Outcomes based on age in the phase III METEOR trial of cabozantinib versus everolimus in patients with advanced renal cell carcinoma

Abstract

Background: Cabozantinib improved progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) compared with everolimus in patients with advanced renal cell carcinoma (RCC) after prior antiangiogenic therapy in the phase III METEOR trial (NCT01865747). Limited data are available on the use of targeted therapies in older patients with advanced RCC. Methods: Efficacy and safety in METEOR were retrospectively analysed for three age subgroups: <65 (n Z 394), 65e74 (n Z 201) and !75 years (n Z 63). Results: PFS, OS and ORR were improved with cabozantinib compared with everolimus in all age subgroups. The PFS hazard ratios (HRs) were 0.53 (95% confidence interval [CI]: 0.41 e0.68), 0.53 (95% CI: 0.37e0.77) and 0.38 (95% CI: 0.18e0.79) for <65, 65e74 and !75 years, respectively, and the OS HRs were 0.72 (95% CI: 0.54e0.95), 0.66 (95% CI: 0.44e0.99) and 0.57 (95% CI: 0.28e1.14). The ORR for cabozantinib versus everolimus was 15% vs 5%, 21% vs 2% and 19% vs 0%, respectively. No significant differences were observed in PFS or OS with age as a categorical or continuous variable. Grade III/IV adverse events (AEs) were generally consistent across subgroups, although fatigue, hypertension and hyponatraemia occurred more frequently in older patients treated with cabozantinib. Dose reductions to manage AEs were more frequent in patients receiving cabozantinib than in those receiving everolimus. Dose reductions and treatment discontinuation due to AEs were more frequent in older patients in both treatment groups. Conclusions: Cabozantinib improved PFS, OS and ORR compared with everolimus in previously treated patients with advanced RCC, irrespective of age group, supporting use in all age categories. Proactive dose modification and supportive care may help to mitigate AEs in older patients while maintaining efficacy.

Outcomes based on age in patients with metastatic renal cell carcinoma treated with first line targeted therapy or checkpoint immunotherapy: Older patients more prone to toxicity

“…Likewise, Miyake et al [27] found that the proportion of older patients undergoing a modified sunitinib regimen, whereby the initial dose was reduced due to toxicity, was larger when compared with younger adults. A similar trend was observed for cabozantinib and everolimus with more frequent dose reductions and discontinuations together with a shorter median time to AE among older patients ≥ 75 years [21]. Notably, a retrospective analysis [20] of the CheckMate 025 trial reported a similar incidence of all-grade toxicity between older and younger individuals treated with nivolumab.…”

“…In accordance with our findings, several other studies have shown that older age does not independently associate with poorer survival in patients with mRCC. These conclusions apply in the case of both targeted agents and CPI, although there is a scarcity of data on the clinical outcomes among older patients treated with CPI [2,3,14,[17][18][19][20][21][22][23]. The impact of age on therapies for mRCC have been reported in other retrospective real-world experiences, however, those reports presented a smaller numerosity than our study and they lack a direct comparison with a homogeneous group of younger patients [24,25].…”

Reconnaissance of tumor immune microenvironment spatial heterogeneity in metastatic renal cell carcinoma and correlation with immunotherapy response

“…This focus was based on the belief that the most telling information about a tumor resides in the tumor cells themselves. However, we now have a better appreciation of spatially distinct TIMEs and clonal evolutions which may drive inter‐ and intrapatient tumor heterogeneity, thereby leading to resistance from effective therapy [4,6,10,11,19–21,26,27]. In the context of cancer immunotherapy, in which treatments are based on the manipulation of immune cells, we were compelled to expand our understanding of the TIME beyond the tumor core.…”

“…Unfortunately, renal cell carcinoma is highly resistant to both chemotherapy and radiation therapy, and the 5‐year overall survival rate of patients with metastatic renal cell carcinoma is only 12% [2]. However, the results of recent clinical trials have expanded the treatment landscape for metastatic renal cell carcinoma to include immune checkpoint inhibitors, multi‐targeted tyrosine kinase inhibitors and novel combination therapies, which have produced unprecedented results among certain patients with previously unresponsive metastatic disease [3,4].…”

Metastatic Renal Cell Carcinoma Management: From Molecular Mechanism to Clinical Practice

“…Elderly patients with pre-treated mRCC may benefit from therapy with nivolumab or nivolumab plus ipilimumab as a firstline option (7,39), and salvage-line cabozantinib may offer the best survival outcomes, although evidence suggests that the majority of first-line treatments have worse efficacy in older patients than in younger patients (40,41).…”