-cell mRCC or mRCC with a clear-cell component. Most (92%) of the participants were men, 68% had undergone prior nephrectomy, and the most common site for SBRT was lung (56%).
Hammers reported that the ORR was 56% during a median follow-up of 24 months for the 25 participants treated with nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks followed by nivolumab monotherapy, with SBRT administered to 1–2 disease sites at a dose of 50 Gy given in five fractions between the first and second cycles of nivolumab–ipilimumab.
Median PFS was 8.21 months and the 1-year PFS rate was 36%, whereas the median OS and duration of response were not reached at the time of data presentation.
Hammers said that overall, the safety profile of the combination treatment in RADVAX RCC was “very similar to what you would see with nivolumab exposure.” A total of 36% of participants experienced grade 3–4 TRAEs, and radiation pneumonitis was reported in two individuals.
The RADVAX RCC results suggest that “the combination of SBRT with dual immune checkpoint inhibition is feasible and associated with an acceptable safety profile,” and the “encouraging antitumor activity” warrants further investigation, concluded Hammers.
And he told medwireNews that although the study was limited by small patient numbers “we are excited and we will move this forward.”
Commenting on the results of NIVES and RADVAX RCC, discussant Thomas Powles (Barts Cancer Institute, London, UK) said that although the trials were worthwhile and timely, the median PFS rates were not higher than those reported previously for nivolumab and nivolumab–ipilimumab without SBRT in the CheckMate 025 and CheckMate 214 trials, respectively.
“The question I put to you […] is that if this was a drug, would we be taking it further in randomized trials, and I suspect the answer to that is probably no,” he added.
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This independent news story was supported by an educational grant from Pfizer and Merck KGaA