The Future of Adjuvant Immunotherapy in RCC

The use of adjuvant immunotherapy has been found to improve overall survival (OS) in patients with renal cell carcinoma (RCC), which has a high disease recurrence. One issue is with immunotherapy, however, is that it is scarcely used in the adjuvant setting.

Pembrolizumab (Keytruda) was approved by the FDA for adjuvant use in RCC with an intermediate-high or high-risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions in mid-November. The approval was based on results of the KEYNOTE-564 study (NCT03142334).

At a data cutoff of 24.1 months, the disease-free survival in the pembrolizumab arm was 77.8% compared with 68.1% in the placebo arm (HR, 0.68; 95% CI, 0.53-0.87; P =.002). Adjuvant pembrolizumab was associated with a 32% reduction in the risk of disease recurrence or death compared with the placebo.

Rana R. McKay, MD, a medical oncologist and associate professor of Medicine at the University of California San Diego Health, discussed the implications of the KEYNOTE-564 study along with the future of adjuvant immunotherapy in RCC, in an interview with Targeted Oncology^TM.

TARGETED ONCOLOGYTM: What is the promise of adjuvant immunotherapy and renal cell carcinoma?

MCKAY: Renal cell carcinoma is a common malignancy in both men and women. While the majority of patients present with localized disease and are cured with curative intent surgery, a subset of those patients goes on to develop disease recurrence. With regards to adjuvant therapies that can decrease the likelihood of the cancer spreading and improving overall survival, there's really been a paucity of agents that have been able to be used in the adjuvant setting. 

In the cytokine era, there was a series of trials that were conducted testing various cytokines in the adjuvant space, all of which were negative. In the targeted therapy era, given the advancements of TKI's for people with advanced disease, these agents were tested in the adjuvant setting through a series of clinical trials, most notably the ASSURE trial (NCT00326898) and the S-TRAC trial (NCT00375674), and ultimately showed mixed results. All the studies were negative with the exception of the S-TRAC trial, which demonstrated some improvement of disease-free survival with adjuvant sunitinib, though in clinical practice this agent is minimally utilized.

The introduction of checkpoint inhibitors for patients with advanced disease has actually allowed for their testing to occur in the adjuvant setting. And the KEYNOTE-564 Study was the first adjuvant immunotherapy trial to report out in renal cell carcinoma. The trial was overall positive. It was a phase 3 randomized trial adjuvant pembrolizumab versus placebo for patients who were post-definitive resection. The trial met its primary end point of improved disease-free survival and overall survival data are still immature, though a signal was beginning to emerge. 

The patients that were enrolled were fairly heterogeneous, and only patients with clear cell RCC were enrolled. I think this trial is a landmark study that catapults us into a new era in renal cell carcinoma of testing the utility of adjuvant checkpoint inhibitors for patients with advanced disease, or localized disease that's high risk of recurring. And there's going to be a series of other trials that are going to report out over the next several years that I think are going to further inform the field. And as we get additional follow-up data from KEYNOTE-564 will begin to understand the implications of the therapy with regards to overall survival.

What does the current immunotherapy landscape look like in renal cell carcinoma?

The current immunotherapy landscape for patients with renal cell carcinoma has been changing. In 2015, we see the introduction of single agent checkpoint inhibition with nivolumab based on the results of CheckMate 025 (NCT01668784) and that was a study that was done in the treatment refractory space for patients who had seen prior VEGF inhibition. In 2018. We see the introduction of doublet therapy combination nivolumab/ipilimumab in the frontline space. Since 2018, there's been a series of combination studies of various immunotherapy checkpoint inhibitors with TKI's that have been tested and demonstrated efficacy in the frontline setting. In the context of the use of these agents for advanced disease, they're being introduced to prevent patients from recurring.

How does the trial you evaluated fill an unmet need in the RCC space?

So, this trial fits an unmet need. Because currently in the clinical setting, we do not really largely utilize adjuvant therapies. Maybe there's a select patient who may be a candidate for adjuvant TKI. But again, there's no overall survival improvement with tyrosine kinase inhibitors. And there's toxicity associated with being on a TKI for one year. And so, in current clinical practice, really patients are treated with definitive surgery. And for the majority of patients, they're monitored. They're not given any additional therapy to decrease the risk of recurrence. And I think this trial begins to introduce a potential viable option to decrease the risk of recurrence for a subset of patients who have advanced or high-risk disease. So, I think we need additional data to understand who is the best person to receive such therapy? How do you maximize the benefit and decrease the toxicity? I think we need additional data to confirm that we are actually not just delaying recurrence, but preventing recurrence in some patients. I think additional time will provide that sort of information.

At the present time, we are largely utilizing clinical parameters, stage and grade to help our risk stratification to categorize which patients should be selected for any given therapy. We do this for patients with advanced disease in selecting immunotherapy and VEGF combinations. We do it in the adjuvant setting for considerations for adjuvant therapy. We have not yet developed biomarkers to help guide therapy selection for patients with advanced disease and even localized disease at high risk of recurrence, whether they be blood-based or tissue-based. So, I think there's a huge need to continue to work on developing better-validated biomarkers to help guide therapy selection.

_REFERENCE:

_{McKay R. The promise of adjuvant immunotherapy in renal-cell carcinoma. N Engl J Med. 2021; 385:756-758 doi: 10.1056/NEJMe2109354}