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Pembrolizumab Investigated as Adjuvant RCC Therapy

Angelica Welch
Published: Monday, Dec 18, 2017

Tian Zhang, MD
Tian Zhang, MD
Immunotherapy has had a major impact on the treatment landscape of renal cell carcinoma (RCC) in 2017. With the intriguing findings of the phase III CheckMate-214 trial, physicians are apt to investigate immunotherapy agents in different settings of this disease.

Currently, the phase III KEYNOTE-564 trial is evaluating pembrolizumab (Keytruda) in the adjuvant setting (NCT03142334). This study is evaluating disease-free survival (DFS) in high-risk patients with RCC post-nephrectomy and is currently enrolling.

In an interview with OncLive, KEYNOTE-564 lead investigator Tian Zhang, MD, assistant professor of medicine, Duke University School of Medicine, Duke Cancer Institute, discussed this phase III study, as well as the progress that immunotherapy has made in the treatment paradigm of patients with RCC.

OncLive: Please provide an overview of the KEYNOTE-564 trial.

Zhang: This is a trial in progress of an adjuvant [therapy] in RCC. We just started accruing patients earlier this year. This study is one of a few aimed at improving adjuvant treatment for [patients with] kidney cancer. The study randomizes patients to either pembrolizumab alone or placebo.

We also have to mention that there has been a recent approval of sunitinib (Sutent) from the FDA in the adjuvant setting. Sunitinib was shown to delay disease recurrence, so it extends DFS, but it does not improve overall survival (OS). There has been a lot of debate about whether the sunitinib approval in the space will lead to delays in accrual for these adjuvant trials. Given that there is some controversy about the benefit, as well as the toxicities associated with sunitinib treatment, we are hoping that enrollment will not be delayed for these adjuvant immunotherapy trials.

Back to KEYNOTE-564—this trial is really looking at DFS as its primary endpoint. We are aimed at enrolling high-risk patients with high-risk features—so pathologic stage T2 with grade 4 features or higher, or pathologic stage T3 or T4 with any grade features—or any nodal metastases at the time of surgery. In addition, this trial will also enroll patients who have had oligometastatic disease, have had metastasectomies, and otherwise have no evidence of disease at time of enrollment. This is a unique feature of KEYNOTE-564, and we think we will accrue a good number of patients. Patients will be stratified for having metastatic disease, as well as based on their tumor staging.

We are targeting an enrollment of 950 patients worldwide; the study is already open in the United States, as well as multiple sites in Asia, Europe, and Australia. I would certainly encourage anyone out there to refer their patients post-nephrectomy. This study recommends referral and enrollment within 3 months of their resection, so we really want to capture those patients within [that time frame]. 

Is it just the high-risk metastatic population who is predicted to benefit from adjuvant therapy?

We know that most patients with these higher-risk features will recur with metastatic disease within the first 1 to 2 years of their surgeries, and over a longer period of time we perform surveillance for these patients through years 3, 4, and 5. Certainly kidney cancer can recur during those first 5 years, and so we think that the high-risk features will delineate patients who are more likely to recur with their disease early on. Therefore, they may benefit from having more treatment upfront in the disease-free setting. 

In particular, immunotherapies represent a unique advantage for these patients because they are so well tolerated. Most patients will not experience as many adverse effects as, for example, those treated with sunitinib.

What would you say to a community oncologist who may be apprehensive about putting their patient on an adjuvant trial?

I would say that, in this space where we don't know what is best for these patients—and in a space where we do not have a standard-of-care treatment—any trial looking at a potential intervention that might improve time to disease recurrence may be beneficial. I would encourage a community urologist, oncologist, or primary care physician to really think about these adjuvant trials in the setting following resection. This represents a unique opportunity to improve upon standard surveillance and delineate the population of patients who may benefit from adjuvant immunotherapies.

In kidney cancer overall, what have the challenges been with implementing immunotherapy?

Most of these patients have been enrolled in the metastatic setting. In general, patients have tolerated immunotherapies well, so toxicities aren't necessarily a challenge. In terms of our current ongoing phase III trials with immunotherapies, these are mostly paired with VEGF inhibitors and are randomized against sunitinib in the first-line setting.

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