Behind The FDA Approval: Adjuvant Pembrolizumab for RCC

Toni Choueiri, MD

In Mid-November, the FDA approved adjuvant pembrolizumab (Keytruda) for renal cell carcinoma (RCC). It is one of only 2 FDA approved agents with such an indication.

Approval of pembrolizumab for this use was based on the KEYNOTE-564 study (NCT03142334), which randomized 994 participants 1:1 to receive either pembrolizumab for a year or a matching placebo. The primary end point was disease-free survival.

At the data cutoff of 24 months, the DFS was 77.3% in the pembrolizumab arm and 68.1% in the placebo arm. Pembrolizumab was associated with a 32% reduction in the risk of recurrence or death compared with the placebo.

In an interview with Targeted Oncology^TM, Toni Choueiri, MD, a medical oncologist at the Dana-Farber Cancer Institute, discusses the impact the approval of adjuvant pembrolizumab has had on the RCC space.

TARGETED ONCOLOGY: What is adjuvant pembrolizumab for RCC designed to do?

CHOUEIRI: We investigated based on the success of adjuvant immune checkpoint inhibitors in metastatic disease. We investigated pembrolizumab, which is a PD-1 inhibitor in earlier disease that's in the resected setting. So that's why we launched KEYNOTE-564, which randomized 994 patients who receive one year of pembrolizumab, or one year of placebo. These patients that are subjected, to curative intent nephrectomy. And we included a subset of patients that had metastases as long as the metastases in the distant organ was resected within 1 year of the nephrectomy. And after 24 months of follow up, the primary end point of the trial, which was investigator assess disease-free survival, the primary end point was met with a 32% reduction in the risk of progression, risk of recurrence, or death. So, the hazard ratio was 0.68.

And in terms of toxicity, it's important because many of these patients are already cured. There was some toxicity certainly higher in the pembrolizumab arm, no deaths on trial, more patient discontinued pembrolizumab compare compared to placebo and 7% of patient needed high dose corticosteroid for immune related adverse events. We also looked specifically at several subgroup, some of them pre specified others not, such as age, gender, PD-L1 status, grades of the tumor. All the hazard ratios were less than 1 favoring pembrolizumab. We can draw strong and firm conclusions there. But there isn't a subgroup that did not completely benefit knowing that many of these confidence intervals do cross one small subgroup.

What we also showed was 2 additional things. One is overall survival from the first interim analysis even, and we only had 51 out of 200 events that were planned. And even with that, the curve started separating after 1 year. And despite this was not statistically significant because of the stringent criteria for P value at that level, that was a bit of encouraging in use here. At least we are on the right track. But again, this was not significant after 24 months of follow-up. The other thing we showed is that quality of life assessment did not show that pembrolizumab worsens quality of life compared to placebo.

What clinical need does it fill?

This is a huge unmet medical need. We do have one other drug approved, sunitinib, based on S-TRAC study (NCT00375674), although the result with sunitinib and other VEGF TKI's were not reproducible in other studies. So, despite the approval in the United States for sunitinib, it's not approved in the European Union. And its use is very, very low in the US. So, this filled a huge unmet need.

Who is the ideal candidate for this type of intervention?

I'm going to follow the eligibility criteria of KEYNOTE-564. And that's a problem in a way, because what if this patient comes after 12 months of resection? What would you do if they come at 14 months? How religiously do you follow that? What if someone has papillary histology? On the other hand, they are really high risk. They have no positive high grade. They're young, they have no comorbidities what would you do? We know pembrolizumab as a single agent in metastatic papillary RCC based on KEYNOTE-427 (NCT02853344) study. These are really going to be very tough scenarios that need to be discussed in a multidisciplinary fashion.

What should community oncologists know about this drug in this patient population?

The community is very familiar with pembrolizumab. They use it in lung cancer, in melanoma in many indications. They're familiar with it certainly, as a single agent, it is usually less toxic than in a combination. And it's for 1 year of therapy. So, I don't expect to hear that they need a new experience with this. But I think the surgeons and the medical oncologists need to discuss these cases in collaboration and offer the patient the opportunity and discuss the trial results.