The decision to use adjuvant therapies in patients with renal-cell carcinoma (RCC) should be based on risk, patient goals, and shared decision-making. This topic was explored in a presentation by Matthew Zibelman, MD, Associate Professor, Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, at the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium.
Although pembrolizumab (Keytruda) is a welcome addition to the adjuvant treatment armamentarium for this population of patients, “it’s likely not for everyone,” he told attendees.
KEYNOTE-564 was the first clinical trial to demonstrate a significant improvement in disease-free survival (DFS) with the use of adjuvant immunotherapy in patients with high- and intermediate-risk RCC following nephrectomy or nephrectomy and resection of metastatic lesions, leading to the FDA approval of pembrolizumab for this indication.
However, the overall survival (OS) data from this trial are not mature, and none of the other studies of adjuvant immunotherapy have demonstrated an OS benefit, Dr Zibelman noted.
“How do we advise our patients without this information?” he asked. “The ideal goal of adjuvant therapy is to increase the curative fraction,” but OS is confounded by subsequent therapies, drug access, and other unmeasured effects, whereas DFS directly measures the effect of the experimental treatment compared with the control in the context of the trial.
Assessing Risks and Benefits in the Adjuvant Setting
He offered the following advice when speaking with potential candidates of adjuvant pembrolizumab therapy. “You need to talk about the benefits with the costs. What are the side effects? What are the other downsides associated with this adjuvant therapy and what do they expect to gain from it? Specifically, in RCC, might patients whose cancer recurs on adjuvant therapy be getting undertreated with single-agent immunotherapy, as opposed to the combination therapy that is standard of care for metastatic patients? I think we can all agree it’s complicated,” Dr Zibelman said.
The European Association of Urology guidelines cite the strength of the evidence of adjuvant pembrolizumab in patients with RCC with a risk for recurrence as defined in KEYNOTE-564 as being “weak,” and emphasize informed decision-making with patients.
When attempting to balance risks and benefits, the use of tools to predict disease recurrence and early progression in patients with high-risk, localized, and locally advanced RCC may be beneficial. One such tool, derived from a study conducted at Fox Chase Cancer Center, is a nomogram available for free to both clinicians and patients (cancernomograms.com/nomograms).
Interpreting the Available Clinical Data
Once risk is assessed, the data from the KEYNOTE-564 trial in the setting of other clinical trials that showed no advantage to adjuvant immunotherapy must be interpreted. Pembrolizumab is an anti–PD-1 treatment; the IMmotion010 trial showed no benefit to atezolizumab (Tecentriq), an anti–PD-L1 agent. There was also no benefit with the PD-1 inhibitor nivolumab (Opdivo) in the CM-914 and PROSPER trials, although the 24-month DFS rates obtained with nivolumab were similar to that with pembrolizumab in KEYNOTE-564, “but the control arms seemed to perform slightly differently, suggesting that maybe there are some differences in the populations of these studies,” said Dr Zibelman.
KEYNOTE-564 enrolled more patients with T3/T4 tumors compared with the CM-914, IMmotion010, and PROSPER trials, and the IMmotion010 and PROSPER trials enrolled patients with non–clear-cell RCC. “These patients [with non–clear-cell RCC] may inherently respond less to immune checkpoint inhibition,” he said.
The KEYNOTE-564 and IMmotion010 trial design also differed in enrollment of patients with M1 disease. In KEYNOTE-564, patients had to have either a synchronous metastasis or have metastasized within 1 year of nephrectomy, whereas in IMmotion010, patients had to have metachronous metastatic disease with recurrence occurring more than 12 months following initial nephrectomy. “So, it may be that the KEYNOTE-564 patients were inherently more sensitive and drove some of the early benefit, while patients in IMmotion010 may have had more indolent disease,” Dr Zibelman said.
Future adjuvant trial designs should prioritize the highest-risk patients, said Dr Zibelman, to find the ones most likely to benefit. “Designs that expand eligibility to hasten accrual don’t always lead to faster answers, and they may just lead to more trials.”