John D. Hainsworth

Abiraterone and Increased Survival in Metastatic Prostate Cancer

BACKGROUND Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy. METHODS We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate. RESULTS After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate-prednisone group than in the placebo-prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate-prednisone group than in the placebo-prednisone group. CONCLUSIONS The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT00638690.).

Efficacy and Safety of Vismodegib in Advanced Basal-Cell Carcinoma

BACKGROUND Alterations in hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. Although most basal-cell carcinomas are treated surgically, no effective therapy exists for locally advanced or metastatic basal-cell carcinoma. A phase 1 study of vismodegib (GDC-0449), a first-in-class, small-molecule inhibitor of the hedgehog pathway, showed a 58% response rate among patients with advanced basal-cell carcinoma. METHODS In this multicenter, international, two-cohort, nonrandomized study, we enrolled patients with metastatic basal-cell carcinoma and those with locally advanced basal-cell carcinoma who had inoperable disease or for whom surgery was inappropriate (because of multiple recurrences and a low likelihood of surgical cure, or substantial anticipated disfigurement). All patients received 150 mg of oral vismodegib daily. The primary end point was the independently assessed objective response rate; the primary hypotheses were that the response rate would be greater than 20% for patients with locally advanced basal-cell carcinoma and greater than 10% for those with metastatic basal-cell carcinoma. RESULTS In 33 patients with metastatic basal-cell carcinoma, the independently assessed response rate was 30% (95% confidence interval [CI], 16 to 48; P=0.001). In 63 patients with locally advanced basal-cell carcinoma, the independently assessed response rate was 43% (95% CI, 31 to 56; P<0.001), with complete responses in 13 patients (21%). The median duration of response was 7.6 months in both cohorts. Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, dysgeusia (taste disturbance), weight loss, and fatigue. Serious adverse events were reported in 25% of patients; seven deaths due to adverse events were noted. CONCLUSIONS Vismodegib is associated with tumor responses in patients with locally advanced or metastatic basal-cell carcinoma. (Funded by Genentech; Erivance BCC ClinicalTrials.gov number, NCT00833417.).

Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study

BACKGROUND Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown antitumour activity in patients with advanced pancreatic neuroendocrine tumours. We aimed to assess the combination of everolimus plus octreotide long-acting repeatable (LAR) in patients with low-grade or intermediate-grade neuroendocrine tumours (carcinoid). METHODS We did a randomised, double-blind, placebo-controlled, phase 3 study comparing 10 mg per day oral everolimus with placebo, both in conjunction with 30 mg intramuscular octreotide LAR every 28 days. Randomisation was by interactive voice response systems. Participants were aged 18 years or older, with low-grade or intermediate-grade advanced (unresectable locally advanced or distant metastatic) neuroendocrine tumours, and disease progression established by radiological assessment within the past 12 months. Our primary endpoint was progression-free survival. Adjusted for two interim analyses, the prespecified boundary at final analysis was p≤0·0246. This study is registered at ClinicalTrials.gov, number NCT00412061. FINDINGS 429 individuals were randomly assigned to study groups; 357 participants discontinued study treatment and one was lost to follow-up. Median progression-free survival by central review was 16·4 (95% CI 13·7-21·2) months in the everolimus plus octreotide LAR group and 11·3 (8·4-14·6) months in the placebo plus octreotide LAR group (hazard ratio 0·77, 95% CI 0·59-1·00; one-sided log-rank test p=0·026). Drug-related adverse events (everolimus plus octreotide LAR vs placebo plus octreotide LAR) were mostly grade 1 or 2, and adverse events of all grades included stomatitis (62%vs 14%), rash (37%vs 12%), fatigue (31%vs 23%), and diarrhoea (27%vs 16%). INTERPRETATION Everolimus plus octreotide LAR, compared with placebo plus octreotide LAR, improved progression-free survival in patients with advanced neuroendocrine tumours associated with carcinoid syndrome. FUNDING Novartis Pharmaceuticals.

Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer.

PURPOSE In a phase III trial, combining bevacizumab (BV)--a recombinant, humanized, monoclonal antibody targeting vascular endothelial growth factor--with irinotecan, bolus fluorouracil (FU), and leucovorin (LV; IFL) increased survival compared with IFL alone in first-line treatment of patients with metastatic colorectal cancer (CRC). Results for the parent study of IFL/BV versus IFL/placebo are reported elsewhere. Here, we describe efficacy and safety results for the third patient cohort in this trial, who received BV combined with FU/LV, and compare them with results for concurrently enrolled patients who received IFL. METHODS Patients (N = 923) were randomly assigned to receive IFL/placebo (control), IFL/BV, or FU/LV/BV. Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA) 5 mg/kg was administered intravenously every 2 weeks. Before an interim analysis confirmed acceptable safety for IFL/BV, 313 patients were concurrently randomly assigned to these three arms; after this analysis, the FU/LV/BV arm was discontinued. RESULTS Median overall survivals were 18.3 and 15.1 months with FU/LV/BV (n = 110) and IFL/placebo (n = 100), respectively. Median progression-free survivals were 8.8 and 6.8 months, respectively. Overall response rates were 40.0% and 37.0%, and median response durations were 8.5 and 7.2 months, respectively. Adverse events consistent with those expected from FU/leucovorin- or IFL-based regimens were seen, as were modest increases in hypertension and bleeding in the bevacizumab arm, which were generally easily managed. CONCLUSION The FU/LV/BV regimen seems as effective as IFL and has an acceptable safety profile. FU/LV/BV is an active alternative treatment regimen for patients with previously untreated metastatic CRC.

Proposal for classifying the acute emetogenicity of cancer chemotherapy.

PURPOSE To propose a classification of the acute emetogenicity of antineoplastic chemotherapy agents, and to develop an algorithm to define the emetogenicity of combination chemotherapy regimens. METHODS A Medline search was conducted to identify (1) clinical trials that used chemotherapy as single-agent therapy, and (2) major reviews of antiemetic therapy. The search was limited to patients who received commonly used doses of chemotherapy agents, primarily by short (< 3 hours) intravenous infusions. Based on review of this information and our collective clinical experience, we assigned chemotherapy agents to one of five emetogenic levels by consensus. A preliminary algorithm to determine the emetogenicity of combination chemotherapy regimens was then designed by consensus. A final algorithm was developed after we analyzed a data base composed of patients treated on the placebo arms of four randomized antiemetic trials. RESULTS Chemotherapy agents were divided into five levels: level 1 (< 10% of patients experience acute [< or = 24 hours after chemotherapy] emesis without antiemetic prophylaxis); level 2 (10% to 30%); level 3 (30% to 60%); level 4 (60% to 90%); and level 5 (> 90%). For combinations, the emetogenic level was determined by identifying the most emetogenic agent in the combination and then assessing the relative contribution of the other agents. The following rules apply: (1) level 1 agents do not contribute to the emetogenic level of a combination; (2) adding > or = one level 2 agent increases the emetogenicity of the combination by one level greater than the most emetogenic agent in the combination; and (3) adding level 3 or 4 agents increases the emetogenicity of the combination by one level per agent. CONCLUSION The proposed classification schema provides a practical means to determine the emetogenic potential of individual chemotherapy agents and combination regimens during the 24 hours after administration. This system can serve as a framework for the development of antiemetic guidelines.

Safety and Efficacy of Oxaliplatin and Fluoropyrimidine Regimens With or Without Bevacizumab As First-Line Treatment of Metastatic Colorectal Cancer: Results of the TREE Study

PURPOSE To evaluate the safety and efficacy of three oxaliplatin and fluoropyrimidine regimens, with or without bevacizumab, as first-line treatment for metastatic colorectal cancer (CRC). PATIENTS AND METHODS Patients with histologically documented metastatic or recurrent CRC and no prior treatment for advanced disease were randomly assigned to mFOLFOX6 (bolus and infusion fluorouracil [FU] and leucovorin [LV] with oxaliplatin), bFOL (bolus FU and low-dose LV with oxaliplatin), or CapeOx (capecitabine with oxaliplatin), respectively (Three Regimens of Eloxatin Evaluation [TREE-1]). The study was later modified such that subsequent patients were randomized to the same regimens plus bevacizumab (TREE-2). RESULTS A total of 150 and 223 patients were randomly assigned in the TREE-1 and TREE-2 cohorts, respectively. Incidence of grade 3/4 treatment-related adverse events during the first 12 weeks of treatment were 59%, 36%, and 67% for mFOLFOX6, bFOL, and CapeOx, respectively, (TREE-1) and 59%, 51%, and 56% for the corresponding treatments plus bevacizumab (TREE-2; primary end point). CapeOx toxicity in TREE-1 included grade 3/4 diarrhea (31%) and dehydration (27%); capecitabine dose reduction to 1,700 mg/m(2)/d in TREE-2 resulted in improved tolerance. Overall response rates were 41%, 20%, and 27% (TREE-1) and 52%, 39%, and 46% (TREE-2); median overall survival (OS) was 19.2, 17.9, and 17.2 months (TREE-1) and 26.1, 20.4, and 24.6 months (TREE-2). For all treated patients, median OS was 18.2 months (95% CI, 14.5 to 21.6; TREE-1) and 23.7 months (95% CI, 21.3 to 26.8; TREE-2). CONCLUSION The addition of bevacizumab to oxaliplatin and fluoropyrimidine regimens is well tolerated as first-line treatment of mCRC and does not markedly change overall toxicity. CapeOx tolerability and efficacy is improved with reduced-dose capecitabine. First-line oxaliplatin and fluoropyrimidine-based therapy plus bevacizumab resulted in a median OS of approximately 2 years.

Rituximab as First-Line and Maintenance Therapy for Patients With Indolent Non-Hodgkin’s Lymphoma

PURPOSE To evaluate response to single-agent rituximab in patients with indolent non-Hodgkins lymphoma (NHL) and no previous systemic therapy, and the feasibility, toxicity, and efficacy of maintenance rituximab, administered at 6-month intervals, in patients with objective response or stable disease after first-line rituximab therapy. PATIENTS AND METHODS Patients with indolent NHL (follicular or small lymphocytic subtypes) previously untreated with systemic therapy received rituximab 375 mg/m(2) intravenously weekly for 4 weeks. Patients were restaged at week 6 for response; those with objective response or stable disease received maintenance rituximab courses (identical dose and schedule) at 6-month intervals. Maintenance was continued for a maximum of four rituximab courses or until progression. Between March 1998 and May 1999, 62 patients were entered onto this trial; minimum follow-up was 24 months. RESULTS Sixty patients (97%) completed the first 4-week course of rituximab and were assessable for response. All have now completed rituximab therapy; 36 (58%) received four courses at 6-month intervals. The objective response rate at 6 weeks was 47%; 45% of patients had stable disease. With continued maintenance, final response rate increased to 73%, with 37% complete responses. Response was similar in patients with follicular versus small lymphocytic subtypes (76% v 70%, respectively). Median actuarial progression-free survival was 34 months. Two patients experienced grade 3/4 toxicity with the first dose; one patient was removed from treatment. No cumulative or additional toxicities were seen with maintenance courses. CONCLUSION Rituximab is highly active and extremely well tolerated as first-line single-agent therapy for indolent NHL. First-line treatment with scheduled maintenance at 6-month intervals produces high overall and complete response rates and a longer progression-free survival (34 months) than has been reported with a standard 4-week treatment.

Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network.

PURPOSE To assess the efficacy and toxicity of first-line single-agent rituximab, followed by re-treatment with rituximab at 6-month intervals, in previously untreated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). PATIENTS AND METHODS Forty-four previously untreated patients with CLL/SLL received rituximab 375 mg/m2 weekly for 4 consecutive weeks. All patients were required to have one or more indications for treatment. Patients with objective response or stable disease continued to receive identical 4-week rituximab courses at 6-month intervals, for a total of four courses. RESULTS The objective response rate after the first course of rituximab was 51% (4% complete responses). Twenty-eight patients received one or more additional courses of rituximab. At present, the overall response rate is 58%, with 9% complete responses. After a median follow-up of 20 months, the median progression-free survival (PFS) time was 18.6 months, and the 1- and 2-year PFS rates were 62% and 49%, respectively. Treatment was well tolerated, with only two episodes of grade 3 to 4 infusion-related toxicity. No cumulative toxicity or opportunistic infections occurred. CONCLUSION Single-agent rituximab, used at a standard dose and schedule, is active in the first-line treatment of patients with CLL/SLL, producing substantially higher response rates than previously reported in relapsed or refractory patients (51% v 13%, respectively). Re-treatment with rituximab at 6-month intervals is well tolerated. The PFS time of 18.6 months in patients with CLL/SLL seems shorter than the 36- to 40-month median PFSs previously reported with first-line plus maintenance rituximab in patients with follicular lymphoma. Additional follow-up is required to fully assess the impact of this treatment strategy.

Maximizing therapeutic benefit of rituximab: Maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin's lymphoma: A randomized phase II trial of the Minnie pearl cancer research network

PURPOSE To compare the benefit of maintenance rituximab therapy versus rituximab re-treatment at progression in patients with previously treated indolent non-Hodgkins lymphoma. PATIENTS AND METHODS Between June 1998 and August 2002, 114 patients who had received previous chemotherapy for indolent non-Hodgkins lymphoma were treated with a standard 4-week course of rituximab. Patients with objective response or stable disease were randomly assigned to receive either maintenance rituximab therapy (standard 4-week courses administered at 6-month intervals) or rituximab re-treatment at the time of lymphoma progression. The duration of rituximab benefit was measured from the date of first rituximab treatment until the date other treatment was required. RESULTS Ninety (79%) of 114 patients had objective response or stable disease after initial rituximab treatment, and were randomly assigned to treatment. Progression-free survival was prolonged in the maintenance group (31.3 v 7.4 months; P = .007). Final overall and complete response rates were higher in the maintenance group. Duration of rituximab benefit was similar in the maintenance and re-treatment groups (31.3 v 27.4 months, respectively). More maintenance patients remain in continuous remission, and more are currently in complete remission. Both treatment approaches were well tolerated. CONCLUSION In patients who have objective response or stable disease with single-agent rituximab therapy, duration of rituximab benefit is substantially prolonged with either scheduled maintenance treatment or rituximab re-treatment at the time of progression. At present, the magnitude of benefit with either approach appears similar. However, additional follow-up of this trial is required, and completion of phase III randomized trials is necessary to definitively answer this question.

Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial

BACKGROUND Bevacizumab and erlotinib target different tumour growth pathways with little overlap in their toxic-effect profiles. On the basis of promising results from a phase 1/2 trial assessing safety and activity of erlotinib plus bevacizumab for recurrent or refractory non-small-cell lung cancer (NSCLC), we aimed to assess efficacy and safety of this combination in a phase 3 trial. METHODS In our double-blind, placebo-controlled, randomised phase 3 trial (BeTa), we enrolled patients with recurrent or refractory NSCLC who presented to 177 study sites in 12 countries after failure of first-line treatment. Patients were randomly allocated in a one-to-one ratio to receive erlotinib plus bevacizumab (bevacizumab group) or erlotinib plus placebo (control group) according to a computer-generated randomisation sequence by use of an interactive voice response system. The primary endpoint was overall survival in all enrolled patients. Patients, study staff, and investigators were masked to treatment assignment. We assessed safety by calculation of incidence of adverse events and tissue was collected for biomarker analyses. This trial is registered with ClinicalTrials.gov, number NCT00130728. FINDINGS Overall survival did not differ between 317 controls and 319 patients in the bevacizumab group (hazard ratio [HR] 0·97, 95% CI 0·80-1·18, p=0·7583). Median overall survival was 9·3 months (IQR 4·1-21·6) for patients in the bevacizumab group compared with 9·2 months (3·8-20·2) for controls. Progression-free survival seemed to be longer in the bevacizumab group (3·4 months [1·4-8·4]) than in the control group (1·7 months [1·3-4·1]; HR 0·62, 95% CI 0·52-0·75) and objective response rate suggested some clinical activity of bevacizumab and erlotinib. However, these secondary endpoint differences could not be defined as significant because the study prespecified that the primary endpoint had to be significant before testing of secondary endpoints could be done, to control type I error rate. In the bevacizumab group, 130 (42%) of 313 patients with safety data had a serious adverse event, compared with 114 (36%) controls. There were 20 (6%) grade 5 adverse events, including two arterial thromboembolic events, in the bevacizumab group, and 14 (4%) in the control group. INTERPRETATION Addition of bevacizumab to erlotinib does not improve survival in patients with recurrent or refractory NSCLC. FUNDING Genentech.