(UroToday.com) The treatment landscape for first-line therapy among patients with metastatic renal cell carcinoma (mRCC) has changed dramatically over the past 2 years. In 2018, the publication of the CheckMate 214 data demonstrated a survival benefit for patients treated with nivolumab and ipilimumab compared with sunitinib in intermediate and poor-risk mRCC, ushering in the immunotherapy era for mRCC. The subsequent publication of the JAVELIN Renal 101 and KEYNOTE-426 studies in 2019 demonstrated the superiority of avelumab and axitinib and pembrolizumab and axitinib, compared to sunitinib in this disease space. These two trials were the first to demonstrate that the combination of immunotherapy with checkpoint inhibition and targeted therapy improved overall survival compared to sunitinib, the previous standard of care. Network meta-analysis following the publication of these data demonstrated the apparent superiority of this combined approach.
In an oral presentation at the First Presidential Symposium at this year’s European Society of Medical Oncology (ESMO) 2020 Virtual Annual Meeting, Dr. Choueiri presented the results of the phase 3 CheckMate-9ER trial evaluating the combination of nivolumab and cabozantinib, as compared to sunitinib, in the first-line treatment of patients with advanced or metastatic renal cell carcinoma. In April 2020, the drug manufacturers announced that the trial had met its primary endpoint of progression-free survival but results have, to date, not been presented thus far.
By way of introduction, Dr. Choueiri highlighted that each of these agents has proven survival benefit in this disease space.
CheckMate—9ER (NCT03141177) is a phase III, open-label, international randomized controlled trial among patients with previously untreated, histologically confirmed advanced or metastatic renal cell carcinoma with a clear cell component. Patients with sarcomatoid features were allowed. As this was a first-line trial, previous systemic therapy was not allowed, apart from a single line of adjuvant or neoadjuvant therapy for resectable disease. Patients with active central nervous system metastases, active or suspected autoimmune disease, those requiring treatment with corticosteroids, and those who have received a live/attenuated vaccine within 30 days of first study treatment were excluded.
Patients were randomized in a 1:1 fashion to receive nivolumab 240mg IV q2 weeks plus cabozantinib 40mg PO daily or sunitinib 50mg PO daily for 4 weeks in repeating 6 week cycles. Randomization was stratified by IMDC risk score, tumor PD-L1 expression, and region. Patients continued on study therapy until disease progression or unacceptable toxicity.
The primary outcome for which the study was powered is progression-free survival. This was assessed by blinded central review. Important secondary outcomes are overall survival, objective response rate, and safety/toxicity. To assess these outcomes, the investigators used a hierarchical testing approach with an overall study alpha of 0.05. As an exploratory endpoint
A total of 651 patients were randomized, 323 to nivolumab plus cabozantinib and 328 to sunitinib. Of the study cohort, 22.6% had favourable risk disease, 57.6% had intermediate risk disease, and 19.7% had poor risk disease. Approximately one-quarter (24.9%) had PD-L1 expression >1%.
With a database lock of March 30, 2020, the median follow up was 18.1 months (range 10.6 to 30.6 months). At this point, all three efficacy endpoints were met. Median progression-free survival was significantly longer among those randomized to nivolumab plus cabozantinib (16.6 months) than those randomized to sunitinib (8.3 months), with a relative difference of 49% (hazard ratio 0.51, 95% confidence interval 0.41 to 0.64). This benefit was somewhat larger in investigator-assessed PFS.
Notably, these benefits were seen consistently across pre-specified subgroups defined according to IMDC risk categories and PD-L1 expression.
Similarly, patients randomized to nivolumab plus cabozantinib had significantly longer overall survival than those receiving sunitinib (medians not reached; hazard ratio 0.60, 98.89% confidence interval 0.40 to 0.89).
Again, the benefit in overall survival was consistent across subgroups.
Further, objective response rate was higher among patients receiving nivolumab plus cabozantinib (55.7%, 95% confidence interval 50.1 to 61.2%) than those receiving sunitinib (27.1%, 95% confidence interval 22.4 to 32.3%; p<0.001). Complete response rates were also higher among those receiving nivolumab plus cabozantinib (8.0% vs 4.6%). Median time to response was shorter and duration of response was longer among those receiving nivolumab plus cabozantinib.
Any grade treatment related adverse events were common in both groups: 96.6% among those receiving nivolumab plus cabozantinib and 93.1% among those receiving sunitinib. High grade events (grade 3 or greater) were somewhat higher among those receiving nivolumab plus cabozantinib (60.6% vs 50.9%). One grade 5 event occurred in the nivolumab plus cabozantinib arm while 2 occurred in the sunitinib treated group.
Specific immune-related AEs were noted among patients in the experimental arm, with 19% requiring corticosteroids to manage these events.
Treatment-related adverse events leading to discontinuation were somewhat more common among those receiving nivolumab plus cabozantinib, those most discontinued one but not both of these agents.
As an exploratory outcome, health-related quality of life was assessed. Notably, quality of life was maintained for those receiving nivolumab plus cabozantinib while there was a decline in quality of life among those receiving sunitinib.
Similar rates of subsequent therapy were received among patients in each arm, with checkpoint inhibitors commonly administered to those patients progressing following sunitinib.
Dr. Choueiri concluded that these data from CheckMate 9ER demonstrate the superiority of nivolumab plus cabozantinib to sunitinib in the first line treatment of patients with advanced renal cell carcinoma and support this approach as a new treatment option for these patients.
Presented by: Toni K. Choueiri, MD, Jerome and Nancy Kohlberg Professor of Medicine, Harvard Medical School, Attending Physician, Solid Tumor Oncology, Dana-Farber Cancer Institute, Director, Genitourinary (GU) Oncology Disease, Center, Dana-Farber Cancer Institute, Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute
Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center, Contact: @WallisCJD on Twitter at the European Society for Medical Oncology Virtual Congress, ESMO Virtual Congress 2020 #ESMO20, 18 Sept - 21 Sept 2020
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ESMO 2020: CheckMate-9ER Study of Nivolumab Combined With Cabozantinib Vs. Sunitinib in Participants With Previously Untreated mRCC - Toni Choueiri