Loading...
Tivozanib — a potent, selective, long half-life, tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3 — demonstrated antitumor activity and an excellent safety profile in patients with renal cell carcinoma in a phase II evaluation (J Clin Oncol 2012; 30:1678). Motzer and colleagues have now conducted a multinational, randomized, phase III trial [Abstract 4501] to test the effectiveness of tivozanib (1.5 mg daily, 3 weeks on and 1 week off) versus sorafenib (400 mg twice daily) in 517 treatment-naive patients with metastatic clear-cell renal cancer. Patients were required to have undergone cytoreductive nephrectomy, to have an Eastern Cooperative Oncology Group performance status of 0 or 1, and to have received no prior VEGF or mammalian target of rapamycin (mTOR) therapy. The majority of patients were defined as having intermediate- or low-risk disease according to Memorial Sloan-Kettering risk criteria.
By independent review, the primary endpoint, progression-free survival (PFS), was superior in tivozanib recipients versus sorafenib recipients (11.9 vs. 9.1 months; hazard ratio, 0.797; P<0.042), as was the objective response rate (33% vs. 23%; P=0.014). Tivozanib was well tolerated; hypertension and hand-foot syndrome were less common with tivozanib than with sorafenib.
The researchers concluded that tivozanib should now be considered a front-line option for the management of metastatic clear-cell renal cancer. Tivozanib is not yet FDA-approved, but if it becomes available, the favorable safety profile might be useful for subsets of patients. Its activity compared to more potent TKIs (sunitinib, axitinib, and pazopanib) is unknown.
Recent developments in both TKIs and mTOR inhibitors have revolutionized the management of metastatic clear-cell renal cancer. Despite such progress, the disease remains incurable, and both of these types of drugs need to be taken chronically and are associated with life-altering adverse effects.
Now, McDermott and colleagues have conducted a large phase I study [Abstract 4505] to characterize the antitumor activity of a fully humanized immunoglobulin G4 antibody (BMS-936558) that blocks the programmed death (PD)-1 receptor, a type I membrane protein and a member of the family of T-cell regulators that seems to negatively regulate immune responses. Nearly 300 patients with melanoma, renal, colon, prostate, or non–small-cell lung cancer received BMS-936558 intravenously every 2 weeks (10 mg/kg in initial patients; 1 mg/kg in additional patients). The current report focused on 33 patients with advanced renal cancer who received 10-mg/kg and 1-mg/kg dose regimens. Of these patients, 19 had received one or two prior renal cancer therapies, and 14 had received three or four prior therapies.
Treatment with BMS-936558 was well tolerated; fatigue was the most common adverse effect. An objective response was achieved by nine patients (27%); duration of response ranged from 5 months to >23 months. Several patients achieved durable, ongoing responses after completion of therapy. BMS-936558 seems to have activity against advanced renal cancer. Given that it is an immune therapy, with activity that is typically manifested by disease control, obtaining regulatory approval will require creative approaches. Meanwhile, new trials in renal cancer are under development.
Intermittent androgen deprivation (IAD) for patients with advanced prostate cancer has been widely accepted on the basis of some prospective data and the belief that this approach is more patient-friendly than continuous androgen deprivation (CAD), given the known adverse effects of androgen deprivation. Now, Hussain and colleagues report results from a large, international, phase III S9346 trial [Abstract 4, which was designed to determine whether survival with IAD was noninferior to survival with CAD.
A total of 3040 patients with newly diagnosed metastatic prostate cancer, prostate-specific antigen (PSA) values ≥5 ng/mL, and Southwest Oncology Group performance status ≤2 were enrolled in the study. Patients were stratified according to extent of disease, with minimal disease defined as involvement of spine, pelvis, or nodes, and extensive disease defined as involvement of ribs, long bones, or visceral organs. All patients initially received 7 months of treatment with goserelin and bicalutamide. A total of 1535 patients with a PSA level ≤4 ng/mL at months 6 and 7 were randomized to IAD or CAD. IAD patients were restarted on treatment when their PSA level reached 20 or if they developed symptoms, and they were allowed to recycle to IAD if their PSA level dropped to <4 at 7 months. The IAD group spent a median of 19 months on the study; 53% of the time they did not receive androgen-deprivation therapy (ADT).
Median overall survival (OS) was shorter in the IAD group versus the CAD group (5.1 vs. 5.8 years; HR, 1.09; 95% confidence interval, 0.95–1.24), leading to the conclusion that IAD is inferior to CAD in patients with metastatic prostate cancer. A post hoc subset analysis suggested that IAD in patients with extensive disease was noninferior to CAD. Many will interpret these findings as meaning that high-risk patients do poorly regardless of how ADT is administered.
During a post-plenary session, several attendees expressed concerns about the interpretation of the trial results, given the broadly held belief that IAD is a standard of care. However, in contrast to the results of a somewhat similar trial that demonstrated noninferiority of IAD in patients with nonmetastatic prostate cancer, these data seem compelling that CAD should be the standard of care for patients with overt metastatic disease.
A prior phase III trial of patients with metastatic castration-resistant prostate cancer (mCRPC) after treatment with docetaxel demonstrated an improvement in median OS of 3.9 months with abiraterone plus prednisone versus placebo plus prednisone (JW Oncol Hematol May 25 2011). Ryan and colleagues have now presented interim results of the phase III Cougar 302 trial [Abstract LBA4518) that compared the same two treatment regimens in 1088 treatment-naive patients with mCRPC. The co-primary endpoints were OS and radiographic PFS (rPFS); the latter was defined using Prostate Cancer Clinical Trials Working Group 2 criteria as ≥2 new lesions at 12-week assessment and ≥2 additional lesions at follow-up to confirm disease progression. At the time of the planned second interim analysis, the Independent Data Monitoring Committee (IDMC) halted the study and recommended that patients receiving placebo plus prednisone be crossed over to receive abiraterone plus prednisone.
At a median follow-up of 22.3 months, the median rPFS was longer in the abiraterone arm versus the placebo arm (not reached vs. 8.3 months; P<0.0001), as was median OS (not reached vs. 27.2 months; strong trend toward significance). Therapy was well tolerated, with typical mineralocorticoid adverse effects in the abiraterone arm. More patients in the placebo arm than the abiraterone arm received subsequent treatment, which included chemotherapy, sipuleucel-T, and ketoconazole. Subsequent abiraterone was received by 4.8% of patients in the abiraterone arm versus 10% of patients in the placebo arm. A final analysis of the survival data is anticipated in the fall.
Despite some controversy regarding the IDMC recommendation to unblind the study and its potential effect on the OS endpoint, these findings, when taken in context with the survival benefit that was demonstrated with abiraterone in the post-docetaxel trial, will likely lead to the use of abiraterone plus prednisone as a second-line hormonal therapy.