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23-09-2022 | ESMO 2022 | Conference coverage | News

Advanced RCC PFS boost with addition of cabozantinib to first-line dual immunotherapy

Author: Shreeya Nanda


medwireNews: People with intermediate- or poor-risk advanced renal cell carcinoma (RCC) derive a significant progression-free survival (PFS) benefit from the addition of cabozantinib to first-line nivolumab plus ipilimumab, indicates the COSMIC-313 trial.

Toni Choueiri (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) – who presented the findings at the ESMO Congress 2022 – explained to the audience in Paris, France, that dual immune checkpoint inhibition with nivolumab plus ipilimumab is a standard of care in this setting, but “approximately 20% of patients experience progressive disease as best response, representing an unmet medical need.”

He added that combining the multitargeted tyrosine kinase inhibitor cabozantinib – which is also a standard of care for advanced RCC – with nivolumab plus ipilimumab “has the potential to improve therapeutic outcomes in patients with metastatic RCC of intermediate and poor risk.”

In the phase 3 trial, 855 treatment-naïve individuals with advanced RCC categorized as intermediate or poor risk as per IMDC criteria were randomly assigned to receive four cycles of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks either with cabozantinib 40 mg/day or placebo, after which cabozantinib and placebo were continued alongside nivolumab 480 mg given every 4 weeks.

The primary endpoint was PFS in the first 550 patients randomized – termed the PFS intention-to-treat (PITT) population – and after a median follow-up of 20.2 months, this was significantly improved among patients who received cabozantinib rather than placebo alongside nivolumab plus ipilimumab, with the median unreached and 11.3 months, respectively. This equated to a significant hazard ratio (HR) for progression or death of 0.73 in favor of the triplet.

The PFS rates at 12 months were 57% in the cabozantinib arm and 49% in the placebo arm.

When the population was stratified by risk group, the PFS benefit of adding cabozantinib was significant for participants with intermediate-risk disease (HR=0.63), but not for those with poor-risk disease (nonsignificant HR=1.04). The median PFS durations with the triplet versus the doublet in the former group were unreached and 11.4 months, respectively, and in the latter group were 9.5 and 11.2 months.

The objective response rate (ORR) in the total PITT population was numerically higher with the addition of cabozantinib than placebo to nivolumab–ipilimumab, at 43% versus 36%. The responses were complete in an identical 3% of patients in each arm and partial in 41% and 32%, respectively. Just 8% of participants in the cabozantinib arm had progressive disease as the best response compared with 20% of those in the placebo arm.

Once again the benefit of adding cabozantinib was more apparent among patients with intermediate-risk RCC (ORR, 45 vs 35%) than those with poor-risk RCC (37 vs 38%).

Choueiri told delegates that “follow-up for the secondary endpoint of [overall survival] is very important and is ongoing.”

With regard to the safety, treatment-related adverse events (TRAEs) of grade 3 or 4 occurred in a higher proportion of triplet- than doublet-treated patients, at 73% versus 41%, with the most common events of this severity in the triplet arm being elevated alanine aminotransferase (26 vs 6%) and aspartate aminotransferase (20 vs 5%).

Grade 5 TRAEs within 30 days of the last dose occurred in three patients each in the cabozantinib and placebo groups, with an additional two events in the cabozantinib group and a further one in the placebo group within 100 days.

A total of 45% of individuals given the triplet discontinued any study treatment due to TRAEs, as did 24% of those who received the doublet. The rate of discontinuation of all treatment components due to the same AE was a respective 12% and 5%.

Discussant Sumanta Pal (City of Hope Comprehensive Cancer Center, Duarte, California, USA) commended the COSMIC-313 investigators for using “a contemporary control arm” and for taking “the bold move of comparing a triplet to a doublet.”

But he added that “it would be incredibly informative for clinical decision-making to see what the overall survival shows” and cautioned that “the toxicity of triplet therapy […] may potentially get in the way of delivery of individual agents.”

Looking to the future, Pal wondered whether “we can use a risk-adapted approach for optimal delivery of triplet therapy,” which is being investigated in the PEDIGREE trial.

He also stressed the need “to invest in biomarker studies of contemporary regimens […] and pivot rapidly to prospective studies that assess these biomarkers,” as well as “to shift towards adding agents with novel [mechanisms of action] that may not yield overlapping toxicities.”

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

ESMO Congress 2022; Paris, France: 9–13 September