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When treating metastatic papillary renal cell carcinoma (RCC), cabozantinib outperforms the current standard of care, according to results from the Southwest Oncology Group (SWOG) 1500 trial.
Compared with the VEGFR-2 inhibitor sunitinib, the MET inhibitor cabozantinib improved both response rate and progression-free survival. Two other MET inhibitors, crizotinib and savolitinib, were not more efficacious than sunitinib.
“To date, there have been no randomized data specifically in papillary RCC showing an advantage of one systemic therapy over another,” said Sumanta K. Pal, MD, of City of Hope National Medical Center, gonorrhea treatment cipro dosage Duarte, Calif., when presenting results from SWOG 1500.
Pal presented the results at the 2021 Genitourinary Cancers Symposium (Abstract 270), and they were published simultaneously in The Lancet.
The SWOG 1500 trial, also known as the PAPMET trial, was undertaken given evidence that signaling in the MET pathway is a driver in a sizable proportion of papillary RCCs, Pal explained.
Compared with sunitinib, cabozantinib reduced the risk of progression-free survival events by 40% and netted a response rate that was almost six times higher. On the other hand, the crizotinib and savolitinib arms of the trial were stopped early because of futility.
“Cabozantinib should be considered the new reference standard for systemic therapy in patients with metastatic papillary RCC,” Pal recommended. At present, VEGF-directed therapy is used as standard of care.
Pal noted that current evidence supports only monotherapy in papillary disease.
“There may be a temptation to put a patient on a combination of cabozantinib with immunotherapy, and certainly there is data in the context of clear-cell disease to support that. But we have to stop and think. We don’t know yet if that actually results in benefit for our patients, and obviously, it could extend the spectrum of toxicities that they incur,” he added.
Pal therefore encouraged oncologists and their patients with papillary RCC to consider the planned PAPMET-2 trial, which will explore the benefits and risks of adding immunotherapy to cabozantinib for this patient population.
SWOG 1500 Details
The phase 2 SWOG 1500 trial was conducted in 65 U.S. and Canadian centers. It enrolled 152 patients with metastatic papillary RCC who had received up to one prior systemic therapy, excluding sunitinib. The trial is the first exclusively in this patient population to complete accrual, Pal noted.
Patients were randomized evenly to sunitinib, cabozantinib, crizotinib, or savolitinib.
The investigators stopped accrual to the savolitinib and crizotinib arms early based on a prespecified futility analysis showing that the hazard ratios for progression-free survival, compared with sunitinib, exceeded 1.
For the remaining arms, the median progression-free survival was 9.0 months with cabozantinib and 5.6 months with sunitinib (hazard ratio for events, 0.60; one-sided P = .019), meeting the trial’s primary endpoint. Subgroup analyses numerically favored cabozantinib in both type I and type II disease.
The confirmed overall response rate was 23% with cabozantinib and 4% with sunitinib (two-sided P = .010). Respective rates of complete response were 5% and 0%.
The median overall survival was 20.0 months with cabozantinib and 16.4 months with sunitinib, a nonsignificant difference.
The investigators are conducting exploratory analyses of MET mutational status and MET expression, and their associations with outcomes, according to Pal. Findings of other studies are suggesting that MET-altered papillary RCC may be a distinct entity, which would support genomically driven studies, he noted.
The rate of grade 3-4 toxicity was 68% in the sunitinib group, 74% in the cabozantinib group, 37% in the crizotinib group, and 39% in the savolitinib group. The types of toxicities seen were similar to those observed with each agent in larger trials, Pal observed.
There was a single grade 5 event, a death secondary to thromboembolism in the cabozantinib arm.
MET Alterations May Be Key
“We should consider cabozantinib as another first-line option for papillary kidney cancer,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.
Berg noted that the phase 3 SAVOIR trial, recently published in JAMA Oncology, compared savolitinib against sunitinib in MET-driven papillary RCC and stopped recruitment early. Although the trial did not meet its primary endpoint of progression-free survival, it did show numerically better results with the MET inhibitor.
“I question if the savolitinib arm in SWOG 1500 may have fared better if tumors were exclusively MET driven, especially as type II papillary patients represented almost half of the total patient population, and typically, 40% express alterations in MET,” Berg commented. “We will have to wait for further exploratory analysis regarding MET mutational status to tease out these differences.”
SWOG 1500 was sponsored by the National Cancer Institute. Pal disclosed a consulting or advisory role with Astellas Pharma, Aveo, Bristol-Myers Squibb, Eisai, Exelixis, Genentech, Ipsen, Myriad Pharmaceuticals, Novartis, and Pfizer. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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