ASCO GU 2018: Best of Journals: Kidney Cancer - Medical Oncology
Dr. Stenberg starts her presentation discussing the results of the CheckMate-214 trial. The CheckMate-214 trial assessed the combination of nivolumab (PD-1inibitor) and Ipilimumab (CTLA-4 inhibitor) versus Sutent in the treatment of patients with newly diagnosed metastatic kidney cancer. The trial recruited approximately 1100 patients with most of them presenting with intermediate (60%) and poor risk (17%) disease. All tumors were tested for PD-L1 expression on trial entry, with those presenting with favorable-risk disease showing significantly lower baseline expression level. The response rate in the NIVO+IPI groups was an astonishing 42% for patients with intermediate and poor-risk disease, compared to 27% in the Sutent group (p<0.0001). The CR rate was also significantly higher with 9% of patients in the NIVO-IPI group achieving and complete response compared to 1% in the Sutent group. On OS assessment, intermediate and poor-risk patients treated with NIVO+IPI has a 37% reduction in the risk of death (HR 0.63 [CI 0.44-.89], p<0.001) at a median follow-up of 25.2 months. PD-L1 tumor expression was noted to be a predictor of NIVO+IPI response in patients with intermediate and poor-risk disease, which will require further evaluation in follow-up trials. Surprisingly, patients with favorable-risk disease showed significantly higher response rates when treated with Sutent (52%) compared to NIVO+IPI (29%). NIVO+IPI is set to become the standard of care for the treatment of intermediate and poor-risk patents with treatment-naïve metastatic kidney cancer.
Cabozantinib, a small oral molecule inhibitor, which not only targets VEGFR pathways but also the MET and AXL pathways was found to be significantly superior to everolimus in the METEOR trial. Following the encouraging results of the METEOR trial, the Cabsun Phase II trial was launched assessing the use of cabozantinib in the first-line setting for patients with intermediate and poor-risk disease. The trial recruited a total of 157 patients who were randomized (1:1) to received cabozantinib or Sutent. The overall response rates for the cabozantinib group was remarkable with 46% of patients showing a response compared to 18% in those receiving Sutent. The trial met their primary end-point, progression-free survival (PFS), with those receiving cabozantinib having a 52% risk reduction of disease progression compared to the Sutent group. An early separation of the overall survival curves was observed but the difference is not yet statistically significant, which may be related to the short follow-up. Cabozantanib has also arisen as a possible new treatment option for untreated intermediate or poor-risk metastatic cancer patients; we would have to wait for the results of the phase III trial currently underway to see if this advantage holds.
Dr. Sternebrg finishes her discussion with a review of the newly published results from the S-TRAC and PROSPER trials. S-TRAC, which randomized 615 patients to sunitinib yielded positive results with a reported median DFS of 6.8 years in the sunitinib group compared to 5.6 years in the placebo group (HR 0.76 [CI 0.59-0.98] p = 0.03). S-TRAC like ASSURE, had a relatively high treatment-related discontinuation rate of 28%, with 48% of patients in the treatment arm experiencing grade 3 or 4 adverse events. Despite a lack of benefit in overall survival in S-TRAC, these data have recently led to FDA approval for the adjuvant use of sunitinib in high risk kidney cancer after surgical resection. The preliminary results of the PROTECT trial107 (adjuvant pozapanib) were recently reported showing a difference in DSF in patients who tolerated the higher dose of pazopanib (HR 0.69 [CI 0.51-0.94], p = 0.02). Unfortunately, only 26% of the cohort was able to tolerate the 800mg dose of pazopanib with the remainder needing the dose to be reduced to 600mg. Analysis of the 600mg group showed no difference in DSF at a median follow-up of 30 months, with neither arm reaching median DFS. A recent report noted the importance of the circulating pazopanib concentration, showing that patients with Cthrough > 20.5 ug.ml had significantly reduced risk of recurrence (HR 0.56 [CI 0.34-0.92], p=0.0055), compared to those with lower concentrations. Future trials focusing on the optimal pazopanib concentrations that optimizes cancer control while reducing side effects are needed in order for adjuvant therapy to become more common.
As we wait for the results of SORCE, EVEREST and ATLAS, the current available evidence does not support the use of TKI therapy in the adjuvant setting. It is yet to be determined how the FDA’s approval of sunitinib in the adjuvant setting for high-risk patients (UISS 2-3) with clear cell histology will affect care or future clinical trial design. The prolonged median DFS intervals noted in the placebo groups in addition to the high rates of side effects in these trials argue for a judicious use of TKIs in the adjuvant setting. The results of these trails have demonstrated that we are in need of better prognostic models and biomarkers.
Presented by: Cora N. Sternberg, MD, FACP, San Camillo-Forlanini Hospital Rome, Italy
Written by: Andres F. Correa, MD, Fox Chase Cancer Center, Philadelphia, PA at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA