Effect of a Proposed Trastuzumab Biosimilar Compared With Trastuzumab on Overall Response Rate in Patients With ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Randomized Clinical Trial.

Importance: Treatment with the anti-ERBB2 humanized monoclonal antibody trastuzumab and chemotherapy significantly improves outcome in patients with ERBB2 (HER2)-positive metastatic breast cancer; a clinically effective biosimilar may help increase access to this therapy. Objective: To compare the overall response rate and assess the safety of a proposed trastuzumab biosimilar plus a taxane or trastuzumab plus a taxane in patients without prior treatment for ERBB2-positive metastatic breast cancer. Design, Setting, and Participants: Multicenter, double-blind, randomized, parallel-group, phase 3 equivalence study in patients with metastatic breast cancer. From December 2012 to August 2015, 500 patients were randomized 1:1 to receive a proposed biosimilar or trastuzumab plus a taxane. Chemotherapy was administered for at least 24 weeks followed by antibody alone until unacceptable toxic effects or disease progression occurred. Interventions: Proposed biosimilar (n = 230) or trastuzumab (n = 228) with a taxane. Main Outcomes and Measures: The primary outcome was week 24 overall response rate (ORR) defined as complete or partial response. Equivalence boundaries were 0.81 to 1.24 with a 90% CI for ORR ratio (proposed biosimilar/trastuzumab) and -15% to 15% with a 95% CI for ORR difference. Secondary outcome measures included time to tumor progression, progression-free and overall survival at week 48, and adverse events. Results: Among 500 women randomized, the intention-to-treat population included 458 women (mean [SD] age, 53.6 [11.11] years) and the safety population included 493 women. The ORR was 69.6% (95% CI, 63.62%-75.51%) for the proposed biosimilar vs 64.0% (95% CI, 57.81%-70.26%) for trastuzumab. The ORR ratio (1.09; 90% CI, 0.974-1.211) and ORR difference (5.53; 95% CI, -3.08 to 14.04) were within the equivalence boundaries. At week 48, there was no statistically significant difference with the proposed biosimilar vs trastuzumab for time to tumor progression (41.3% vs 43.0%; -1.7%; 95% CI, -11.1% to 6.9%), progression-free survival (44.3% vs 44.7%; -0.4%; 95% CI, -9.4% to 8.7%), or overall survival (89.1% vs 85.1%; 4.0%; 95% CI, -2.1% to 10.3%). In the proposed biosimilar and trastuzumab groups, 239 (98.6%) and 233 (94.7%) had at least 1 adverse event, the most common including neutropenia (57.5% vs 53.3%), peripheral neuropathy (23.1% vs 24.8%), and diarrhea (20.6% vs 20.7%). Conclusions and Relevance: Among women with ERBB2-positive metastatic breast cancer receiving taxanes, the use of a proposed trastuzumab biosimilar compared with trastuzumab resulted in an equivalent overall response rate at 24 weeks. Further study is needed to assess safety and long-term clinical outcome. Trial Registration: clinicaltrials.gov Identifier: NCT02472964; EudraCT Identifier: 2011-001965-42.

Sunitinib in metastatic renal cell carcinoma: an ethnic Asian subpopulation analysis for safety and efficacy.

AIMS: We evaluated and compared the safety and efficacy of sunitinib in Asian and non-Asian patients with metastatic renal cell carcinoma enrolled in a previously reported global expanded access program. METHODS: Previously treated and treatment-naïve patients received open-label sunitinib at a starting dose of 50 mg/day for 4 weeks, followed by 2 weeks off treatment, in repeated 6-week cycles. Safety was assessed regularly, tumor measurements were performed per local practice, and survival data collected where possible. RESULTS: Data were available for 212 Asian patients from Asian sites (Asian-A), 113 Asian patients from non-Asian sites (Asian-O) and 4046 non-Asian patients. The most common grade 3/4 treatment-related adverse events were neutropenia, thrombocytopenia, hand-foot syndrome, diarrhea, asthenia and fatigue. The incidence of many adverse events was greater in Asian-A than in Asian-O or non-Asian patients. Sunitinib efficacy was comparable between Asian and non-Asian patients, with an objective response rate of 18% versus 14%; median progression-free survival of 8.7 versus 10.9 months; and overall survival of 18.9 versus 18.4 months, respectively. CONCLUSIONS: Sunitinib demonstrated tolerable safety and similar efficacy in Asian and non-Asian patients. Geographic differences in the reported frequency of specific adverse events were noted across Asian patients.

Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma.

PURPOSE: Sunitinib has shown antitumor activity with a manageable safety profile as metastatic renal cell carcinoma (RCC) treatment, when given by the standard intermittent schedule as well as a continuous daily dosing (CDD) schedule. A trial was conducted to compare the schedules. PATIENTS AND METHODS: Patients with treatment-naive, clear cell advanced RCC were randomly assigned 1:1 to receive sunitinib 50 mg/d for 4 weeks followed by 2 weeks off treatment (schedule 4/2; n = 146) or 37.5 mg/d on the CDD schedule (n = 146) for up to 2 years. The primary end point was time to tumor progression. RESULTS: Median time to tumor progression was 9.9 months for schedule 4/2 and 7.1 months for the CDD schedule (hazard ratio, 0.77; 95% CI, 0.57 to 1.04; P = .090). No significant difference was observed in overall survival (23.1 v 23.5 months; P = .615), commonly reported adverse events, or patient-reported kidney cancer symptoms. Schedule 4/2 was statistically superior to CDD in time to deterioration, a composite end point of death, progression, and disease-related symptoms (P = .034). CONCLUSION; There was no benefit in efficacy or safety for continuous dosing of sunitinib compared with the approved 50 mg/d dose on schedule 4/2. Given the numerically longer time to tumor progression with the approved 50 mg/d dose on schedule 4/2, adherence to this dose and schedule remains the treatment goal for patients with advanced RCC.

Phase II trial of continuous once-daily dosing of sunitinib as first-line treatment in patients with metastatic renal cell carcinoma.

BACKGROUND: Sunitinib at 50 mg/day on the 4-weeks-on-2-weeks-off schedule is the current approved regimen for advanced/metastatic renal cell carcinoma (mRCC). Escudier et al reported that continuous, once-daily dosing with sunitinib 37.5 mg had a manageable safety profile and significant antitumor activity as second-line mRCC therapy. In this prospective, multicenter, phase II study, we evaluated the activity of continuous once-daily dosing with sunitinib 37.5 mg as first-line mRCC treatment. METHODS: One hundred nineteen treatment-naive patients with measurable mRCC received sunitinib. The primary endpoint was objective response; secondary endpoints included progression-free survival (PFS), safety, pharmacokinetic measurements, exploration of response biomarkers, and patient reported outcomes (PRO). RESULTS: Objective response rate (ORR) was 35.3%; median response duration was 10.4 months; 36% of patients had stable disease ≥12 weeks. Median PFS at 1 year was 9 months, and 1-year survival probability was 67.8%. The most common any-grade treatment-related adverse events (AEs) were diarrhea (50%) and hand-foot syndrome (43%); the most common grade 3-4 treatment-related AEs were hand-foot syndrome (13%), neutropenia (11%), and diarrhea (9%). Steady-state pharmacokinetics were reached within 3 weeks, with no disproportionate accumulation of sunitinib or its active metabolite throughout the study. No significant correlations between trough drug, active metabolite, or soluble protein levels and clinical response were observed. PRO was largely maintained, although fatigue appeared to worsen after treatment started, with improvement over time. CONCLUSIONS: Continuous once-daily dosing with sunitinib 37.5 mg was active with a manageable safety profile as first-line mRCC therapy, making this a feasible alternative dosing regimen.

Sunitinib in metastatic renal cell carcinoma patients with brain metastases.

BACKGROUND: In a broad patient population with metastatic renal cell carcinoma (RCC), enrolled in an open-label, expanded access program (EAP), the safety profile of sunitinib was manageable, and efficacy results were encouraging. Here, the authors report results for patients with baseline brain metastases participating in this global EAP. METHODS: Previously treated and treatment-naive metastatic RCC patients ≥18 years received sunitinib 50 mg orally, once daily, on Schedule 4/2. Safety was assessed regularly, tumor measurements done per local practice, and survival data collected where possible. Analyses were done in the modified intention-to-treat (ITT) population, consisting of all patients who received ≥1 dose of sunitinib. RESULTS: As of December 2007, 4564 patients had enrolled in 52 countries. Of these enrollees, 4371 were included in the modified ITT population, of whom 321 (7%) had baseline brain metastases and had received a median of 3 treatment cycles (range 1-25). Reasons for their discontinuation included lack of efficacy (32%) and adverse events (8%). The most common grade 3-4 treatment-related adverse events were fatigue and asthenia (both 7%), thrombocytopenia (6%), and neutropenia (5%), the incidence of which were comparable to that for the overall EAP population. Of 213 evaluable patients, 26 (12%) had an objective response. Median progression-free survival and overall survival were 5.6 months (95% CI, 5.2-6.1) and 9.2 months (95% CI, 7.8-10.9), respectively. CONCLUSIONS: In patients with brain metastases from RCC, the safety profile of sunitinib was comparable to that in the general metastatic RCC population, and sunitinib showed evidence of antitumor activity.

Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial.

BACKGROUND: Results from clinical trials have established sunitinib as a standard of care for first-line treatment of advanced or metastatic renal-cell carcinoma (RCC); however, many patients, particularly those with a poorer prognosis, do not meet inclusion criteria and little is known about the activity of sunitinib in these subgroups. The primary objective of this trial was to provide sunitinib on a compassionate-use basis to trial-ineligible patients with RCC from countries where regulatory approval had not been granted. METHODS: Previously treated and treatment-naive patients at least 18 years of age with metastatic RCC were eligible. All patients received open-label sunitinib 50 mg orally once daily on schedule 4-2 (4 weeks on treatment, 2 weeks off). Safety was assessed regularly, tumour measurements done per local practice, and survival data collected where possible. Analyses were done in the modified intention-to-treat (ITT) population, which consisted of all patients who received at least one dose of sunitinib. This study is registered with ClinicalTrials.gov, NCT00130897. FINDINGS: As of December, 2007, 4564 patients were enrolled in 52 countries. 4371 patients were included in the modified ITT population. This population included 321 (7%) patients with brain metastases, 582 (13%) with Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher, 588 (13%) non-clear-cell RCC, and 1418 (32%) aged 65 years or more. Patients received a median of five treatment cycles (range 1-25). Reasons for discontinuation included lack of efficacy (n=1168 [27%]) and adverse events (n=362 [8%]). The most common treatment-related adverse events were diarrhoea (n=1936 [44%]) and fatigue (n=1606 [37%]). The most common grade 3-4 adverse events were fatigue (n=344 [8%]) and thrombocytopenia (n=338 [8%]) with incidences of grade 3-4 adverse events similar across subgroups. In 3464 evaluable patients, the objective response rate (ORR) was 17% (n=603), with subgroup ORR as follows: brain metastases (26 of 213 [12%]), ECOG performance status 2 or higher (29 of 319 [9%]), non-clear-cell RCC (48 of 437 [11%]) and age 65 years or more (176 of 1056 [17%]). Median progression-free survival was 10.9 months (95% CI 10.3-11.2) and overall survival was 18.4 months (17.4-19.2). INTERPRETATION: In a broad population of patients with metastatic RCC, the safety profile of sunitinib 50 mg once-daily (initial dose) on schedule 4-2 was manageable and efficacy results were encouraging, particularly in subgroups associated with poor prognosis who are not usually entered into clinical trials. FUNDING: Pfizer Inc.

Influence of taranabant, an orally active, highly selective, potent cannabinoid-1 receptor (CB1R) inverse agonist, on ethinyl estradiol and norelgestromin plasma pharmacokinetics.

Taranabant, an orally active, potent, and highly selective CB-1 receptor inverse agonist, is being developed for the treatment of obesity. This randomized, placebo-controlled, multiple-dose, crossover study evaluated the effect of taranabant on the pharmacokinetics of ethinyl estradiol and norelgestromin in healthy women receiving > or =3 months of therapy with oral contraceptives. Nineteen participants with normal menstrual cycles received oral contraceptives on days 1 to 21 during 2 consecutive contraceptive cycles. Participants received taranabant 6 mg/day or placebo on days 1 to 21 of each contraceptive cycle. Plasma samples were collected predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose on day 21 of each cycle for determination of AUC0-24 h and Cmax of ethinyl estradiol and norelgestromin. Lack of a clinically important effect was declared if the 90% confidence intervals for the geometric mean ratio of AUC0-24 h and Cmax in the absence and presence of taranabant were contained within the predefined bounds of (0.8, 1.25). The geometric mean ratios and 90% confidence intervals of ethinyl estradiol and norelgestromin, respectively, were 0.93 (0.87, 1.00) and 1.02 (0.96, 1.09) for AUC0-24 h and 0.95 (0.88, 1.01) and 0.95 (0.88, 1.01) for Cmax. In summary, coadministration of multiple-dose taranabant 6 mg with oral contraceptives did not lead to clinically meaningful alterations in the pharmacokinetic profiles of ethinyl estradiol or norelgestromin.