According to results of the randomized phase II CABOSUN trial,<span style="font-size:10.8333px"> </span>PFS was improved with sunitinib as initial systemic therapy across subgroups of patients with intermediate- and poor-risk advanced renal cell carcinoma. The advantage to cabozantinib on PFS was particularly strong in patients who were MET-positive.
Daniel J. George, MD
According to results of the randomized phase II CABOSUN trial,1progression-free survival (PFS) was improved with sunitinib (Sutent) as initial systemic therapy across subgroups of patients with intermediate- and poor-risk advanced renal cell carcinoma (RCC). The advantage to cabozantinib on PFS was particularly strong in patients who were MET-positive.
Daniel J. George, MD, presented CABOSUN outcomes by subgroup at the 2018 Genitourinary Cancers Symposium.
The hazard ratio (HR) for PFS, as well as the objective response rate (ORR), favored cabozantinib across all subgroups analyzed. The HR for PFS in favor of cabozantinib was improved dramatically in patients with positive MET status (HR, 0.32; 95% CI, 0.16-0.63), reported George, professor of medicine at Duke University Cancer Center, Durham, North Carolina.
CABOSUN compared cabozantinib with sunitinib in 157 previously untreated patients with RCC of poor and intermediate risk. Patients were randomized 1:1 to receive oral cabozantinib, 60 mg once daily (n = 79), or oral sunitinib, 50 mg once daily, for 4 weeks on/2 weeks off (n = 78). Treatment was administered until disease progression or intolerable toxicity. Approximately two-thirds of patients in each group received subsequent cancer therapy at progression.
In the overall study population, cabozantinib-treated patients had a median PFS per an independent review committee of 8.6 months compared with 5.3 months for patients treated initially with sunitinib.2The difference represented a 52% reduction in the hazard for disease progression or death. The ORR was 20% with cabozantinib and 9% with sunitinib. Intermediate-risk patients accounted for 81% of the study population. Key clinical features included bone metastases in about 36% of patients, prior nephrectomy in 75%, and 3 or more metastatic sites in about 35%. The most common sites of metastasis were lung (70%), lymph nodes (55%), and bone (38%).
When PFS and ORR were examined by subgroup based on age, sex, risk group, presence or absence of bone metastases, MET status, Eastern Cooperative Oncology Group performance status, the time from diagnosis to randomization, receipt/no receipt of prior nephrectomy, tumor volume, the number of metastatic sites, and location of metastases, HRs and odds ratios favored cabozantinib over sunitinib in each.
“MET status is something we looked at in the primary tumors, and about half of the patients were MET-positive, and in that subgroup, we saw a significant shift in favor of cabozantinib treatment, which validates the MET inhibition that comes with cabozantinib and the clinical significance that comes with that,” George said.
In patients with positive MET status, median PFS was 13.8 months in the cabozantinib arm versus 3.0 months in the sunitinib. In patients with negative MET status, median PFS was 6.9 and 6.1 months in favor of cabozantinib (HR, 0.67; 95% CI, 0.37-1.23). “This is both a negative prognostic factor for this population and a predictive factor for benefit with cabozantinib,” George said.
Patients with lower tumor volume and with 1 metastatic organ site involved appeared to have a more robust benefit with cabozantinib.
When assessed by risk group, cabozantinib again proved superior on PFS in both intermediate-risk and poor-risk subsets. In the former, the median PFS was 11.4 months with cabozantinib and 6.1 months with sunitinib (HR, 0.52; 95% CI, 0.32-0.82). In the poor-risk subset, the median PFS was 6.8 months in the cabozantinib arm versus 2.7 months in the sunitinib arm (HR, 0.31; 95% CI, 0.11-0.92).
Patients with and without bone metastases also had better PFS with cabozantinib. In those with bone metastases, median PFS was 5.5 and 3.3 months (HR, 0.51; 95% CI, 0.26-0.99) in the cabozantinib and sunitinib arms, respectively. In those without bone metastases, median PFS was 11.4 and 5.7 months in favor of cabozantinib (HR, 0.50; 95% CI, 0.29-0.85).
When asked if cabozantinib should be first-line treatment in a MET-negative intermediate- or poor-risk patients, George replied that subgroup data should be used to generate hypotheses. “I think we have to recognize this as not necessarily a definitive analysis, either by threshold…or by positive or negative status,” he said. “The fact is that we still see a trend in favor of cabozantinib in the MET-negative patients, so I wouldn’t go so far as to say that’s a population that shouldn’t get cabozantinib.”