Cabozantinib prolongs progression-free survival compared to sunitinib in metastatic papillary renal cell carcinoma

Results of the phase II SWOG 1500 trial show that the MET inhibitor cabozantinib significantly delays disease progression compared to sunitinib in the treatment of patients with metastatic papillary renal cell carcinoma (pRCC). Cabozantinib was also associated with a significantly higher response rate than sunitinib and even induced a complete response in a proportion of patients. As such, these data identify cabozantinib as a potential new standard of care for the treatment of this patient population, which has largely been ignored in clinical trials for RCC.

Introduction

pRCC is rare type of kidney cancer, constituting approximately 15% of all RCC cases. For these patients, VEGF-directed therapies have become the standard of care, although the estimate of survival benefit varies in clinical trials. Meanwhile, multiple studies have identified the proto-oncogene MET as a potential driver in pRCC. Moreover, MET is expressed in both type I and type II pRCC subtypes making it an interesting therapeutic target, In the phase II SWOG 1500 trial three different MET inhibitors were compared to sunitinib as a treatment modality for patients with metastatic pRCC.

The study at hand enrolled 152 pRCC patients with metastatic disease to receive either cabozantinib (60 mg daily) (N= 44), sunitinib (50 mg daily, 4 weeks on, 2 weeks off) (N= 46), crizotinib or savolitinib. Previously, the crizotinib and savolitinib arms were terminated for futility. Participants were allowed to be pre-treated with up to 1 prior systemic therapy, excluding VEGF- or MET-directed agents, and were stratified by pRCC subtype (type 1 vs. type 2 vs. not otherwise specified [NOS]). The primary outcome of this study was progression-free survival (PFS), with secondary objectives including overall survival (OS), response rate and safety.

Benefit with cabozantinib observed in both Type I & II pRCC

The median age of patients in the study was 65 years old in both the sunitinib and cabozantinib arms, with approximately 80% of patients being male. In both arms, about 5% of patients received prior systemic therapy. When assessed centrally, 32% of patients in both arms were found to have type I disease, with 36% and 46% of sunitinib and cabozantinib patients having type II disease. The vast majority of patients had a favourable or intermediate risk according to IMDC criteria (87% in both arms) and over 70% of participants had a prior nephrectomy.

Cabozantinib significantly improved the PFS compared to sunitinib, with a median PFS of 9.0 and 5.6 months, respectively (HR[95%CI]: 0.60[0.37-0.97], P= 0.019). Importantly, botho type I and type II patients derived a similar PFS benefit from cabozantinib (Type I HR[95%CI]: 0.56[0.22-1.45]. Type II HR[95%CI]: 0.62[0.31-1.24]). Also the overall response rate (ORR) was significantly improved with cabozantinib compared to sunitinib with rates of 23% and 4%, respectively (P= 0.010). Of note, 5% of the patients in the cabozantinib arm obtained a complete response (vs. no complete responses were achieved with sunitinib. At the time of this analysis, OS data were not yet mature but indicated a median OS of 20.0 months with cabozantinib as compared to 16.4 months with sunitinib.

Grade ≥3 toxicities with sunitinib and cabozantinib were reported in 68% and 74%, respectively. The type of these adverse events was consistent with the known toxicity profiles of both drugs. Treatment-emergent adverse events (TEAEs) leading to treatment discontinuation occurred in 24% of patients receiving sunitinib, and in 23% of those receiving cabozantinib. One grade 5 haematological toxicity occurred with cabozantinib, following a thromboembolic event.

Conclusion

The phase II SWOG 1500 trial is the first study of pRCC to complete accrual. The study showed that cabozantinib significantly prolongs the PFS compared to sunitinib with a significantly higher response rate. This PFS benefit was observed regardless of pRCC subtype. In contrast, savolitinib and crizotinib did not improve PFS during futility analysis and these study arms were subsequently terminated. At this time, OS data were inconclusive, but follow-up will continue. Combined with a manageable safety profile of cabozantinib, these data identify cabozantinib as a potential new therapeutic standard for patients with metastatic pRCC.

Reference

Pal SK et al., Sunitinib versus cabozantinib, crizotinib or savolitinib in metastatic papillary renal cell carcinoma (pRCC): Results from the randomized phase II SWOG 1500 study. Presented at ASCO GU 2021; Abstract 270.