Promoting to the front line two drugs normally used in rearguard action to treat advanced renal cell carcinoma (RCC) ― nivolumab (Opdivo) and cabozantinib (Cabometyx) ― doubled overall response rates and progression-free survival (PFS) and significantly improved overall survival (OS) compared with first-line sunitinib (Sutent), investigators in the Checkmate 9ER trial reported.
Median PFS among patients with advanced RCC, which was the trial’s primary endpoint, was 16.6 months with nivolumab plus cabozantinib, compared with 8.3 months with sunitinib, translating into a hazard ratio (HR) of 0.51 for the combination (P < .0001). The median follow-up was 18.1 months.
Median OS had not been reached in either arm at the time of data cutoff, but the survival curves at the time of the analysis clearly favored nivolumab-cabozatinib, with an HR for death of .060 (P = .0010), said Tony K. Choueri, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts.
“With expanding options in our patients with advanced RCC, the overall efficacy, safety, and quality-of-life benefit, as well as individual patient characteristics, are very important considerations when you select appropriate therapy,” he said in a press briefing prior to his presentation of the data in a presidential symposium at the European Society of Medical Oncology (ESMO) Virtual Congress 2020.
Although the nivolumab-cabozantinib combination therapy looks good, however, it’s late to the game, commented Dominik Berthold, MD, from the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, the invited discussant for the briefing.
“The question is, what’s the only drawback of this trial? It’s probably the fact that it’s not first in class in this situation,” he said.
Berthold noted that nivolumab-cabozantinib, if approved for the frontline setting, will join the combination of the tyrosine kinase inhibitor (TKI) axitinib (Inlyta) plus pembrolizumab (Keytruda), which, as previously reported, was associated with a nearly 50% reduction in the risk for death in the KEYNOTE-426 trial. This combination was approved by the US Food and Drug Administration (FDA) for the frontline setting in April 2019.
As shown in the CheckMate-214 study, the combination of the programmed cell death protein–1 (PD-1) inhibitor nivolumab with the CTLA-4 inhibitor ipilimumab (Yervoy) was associated with significantly higher objective response rates and OS rates compared with sunitinib. This combination was approved by the FDA in April 2018 as first-line therapy for patients with advanced intermediate- or poor-risk RCC.
CheckMate 9ER Details
A total of 651 patients with previously untreated advanced or metastatic RCC that had a clear cell component in all International Metastatic RCC Database Consortium risk groups were enrolled and randomly assigned to receive either intravenous nivolumab 240 mg every 2 weeks plus oral cabozantinib 40 mg daily or oral sunitinib 50 mg daily in cycles of 4 weeks on therapy/2 weeks off therapy. Patients were treated until disease progression or unacceptable toxicities occurred.
The primary PFS endpoint and the secondary OS endpoint both favored the combination, as did the objective response rate, which was 55.7% with nivolumab-cabozantinib vs 27.1% with sunitinib (P < .0001). Complete responses were seen in 8% of patients who received the combination vs 4.6% with the patients who received sunitinib. Partial responses were seen in 47.7% and 22.6%, respectively.
Patients generally tolerated the combination. The incidence of the most common high-grade treatment-emergent adverse events and other adverse events of any grade was similar to that seen with sunitinib, Choueri said.
The rates of treatment-related events that led to discontinuation was 3.1% among patients who received the combination, 5.6% among patients who received the nivolumab component only, and 6.6% among patients who received cabozantinib only. It was 8.8% among patients who received to sunitinib. More than 50% of patients in the combination arm needed a dose reduction of nivolumab-cabozantinib because of adverse events, however.
“Overall, it seems that the combination has somewhat a manageable safety profile in patients with advanced RCC,” Choueri said.
Patient-reported quality of life, as measured by the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy–Kidney Symptom Index 19 total score, was an exploratory endpoint. It was maintained over time with the combination but deteriorated over time with sunitinib, with statistically significant differences between the study arms at most time points to 91 weeks, he reported.
Press briefing discussant Berthold acknowledged the benefit that having an additional therapy offers clinicians and patients.
“What we still need to learn here is, are there any patient populations who may benefit more on this combination compared with other combinations?,” he said. “Cabozantinib is quite a unique TKI which may target better bone metastases, for example, so I think there are things we need to learn from further data and longer follow-up.”
Camillo Porta, MD, from the University of Bari, Bari, Italy, the invited discussant for the presidential symposium, urged caution in comparing the three regimens, owing to differences in the drug used, study endpoints, baseline patient characteristics, and the distribution of patients among different prognostic groups.
When it comes to deciding between frontline regimens, “the only possible, though highly empiric, driver of our therapeutical choice should be the biological aggressiveness of the tumor,” he said.
For patients with highly aggressive disease, the use of an immune checkpoint inhibitor plus a vascular endothelial growth factor receptor (VEGFR)–directed TKI may help control disease long enough to give the checkpoint inhibitor time to work.
“Otherwise, one could head for the long-term benefit of the immune combo as well as for complete responses, trying to spare [patients] the additional toxicities deriving from the continuous use of the VEGFR TKI,” he added.
Porta noted that when considering the trade-off between efficacy and safety in the first-line setting, many patients are willing to accept more toxicities in exchange for clinical benefit.
The study was sponsored by Bristol-Myers Squibb. Choueri disclosed consultancy fees, advisory board activity, manuscript preparation, travel/lodging, honoraria, and grants for clinical trials from BMS and others. Berthold disclosed an advisory role for Ipsen, Bristol-Myers Squibb, Merck, and Pfizer. Porta disclosed advisory/consulting activities and speakers bureau participation for BMS and others.
European Society for Medical Oncology (ESMO) Annual Meeting 2020: Abstract 6960, presented September 19, 2020.
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