Cabozantinib improves PFS, response in metastatic papillary RCC

In patients with metastatic papillary renal cell carcinoma (PRCC), cabozantinib led to greater progression-free survival (PFS) and overall response rate (ORR) than sunitinib, results of the phase II SWOG 1500 study showed.

The participants, enrolled from 65 centres in US or Canada between April 2016 and December 2019, were 152 adults with metastatic PRCC and a Zubrod performance status of 0–1 who had received up to one prior systemic therapy (except VEGF*- or MET-directed agents [no prior sunitinib]). They were randomized (open-label) 1:1:1:1 to one of four oral treatments – sunitinib (50 mg/day on a 4-weeks-on, 2-weeks-off schedule), cabozantinib (60 mg/day), crizotinib (250 mg BID), or savolitinib (600 mg/day) until radiographic progression, clinical deterioration, or unacceptable toxicity, with specific dose reductions permitted**.

Of the 147 patients included in the analysis (median age 66 years, 76 percent male), 46, 44, 29, and 28 were assigned to the sunitinib, cabozantinib, savolitinib, and crizotinib arms, respectively. Seven percent had previously received systemic therapy, 77 percent had undergone nephrectomy, and 61 percent were IMDC*** intermediate risk group. A majority of patients had type 2 histologic subtype (54 and 43 percent as per local and central assessment, respectively).

PFS was significantly longer in patients assigned to cabozantinib than sunitinib (median 9.0 vs 5.6 months; hazard ratio [HR], 0.60, 95 percent confidence interval [CI], 0.37–0.97; 1-sided p=0.019). [ASCO GU 2021, abstract 270; Lancet 2021;doi:10.1016/S0140-6736(21)00152-5]

“The estimated treatment effect within each histological subset was consistently in the favourable direction for cabozantinib,” said the authors.

The ORR with cabozantinib was also greater than that with sunitinib (23 percent vs 4 percent; 2-sided p=0.010). Complete response was observed in two patients in the cabozantinib group (5 percent) and none in the other treatment groups. Partial response occurred in two, eight, and one patient in the sunitinib, cabozantinib, and savolitinib groups, respectively.

With no PFS improvement with savolitinib or crizotinib vs sunitinib, enrolment to these arms was closed following prespecified futility analysis (after 15 PFS events in each experimental arm) in December 2018 (median PFS 3.0 and 2.8 months, respectively; ORRs, 3 and 0 percent, respectively).

Overall survival (OS) did not significantly differ between groups (median 16.4, 20.0, 19.9, and 11.7 months with sunitinib, cabozantinib, crizotinib, and savolitinib respectively), though there was a trend toward improved OS with cabozantinib vs sunitinib (HR, 0.84, 95 percent CI, 0.47–1.51).

Grade 3–4 adverse events (AEs) occurred more frequently in sunitinib (69 percent) and cabozantinib (74 percent) than crizotinib (37 percent) or savolitinib (39 percent) recipients. The most common grade 3–4 AEs were hypertension, anaemia, and decreased white blood cell count with sunitinib, hypertension, hand-foot syndrome, and fatigue with cabozantinib, fatigue and increased ALT with crizotinib, and hyponatraemia, thrombocytopenia, and limb swelling with savolitinib. One grade 5 thromboembolic event occurred in a cabozantinib recipient.

“The safety profiles of all drugs were consistent with previous studies,” the authors noted.

Study drug AE-related treatment discontinuation occurred in 24, 23, 14, and 10 percent of sunitinib, cabozantinib, crizotinib, and savolitinib recipients, respectively. At last follow-up, 16 patients remained on protocol treatment.

Cabozantinib: A new standard for PRCC?

“PRCC is a rare entity, constituting 15 percent of cases of RCC,” presented Professor Sumanta Pal from the City of Hope Comprehensive Cancer Center, Duarte, California, US, at ASCO GU 2021.

“VEGF-directed therapies have constituted a standard of care in this disease, but the estimates of efficacy of VEGF-directed therapy vary.” Response rates range from 0–24 percent and PFS from 1.6–8 months, he said.

“[The SWOG 1500 results suggest that] cabozantinib should be considered the new reference standard for systemic therapy in patients with metastatic PRCC,” concluded Pal.

“Our findings [also] imply that PRCC might be driven by both VEGF-signalling and MET-signalling pathways, and thus might be more amenable to targeting with a dual VEGF-MET inhibitor such as cabozantinib,” said Pal and co-authors.