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The management of advanced renal cell cancer (RCC) has evolved into a sequential paradigm since the current generation of agents targeting the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin (mTOR) pathways have demonstrated clinical activity. However, essentially no patients achieve complete response to these agents.
In the phase III AXIS trial, axitinib (a second-generation inhibitor of VEGFR) was compared to sorafenib (a first-generation VEGFR inhibitor) in 723 patients with advanced RCC following disease progression after one initial treatment regimen; 54% had received sunitinib therapy, and 35% had received cytokine therapy. Most patients were considered to have good- or intermediate-risk disease according to Memorial Sloan Kettering criteria. Patients were randomized to axitinib (5 mg twice daily, titrated up to 10 mg twice daily) or sorafenib (400 mg twice daily).
Axitinib recipients achieved longer median progression-free survival (PFS; the primary endpoint) than did sorafenib recipients (6.7 vs. 4.7 months; hazard ratio, 0.665; P<0.0001). The two agents had similar safety profiles, except that axitinib was associated with more hypertension and hypothyroidism but less hand-foot syndrome, rash, and alopecia.
The management of advanced prostate cancer has been shifting rapidly since the recent approvals of sipuleucel-T (JW Oncol Hematol Jul 28 2010), cabazitaxel (JW Oncol Hematol Oct 26 2010), denosumab (JW Oncol Hematol Apr 5 2011, and abiraterone (JW Oncol Hematol May 25 2011). Now, given that high levels of hepatocyte growth factor receptor MET are associated with bone metastases, and that cabozantinib is known to block both VEGFR and MET in vivo, investigators have conducted a randomized, phase II discontinuation study to evaluate the objective response rate and PFS associated with the tyrosine kinase inhibitor (TKI) cabozantinib in patients with metastatic castration-resistant prostate cancer (mCRPC).
Patients with progressive, measurable mCRPC who had received ≤1 prior chemotherapy regimen were administered cabozantinib (100 mg daily) during a 12-week, open-label, lead-in stage. Patients who achieved a partial or complete response continued receiving cabozantinib, and those with stable disease were randomized to cabozantinib versus placebo. A total of 171 were enrolled, but randomization was stopped at 122 patients after a clinical benefit of cabozantinib was demonstrated.
Seven patients (4%) achieved a partial response, and 135 (79%) achieved stable disease. Most patients experienced regression of soft-tissue disease, and many achieved partial or complete resolution of lesions on bone scans at 12 weeks. Improvement on bone scans seems to be correlated with decreases in bone pain and opioid requirements and improvement in PFS at 6 months. Toxicities with cabozantinib were similar to those with other TKIs, including fatigue, hypertension, decreased appetite, diarrhea, and hand-foot syndrome. Prospective studies of this agent in prechemotherapy mCRPC patients are ongoing.
Following an interim analysis of the COU-AA-301 trial (JW Oncol Hematol May 25 2011), the FDA approved abiraterone for men with progressive mCRPC after docetaxel-based chemotherapy. Now, data from the second preplanned interim analysis of COU-AA-301 show that median overall survival (OS) with abiraterone versus placebo improved from 3.9 months (at median follow-up of 12.8 months) to 4.6 months (at median follow-up of 20.2 months).
Given the recent FDA approvals of sipuleucel-T, abiraterone, and cabazitaxel — all of which demonstrated improvement in OS — concern is emerging that additional drug approval might be slowed by the regulatory requirement to show OS improvement. To explore the potential for using surrogate biomarkers for regulatory qualification, investigators in the COU-AA-301 trial included assessment of circulating tumor cells (CTCs) using the FDA-validated Veridex CellSearch system.
In trials involving docetaxel-based chemotherapy, CTC number was shown to be prognostic for OS at baseline and more prognostic posttreatment than a 50% decline in prostate-specific antigen (PSA) level. Of note, because PSA production is mediated by the androgen receptor (AR), therapies that target the AR might lead to PSA changes unrelated to an antitumor effect. Using predefined cutoffs of CTC ≥5 as unfavorable counts and CTC <5 as favorable counts, abiraterone was associated with a higher conversion rate to favorable CTC numbers in patients receiving abiraterone versus placebo. An initial biomarker panel consisting of CTC counts and lactate dehydrogenase (LDH) seems to be strongly correlated with OS. The surrogacy of this panel will be explored in subsequent trials.