Immunotherapy combo fails to extend disease-free survival in high-risk kidney cancer
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The combination of nivolumab and ipilimumab after nephrectomy failed to extend DFS among patients with localized renal cell carcinoma at high risk for relapse, results of the phase 3 CheckMate 914 trial showed.
An analysis of the randomized study presented at ESMO Congress revealed a high rate of therapy discontinuation due to treatment-related adverse events, the investigators noted.
Background
New effective adjuvant therapies are needed for patients with localized renal cell carcinoma at high risk for relapse after radical or partial nephrectomy, according to Robert J. Motzer, MD, section head for kidney cancer and Dorothy Byrne chair in clinical oncology at Memorial Sloan Kettering Cancer Center.
“Patients with stage II or stage III tumors have a substantial risk [for] post-nephrectomy relapse,” he said during a presentation.
Approved adjuvant options include sunitinib (Sutent, Pfizer) — which is rarely used — in the United States and the anti-PD-1 therapy pembrolizumab (Keytruda, Merck), he added.
“Dual immune checkpoint inhibition with nivolumab [Opdivo, Bristol Myers Squibb] and ipilimumab [Yervoy, Bristol Myers Squibb] has demonstrated long-term improvements vs. sunitinib in patients with untreated advanced renal cell carcinoma,” Motzer said. “Part A of the phase 3 CheckMate 914 trial was designed to study clinical outcomes with adjuvant nivolumab plus ipilimumab in the setting of surgically resected stage II or stage III clear cell renal cell carcinoma with a high risk [for] recurrence.”
Methodology
Part A of CheckMate 914 enrolled 816 patients with localized renal cell carcinoma at high risk for disease relapse after nephrectomy and randomly assigned in a 1:1 ratio to adjuvant therapy with IV nivolumab dosed at 240 mg every 2 weeks (up to 12 doses) plus IV ipilimumab dosed at 1 mg/kg every 6 weeks (up to 4 doses) or placebo.
DFS as determined by a blinded independent central review committee served as the study’s primary endpoint. Secondary endpoints included OS and safety.
Median follow-up was 37 months (range, 15.4-58), with a data cutoff date of June 28.
Key findings
The trial did not meet its prespecified primary endpoint, with median DFS not reached with nivolumab plus ipilimumab vs. 50.7 months with placebo (HR = 0.92; 95% CI, 0.71-1.19) and an estimated 24-month DFS rate of 76.4% for nivolumab plus ipilimumab vs. 74% for placebo per blinded independent central review.
DFS results per investigator assessment showed an estimated 24-month DFS rate of 77.1% for the combination therapy and 74.1% for placebo (HR = 0.92; 95% CI, 0.71-1.2).
The investigators did not formally analyze OS because the study failed to meet its primary endpoint.
Eighty-nine percent of patients in the combination therapy group experienced grade 3 or greater treatment-related adverse events, compared with 57% in the placebo group. This led to a treatment discontinuation rate of 29% in the combination therapy group compared with 1% in the placebo group.
Clinical implications
The results of part A of the CheckMate 914 trial will continue to be analyzed to determine why the combination immunotherapy did not significantly extend DFS in this group of patients, Motzer noted.
Part B of the study is ongoing and will evaluate adjuvant nivolumab vs. placebo in patients with a high risk for disease relapse after undergoing radical or partial nephrectomy for localized renal cell carcinoma, he added.
Perspective
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John Connolly, PhD
Although a solid study, CheckMate 914 could not replicate the positive results of an earlier trial of anti-PD-1 therapy in this setting.
It is disappointing that CheckMate 914 did not show a broad benefit for the immunotherapy combination in this setting. However, there’s still much to be learned from the trial by digging deeper into the data.
The essential first step is to stratify patients by seeking biomarkers that distinguish the subpopulation(s) of patients who responded from those who did not. This is important because the mechanism by which patients respond to immunotherapy is not completely understood. It is thought to involve tumor neoantigens that are recognized by immune system cells, which then attack the tumor. But patients’ neoantigens are often highly personalized, meaning one patient may respond well whereas another patient may not. Biomarkers defining likely responders would enable the design of trials specifically for those patient subpopulations and better guide therapy in the setting of metastatic renal cell carcinoma. That’s the true take-home message of the CheckMate 914 trial.
We must also remember that not all immunotherapies are created equal; other forms of immunotherapy in other combinations currently in clinical trials may show DFS benefits in the setting of metastatic colorectal cancer. We’re watching and waiting for those trials to read out, because there may be a combination that better addresses the resistance profile found in these patients with metastatic renal cell carcinoma.
Reference:
Choueiri TK, et al. N Eng J Med. 2021;doi:10.1056/NEJMoa2106391.
Perspective
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Sumanta “Monty” Pal, MD
Ultimately, the phase 3 CheckMate 914 study failed to meet its primary endpoint of DFS, with a hazard ratio 0.92. No subset appeared to derive particular benefit with the regimen. There was a trend toward benefit in patients with sarcomatoid features, but this was an exceptionally small subgroup.
Toxicities encountered with nivolumab/ipilimumab were more substantial than those encountered with placebo, which is unlikely a surprise to most. A potential cause of the lack of clinical efficacy was a substantial number of patients who developed serious grade 3 treatment-related adverse events. Discontinuation of nivolumab with ipilimumab occurred in 29% of patients and only 1% of patients treated with placebo. The trial, therefore, gives rise to discussion of whether the toxicity associated with the doublet might potentially get in the way of successful administration of the regimen in the adjuvant setting.
As of now, the current standard of care remains pembrolizumab in this setting, given the results of the KEYNOTE 564 study, which demonstrated a substantial benefit in DFS with pembrolizumab over placebo.
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Motzer RJ, et al. Abstract LBA4. Presented at: European Society for Medical Oncology Congress; Sept. 9-13, 2022; Paris.
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