Cabozantinib May ‘Supplant Sunitinib’ For Metastatic Papillary RCC

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Phase II trial results suggest that cabozantinib may offer significantly better progression-free survival (PFS) for metastatic papillary renal cell carcinoma (PRCC) patients than sunitinib, savolitinib or crizotinib. 

The SWOG 1500 study findings were presented at the 2021 Genitourinary Cancers Symposium by Sumanta Pal, from City of Hope Comprehensive Cancer Center in Duarte, California, USA, and reported simultaneously in The Lancet. 

“The response rate and progression-free survival associated with cabozantinib in this study establish a benchmark for future trials in this disease state”, the investigators say.  

And noting that US and European regulatory agencies do not specify advanced RCC histological features on their current approvals, the authors suggest that the SWOG 1500 results may mean “cabozantinib could supplant sunitinib as a clinical standard of care for patients with metastatic papillary kidney cancer.” 

The open-label trial included 147 PRCC patients who had received no more than one prior treatment for metastatic disease, and had not previously received VEGF- or MET-directed agents.  

PFS was longer for the 44 patients who were randomly assigned to receive cabozantinib 60 mg/day than for the 46 patients who instead were given sunitinib 50 mg on a 4-week on, 2-week off regimen, at a median 9.0 and 5.6 months, respectively. The hazard ratio (HR) for progression or death was a significant 0.60. 

A prespecified futility analysis halted patient accrual to the treatment arms for savolitinib 600 mg/day and crizotinib 250 mg twice daily when neither treatment showed an improvement in PFS compared with sunitinib. At final analysis, the median PFS durations were 3.0 and 2.8 months, respectively, say Pal et al. 

The overall response rate was 23% for cabozantinib, significantly higher than the 4% rate with sunitinib, and both complete responses occurred in the cabozantinib arm. 

At preliminary assessment, median overall survival was a comparable 20.0 months with cabozantinib and 16.4 months with sunitinib, and follow-up continues. 

Overall, 74% of cabozantinib-treated patients developed grade 3 or 4 adverse events, as did 69% of those given sunitinib, and 39% and 37% of the savolitinib and crizotinib arms, respectively. 

One patient died from a thromboembolic event within 30 days of their last cabozantinib dose. 

While recognising the potential benefits of a phase III trial to confirm their findings, the investigators say that the “feasibility of such an endeavour is questionable” as earlier attempts have failed to accrue enough patients. 

“Given the emerging activity with cabozantinib-based combinations with checkpoint inhibitors in both patients with clear-cell and those with non-clear-cell renal cell carcinoma, a study comparing cabozantinib with or without checkpoint inhibitor in patients with PRCC would be of interest”, they conclude. 

Writing in a linked comment, Delphine Borchiellini, from Université Côte d’Azur in Nice, France, and Philippe Barthélémy, from Institut de Cancérologie Strasbourg Europe in France, note that up to 24% of tumours initially thought to be PRCC in the study were subsequently found in central review to have a different histology, leading to a difference in the proportion of poor prognosis type 2 PRCC tumours across the treatment groups.

“However, Pal and colleagues provided a prespecified estimation of the cabozantinib effect within each histological subset according to local or central assessment, which did not seem to modify the favourable results for cabozantinib”, they observe.

The commentators suggest: “Ideally, the next step might be to assess the efficacy of first-line combinations of either cabozantinib (in allcomers) or MET inhibitors (in MET-driven tumours) with immunotherapy in a randomised clinical trial dedicated to metastatic PRCC, providing a central histological review before inclusion.

“But to date, Pal and colleagues’ study provides the best level of evidence currently available for patients with advanced PRCC, and cabozantinib could be contemplated as a new option in this situation”, they conclude. 

References 

Pal SK, Tangen C, Thompson Jr, et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial. Lancet; Advance online publication 13 February 2021. DOI: 10.1016/ S0140-6736(21)00152-5

Borchiellini D, Barthélémy P. Cabozantinib: a new first-line option for papillary renal cell carcinoma? Lancet; Advance online publication 13 February 2021. DOI:10.1016/S0140-6736(21)00316-0