June 8, 2021 — Editor's note: This article has been updated with comments from discussant.
For patients with high-risk clear-cell renal carcinoma (RCC) who had undergone surgery, disease-free survival (DFS) was significantly longer if they received adjuvant pembrolizumab (Keytruda) compared with placebo.
The results also indicate that overall survival will be improved in comparison with placebo, but these data are not yet mature, said lead researcher Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston, Massachusetts.
The results come from the international phase 3 study KEYNOTE-564. They will be presented on June 6 at a plenary session at the virtual American Society of Clinical Oncology (ASCO) 2021 meeting, but some details were released at a premeeting press briefing.
This is the "first positive phase 3 study of an adjuvant immunotherapy for patients with renal cell cancer, and pembrolizumab is a potential new standard of care of patients with RCC in the adjuvant setting," Choueri said.
Adjuvant immunotherapies have already been approved for treating melanoma. Those approvals were based on improved relapse-free survival in phase 3 trials, noted Suzanne L. Topalian, MD, so the "precedent has been set" regarding pembrolizumab in this setting.
"Thus, it's reasonable to anticipate that the results from KEYNOTE-564 may also lead to a new standard of care for clear-cell RCC," said Topalian, professor of cancer immunotherapy at Johns Hopkins University School of Medicine, Baltimore, Maryland.
She told Medscape Medical News that, as with immunotherapies for other types of cancer, such therapies that are "found to be effective and safe in the advanced unresectable treatment setting may also be effective as adjuvant therapies."
Consequently, "beyond the anti-PD-1 monotherapy reported in KEYNOTE-564...such therapies that are candidates for adjuvant testing include" combinations of anti–PD-L1 drugs with the anti-CTLA-4 drug ipilimumab (Yervoy), "or with specific kinase inhibitors."
Topalian also noted that "a growing body of data suggests that neoadjuvant immunotherapy...may be superior to adjuvant therapy in improving systemic antitumor immunity and, hence, disease-free and overall survival," and this is an area of very active research.
Surgery for Kidney Cancer
Surgery is the standard-of-care treatment for locoregional RCC, noted Choueri, but almost half of patients eventually experience disease recurrence, "and they become largely incurable," he said.
Moreover, there is "no globally accepted standard adjuvant therapy" in this patient group that is "supported by a high level of evidence," he noted.
The researchers therefore conducted the phase 3, double-blind, multicenter KEYNOTE-563 study, which involved patients with confirmed clear-cell RCC who had undergone nephrectomy no more than 12 weeks prior to randomization.
They included patients who had metastatic disease as long as it had been resected and there was no evidence of disease after surgery.
The patients who had received no prior systemic therapy were randomly assigned between June 30, 2017, and September 20, 2019, in a 1:1 ratio to receive either pembrolizumab (n = 496) or placebo (n = 498) every 3 weeks for 17 cycles, which equated to approximately 1 year of treatment.
After a median follow-up of 24.1 months, the study met its primary endpoint of a significant improvement in DFS by investigator assessment.
The median DFS was not reached in either the pembrolizumab or the placebo arm, but the active drug was associated with a hazard ratio of progression in comparison with placebo of 0.68 (P = .0010).
At 12 months, the estimated DFS rate was 85.7% with pembrolizumab, vs 76.2% with placebo. The estimated DFS rate at 24 months was 77.3% and 68.1%, respectively.
There was also a significant improvement in the key secondary endpoint of overall survival with pembrolizumab.
Although the median overall survival was not reached, use of pembrolizumab was associated with a hazard ratio for death in comparison with placebo of 0.54 (P = .0164).
At 24 months, 96.6% of the patients who received the checkpoint inhibitor were still alive, compared to 93.5% of those given placebo.
However, Choueiri pointed out that "only 26% of overall survival events required for final analysis occurred." He noted that the data are "therefore really immature."
He also highlighted that the P value for overall survival did not cross the prespecified boundary for statistical significance.
"Additional follow-up is planned for this key secondary endpoint," Choueiri emphasized.
The safety analysis showed, as expected, that grade 3–5 adverse events were more common with pembrolizumab than with placebo, at 32.4% vs 17.7%.
Similarly, grade 3–5 treatment-related adverse events were seen in 18.9% of patients who received the immunotherapy, vs 1.2% of those given placebo.
None of the adverse events led to death.
Invited to discuss the results, Rana R. McKay, MD, a medical oncologist at the University of California, San Diego, described the results as a "quantum leap forward" in adjuvant immunotherapy.
She said that adjuvant cytokine therapy has not been associated with improvements in survival and that the results have been "mixed" in terms of improving DFS. Only sunitinib (Sutent) offers a significant benefit in DFS over placebo.
However, McKay pointed out, not only is sunitinib not associated with an overall survival benefit, it is also linked to increased toxicity and lower quality-of-life scores. Consequently, it was not approved by the European Medicines Agency for this indication.
She noted that, being a randomized, double-blind, placebo-controlled trial, KEYNOTE-564 was designed to provide the "strongest possible evidence of causation," although she said that giving adjuvant therapy for 1 year is "somewhat arbitrary,... and it is unclear if shorter duration of therapy will provide the same benefit."
McRay also warned that, given the limited number of patients left at risk by 36 months' follow-up, the results should be interpreted "with caution" and that longer follow-up is required, especially to determine the impact on overall survival.
She said that any decision to administer adjuvant therapy "needs to take into account the potential benefits of therapy with regards to curability and survival, balanced with the risks of treatment, including toxicities, impact on quality of life, and also financial cost."
Nevertheless, McRay would argue that the current results are practice changing and that the data "represent a paradigm shift as the first positive phase 3 study of adjuvant immunotherapy in RCC."
Moreover, the improvement in DFS represents a "clinical benefit," given the "limited toxicity."
But if the drug is adopted, "new questions will arise," McKay said, "including, Will there be broad implementation for all patients? What about the application for non–clear-cell patients? And if recurrence does develop, how does this alter first-line treatment for advanced disease?"
The study was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, New Jersey. Choueiri reports relationships with numerous pharmaceutical companies and holds severas patents, as listed in the abstract.
American Society of Clinical Oncology (ASCO) 2021: Abstract LBA5. To be presented June 6, 2021.
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Cite this: Adjuvant Immunotherapy Benefit in Resected Kidney Cancer - Medscape - Jun 03, 2021.