Behind the FDA Approval: Adjuvant Pembrolizumab for Subgroup of Patients With RCC

Viraj Master, MD, PhD, FACS

In patients with renal cell carcinoma (RCC) with an intermediate-high or high risk of disease recurrence following nephrectomy and resection of metastatic lesions, adjuvant pembrolizumab (Keytruda) is now an FDA approved treatment option.

The treatment strategy was granted approval by the FDA on November 18, 2021, based on phase study findings (KEYNOTE-564, NCT03142334). In the study, treatment with pembrolizumab in the adjuvant setting significantly improved disease-free survival (DFS) compared with placebo. The DFS rate at 24 months with adjuvant pembrolizumab was 77.3% versus 68.1% in the placebo arm (HR, 0.68; 95% CI, 0.53-0.87; P =.002).

At the time adjuvant pembrolizumab was approved for the RCC subgroup, lead author of the published KEYNOTE-564 data stated that it may address a critical unmet need in the field. Viraj Master, MD, PhD, FACS another expert in the treatment of RCC agrees with the potential of adjuvant pembrolizumab in this patient population.

In an interview with Targeted Oncology™, Master, professor and Fray F. Marshall chair in Clinical Urologic Research, Department of Urology and director of Clinical Research Department of Urology at Emory University School of Medicine and Integrative Oncology and Survivorship at Winship Cancer Institute, discussed how adjuvant pembrolizumab may impact the treatment landscape of RCC. He also touches upon other studies which may advance the field in the near future.

TARGETED ONCOLOGY™: What adjuvant immunotherapy agents are available to treat RCC?

Currently, the treatment landscape for adjuvant treatment for advanced RCC in the nonmetastatic setting is somewhat limited. There is one approved medication sunitinib [Sutent], which improves disease-free survival, but not necessarily overall survival. The other one that is hot off the presses is a drug that was most recently approved. That's pembrolizumab, on the basis of recent data published last year and this year. The thought processes is to give these medications for a year after nephrectomy, with the hope to prevent disease recurrence.

What were the efficacy and safety results of adjuvant pembrolizumab in RCC?

Pembrolizumab has a safety profile that is certainly acceptable. On the other hand, the toxicity of this medication is significant with upwards of half of patients experiencing fairly significant toxicities that result in the need to either reduce the dose in very many cases or sometimes stop the therapy, the grade 3 and higher adverse event profile for pembrolizumab is around 20%. So, 1 out of 5 patients will experience a significant adverse event and these are all in the immune-mediated context, which is to say itis, most commonly hypothyroidism.

During the recent 2021 International Kidney Cancer Symposium: North America, you spoke on a panel about the use of adjuvant pembrolizumab for a specific patient case. Can you describe the case?

We discussed a very common case of a 62-year-old, fairly healthy gentleman who had a very large kidney tumor with some advert features. And on the basis of that, that patient was placed on adjuvant pembrolizumab. But during routine surveillance, CT scans found that the patient had 2 enlarging chest nodules. This is a scenario that is applicable to almost any patient with advanced kidney cancer. So, it’s a typical case that we see all the time in our clinics.

How would you approach further treatment of this patient?

In my institution, if we had a patient who had in good health and young age, and if they only had 2 chest nodules that were slowly growing over time, there is ample opportunity to observe the patient. With surveillance scans, we would see whether things are really changing rapidly and require systemic therapy, or whether those 2 nodules are staying the same size, in which case we'd keep surveilling them.

Finally, there may be opportunity to consolidate for cure or control of disease by removal of those 2 nodules. Usually that's done with a minimally invasive surgery. The 2 lung nodules being removed takes about an hour in the operating room, and the patient would spend a day in the hospital and would then be discharged to home.

Outside of adjuvant pembrolizumab, are there any novel strategies showing promise for these patients?

There are a number of adjuvant trials that are in middle stages. I do know that in the next 2 to 3 years, we are going to see the results from a number of large studies which have accrued hundreds of patients, both the United States as well as worldwide. We will learn quite a bit about the influence of some of these agents, either single agents or in smaller trials of doublet agents.

What unmet needs exist in kidney cancer management?

The key unmet needs in kidney cancer management are vast. First off, we need to partner closely with our patients, patient advocates, and other caregivers understand well, what is the perspective of the patient? Many times, in clinical trial design, it's done in conference rooms that are seemingly disconnected from the patient perspective. We have an opportunity to involve caregivers.

We need to understand how long we need to maintain systemic therapies for when patients are on systemic therapies. How many systemic therapies do we need to give to a patient? How do we deal with the treatment-related toxicities? And by treatment-related toxicities, I don't just mean a side effects of medical drugs. But how does the patient feel? Are they able to work, go through their day, and interact with their loved ones? Also, what about the very real issue of financial toxicity? These drugs, while remarkable in their scientific achievements are also remarkably expensive.

_Reference:

_{Choueiri TK, Tomczak P, Park S, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;395(8):683-694. doi:10.1056/NEJMoa2106391}