KEYNOTE-564 Confirms Clinical Benefit of Adjuvant Pembrolizumab in RCC

Toni K. Choueiri, MD

Following positive results for the primary end point of disease-free survival (DFS), the KEYNOTE-564 clinical trial (NCT03142334) demonstrated sustained clinical benefit with adjuvant pembrolizumab (Keytruda) treatment in patients with post nephrectomy renal cell carcinoma (RCC).¹

Adjuvant pembrolizumab specifically achieved a 24-month DFS of 77.3% compared with 68.1% in the placebo arm (HR, 0.68; 95% CI, 0.53-0.87; 2-sided P =0.002). It was also estimated at the time of the primary analysis that 96.6% of patients in the pembrolizumab group would remain alive at 24 months vs 93.5% in the placebo group (HR, 0.54; 95% CI, 0.30 to 0.96), signaling a trend toward overall survival (OS) improvement.²

Results from an efficacy analysis of the post nephrectomy subgroup were presented during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting. The analysis included 67 patients, of which 13.5% received pembrolizumab and 19.9% received placebo. In terms of time to first subsequent drug treatment or any-cause death, time was delayed with pembrolizumab compared with placebo (HR, 0.67; 95% CI, 0.50-0.90). Fewer progression-free survival events were also observed in the pembrolizumab arm compared with the placebo arm (HR, 0.57; 95% CI, 0.39-0.85).¹

In an interview with Targeted Oncology™, Toni K. Choueiri, MD, medical director, International Strategic Initiatives, director, Lank Center for Genitourinary Oncology, director, Kidney Cancer Center, senior physician, at Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg chair and professor of Medicine, Harvard Medical School, discusses results from the KEYNOTE-564 efficacy analysis and what will come next for pembrolizumab treatment in RCC.

TARGETED ONCOLOGY: Can you talk about the KEYNOTE-564 study? What was investigated in the expanded efficacy analyses for this study?

Choueiri: KEYNOTE-564 is the first randomized phase 3 trial that showed adjuvant immunotherapy works in kidney cancer patients who are at a high-risk for recurrence. It was presented initially at the plenary session at the 2021 ASCO, followed by a New England Journal of Medicine publication. One year later at the 2022 ASCO, we presented additional post hoc analysis for the efficacy end points.

While waiting for the overall survival end point, which is still not mature, we investigated 3 important secondary end point of efficacy besides disease-free survival, which is what we reported on initially. We investigated distant metastasis-free survival, which is the time to detectable metastatic disease or death, we investigated time to first subsequent drug treatment, which is timed to the first subsequent therapy from randomization, [and]we also looked at progression-free survival 2, which is the time to second progression on next line of therapy from randomization to progression on next line therapy or any cause of death.

What were the findings of the analyses?

For distance metastasis-free survival, there were 140 events for placebo and 95 for pembrolizumab. There was a of 9% absolute difference in the metastases with hazard ratio of 0.63, so a 37% decrease in that specific risk. The time to first subsequent anti-cancer therapy, including drug therapy, radiation therapy surgery, no matter what you look at, the events were higher in placebo treated patients. The hazard ratio was 0.67. There was a 33% decrease in the risk. In the time to second disease progression, PFS2, the hazard ratio was 0.57. There was a 43% decrease in their risk of having time to second disease progression with pembrolizumab.

We used the cut off of 30 months follow-up, and the 3 end points were all statistically significant. We believe it to be clinically relevant too, which is consistent with the primary analysis of disease-free survival.

What do these findings tell you about pembrolizumab specifically for use in patient who have undergone nephrectomy?

It affirms the clinical benefit of adjuvant pembrolizumab and further supports using pembrolizumab after nephrectomy, as a standard of care with localized renal cell cancer at increased risk for recurrence.

Again, these are reassuring results. The drug was approved last year, 2021 in November, by the FDA, and these are all encouraging end points that further support the primary hypothesis of KEYNOTE-564.

What is a key next step with pembrolizumab for the treatment of RCC?

The results of KEYNOTE-564 are important for future work. Now, we have a phase 3 trial where we are using pembrolizumab as control. It is called LITESPARK-022 [NCT05239728]. Pembrolizumab, which was used in the experimental of KEYNOTE-564 will be used in the control arm of LITESPARK-022. Then, we are adding an experimental agent called belzutifan [Welireg], which is a HIF-2α inhibitor that showed efficacy in metastatic disease.

We're adding it to pembrolizumab in the adjuvant setting to see if we can improve on pembrolizumab efficacy because despite the benefit over placebo, there will be patients who will not respond to pembrolizumab. Also, despite adjuvant pembrolizumab, patients will experience cancer that will come back.

_REFERENCES:

_{1. Choueiri TK, Tomczak, Park SH, et al. Adjuvant pembrolizumab for postnephrectomy renal cell carcinoma (RCC): Expanded efficacy analyses from KEYNOTE-564. J Clin Oncol. 40(suppl 16). 4512-4512. doi: 10.1200/JCO.2022.40.16_suppl.4512}

_{2. Choueiri TK, Tomczak, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021; 385(8):683-694. doi: 10.1056/NEJMoa2106391}