Ari David Baron

Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial

BACKGROUND Patients with metastatic urothelial carcinoma have a dismal prognosis and few treatment options after first-line chemotherapy. Responses to second-line treatment are uncommon. We assessed nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for safety and activity in patients with metastatic or surgically unresectable urothelial carcinoma whose disease progressed or recurred despite previous treatment with at least one platinum-based chemotherapy regimen. METHODS In this multicentre, phase 2, single-arm study, patients aged 18 years or older with metastatic or surgically unresectable locally advanced urothelial carcinoma, measurable disease (according to Response Evaluation Criteria In Solid Tumors v1.1), Eastern Cooperative Oncology Group performance statuses of 0 or 1, and available tumour samples for biomarker analysis received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression and clinical deterioration, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was overall objective response confirmed by blinded independent review committee in all treated patients and by tumour PD-L1 expression (≥5% and ≥1%). This trial is registered with ClinicalTrials.gov, number NCT02387996, and is completed. Follow-up is still ongoing. FINDINGS Between March 9, 2015, and Oct 16, 2015, 270 patients from 63 sites in 11 countries received nivolumab, and 265 were evaluated for activity. Median follow-up for overall survival was 7·00 months (IQR 2·96-8·77). Confirmed objective response was achieved in 52 (19·6%, 95% CI 15·0-24·9) of 265 patients. Confirmed objective response was achieved in 23 (28·4%, 95% CI 18·9-39·5) of the 81 patients with PD-L1 expression of 5% or greater, 29 (23·8%, 95% CI 16·5-32·3) of the 122 patients with PD-L1 expression of 1% or greater, and 23 (16·1%, 95% CI 10·5-23·1) of the 143 patients with PD-L1 expression of less than 1%. Grade 3-4 treatment-related adverse events occurred in 48 (18%) of 270 patients-most commonly grade 3 fatigue and diarrhoea, which each occurred in five patients. Three deaths were attributed to treatment (pneumonitis, acute respiratory failure, and cardiovascular failure). INTERPRETATION Nivolumab monotherapy provided meaningful clinical benefit, irrespective of PD-L1 expression, and was associated with an acceptable safety profile in previously treated patients with metastatic or surgically unresectable urothelial carcinoma. FUNDING Bristol-Myers Squibb.

Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial

BACKGROUND VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. METHODS In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01140347. FINDINGS Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0-10·6) versus 7·6 months (6·0-9·3) for the placebo group (HR 0·87 [95% CI 0·72-1·05]; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated with placebo), hypertension (34 [12%] vs ten [4%]), asthenia (14 [5%] vs five [2%]), malignant neoplasm progression (18 [6%] vs 11 [4%]), increased aspartate aminotransferase concentration (15 [5%] vs 23 [8%]), thrombocytopenia (13 [5%] vs one [<1%]), hyperbilirubinaemia (three [1%] vs 13 [5%]), and increased blood bilirubin (five [2%] vs 14 [5%]). The most frequently reported (≥1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression. INTERPRETATION Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable. FUNDING Eli Lilly and Co.

Trastuzumab plus vinorelbine or taxane chemotherapy for HER2‐overexpressing metastatic breast cancer: The trastuzumab and vinorelbine or taxane study

The optimal trastuzumab‐based chemotherapy regimen for HER2‐overexpressing, metastatic breast cancer is not known. The trastuzumab and vinorelbine or taxane (TRAVIOTA) study was a prospective, multicenter, randomized trial that was designed to compare these regimens.

Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial

BACKGROUND In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma. METHODS This was an open-label, phase 3, multicentre, non-inferiority trial that recruited patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease, at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions. Patients were randomly assigned (1:1) via an interactive voice-web response system-with region; macroscopic portal vein invasion, extrahepatic spread, or both; Eastern Cooperative Oncology Group performance status; and bodyweight as stratification factors-to receive oral lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg) or sorafenib 400 mg twice-daily in 28-day cycles. The primary endpoint was overall survival, measured from the date of randomisation until the date of death from any cause. The efficacy analysis followed the intention-to-treat principle, and only patients who received treatment were included in the safety analysis. The non-inferiority margin was set at 1·08. The trial is registered with ClinicalTrials.gov, number NCT01761266. FINDINGS Between March 1, 2013 and July 30, 2015, 1492 patients were recruited. 954 eligible patients were randomly assigned to lenvatinib (n=478) or sorafenib (n=476). Median survival time for lenvatinib of 13·6 months (95% CI 12·1-14·9) was non-inferior to sorafenib (12·3 months, 10·4-13·9; hazard ratio 0·92, 95% CI 0·79-1·06), meeting criteria for non-inferiority. The most common any-grade adverse events were hypertension (201 [42%]), diarrhoea (184 [39%]), decreased appetite (162 [34%]), and decreased weight (147 [31%]) for lenvatinib, and palmar-plantar erythrodysaesthesia (249 [52%]), diarrhoea (220 [46%]), hypertension (144 [30%]), and decreased appetite (127 [27%]) for sorafenib. INTERPRETATION Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma. The safety and tolerability profiles of lenvatinib were consistent with those previously observed. FUNDING Eisai Inc.

Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma analysis of REACH trial results by child-pugh score

Importance REACH is the first phase 3 trial to provide information on hepatocellular cancer (HCC) in the second-line (postsorafenib) setting categorized by Child-Pugh score, a scoring system used to measure the severity of chronic liver disease. This exploratory analysis demonstrates the relationship between a potential ramucirumab survival benefit, severity of liver disease, and baseline &agr;-fetoprotein (&agr;FP). Objective To assess treatment effects and tolerability of ramucirumab by Child-Pugh score in patients with HCC enrolled in the REACH trial. Design, Settings, and Participants Randomized, double-blind, phase 3 trial of ramucirumab and best supportive care vs placebo and best supportive care as second-line treatment in patients with HCC enrolled between November 4, 2010 and April 18, 2013, from 154 global sites. Overall, 643 patients were randomized and included in this analysis; 565 patients considered Child-Pugh class A (Child-Pugh scores 5 and 6) and 78 patients considered class B (Child-Pugh scores 7 and 8). Interventions Ramucirumab (8 mg/kg) or placebo intravenously plus best supportive care every 2 weeks. Main Outcomes and Measures Overall survival (OS), defined as time from randomization to death from any cause. Results In the randomized population of 643 patients (mean [SD] age, 62.8 [11.1] years) in this analysis, a potential ramucirumab OS benefit was observed for patients with a Child-Pugh score of 5 (hazard ratio [HR], 0.80; 95% CI, 0.63-1.02; P = .06) but no apparent benefit for patients with Child-Pugh scores of 6 or 7 and 8. In patients with baseline &agr;FP levels of 400 ng/mL (to convert ng/mL to &mgr;g/L, multiply by 1.0) or more, a ramucirumab OS benefit was significant for a score of Child-Pugh 5 (HR, 0.61; 95% CI, 0.43-0.87; P = .01) and Child-Pugh 6 (HR, 0.64; 95% CI, 0.42-0.98; P = .04), but was not significant for Child-Pugh 7 and 8. The overall safety profile of ramucirumab, regardless of Child-Pugh score, was considered manageable. Regardless of treatment arm, patients with Child-Pugh scores of 7 and 8 experienced a higher incidence of grade 3 or higher treatment–emergent adverse events, including ascites and asthenia, and special-interest events, including liver injury and/or failure and bleeding, compared with patients with Child-Pugh scores of 5 or 6. Conclusions and Relevance In unselected patients, a trend for ramucirumab survival benefit was observed only for patients with a Child-Pugh score of 5. In patients with baseline &agr;FP levels of 400 ng/mL or more, a ramucirumab survival benefit was observed for Child-Pugh scores of 5 and 6. Ramucirumab had a manageable toxic effect profile. These results support the ongoing REACH-2 study of ramucirumab in patients with advanced HCC with underlying Child-Pugh A cirrhosis and baseline &agr;FP levels of 400 ng/mL or more. Trial Registration clinicaltrials.gov Identifier: NCT01140347

A QTc study of cabazitaxel in patients with advanced solid tumors.

257 Background: Cabazitaxel (Cbz) improves overall survival in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel failure, compared with mitoxantrone (HR 0.70; 95% CI 0.59-0.83; P < 0.0001). Following Cbz approval for the treatment of mCRPC, this study was undertaken to evaluate any effect of Cbz on the QTc interval. METHODS This prospective, multinational, open-label study ( NCT01087021 ) enrolled pts with advanced solid tumors (without other therapeutic options). Cbz 25 mg/m² IV was administered on Day 1 Q3W. QTc and other ECG intervals were assessed on Day 1 of Cycle 1. Triplicate ECGs were obtained from 12-lead Holter recordings and concomitant serial blood samples were collected for pharmacokinetic (PK) analysis. The primary endpoint was change from baseline in the corrected QTc interval (according to the Fridericia formula QTcF). RESULTS A total of 96 pts were enrolled; 32 pts under the original protocol (6-h Holter) and 64 pts following protocol amendment 1, which extended ECG and PK monitoring (24-h Holter). Median age was 63 yrs (69.8% male), 30.5% and 57.9% of pts were ECOG PS 0 and 1 respectively; 33 pts (34.4%) had prostate cancer. Screening ECG was abnormal but not clinically significant in 39.6% of pts. The majority (n = 65) of pts received ≥ 3 treatment cycles; safety and ECG parameters were evaluated in 95 and 94 pts, respectively. In the 24-h Holter group (n = 63), the maximum least squares (LS) mean change from baseline in QTcF was 4.8 msec (90% CI 2.1-7.5), returning to baseline by 24 h. Similar results were observed in the overall population (n = 94). At Cmax, Cbz concentration had no effect on QTcF change from baseline; the mean (CV%) Cmax (n = 91) and AUC (n = 92) were 276 ng/ml (63%) and 1245 ng.h/ml (82%). The LS mean change from baseline in heart rate increased up to 24 h but remained < 10 beats per minute. The most common Grade 3/4 AEs were neutropenia (27.4%), febrile neutropenia (12.6%), fatigue (12.6%) and dehydration (5.3%). No Grade 3/4 cardiac AEs were reported. Of the 6 deaths reported, 1 (infection) was study drug related. CONCLUSIONS Cbz had no significant effect on QTc interval in pts with advanced tumors. The Cbz safety profile is consistent with previous findings and with other taxane-based therapies.

A Randomized Phase II Open-Label Multi-Institution Study of the Combination of Bevacizumab and Erlotinib Compared to Sorafenib in the First-Line Treatment of Patients with Advanced Hepatocellular Carcinoma

Objectives: To investigate the clinical efficacy and tolerability of the combination of bevacizumab (B) and erlotinib (E) compared to sorafenib (S) as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Methods: A total of 90 patients with advanced HCC, Child-Pugh class A–B7 cirrhosis, and no prior systemic therapy were randomly assigned (1: 1) to receive either 10 mg/kg B intravenously every 14 days and 150 mg E orally daily (n = 47) (B+E) or 400 mg S orally twice daily (n = 43). The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), objective response rate based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1), time to progression, and safety and tolerability. Results: The median OS was 8.55 months (95% CI: 7.00–13.9) for patients treated with B+E and 8.55 months (95% CI: 5.69–12.2) for patients receiving S. The hazard ratio (HR) for OS was 0.92 (95% CI: 0.57–1.47). The median EFS was 4.37 months (95% CI: 2.99–7.36) for patients receiving B+E and 2.76 months (95% CI: 1.84–4.80) for patients receiving S. The HR for EFS was 0.67 (95% CI: 0.42–1.07; p = 0.09), favoring B+E over S. When OS was assessed among patients who were Child-Pugh class A, the median OS was 11.4 months (95% CI: 7.5–15.7) for patients treated with B+E (n = 39) and 10.26 months (95% CI: 5.9–13.0) for patients treated with S (n = 38) (HR = 0.88; 95% CI: 0.53–1.46). Conclusions: There was no difference in efficacy between the B+E and S arms, although the safety and tolerability profile tended to favor B+E over S based on competing risk analysis.

The DASH Study: A phase 1b study of dalantercept plus sorafenib in advanced hepatocellular carcinoma.

TPS495 Background: The activin receptor-like kinase (ALK1) pathway is a novel target in angiogenesis that promotes blood vessel maturation and stabilization. ALK1 binds to the ligand bone morphogenetic protein 9 (BMP9) which is overexpressed in hepatocellular carcinoma (HCC) compared to normal hepatocytes. Dalantercept is an ALK1 receptor fusion protein that binds BMP9 and acts as a ligand trap. Sorafenib, a multi-kinase and vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI), is the standard therapy for advanced HCC. In a preclinical model of HCC, simultaneous blockade of ALK1 and VEGF signaling with dalantercept and sorafenib resulted in additive tumor growth inhibition. In a completed Phase 1 study in thirty-seven subjects with solid tumors, dalantercept monotherapy demonstrated preliminary anti-tumor activity and a safety profile that was generally non-overlapping with VEGFR TKIs. Methods: An open label, multi-center, dose escalating, phase 1b study to evaluate dalanterce...

A randomized phase II open label multi-institution study of the combination of bevacizumab (B) and erlotinib (E) compared to sorafenib (S) in the first-line treatment of patients (pts) with advanced hepatocellular carcinoma (HCC).

337 Background: HCC is the 2nd most common cancer worldwide. Most pts present with advanced disease and require systemic therapy. S, a multi-targeted tyrosine kinase inhibitor (TKI) is the only approved drug for HCC. B is a mAb that binds circulating ligand of the transmembrane VEGF receptor; E is a TKI that inhibits EGFR signal transduction. Published single-arm trial data suggest clinical benefit from B+E in HCC. Methods: The study was designed to estimate the HR for OS of B+E vs S with its 95% confidence interval for a sample size of 90 evaluable pts. A difference in OS favoring the B+E arm with a HR of 0.67 was expected and of interest, based on median OS for B+E and S of 15 and 11 mos. seen in previous trials.Secondary endpoints include event-free survival (EFS), toxicity, and RR. Eligible pts had advanced HCC, Childs-Pugh Class A-B7, no prior systemic therapy, preserved organ function, ECOG PS 0-2. Patients were randomized 1:1 to receive S 400 mg orally twice daily, continuously, or B 10 mg/kg IV ev...

A Phase II, single-arm study of nivolumab in patients with metastatic or unresectable urothelial cancer who have progressed following treatment with a platinum agent

Meeting abstracts Clinical trials in patients with advanced bladder cancer have reported response rates of up to approximately 30% and 60% with single-agent and multi-agent regimens, respectively, and minimal improvements in survival over best supportive care. Guidance on second-line treatment