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We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade.
Overexpression of vascular endothelial growth factor in renal cell carcinoma (RCC) leads to angiogenesis, tumor progression, and inhibition of immune function. We conducted the first phase II study to estimate the efficacy and safety of bevacizumab with high-dose interleukin-2 (IL-2) therapy in patients with metastatic RCC. Eligible patients had predominantly clear cell metastatic RCC, measurable disease, a Karnofsky Performance Status of ≥80%, and adequate end-organ function. IL-2 (600,000 IU/kg) was infused intravenously every 8 hours (maximum 28 doses) during two 5-day cycles on days 1 and 15 of each 84-day course. Bevacizumab (10 mg/kg) was infused intravenously every 2 weeks beginning 2 weeks before initiating IL-2. Fifty of 51 eligible patients from 8 centers were enrolled. Median progression-free survival (PFS) was 11.2 months (90% confidence interval, 5.7-17.7), and 2-year PFS was 18% (90% confidence interval, 8%-27%). Responses included 4 complete (8%) and 11 partial (22%) responses. Toxicities did not exceed those expected from each agent alone. Combining IL-2 plus bevacizumab is feasible, with a response rate and PFS at least as high as reported previously for the single agents. The regimen did not appear to enhance the rate of durable major responses over that of IL-2 alone.
PURPOSE - Vismodegib, a Hedgehog pathway inhibitor, has preclinical activity in colorectal cancer (CRC) models. This trial assessed the efficacy, safety, and pharmacokinetics of adding vismodegib to first-line treatment for metastatic CRC (mCRC).
EXPERIMENTAL DESIGN - Patients were randomized to receive vismodegib (150 mg/day orally) or placebo, in combination with FOLFOX or FOLFIRI chemotherapy plus bevacizumab (5 mg/kg) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary objectives included evaluation of predictive biomarkers and pharmacokinetic drug interactions.
RESULTS - A total of 199 patients with mCRC were treated on protocol (124 FOLFOX, 75 FOLFIRI). The median PFS hazard ratio (HR) for vismodegib treatment compared with placebo was 1.25 (90% CI: 0.89-1.76; P = 0.28). The overall response rates for placebo-treated and vismodegib-treated patients were 51% (90% CI: 43-60) and 46% (90% CI: 37-55), respectively. No vismodegib-associated benefit was observed in combination with either FOLFOX or FOLFIRI. Increased tumor tissue Hedgehog expression did not predict clinical benefit. Grade 3 to 5 adverse events reported for more than 5% of patients that occurred more frequently in the vismodegib-treated group were fatigue, nausea, asthenia, mucositis, peripheral sensory neuropathy, weight loss, decreased appetite, and dehydration. Vismodegib did not alter the pharmacokinetics of FOLFOX, FOLFIRI, or bevacizumab.
CONCLUSIONS - Vismodegib does not add to the efficacy of standard therapy for mCRC. Compared with placebo, treatment intensity was lower for all regimen components in vismodegib-treated patients, suggesting that combined toxicity may have contributed to lack of efficacy.
BACKGROUND AND OBJECTIVE - Ovarian cancer is usually diagnosed at an advanced stage, with most patients undergoing surgery followed by platinum- and taxane-based chemotherapy. After initial clinical remission, the majority recur, leading to additional treatments, including not only platinums and taxanes but also pegylated liposomal doxorubicin (PLD), gemcitabine, topotecan, and, more recently, bevacizumab, which may extend survival times. PLD, in particular, has been extensively studied by our group, with encouraging therapeutic results. We, however, observed instances of chronic kidney disease (CKD) developing among patients who received long-term treatment for recurrent ovarian cancer. To document the frequency and contributing factors to the emergence of CKD, we initiated a retrospective review at two institutions.
PATIENTS AND METHODS - Fifty-six consecutive patients with recurrent ovarian cancer receiving treatment at New York University Cancer Institute were reviewed for the presence of renal disease in 1997-2010. At Shaare Zedek Medical Center, 73 consecutive patients with ovarian cancer were reviewed in 2002-2010. Patients were diagnosed with CKD if they had an estimated GFR <60 mL/minute per 1.73 m2 for >3 months and were staged according to the National Kidney Foundation guidelines.
RESULTS - Thirteen patients (23%) developed stage ≥3 CKD. Three patients had renal biopsies performed that showed thrombotic microangiopathy.
CONCLUSIONS - CKD is emerging as a potential long-term consequence of current chemotherapy for recurrent ovarian cancer.
Frequently, bevacizumab is combined with chemotherapeutics such as irinotecan, motivated by studies showing improved clinical outcomes compared with historical controls. However, no systematic studies have been performed to determine if and how these drugs should be combined for optimal therapeutic response. The purpose of this study was to characterize the temporal combinations of bevacizumab and irinotecan by measuring the contrast-agent enhanced tumor volumes and relative cerebral blood volume using dynamic susceptibility contrast imaging. The studies, performed in the U87 brain tumor model, show a vascular normalization window with bevacizumab monotherapy and are consistent with clinical indications of no additional benefit in the addition of irinotecan to bevacizumab therapy.
Copyright © 2011 Wiley Periodicals, Inc.
PURPOSE - Metastatic melanoma, a highly vascularized tumor with strong expression of vascular endothelial growth factor, has an overall poor prognosis. We conducted a placebo-controlled, double-blind phase II study of carboplatin plus paclitaxel with or without bevacizumab in patients with previously untreated metastatic melanoma.
PATIENTS AND METHODS - Patients were randomly assigned in a two-to-one ratio to carboplatin (area under the curve, 5) plus paclitaxel (175 mg/m(2)) and bevacizumab (15 mg/kg; CPB) or placebo (CP) administered intravenously once every 3 weeks. Progression-free survival (PFS) was the primary end point. Secondary end points included overall survival (OS) and safety.
RESULTS - Two hundred fourteen patients (73% with M1c disease) were randomly assigned. With a median follow-up of 13 months, median PFS was 4.2 months for the CP arm (n = 71) and 5.6 months for the CPB arm (n = 143; hazard ratio [HR], 0.78; P = .1414). Overall response rates were 16.4% and 25.5%, respectively (P = .1577). With 13-month follow-up, median OS was 8.6 months in the CP arm versus 12.3 months in the CPB arm (HR, 0.67; P = .0366), whereas in an evaluation 4 months later, it was 9.2 versus 12.3 months, respectively (HR, 0.79; P = .1916). In patients with elevated serum lactate dehydrogenase (n = 84), median PFS and OS were longer in the CPB arm (PFS: 4.4 v 2.7 months; HR, 0.62; OS: 8.5 v 7.5 months; HR, 0.52). No new safety signals were observed.
CONCLUSION - The study did not meet the primary objective of statistically significant improvement in PFS with the addition of bevacizumab to carboplatin plus paclitaxel. A larger phase III study will be necessary to determine whether there is benefit to the addition of bevacizumab to carboplatin plus paclitaxel in this disease setting.
BACKGROUND - African Americans are more likely to be diagnosed with metastatic colorectal cancer than whites and have shorter survival once they are diagnosed. In this analysis, the authors examined racial differences in clinical outcomes among patients with metastatic colorectal cancer (mCRC) who received bevacizumab.
METHODS - The study cohort consisted of 1589 white patients (81.4%) and 227 African American patients (11.6%) with mCRC who received front-line bevacizumab therapy and who were enrolled in a large, predominantly community-based, prospective, observational cohort study. Differences in time-to-event endpoints and response rates were examined by race. Differences in the incidence of baseline and treatment-related toxicities associated with bevacizumab also were examined. Finally, differences in patterns of care by race were explored.
RESULTS - The median overall survival was 22.6 months for African Americans and 22.9 months for whites, and the median progression-free survival was 9.5 months for African Americans and 9.8 months for whites. Response rates (complete responses plus partial responses) were 37.5% for African Americans and 46.3% for whites (adjusted odds ratio, 0.67; 95% confidence interval, 0.50-0.90). African Americans had higher rates of baseline diabetes (18.9% vs 11%; P = .002), higher rates of hypertension (52.9% vs 41.4%; P = .001), and worsening hypertension while on therapy (13.7% vs 8.9%; P = .02), but no differences in on-treatment arterial thromboembolic events were observed.
CONCLUSIONS - This large observational cohort study of patients with mCRC demonstrated that, when treated in a similar fashion with modern chemotherapy, African Americans and whites had equivalent cancer outcomes. No significant differences in bevacizumab-related toxicity or patterns of care were observed between African Americans and whites. The lower response rate among African Americans deserves further study.
Copyright © 2011 American Cancer Society.
Despite the early promising results with the anti-angiogenic agent, bevacizumab, to prolong time to progression in patients with brain tumors, the optimal dose and drug combinations have not yet been defined. The purpose of this study was to characterize the bevacizumab dose-response relationship for brain tumors by measuring the contrast-agent enhanced tumor volumes and relative cerebral blood volume (rCBV) using dynamic susceptibility contrast (DSC) imaging. The studies, performed in the U87 brain tumor model using doses of bevacizumab ranging from 0 to 10 mg/kg, demonstrate that tumor growth and vascularity are inhibited at all doses used, compared to untreated controls. However, only the maximum dose showed a statistically significant difference in growth rate. Conversely tumor vascularity, as measured with rCBV, was inhibited equally well for all doses used with no clear indication that higher doses are more effective.