Patients with metastatic renal cell carcinoma treated in a phase 2 trial had statistically significant and clinically significant improvements in survival without progression (PFS) with cabozantinib (Cabometyx) versus sunitinib (Sutent), followed by to a 40% reduction in disease risk. progress or death and achievement of the main end point of the tests.
These results were taken from a randomized study SWOG 1500 (NCT02761057) presented during the 2021 Genitourinary Cancer Symposium. The median SDP with cabozantinib was 9.0 months versus 5.6 months with sunitinib (HR 0.60; 95% CI, 0.37–0.97; 1-sided P. = .019).
The representative also had a significantly higher response rate compared to sunitinib, at 23% versus 4.0%, respectively, in this population (bilateral P. = .010). Complete responses were observed only among those who received cabozantinib. Furthermore, although sunitinib was also compared with crizotinib (Xalkori) and savolitinib (AZD6094), those arms of the study were terminated prematurely in an income study, as it did not show none of them have an advantage in PFS compared to sunitinib.
“Although disorders were observed in subtype classification, cabozantinib had a homogenous effect across treatment groups,” points out the author Sumanta K. Pal, MD, FASCO, who is also a medical oncologist and senior assistant clinical professor in the Department of Medical Oncology and Medicine Research at City of Hope said, in an oral presentation of the data. “With this in mind, cabozantinib should be considered as the new reference level for systemic treatment in patients with metastatic papillary RCC.”
Papillary RCC is a malignancy, making up 15% of all RCC cases. Targeted VEGF therapies, such as sunitinib, have previously improved the status of care in these patients; however, estimates of the effectiveness of these options differ, Pal noted. Response rates for these treatments across postoperative and prospective series range from 0% to 24% and SDP has gone from 1.6 months to 8.0 months.
“So far, no random data has been specifically entered [patients with] Papillary RCC shows the benefit of 1 systemic therapy over another, ”said Pal.
Multiple studies have suggested that the MET proto-oncogene may be a potential driver of papillary RCC. Although it is more common in type I compared to type II disease, the MET mutation and copy change occur in a proportion of both subtypes. In the SWOG 1500 trial, researchers attempted to determine whether different MET inhibitors could improve clinical outcomes compared with sunitinib in patients with metastatic papillary RCC.
In particular, the SWOG 1500 is the first randomized trial to enroll patients with metastatic papillary RCC only and complete ejaculation. To be eligible for enrollment, patients had to be histologically diagnosed with papillary RCC and measurable disease. Patients were allowed to be admitted if they had received 0 to 1 line of prior treatment, as long as they had not previously received treatment with sunitinib. In addition, patients had to have a Zubrod performance status from 0 to 1.
Patients were randomized 1: 1: 1: 1 to arms sunitinib, cabozantinib, crizotinib, or savolitinib. Participants were confirmed based on disease subtype (type I vs II vs. not otherwise identified [NOS] per local study) and the number of prior treatments (0 vs. 1). The main endpoint of the SDP study was, while secondary endpoints included total survival (OS), response rate, adverse effects (AEs). Monitoring assessments on MET mutational status and MET feeling persists.
A key part of the overall study design was the use of a coordinated moderate pathologic review, Pal noted. Images of locally reviewed figs were reviewed with 3 main pathologies and were classified as either type I pRCC, type II pRCC, or pRCC NOS. Mixed traits in samples were seen as pRCC NOS, and any discrepancies in sample type were classified according to majority opinion. If no agreement was reached, samples were reviewed or classified as pRCC NOS, Pal explained.
In particular, the design of the study allowed dose reduction for each agent used. In the trial, oral sunitinib was delivered on the usual 4-week-ahead, 2-week-off schedule, at a daily dose of 50 mg, with a dose reduction to 37.5 mg and 25 mg allowed. Oral cabozantinib was delivered at a daily dose of 60 mg, with dose reduction to 40 mg and 20 mg allowed. In addition, oral crizotinib was administered at a twice – daily dose of 250 mg, with reductions to twice daily 200 mg and 250 mg once daily permissible. Finally, oral savolitinib was administered at a daily dose of 600 mg, with dose reduction to 400 mg and 200 mg allowed.
The researchers ’main assumptions were that PFS for sunitinib would be around 6 months, with comparable arms achieving a PFS of 10.5 months. As is typical for a randomized phase 2 study, researchers studied a 1-sided alpha with 0.1 with a beta of 85%. With these considerations in mind, 41 patients per study arm would be required, for a total of 164 patients. In making up 10% of ineligible patients, investigators assumed that they needed to have 4 additional patients for each examination arm, for a total of 180 patients.
In addition, ordered income analysis was performed after 15 SDP events were reported in each experimental arm and 20 SDP events occurred in the sunitinib arm. If the HR PFS was greater than 1 for MET inhibitor against sunitinib, the arm was recommended for closure.
From April 2016 to December 2019, a total of 152 patients were enrolled for the SWOG 1500 test at 65 cancer centers across the United States and Canada. As a result of the future analysis, the savolitinib and crizotinib arms were shut down in December 2018.
Patients had a median age of 66 years (range, 29–89), and the majority were male (75%) and white (77%). Very few patients received prior systemic treatment (7%), and as expected by researchers, a minority of patients had type I histology, ranging from 17% to 20% over study arms. In addition, the majority of patients were at moderate risk according to the International RCC Metastatic Database Risk Group criteria (61%). In addition, 61% had a performance rating of 0, and 39% had a rating of 1.. Mixed histologies were observed in 15% to 24% of patients and over 70% of patients had preoperative nephrectomy. Very few patients with metastases of the central nervous system (less than 1%).
Disorders based on pathologic subtype have also been predicted. Thirteen patients were classified according to local assessment with type I disease and were noted to have type 2 disease on moderate assessment, Pal said. In contrast, 3 patients with type II disease per local assessment were identified as having type I with moderate assessment.
“Ultimately these did not appear to have a significant impact on the key findings from our study,” said Pal. “Regardless of the median and local assessment, patients with type I and type II disease appeared to benefit from cabozantinib. ”
OS will continue to follow among the arms of studies, but in projections, no significant differences were observed between the arms examined, Pal said. Notably, however, a slight shift toward OS is better in the cabozantinib arm compared to the sunitinib arm, at 20.0 months versus 16.4 months, respectively.
Level 3/4 AE was reported in 68% of patients in the sunitinib arm, 74% of patients in the cabozantinib arm, 37% of patients in the crizotinib arm, and 39% of patients in the arm savolitinib. Toxins observed by the reps in SWOG 1500 were similar to those reported in larger studies, Pal noted. Moreover, the rate of treatment discontinuation due to AEs was associated with study medication at the highest level with sunitinib (24%), followed by cabozantinib (23%), crizotinib (16%), and savolitinib (10%). Sixteen patients remained on protocol at the time of the last follow-up.
Level 3/4 laboratory toxins with sunitinib, cabozantinib, crizotinib, and savolitinib have occurred in 68%, 74%, 37%, and 39%, of patients, respectively. One stage 5 effect was observed in the cabozantinib arm, secondary to thromboembolic event, Pal concluded.
Information:
Sumanta K. Pal, Catherine Tangen, et al. Sunitinib versus cabozantinib, crizotinib or savolitinib in papillary metastatic renal cell carcinoma (pRCC): Results from the SWOG 1500 stage II randomized study. J Clin Oncol. 2021; 339 (solair 6): 270. doi: 10.1200 / JCO.2021.39.6_suppl.270