Cabozantinib Improved PFS in Firstline Papillary Renal Cell Carcinoma

By Michael Vlessides, /alert Contributor

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New research has demonstrated the efficacy of cabozantinib (Cabometyx; Exelixis, Inc.) in patients with metastatic papillary renal cell carcinoma.

The so-called SWOG 1500 study (NCT02761057) – which compared sunitinib (Sutent; Pfizer) with cabozantinib, crizotinib (Xalkori; Pfizer), and savolitinib (AstraZeneca) – concluded that when compared to sunitinib, only cabozantinib resulted in a statistically significant and clinically meaningful prolongation of progression-free survival in these patients. 

Presenting at the American Society of Clinical Oncology’s 2021 Genitourinary Cancers Symposium (abstract 270), the international, multi-center team of researchers explained that MET signaling is a key molecular driver in papillary renal cell carcinoma. “Given that there is no optimal therapy for metastatic papillary renal cell carcinoma, we sought to compare an existing standard (sunitinib) to putative MET kinase inhibitors,” they wrote. 

To that end, they enrolled 152 patients into the phase II trial, all of whom had pathologically verified papillary renal cell carcinoma, a Zubrod Performance Status of 0 or 1, and measurable metastatic disease. Patients who had received up to one prior systemic therapy – excluding VEGF-directed agents – were also eligible.

The participants were all randomized in equal fashion to receive one of four study drugs:

  • 50 mg oral once-daily sunitinib (4 weeks on/2 weeks off);

  • 60 mg oral once-daily cabozantinib;  

  • 250 mg oral twice-daily crizotinib; or 

  • 600 mg oral once-daily savolitinib. 

Patients were stratified according to both prior therapy and papillary renal cell carcinoma subtype (I vs II vs not otherwise specified) based on local review. The trial’s primary endpoint was progression-free survival. Secondary endpoints included response rate, overall survival, and toxicity. The investigators performed a pre-planned futility analysis after 50% of progression-free survival events had occurred.

According to lead investigator Sumanta K. Pal, MD, of the City of Hope National Medical Center in Duarte, California, the final study population comprised 147 patients (median age 66 years; 76% male) enrolled between April 2016 and December 2019. The overwhelming majority (92%) had no prior therapy. 

Local pathologic review characterized 18% with type I histology, 54% with type II histology, and the remaining 28% with not otherwise specified histology. By comparison, the frequency of type I, type II, and not otherwise specified histologies by central review was 30%, 45% and 25%, respectively. 

Pal reported that patient accrual was halted early in the savolitinib and crizotinib groups due to treatment futility (progression-free survival hazard ratio >1.0 for both). Nevertheless, accrual continued to completion in the sunitinib and cabozantinib arms. 

The study found that among these remaining patients, median progression-free survival was significantly greater with cabozantinib than it was with sunitinib. Specifically, in 39 events among 46 eligible sunitinib patients, median progression-free survival was 5.6 months. In 31 events among 44 cabozantinib patients, on the other hand, median progression-free survival was 9.2 months (0.61 hazard ratio; p=0.021). 

Median progression-free survival was 3.0 months among savolitinib patients (HR 1.25; p=0.81) and 2.8 months among crizotinib patients (HR 1.14; p=0.69).

Adverse events of either grade 3 or grade 4 were observed in 69% of sunitinib patients, 72% of cabozantinib patients, 37% of crizotinib patients, and 39% savolitinib patients. One grade 5 adverse event was seen with cabozantinib. 

These findings, the investigators concluded, demonstrate that only cabozantinib treatment yielded a statistically significant and clinically meaningful prolongation of progression-free survival relative to sunitinib. “These data,” they wrote, “support cabozantinib as a reference standard for eligible patients with metastatic papillary renal cell carcinoma.”

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