Adjuvant Pembrolizumab Keeps Survival Benefit in RCC

ALTHOUGH UPDATED OVERALL survival (OS) findings from KEYNOTE-564 (NCT03142334) demonstrated continued benefit in patients with clear cell renal cell carcinoma (ccRCC) who received adjuvant pembrolizumab (Keytruda), a subset of unresponsive patients remains. Jens Bedke, MD, discussed the updated results and explored potential biomarkers undergoing evaluation in a presentation during the 16th European Multidisciplinary Congress on Urological Cancers (EMUC24) in Lisbon, Portugal, November 7 to 10, 2024.¹

“In KEYNOTE-564, data from patients who were in the intermediate-high–risk, high-risk, and M1 with-no-evidence-of-disease [NED] population were analyzed,” Jens Bedke, MD, senior consultant, Department of Urology and Transplantation Surgery, Klinikum Stuttgart in Germany, said.

Updated Results From ASCO

During the 2024 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, Choueiri et al2 had shown that adjuvant pembrolizumab improved disease-free survival (DFS) compared with placebo following nephrectomy in patients with ccRCC who are at an increased risk of recurrence. A statistically significant improvement in OS was observed with pembrolizumab vs placebo (medians not reached; HR, 0.62; 95% CI, 0.44-0.87; P = .0024).

In addition, the investigators noted a 38% reduction in risk of death associated with adjuvant pembrolizumab along with survival benefits across key subgroups (HR, 0.72; 95% CI, 0.59-0.87).² During further follow-up, they observed continuing DFS benefit and no new safety signals.

Bedke emphasized the OS by risk category: the M0 intermediate-high (HR, 0.59; 95% CI, 0.400.87), the M0 high (HR, 0.78; 95% CI, 0.32-1.93), and the M1 NED subgroups (HR, 0.51; 95% CI, 0.15-1.75) all benefited from pembrolizumab. He also noted that the presence or absence of sarcomatoid features had no bearing on the OS benefit. “Both subgroups responded in the same way; however, this is a small subgroup and sample size,” Bedke cautioned.

In the intention-to-treat population, the updated DFS was also consistent, with a 28% reduction in risk of death (HR, 0.72; 95% CI, 0.59-0.87). “The improvement curves are stable, and the medians for both arms have not been reached after 4 years,” Bedke said. “We see that 57% of the patients are disease free after undergoing surgery, and the delta is about 9% when compared with the pembrolizumab arm,” he continued.

Exploring Prognostic Markers

Turning to prognostic markers, Bedke explored KIM-1, based on findings from the phase 3 IMmotion010 trial (NCT03024996), which evaluated atezolizumab (Tecentriq) in patients with RCC at high risk for developing metastasis following nephrectomy.³

“KIM-1 is prognostic for disease recurrence,” Bedke said. At baseline, investigators noted that having high levels of KIM-1 was associated with worse DFS in IMmotion010 (HR, 1.75; 95% CI, 1.40-2.17). In addition, KIM-1 is predictive for adjuvant atezolizumab, with investigators reporting that atezolizumab improved DFS vs placebo in the baseline KIM-1–high subgroup.⁴

Other molecular subtypes have also been explored. In the JAVELIN Renal 101 trial (NCT02684006), the highest efficacy was seen in heterogeneous tumors. The trial evaluated avelumab (Bavencio) plus axitinib (Inlyta) vs sunitinib (Sutent).5 The trial enrolled patients who were in 3 prognostic risk groups: favorable, intermediate, and poor risk. Patients with positive, negative, or unknown PD-L1 expression were also included. Investigators reported that longer PFS and higher objective response rate were observed in patients who received avelumab plus axitinib than among those who received sunitinib in patients with PD-L1–positive tumors and in the overall population, as well as across risk groups in both populations.

KEYNOTE-564 Background

In the KEYNOTE-564 trial, investigators randomly assigned 994 patients in a 1:1 fashion to receive 200 mg of pembrolizumab or placebo every 3 weeks for about 1 year. The primary end point was disease- free survival (DFS), and the secondary end points were OS and safety. The median time from randomization to data cutoff was 30.1 months (range, 20.8-47.5).

The primary analysis after 24.1 months of follow-up showed that patients in the pembrolizumab arm had a DFS of 77.3% vs 68.1% for patients in the placebo arm (HR, 0.68; 95% CI, 0.53-0.87; P = .001). At the updated analysis at 30.1 months, patients who received pembrolizumab had a DFS of 78.3% vs 67.3% for patients in the placebo arm (HR, 0.63; 95% CI, 0.50-0.80; nominal P < .0001).

An analysis of DFS by recurrence-risk subgroups revealed that for DFS at 24 months, the intermediate-high–risk group rate was 81.1% in the pembrolizumab group vs 72% in the placebo group (HR, 0.68; 95% CI, 0.520.89). In the high-risk group, the DFS rate was 48.7% vs 35.4%, respectively (HR, 0.60; 95% CI, 0.33-1.10). In the M1 NED group, the rate was 78.4% vs 37.9%, respectively (HR, 0.28; 95% CI, 0.12-0.66). “We observed that the benefit is detectable in all risk groups, particularly in the intermediate-high–risk group,” Bedke said.

Approximately 80% (79.5%) of patients in the pembrolizumab arm received subsequent therapy overall; similarly, 81.4% of patients who received placebo were given subsequent therapy.

In conclusion, Bedke noted that “pembrolizumab is the first adjuvant treatment in RCC that has shown an improved overall survival as observed by KEYNOTE-564 and KIM-1 [investigators and] could be a prospective and predictive biomarker.”

REFERENCES

1. Bedke J. Practice-changing papers: KEYNOTE 564 OS. Presented at: EMUC24; November 7-10, 2024; Lisbon, Portugal. Accessed December 3, 2024. https://urosource.uroweb.org/261485/webcast

2. Choueiri TK, Tomczak P, Park SH, et al. Overall survival results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab versus placebo for the treatment of clear cell renal cell carcinoma (ccRCC). J Clin Oncol. 2024;42(suppl 4):LBA359. doi:10.1200/JCO.2024.42.4_suppl.LBA359

3. Pal SK, Uzzo R, Karam JA, et al. Adjuvant atezolizumab versus placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2022;400(10358):1103-1116. doi:10.1016/S0140-6736(22)01658-0

4. Albiges L, Bex A, Suárez C, et al. Circulating kidney injury molecule-1 (KIM-1) biomarker analysis in IMmotion010: a randomized phase 3 study of adjuvant (adj) atezolizumab (atezo) vs placebo (pbo) in patients (pts) with renal cell carcinoma (RCC) at increased risk of recurrence after resection. J Clin Oncol. 2024;42(suppl 16):4506. doi:10.1200/JCO.2024.42.16suppl.4506

5. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1103-1115. doi:10.1056/NEJMoa1816047