Pembrolizumab Investigated as Adjuvant RCC Therapy

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.

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

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.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.

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

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]. 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.

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

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

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.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.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.

What do you believe to be the biggest advancement in kidney cancer this year?

Therefore, there are multiple ongoing phase III combination trials with VEGF and immunotherapy. Some have completely enrolled, and we are awaiting the final results and follow-up for these patients while others are still ongoing. In the setting of the ipilimumab (Yervoy)/nivolumab (Opdivo) data coming out from CheckMate-214 earlier this year at the 2017 ESMO Congress, the ongoing studies may have trouble enrolling patients and randomizing them to sunitinib as the standard-of-care treatment arm.In 2017 in RCC, the major breakthrough was the report of the CheckMate-214 study. The study randomized patients to the combination of nivolumab and ipilimumab for 4 doses, followed by nivolumab maintenance versus standard-of-care sunitinib. It showed that, in metastatic patients with intermediate- and poor-risk disease, the combination improved OS. The median OS was not yet reached at the time of report at [the meeting]. In addition, it numerically extended progression-free survival by about 3 months, but it did not reach statistical significance…We look forward to hearing further results as the OS endpoint matures, but the landscape is certainly changing for first-line treatment of [patients with] metastatic RCC based on these data.

Importantly, the study showed a complete response (CR) rate of 9% for patients with intermediate- and poor-risk disease in the metastatic setting. We haven't seen this type of CR rate since the era of interleukin-2 studies. This is a promising area of creating durable, lasting responses for our patients, and we are really excited about the opportunities that immunotherapy—particularly the combination of nivolumab plus ipilimumab—affords.

There may be patients who develop treatment resistance at some point, so there are always opportunities to improve upon these response rates. We are currently proposing further studies to build upon the results of CheckMate-214.