Pembrolizumab after nephrectomy extends DFS in high-risk clear cell renal cell carcinoma
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Adjuvant pembrolizumab appeared associated with a significant and clinically meaningful improvement in DFS vs. placebo among patients with clear cell renal carcinoma, according to results of the KEYNOTE-564 trial.
The randomized, double-blind, international trial is the first phase 3 study of a checkpoint inhibitor in the adjuvant setting to show a DFS benefit for patients with high-risk, fully resected clear cell renal carcinoma (RCC), according to researchers. The results are scheduled for presentation during the plenary session of the virtual ASCO Annual Meeting.
“Adjuvant therapies in RCC remain an unmet medical need, and in particular immunotherapy. Randomized trials of immunotherapy have yielded negative results since the 1990s,” Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology and Kidney Cancer Center at Dana-Farber Cancer Institute, and Jerome and Nancy Kohlberg chair and professor of medicine at Harvard Medical School, told Healio. “Now, with immune checkpoint blockers that are standard in metastatic RCC, we thought they should be tested in earlier-stage RCC.”
The study included 994 patients with clear cell RCC who had intermediate high-risk or high-risk disease or no evidence of disease after complete resection of the primary tumor and soft tissue metastases at least 1 year after nephrectomy. Patients had no prior systemic therapy and an ECOG performance status of 0 or 1.
Researchers randomly assigned patients at least 12 weeks after surgery to receive either the PD-1 inhibitor pembrolizumab (Keytruda, Merck; n = 496), dosed at 200 mg, or placebo (n = 498) every 3 weeks for up to 17 cycles. Treatment groups were balanced with regard to baseline characteristics.
DFS per investigator assessment in the intent-to-treat population served as the primary endpoint, with OS as a key secondary endpoint. Researchers also assessed safety among all patients who received treatment.
Median follow-up from randomization to data cutoff on Dec. 14, 2020, was 24.1 months (range, 14.9-41.5).
The study met the primary endpoint at the prespecified interim analysis, with median DFS not reached in either group (HR = 0.68; 95% CI, 0.53-0.87). Estimated DFS rates were 85.7% with pembrolizumab and 76.2% with placebo at 12 months, and 77.3% vs. 68.1% at 24 months. The DFS benefit appeared consistent across subgroups, Choueiri said.
Researchers observed 51 total OS events, including 18 (3.6%) in the pembrolizumab group and 33 (6.6%) in the placebo group. Median OS was not reached in either group (HR = 0.54, 95% CI, 0.3-0.96); the P value failed to cross the statistical hypothesis testing boundary. Estimated 24-month OS rates were 96.6% with pembrolizumab and 93.5% with placebo.
“Pembrolizumab shows a clinically meaningful advantage over placebo in the population we tested,” Choueiri said. “This has implications for this population of patients, and pembrolizumab may become a standard therapy in high-risk RCC.”
No deaths related to pembrolizumab treatment occurred. A greater proportion of patients in the pembrolizumab group experienced at least one all-cause adverse event (any-grade, 96.3% vs. 91.1%; grade 3 to grade 5, 32.4% vs. 17.7%), and at least one treatment-related adverse event (any-grade, 79.1% vs. 53.4%; grade 3 to grade 5, 18.9% vs. 1.2%).
“We will continue looking at the maturity of the data, especially with OS, some high-risk subgroups, and quality of life and biomarkers,” Choueiri said.
Perspective
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Kai Tsao, MD
Given the high rate of recurrence among patients with high-risk localized clear cell RCC after nephrectomy, an effective and safe perioperative treatment to reduce recurrence remains an urgent need. Adjuvant sunitinib (Sutent, Pfizer) has been approved by the FDA after demonstrating a definitive DFS benefit vs. placebo in the randomized phase 3 S-TRAC study, but to date this treatment approach has been largely underutilized.
The KEYNOTE-564 trial tested pembrolizumab — a PD-1 inhibitor that has demonstrated promising efficacy and a favorable toxicity profile both as monotherapy and in combination with axitinib (Inlyta, Pfizer) among patients with metastatic RCC — in the adjuvant treatment setting among patients with localized RCC after nephrectomy.
KEYNOTE-564 differed from S-TRAC in that it included a larger population of patients (n = 994 vs. 615) and was not limited to those with high-risk localized disease. It showed a 32% risk reduction in DFS with pembrolizumab, compared with a 24% risk reduction (HR = 0.76, 95% CI, 0.59-0.98) with sunitinib in the S-TRAC study. The trend in OS with pembrolizumab is quite promising, as no prior adjuvant therapy has demonstrated an OS benefit. Pembrolizumab also had a favorable toxicity profile, with grade 3 to grade 5 adverse events observed among 32.4% of patients and, importantly, no treatment-related deaths. In S-TRAC, 48.4% of patients in the sunitinib group experienced grade 3 adverse events and 12.1% experienced grade 4 adverse events.
Given the definitive DFS (primary) and OS (secondary) benefit demonstrated in KEYNOTE-564, we expect pembrolizumab will become a standard-of-care option in the adjuvant setting to delay disease recurrence for patients with fully resected clear cell RCC.
Reference:
Ravaud A, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1611406.Perspective
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Philippe E. Spiess, MD, MS, FRCS(C), FACS
This international, prospective phase 3 study is truly a landmark study, as it is the first to show a benefit of immunotherapy in intermediate/high-risk localized kidney cancer exhibiting clear cell features following surgical resection, with a 32% reduction in risk for recurrence or death.
Importantly, severe adverse effects (grade 3 to grade 5) were acceptable in the treatment group, with no treatment-related deaths reported in either group.
I very much believe these results are practice-changing as they convincingly show a clinical benefit of adjuvant pembrolizumab in patients with intermediate/high-risk localized kidney cancer and in those with metastatic disease completely resected, provided the kidney tumors had a clear cell histology component. Of note, patients in this trial received adjuvant therapy for 17 cycles, representing approximately 1 year of treatment. My colleagues should take note of the highly encouraging and impactful findings.
Some oncologists may question the definitive nature of these findings, being that the primary endpoint was DFS; nevertheless, the results reported by Choueiri during the plenary session were quite convincing and the OS data, albeit premature, showed an estimated 24 month OS rate of 96.6% in the pembrolizumab group vs. 93.5% in the placebo group. This constitutes a 46% reduction in mortality for the pembrolizumab treatment group.
It's worth noting that a few additional adjuvant studies are evaluating immunotherapy in high-risk localized RCC after resection, such as iMmotion010, PROSPER, RAMPART, CheckMate 914 and NEOAVAX. It is hard to know if adjuvant pembrolizumab is the optimal agent to use in this setting until we see the results of these emerging studies in the coming years. But there is no question we are embarking on a new era of novel and effective treatments to decrease recurrence risk and mortality in these patients with intermediate/high-risk localized (and metastatic) surgically resected kidney tumors exhibiting clear cell features. Lastly, an unanswered question is the role of adjuvant immunotherapy in this patient population with non-clear histology kidney tumors.
These results from Choueiri and colleagues are exciting and paradigm-shifting in the care of kidney cancer, but we require the publication of this work as a comprehensive peer-reviewed manuscript in a likely high-impact journal such that the data can be adequately scrutinized and accepted by the global oncology community. In addition, to enter routine clinical practice, the FDA will need to review and approve this specific indication for the use of pembrolizumab in the care of patients with kidney cancer.
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Choueiri TK, et al. Abstract LBA5. Scheduled for presentation at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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