麻豆传媒

Prior to the at last year's American Society of Clinical Oncology meeting, adjuvant treatment for patients with advanced renal cell carcinoma (RCC) was limited.

The only treatment with FDA as an adjuvant therapy in this patient population was sunitinib (Sutent), which had gained approval based on results of the S-TRAC trial showing improved disease-free survival among patients treated with sunitinib compared with placebo (HR 0.76, 95% CI 0.59-0.98, P=0.03).

"S-TRAC looked at the highest-risk clear-cell RCC patients and did show disease-free survival benefit, but not overall survival benefit," said Naomi Haas, MD, of Perelman School of Medicine at the University of Pennsylvania in Philadelphia.

She said that despite sunitinib's approval, the majority of these patients decided to forgo sunitinib in favor of observation. The lack of uptake of sunitinib was likely due in part to the lack of an overall survival benefit. She added that the other factor that may have affected uptake was that the was the only study out of five testing vascular endothelial growth factor (VEGF) receptor inhibitors as adjuvant therapy for kidney cancer – i.e., S-TRAC, , , , and -- that showed a benefit.

"About 60% of patients on trials looking at adjuvant therapies had pretty significant toxicities, causing a lot of discontinuation," Haas said. "S-TRAC improved disease-free survival by a year, so patients had to decide whether to spend a year getting side effects or take their chances with surveillance."

The phase III KEYNOTE-564 study found that adjuvant pembrolizumab (Keytruda) significantly improved disease-free survival compared with placebo in patients with intermediate-high or high-risk RCC (HR 0.68, 95% CI 0.53-0.87).

"While the overall survival data are still immature, the safety profile was well tolerated," said Rana McKay, MD, of the University of California San Diego. "In light of these data, adjuvant pembrolizumab is definitely being offered to patients in the clinic."

Haas has also begun offering adjuvant pembrolizumab to certain patients in her practice, she noted. "We are discussing it on a case-by-case basis. We discuss it with patients that have pT2 high-grade or pT3 disease, those who are node-positive, or who have had recent metastasectomy."

McKay agreed that not all patients will be good candidates for adjuvant pembrolizumab. If clinicians think of the two extremes, adjuvant therapy of any kind is likely undertreating the highest-risk patients and overtreating the lowest-risk patients, she said.

"With adjuvant therapy, by definition, you are going to overtreat patients. There is always a certain risk for recurrence, but on the other side there is a certain likelihood that a portion of patients will be cured without additional treatment," McKay said.

Part of the problem is that there are currently no good biomarkers to guide the selection of therapy.

"There are a lot of really interesting markers in development, like methylated ct[circulating tumor]DNA, but none that are ready for use in clinical practice," she explained. "The best thing to guide therapy is AJCC [American Joint Committee on Cancer] staging, tumor grade, and other risk nomograms that incorporate clinical parameters, performance status, and some routine laboratory parameters are sometimes used."

In addition to better biomarkers, there are several other remaining questions related to clinical application of adjuvant therapy.

One involves the duration of adjuvant treatment: "The 1-year duration is arbitrary and based off of what was used in trials of adjuvant VEGF receptor inhibitor trials," Haas noted.

Other ongoing trials are looking at different durations of therapy. For example, the trial will look at the use of ipilimumab (Yervoy) plus nivolumab (Opdivo) or nivolumab alone for a 6-month duration. Another question involves the use of adjuvant therapy in variant-histology RCC.

"That testing still needs to be done despite the FDA's blanket approval of pembrolizumab," Haas said. "Studies need to be done in patients with variant histology."

Additionally, clinicians still face a challenge when deciding on which therapy to employ if disease progresses after receipt of adjuvant immune checkpoint blockade.

McKay said the timing of progression definitely impacts clinical decision-making, though prospective data are lacking on the optimal strategy.

"If progression occurs while the patient is actively receiving immunotherapy, that is a very different picture than if someone develops disease recurrence after completing treatment," McKay said. "If they progressed on treatment, I would be hard pressed to continue to challenge them with immunotherapy, but if they are several years out I could envision immunotherapy rechallenge, though we currently don't have prospective data to guide clinical decision-making on either of these strategies."

If not immunotherapy, there are multiple other options such as an immune checkpoint inhibitor in combination with a VEGF inhibitor, combination ipilimumab/nivolumab, or a VEGF inhibitor alone, she added. "Which is best is what industry and cooperative groups are trying to figure out."

In addition to waiting for the final overall survival results from KEYNOTE-564, observers are also looking to the results of several ongoing clinical trials to better inform the use of adjuvant therapy.

For example, in addition to the CheckMate 914, the is evaluating adjuvant atezolizumab (Tecentriq) versus placebo in high-risk RCC. And, McKay noted, the , which was evaluating neoadjuvant and adjuvant nivolumab compared with nephrectomy alone was recently stopped for futility (although the results have not yet become available). In addition, the will evaluate adjuvant checkpoint inhibitors in patients with clear-cell and non-clear cell histology.

Until then, McKay said, clinicians will have to continue to consider whether or not to use adjuvant pembrolizumab on a case-by-case basis.

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