In an interview with Targeted Oncology, Toni K. Choueiri, MD, discussed the results of the KEYNOTE-564 trial as well as the potential effects of these findings.
Immunotherapy-based regimens have been a major focus of research and clinical trials for the treatment of patients with renal cell carcinoma (RCC) in recent years due to the success seen with the use of immune checkpoint inhibitors, especially in the frontline setting. The focus remained on immunotherapy agents even at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.
For example, in the plenary session of the ASCO meeting, the first results were presented from the phase 3 KEYNOTE-564 trial (NCT03142334) of adjuvant pembrolizumab (Keytruda) in patients with clear cell RCC following nephrectomy.1 The study showed a significant improvement in disease-free survival over placebo.
Additionally, updates were provided for the KEYNOTE-426 trial (NCT02853331) of pembrolizumab and axitinib (Inlyta) for previously untreated patients with RCC and showed that even with longer follow-up, survival benefit was maintained for the combination over single-agent sunitinib (Sutent).2
Several analyses were also explored during ASCO from the phase 3 CLEAR trial (NCT02811861) of pembrolizumab and lenvatinib (Lenvima), lenvatinib and everolimus (Afinitor), and sunitinib in patients with treatment-naive RCC. Analyses supported the benefit of both lenvatinib-containing regimens among subgroups, with adjustment for subsequent therapy, and in health-related quality-of-life findings.
These studies and others may have a big impact on the RCC field in the near future.
In an interview with Targeted OncologyTM, Toni K. Choueiri, MD, discussed the results of the KEYNOTE-564 trial as well as the potential effects of these findings. Choueiri, the director of the Lank Center for Genitourinary Oncology, director of the Kidney Cancer Center, and senior physician at Dana-Farber Cancer Institute, as well as Jerome and Nancy Kohlberg chair and professor of medicine at Harvard Medical School, also discussed other significant RCC studies presented during the 2021 ASCO Annual Meeting.
Targeted OncologyTM: Could you speak to the rationale for the KEYNOTE-564 trial in RCC?
Choueiri: For many years, researchers tried to find an optimal way to help prevent recurrence in patients with RCC that are at risk for recurrence that already had their surgery, but we know based on their stage, grade, based on the risk [group], they are at risk for recurrence. So there has been trials since the 70s, randomized trials with all sorts of interventions—radiation, chemotherapy, cytokines, interferon, and more recently in the past 5 to 10 years with VEGF-targeted therapy. And all the results were actually quite disappointing. The results were kind of confusing because there was one positive study with sunitinib, but several others were negative, including another study with sunitinib and with drugs that in the metastatic setting are as effective as sunitinib, like pazopanib [Votrient]. And so, even that approval with sunitinib did not translate into clinical practice. And actually, while it's approved in the United States and not approved in Europe, we continued the quest for drugs that work. Pembrolizumab is an immune checkpoint inhibitor, a PD-1 inhibitor approved in multiple indications and in renal cell cancer it’s already approved in combination as of today with axitinib in metastatic disease.
We launched KEYNOTE-564 several years ago. And we took a population of patients at high risk of recurrence. So these are patients who had a nephrectomy, and had stage T2 high-grade stage IV [disease], or T3 stage III of any grade, or had node positive or had the M1 NED [no evidence of disease], which means they had metastatic disease. But this was resected at the time of nephrectomy, or within a year of nephrectomy, and these patients were randomized to 1 year of placebo or no therapy, or 1 year of pembrolizumab.
What were the results of the study presented at the meeting?
The result was the first interim analysis that we just saw in the plenary session at ASCO 21, showed that pembrolizumab cuts the risk of recurrence or death, by 32%, the hazard ratio [HR] was 0.68. This is statistically significant; this is clinically relevant. The study also had key secondary end points, such as overall survival [OS] and safety. OS is quite immature, we didn't have enough events. But even with that, it wasn't statistically significant per se, but the HR for OS was 0.54. So, encouraging, and actually the first year there were barely any events. So we're going to continue following on this very important end point. Safety was not surprising, there were more toxicities, more treatment discontinuations, more patients on steroids with the pembrolizumab arm, but nothing that was not manageable. And the good thing [was that] there were no treatment-related deaths from pembrolizumab.
Now, we looked at some subgroups to see if there is anything stands out, a HR of over one in the experimental arm pembrolizumab. Actually, the good thing is that all the HRs [with] multiple subgroups—age, gender, location in the world, as well as PD-L1 and others—all the HRs for disease-free survival [DFS] were less than one, so that's reassuring. This is the first interim result, the study still has a significant amount of data, quality of life, and other subgroup analyses and will continue until the maturity of the events, especially for OS.
If the results continue to be positive, what do you think is going to be the clinical impact of this research?
I see this drug potentially approved for patients. I see this happening based on DFS, because DFS is an accepted end point. With the prior approval of sunitinib in the adjuvant setting, it was [based] on the same end point; also in colorectal cancer, breast cancer. So I think, especially when OS events lag behind DFS, we know from a document from the FDA guidance in 2018, that is reasonable. And then hopefully, for the right patient, this could be a potential option.
What would you say is the take home message here?
I think the take home message is, hopefully, finally we have an option in these patients with high risk of recurrence of renal cell cancer, because when renal cell cancer recurs, the majority of time it becomes incurable. And it doesn't recur locally, where it's resectable, commonly it recurs in distant metastatic sites. So I think this is good news for the field. We are very happy and very grateful for ASCO in highlighting this in the plenary session. And hopefully, we'll have more and more data out of this large study that included almost 1000 participants.
Looking at ASCO, in general, is there anything in particular in the RCC space that you were excited to see the results of?
There are some studies that are not presented for the first time but have more analysis. KEYNOTE-426, for example, that they come for approval, pembrolizumab, and axitinib, has now a long, medium follow up. I think one of the issues with these VEGF-IO [immunotherapy] combinations, they never had the same follow-up as the IO-IO combination nivolumab [Opdivo]/ipilimumab [Yervoy]. So now pembrolizumab [has been] accepted and has more follow-up. There are data also for a newer, complicated combination of pembrolizumab and lenvatinib. That was presented a couple of months ago, there is data now about quality of life. There's a lot of good stuff being presented, and I hope folks will follow all the data that is coming in renal cell cancer, but also in [genitourinary] cancers in general.
1. Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab vs placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: randomized, double-blind, phase 3 KEYNOTE-564 study. J Clin Oncol. 2021;39(suppl 15):LBA5. doi:10.1200/JCO.2021.39.15_suppl.LBA5
2. Rini B, Plimack R, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Results from 42-month follow-up of KEYNOTE-426. J Clin Oncol. 2021;39(suppl 15):4500. doi:10.1200/JCO.2021.39.15_suppl.4500