Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.

BACKGROUND: Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS. METHODS: We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response--ypT0 ypN0, ypT0/is ypN0, and ypT0/is--for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS. FINDINGS: We obtained data from 12 identified international trials and 11 955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0·44, 95% CI 0·39-0·51; ypT0/is ypN0: 0·48, 0·43-0·54) and OS (0·36, 0·30-0·44; 0·36, 0·31-0·42) than was tumour eradication from the breast alone (ypT0/is; EFS: HR 0·60, 95% CI 0·55-0·66; OS 0·51, 0·45-0·58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0·24, 95% CI 0·18-0·33; OS: 0·16, 0·11-0·25) and in those with HER2-positive, hormone-receptor-negative tumours who received trastuzumab (EFS: 0·15, 0·09-0·27; OS: 0·08, 0·03, 0·22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R(2)=0·03, 95% CI 0·00-0·25) and OS (R(2)=0·24, 0·00-0·70). INTERPRETATION: Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS. FUNDING: US Food and Drug Administration.

Pain palliation measurement in cancer clinical trials: the US Food and Drug Administration perspective.

BACKGROUND: Pain palliation resulting from antitumor therapy provides direct evidence of treatment benefit when combined with evidence of antitumor activity. The US Food and Drug Administration (FDA) previously issued guidance regarding the use of patient-reported outcome (PRO) measures to support labeling claims. The purpose of this article is to identify common challenges and key design strategies when measuring pain palliation in antitumor therapy clinical trials that are consistent with PRO Guidance principles. METHODS: Antitumor clinical protocols submitted to the FDA between 1995 and 2012 that included pain palliation as a primary or secondary endpoint were reviewed. Challenges in critical trial design components were identified. Design strategies consistent with PRO Guidance principles are proposed. RESULTS: The challenges identified were measurement of pain intensity and analgesic use, enrollment eligibility criteria, data collection methods, responder definitions, missing data, and blinding. Strategies included the use of well-defined, reliable, PRO assessments of pain intensity and analgesics; ensuring that enrollment criteria define patients with clinically significant pain attributable to cancer on an optimal analgesic regimen; defining responders using both pain and analgesic use criteria; incorporating an analysis of tumor response to support evidence of pain response; and minimizing missing data and inadvertent unblinding. CONCLUSIONS: Improvement in cancer-related pain resulting from antitumor therapy is an important treatment benefit that can support drug approval and labeling claims when adequately measured if study results demonstrate statistically and clinically significant findings. Sponsors are encouraged to discuss pain palliation assessment methods with the FDA early in and throughout product development.

U.S. Food and Drug Administration approval summary: Erlotinib for the first-line treatment of metastatic non-small cell lung cancer with epidermal growth factor receptor exon 19 deletions or exon 21 (L858R) substitution mutations.

On May 14, 2013, the U.S. Food and Drug Administration approved erlotinib (Tarceva, Astellas Pharma Inc., Northbrook, IL, http://www.us.astellas.com/) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. This indication for erlotinib was approved concurrently with the cobas EGFR Mutation Test (Roche Molecular Systems, Inc., Basel, Switzerland, http://www.molecular.roche.com), a companion diagnostic test for patient selection. The approval was based on clinically important improvements in progression-free survival (PFS) and objective response rate (ORR) and an acceptable toxicity profile demonstrated in a multicenter, open label trial enrolling 174 patients with metastatic NSCLC whose tumors had EGFR mutations as determined by a laboratory-developed test. Patients were randomized (1:1) to receive erlotinib (150 mg/day) or platinum-based doublet chemotherapy. The primary endpoint was investigator-assessed PFS. Secondary endpoints included overall survival (OS) and ORR. Superior PFS (hazard ratio [HR] 0.34; 95% confidence interval [CI]: 0.23, 0.49; p < .001) and ORR (65% vs. 16%) were observed in the erlotinib arm. Median PFS was 10.4 months and 5.2 months in the erlotinib and chemotherapy arms, respectively. There was no difference in OS (HR 0.93; 95% CI: 0.64, 1.35) with median OS of 22.9 months and 19.5 months in the erlotinib and chemotherapy arms, respectively. The most frequent (≥30%) adverse reactions in the erlotinib-treated patients were rash, diarrhea, asthenia, cough, dyspnea, and decreased appetite. The most frequent (≥5%) grade 3 and 4 adverse reactions were rash and diarrhea.

FDA approval summary: crizotinib for the treatment of metastatic non-small cell lung cancer with anaplastic lymphoma kinase rearrangements.

On August 26, 2011, crizotinib received accelerated approval for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is ALK-positive as detected by a test approved by the U.S. Food and Drug Administration (FDA). Approval was based on two single-arm trials demonstrating objective response rates (ORRs) of 50% and 61% and median response durations of 42 and 48 weeks. On November 20, 2013, crizotinib received regular approval based on confirmation of clinical benefit in study A8081007, a randomized trial in 347 patients with ALK-positive advanced NSCLC who had previously received one platinum-containing regimen. Patients were assigned (1:1) to receive crizotinib 250 mg orally twice daily or standard of care (docetaxel or pemetrexed). The primary endpoint was progression-free survival (PFS) determined by independent radiology review; secondary endpoints were ORR and overall survival (OS). PFS was significantly longer in the crizotinib arm, with median PFS of 7.7 and 3.0 months in the crizotinib and chemotherapy arms, respectively, and a 46% absolute increase in ORR but no difference in OS between treatment arms at the interim analysis. The most common adverse drug reactions (>25%) in crizotinib-treated patients were vision disorders, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue. The most serious toxicities of crizotinib were hepatotoxicity, interstitial lung disease or pneumonitis, and QT-interval prolongation. Crizotinib's rapid clinical development program (6 years from identification of ALK rearrangements in a subset of NSCLC to full FDA approval) is a model of efficient drug development in this new era of molecularly targeted oncology therapy.

Approval summary: imatinib mesylate for one or three years in the adjuvant treatment of gastrointestinal stromal tumors.

On January 31, 2012, the U.S. Food and Drug Administration granted regular approval of imatinib mesylate tablets (Gleevec®; Novartis Pharmaceuticals Corporation, East Hanover, NJ) for the adjuvant treatment of adult patients following complete gross resection of Kit(+) (CD117(+)) gastrointestinal stromal tumors (GISTs). The recommended dose of imatinib is 400 mg/day administered daily for 3 years. Three hundred ninety-seven patients were enrolled in a randomized adjuvant, multicenter, open label, phase III trial comparing 12 months with 36 months of imatinib treatment. Eligible patients had one of the following: tumor diameter >5 cm and mitotic count >5 per 50 high power fields (HPFs); tumor diameter >10 cm and any mitotic count; tumor of any size with mitotic count >10/50 HPFs; or tumor ruptured into the peritoneal cavity. The primary endpoint was the recurrence-free survival (RFS) interval. The median follow-up for patients without an RFS event was 42 months. There were 84 (42%) RFS events in the 12-month treatment arm and 50 (25%) RFS events in the 36-month treatment arm. Thirty-six months of imatinib treatment led to a significantly longer RFS interval than with 12 months of treatment. The median follow-up for overall survival (OS) evaluation in patients still living was 48 months. Thirty-six months of imatinib treatment led to a significantly longer OS time than with 12 months of imatinib treatment. The most common adverse reactions, as noted in previous imatinib studies, were diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain.

FDA approval summary: sunitinib for the treatment of progressive well-differentiated locally advanced or metastatic pancreatic neuroendocrine tumors.

On May 20, 2011, the U.S. Food and Drug Administration (FDA) approved sunitinib malate capsules (Sutent®; Pfizer, Inc., New York) for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs) in patients with unresectable locally advanced or metastatic disease. In a phase III randomized trial, 171 patients received either sunitinib (37.5 mg) or placebo once daily. The progression-free survival (PFS) interval was the primary efficacy endpoint. Secondary endpoints included the overall survival (OS) time, objective response rate (ORR), patient-reported outcomes, and safety. Based on early results favoring sunitinib, the independent data monitoring committee recommended trial termination prior to the prespecified interim analysis. This premature analysis may have led to an overestimate of the treatment effect. In the FDA analysis of investigator-assessed PFS times, the median values for the sunitinib and placebo arms were 10.2 months and 5.4 months, respectively. The ORRs were 9.3% and 0% in the sunitinib and placebo arms, respectively. The OS data were not mature at the time of approval and were confounded by 69% crossover. Common adverse reactions in patients receiving sunitinib included diarrhea, nausea, asthenia, fatigue, neutropenia, hypertension, and palmar-plantar erythrodysesthesia syndrome. Two patients on sunitinib died as a result of cardiac failure. The Oncologic Drugs Advisory Committee voted eight to two that, despite residual uncertainty about the magnitude of the PFS effect because of early trial termination, sunitinib demonstrated a favorable benefit-risk profile in pNET patients. The FDA concurred with the committee's assessment and granted sunitinib regular approval for this rare malignancy with few available therapies.

Approval summary: letrozole (Femara® tablets) for adjuvant and extended adjuvant postmenopausal breast cancer treatment: conversion of accelerated to full approval.

On April 30, 2010, the U.S. Food and Drug Administration converted letrozole (Femara®; Novartis Pharmaceuticals Corporation, East Hanover, NJ) from accelerated to full approval for adjuvant and extended adjuvant (following 5 years of tamoxifen) treatment of postmenopausal women with hormone receptor-positive early breast cancer. The initial accelerated approvals of letrozole for adjuvant and extended adjuvant treatment on December 28, 2005 and October 29, 2004, respectively, were based on an analysis of the disease-free survival (DFS) outcome of patients followed for medians of 26 months and 28 months, respectively. Both trials were double-blind, multicenter studies. Both trials were unblinded early when an interim analysis showed a favorable letrozole effect on DFS. In updated intention-to-treat analyses of both trials, the risk for a DFS event was lower with letrozole than with tamoxifen (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.77-0.99; p = .03) in the adjuvant trial and was lower than with placebo (HR, 0.89; 95% CI, 0.76-1.03; p = .12) in the extended adjuvant trial. The latter analysis ignores the interim switch of 60% of placebo-treated patients to letrozole. Bone fractures and osteoporosis were reported more frequently following treatment with letrozole whereas tamoxifen was associated with a higher risk for endometrial proliferation and endometrial cancer. Myocardial infarction was more frequently reported with letrozole than with tamoxifen, but the incidence of thromboembolic events was higher with tamoxifen than with letrozole. Lipid-lowering medications were required for 25% of patients on letrozole and 16% of patients on tamoxifen.

Approval summary: imatinib mesylate in the adjuvant treatment of malignant gastrointestinal stromal tumors.

On December 19, 2008, the U.S. Food and Drug Administration approved imatinib mesylate tablets for oral use (Gleevec(R); Novartis Pharmaceuticals Corporation, East Hanover, NJ) for the adjuvant treatment of adult patients following complete gross resection of Kit(+) (CD117(+)) gastrointestinal stromal tumor (GIST). A randomized, double-blind, placebo-controlled study enrolling 713 patients was submitted. The primary objective of the clinical trial was to compare the recurrence-free survival (RFS) intervals of the two groups. Overall survival (OS) was a secondary endpoint. Eligible patients were > or =18 years of age with a histological diagnosis of GIST (Kit(+)), resected tumor size > or =3 cm, and a complete gross resection within 14-70 days prior to registration. Imatinib, 400 mg orally, was administered once daily for 1 year. The study was terminated after completion of the third protocol-specified interim analysis. At that time, 100 RFS events were confirmed by a blinded central independent review. With a median follow-up of 14 months, 30 RFS events were observed in the imatinib group and 70 were observed in the placebo group (hazard ratio, 0.398; 95% confidence interval, 0.259-0.610; two-sided p-value < .0001). OS results are immature. Most patients in both groups experienced at least one adverse reaction, and 31% of the imatinib group and 18% of the placebo group experienced grade > or =3 adverse reactions. The most frequently reported adverse reactions (> or =20%) were diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain. Drug was discontinued for adverse reactions in 17% and 3% of the imatinib and placebo-treated patients, respectively.

Approval summary: pemetrexed maintenance therapy of advanced/metastatic nonsquamous, non-small cell lung cancer (NSCLC).

On July 2, 2009, the U.S. Food and Drug Administration approved pemetrexed injection (Alimta® Injection; Eli Lilly and Company, Indianapolis, IN) for maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based doublet induction chemotherapy. A double-blind study of pemetrexed plus best supportive care versus placebo plus best supportive care was conducted. Pemetrexed, 500 mg/m(2) i.v., was administered every 21 days until disease progression. Folic acid, vitamin B(12), and a corticosteroid were given to all study patients. There were 663 randomized patients (pemetrexed, 441; placebo, 222). Treatments were well balanced with respect to baseline disease characteristics and stratification factors. The median overall survival (OS) time for intent-to-treat (ITT) patients was 13.4 months for patients receiving pemetrexed and 10.6 months for those receiving placebo (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.65-0.95; p = .012). Median OS times were 15.5 months versus 10.3 months for patients with nonsquamous histologies receiving pemetrexed and placebo, respectively (HR, 0.70; 95% CI, 0.56-0.88). The median OS time in patients with squamous histology receiving pemetrexed was 9.9 months, versus 10.8 months for those receiving placebo (HR, 1.07; 95% CI, 0.77-1.50). A significantly longer progression-free survival interval for both the ITT and nonsquamous patient populations receiving pemetrexed maintenance therapy was also observed. The most common (>5%) adverse reactions in patients receiving pemetrexed were hematologic toxicity, an increase in hepatic enzymes, fatigue, gastrointestinal toxicity, sensory neuropathy, and skin rash.

FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma.

This report summarizes the U.S. Food and Drug Administration (FDA)'s approval of temsirolimus (Torisel), on May 30, 2007, for the treatment of advanced renal cell carcinoma (RCC). Information provided includes regulatory history, study design, study results, and literature review. A multicenter, three-arm, randomized, open-label study was conducted in previously untreated patients with poor-prognosis, advanced RCC. The study objectives were to compare overall survival (OS), progression-free survival (PFS), objective response rate, and safety in patients receiving interferon (IFN)-alpha versus those receiving temsirolimus alone or in combination with IFN-alpha. In the second planned interim analysis of the intent-to-treat population (n = 626), there was a statistically significant longer OS time in the temsirolimus (25 mg) arm than in the IFN-alpha arm (median, 10.9 months versus 7.3 months; hazard ratio [HR], 0.73; p = .0078). The combination of temsirolimus (15 mg) and IFN-alpha did not lead to a significant difference in OS compared with IFN-alpha alone. There was also a statistically significant longer PFS time for the temsirolimus (25 mg) arm than for the IFN-alpha arm (median, 5.5 months versus 3.1 months; HR, 0.66, p = .0001). Common adverse reactions reported in patients receiving temsirolimus were rash, asthenia, and mucositis. Common laboratory abnormalities were anemia, hyperglycemia, hyperlipidemia, and hypertriglyceridemia. Serious but rare cases of interstitial lung disease, bowel perforation, and acute renal failure were observed. Temsirolimus has demonstrated superiority in terms of OS and PFS over IFN-alpha and provides an additional treatment option for patients with advanced RCC.

Approval summary: erlotinib maintenance therapy of advanced/metastatic non-small cell lung cancer (NSCLC).

On April 16, 2010, the U. S. Food and Drug Administration (FDA) approved erlotinib tablets (Tarceva®; OSI Pharmaceuticals, Inc., Melville, NY) for maintenance treatment of patients with stage IIIB/IV non-small cell lung cancer (NSCLC) whose disease had not progressed after four cycles of platinum-based first-line chemotherapy. In total, 889 patients received either erlotinib (150 mg) or placebo once daily. Progression-free survival (PFS), in all patients and in patients with epidermal growth factor receptor (EGFR)(+) tumors by immunohistochemistry (IHC), was the primary efficacy endpoint. Overall survival (OS) was a secondary sponsor endpoint but was the primary regulatory endpoint. Median PFS times were 2.8 months and 2.6 months in the erlotinib and placebo arms, respectively (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.62-0.82; p < .001). Median OS times were 12.0 months and 11.0 months, favoring erlotinib (HR, 0.81; 95% CI, 0.70-0.95). The PFS and OS HRs in patients with EGFR(+) tumors by IHC were 0.69 (95% CI, 0.58-0.82) and 0.77 (95% CI, 0.64-0.93), respectively. The PFS and OS HRs in patients with EGFR(-) tumors by IHC were 0.77 (95% CI, 0.51-1.14) and 0.91 (95% CI, 0.59-1.38), respectively. Following disease progression, 57% of placebo-treated patients received additional chemotherapy, compared with 47% of erlotinib-treated patients. Fourteen percent of placebo-treated patients received erlotinib or gefitinib, 31% received docetaxel, and 14% received pemetrexed. In total, 59% of placebo-treated patients who received treatment received FDA approved second-line NSCLC drugs. The most common adverse reactions in patients receiving erlotinib were rash and diarrhea.

FDA review summary: Mozobil in combination with granulocyte colony-stimulating factor to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation.

PURPOSE: On December 15, 2008, the US Food and Drug Administration approved plerixafor (Mozobil; Genzyme Corp.), a new small-molecule inhibitor of the CXCR4 chemokine receptor, for use in combination with granulocyte colony-stimulating factor (G-CSF) to mobilize hematopoietic stem cells (HSC) to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). This summary reviews the database supporting this approval. EXPERIMENTAL DESIGN: The safety and efficacy of plerixafor were demonstrated by 2 multicenter, randomized, placebo-controlled studies in patients with NHL and MM who were eligible for autologous HSC transplantation. The primary efficacy end points were the collection of > or = 5 x 10(6) CD34+ cells/kg from the peripheral blood in 4 or fewer apheresis sessions in patients with NHL or > or = 6 x 10(6) CD34+ cells/kg from the peripheral blood in 2 or fewer apheresis sessions in patients with MM. RESULTS: The 2 randomized studies combined enrolled 600 patients (298 with NHL and 302 with MM). Fifty-nine percent of patients with NHL who were mobilized with G-CSF and plerixafor had peripheral blood HSC collections of > or = 5 x 10(6) CD34+ cells/kg in 4 or fewer apheresis sessions, compared with 20% of patients with NHL who were mobilized with G-CSF and placebo (p < 0.001). Seventy-two percent of patients with MM who were mobilized with Mozobil and G-CSF had peripheral blood HSC collections of > or = 6 x 10(6) CD34+ cells/kg in 2 or fewer apheresis sessions, compared with 34% of patients with MM who were mobilized with placebo and G-CSF (p < 0.001). Common adverse reactions included diarrhea, nausea, vomiting, flatulence, injection site reactions, fatigue, arthralgia, headache, dizziness, and insomnia. CONCLUSIONS: This report describes the Food and Drug Administration review supporting the approval of plerixafor.

Approval summary: pemetrexed in the initial treatment of advanced/metastatic non-small cell lung cancer.

On September 26, 2008, the U.S. Food and Drug Administration approved pemetrexed injection (Alimta Injection; Eli Lilly and Company, Indianapolis, IN) for use in combination with cisplatin for the initial treatment of patients with stage IIIB/IV nonsquamous non-small cell lung cancer (NSCLC). A randomized, phase III, open-label study was conducted in 1,725 patients. Patients were randomly assigned to receive 21-day cycles of pemetrexed plus cisplatin (AC) or gemcitabine plus cisplatin (GC). The primary objective was overall survival. The median survival time was 10.3 months in both the AC arm and the GC arm (adjusted hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.84-1.05). The median progression-free survival times were 4.8 and 5.1 months for the AC and GC arms, respectively (adjusted HR, 1.04; 95% CI, 0.94-1.15). The overall response rates were 27.1% and 24.7% for the AC and GC arms, respectively. A prespecified analysis of the impact of NSCLC histology on overall survival was conducted. In the nonsquamous NSCLC subgroup, the median survival times were 11.0 and 10.1 months in the AC and GC groups, respectively (unadjusted HR, 0.84; 95% CI, 0.74-0.96). However, in the squamous cell histology subgroup, the median survival times were 9.4 versus 10.8 months in the AC and GC groups, respectively (unadjusted HR, 1.22; 95% CI, 0.99-1.50). This unfavorable effect of squamous histology on overall survival was also noted in a retrospective analysis of a trial that compared pemetrexed with docetaxel in NSCLC patients who received prior chemotherapy. No new pemetrexed safety signals were observed.

Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors.

The purpose of the present application was to fulfill a postmarketing commitment to provide long-term efficacy and safety data on treatment with imatinib mesylate (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) in patients with CD117(+) unresectable and/or metastatic malignant gastrointestinal stromal tumors (GISTs). In addition, this application also provides evidence to support a change in the label to allow for an escalation of imatinib dosing to 800 mg/day for patients with progressive disease on a lower dose. Two open-label, controlled, multicenter, intergroup, international, randomized phase III studies were submitted -- one conducted by the European Organization for Research and Treatment of Cancer (n = 946) and the other by the Southwest Oncology Group (n = 746). These studies compared 400 mg/day of imatinib with 800 mg/day of imatinib. A combined analysis of the two studies was prospectively defined and agreed to by both groups. Both protocols allowed patients randomized to the 400-mg/day imatinib arm to cross over to 800 mg/day imatinib at progression. Objective responses were achieved in >50% of patients receiving either imatinib dose. The median progression-free survival time was approximately 20 months and the median overall survival (OS) time was approximately 49 months. In the combined analysis, 347 patients crossed over to 800 mg/day imatinib at the time of progression. The median OS time after crossover was 14.3 months. The most common adverse events (AEs) were fluid retention, nausea, fatigue, skin rash, gastrointestinal complaints, and myalgia. The most common laboratory abnormality was anemia. Most often the AEs were of mild-to-moderate severity. Fluid retention events and skin rash were numerically reported more often in the 800-mg/day treatment cohort of patients.

Sorafenib for the treatment of unresectable hepatocellular carcinoma.

PURPOSE: To describe the U.S. Food and Drug Administration (FDA) review and approval of sorafenib (Nexavar; Bayer Pharmaceuticals Corp., Montville, NJ, and Onyx Pharmaceuticals Corp., Emeryville, CA), an oral kinase inhibitor, for the treatment of patients with unresectable hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: The FDA independently analyzed an international, double-blind, placebo-controlled trial comparing the effect of best supportive care plus sorafenib or matching placebo on overall survival. Eligible patients had unresectable, biopsy-proven HCC and had not received prior systemic therapy. RESULTS: Among the 602 randomized patients (placebo, 303; sorafenib, 299), baseline characteristics were well balanced, and 97% were Child-Pugh score A. HCC was "advanced" in 70% overall, as defined by extrahepatic metastases or by tumor radiographically visible in venous structures outside the liver. Underlying liver diseases included hepatitis B (18%), hepatitis C (28%), and alcohol-related (26%). The trial was stopped following a prespecified second interim analysis showing a statistically significant survival advantage for sorafenib [median, 10.7 vs 7.9 months; hazard ratio, 0.69 (95% confidence interval, (0.55, 0.87)), p = 0.00058]. Adverse events in sorafenib-treated patients included diarrhea in 55% (grade 3, 10%), hand-foot syndrome in 21% (grade 3, 8%), rash in 19% (grade 3, 1%), and cardiac ischemia or infarction in 2.7% (versus 1.3% for placebo). On sorafenib, treatment-emergent hypertension occurred in 9% of patients (placebo, 4%) and was grade 3 in 4% (placebo, 1%); elevated serum lipase occurred in 40% (placebo, 37%); hypophosphatemia occurred in 35% (placebo, 11%). CONCLUSIONS: Sorafenib is the first systemic therapy to demonstrate a survival benefit in a randomized trial for unresectable HCC and has received FDA approval for this indication.

Assessing proarrhythmic potential of drugs when optimal studies are infeasible.

Assessing the potential for a new drug to cause life-threatening arrhythmias is now an integral component of premarketing safety assessment. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Guideline (ICH) E14 recommends the "Thorough QT Study" (TQT) to assess clinical QT risk. Such a study calls for careful evaluation of drug effects on the electrocardiographic QT interval at multiples of therapeutic exposure and with a positive control to confirm assay sensitivity. Yet for some drugs and diseases, elements of the TQT Study may be impractical or unethical. In these instances, alternative approaches to QT risk assessment must be considered. This article presents points to consider for evaluation of QT risk when alternative approaches are needed.

Ixabepilone in combination with capecitabine and as monotherapy for treatment of advanced breast cancer refractory to previous chemotherapies.

PURPOSE: To describe the considerations leading to marketing approval of ixabepilone in combination with capecitabine and as monotherapy for the treatment of advanced breast cancer that is refractory to other chemotherapies. EXPERIMENTAL DESIGN: Data from one randomized multicenter trial comparing combination therapy with ixabepilone and capecitabine to capecitabine alone were analyzed for support of the combination therapy indication. For monotherapy, a single-arm trial of ixabepilone was analyzed. Supporting data came from an additional single-arm combination therapy study and two single-arm monotherapy studies. RESULTS: In patients with metastatic or locally advanced breast cancer who had disease progression on or following an anthracycline and a taxane, ixabepilone plus capecitabine showed an improvement in progression-free survival compared with capecitabine alone {median progression-free survival, 5.7 [95% confidence interval (95% CI), 4.8-6.7] versus 4.1 (95% CI, 3.1-4.3) months, stratified log-rank P < 0.0001; hazard ratio, 0.69 (95% CI, 0.58-0.83)}. As monotherapy for patients who had disease progression on or following an anthracycline, a taxane, and capecitabine, ixabepilone as monotherapy showed a 12% objective response rate by independent blinded review and 18% by investigator assessment. The major toxicities from ixabepilone therapy were peripheral neuropathy and myelosuppression, particularly neutropenia. CONCLUSIONS: On October 16, 2007, the Food and Drug Administration approved ixabepilone for injection in combination with capecitabine or as monotherapy for the treatment of patients with advanced breast cancer who have experienced disease progression on previous chemotherapies.

Tasigna for chronic and accelerated phase Philadelphia chromosome--positive chronic myelogenous leukemia resistant to or intolerant of imatinib.

PURPOSE: This Food and Drug Administration (FDA) approval report describes the data and analyses leading to the approval by the FDA of nilotinib (Tasigna, AMN-107; Novartis Pharmaceuticals Corporation), an inhibitor of Bcr-Abl tyrosine kinase, for the treatment of chronic-phase (CP) and accelerated-phase (AP) chronic myelogenous leukemia (CML) resistant to or intolerant of imatinib. EXPERIMENTAL DESIGN: The FDA approval of the efficacy and safety of nilotinib was based on the results of an ongoing single-arm, open-label, phase 2 clinical trial. The primary end point for CML-CP was unconfirmed major cytogenetic response. The efficacy end point for CML-AP was confirmed hematologic response. RESULTS: The major cytogenetic response rate in 232 evaluable CP patients was 40% (95% confidence interval, 33%, 46%). The hematologic response rate in 105 evaluable AP patients was 26% (95% confidence interval, 18%, 35%). The median duration of response has not been reached for both CML-CP and CML-AP responding patients. In CML-CP patients, the common serious drug-related adverse reactions were thrombocytopenia and neutropenia. In CML-AP patients, the common serious drug-related adverse reactions were thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase, and pyrexia. Nilotinib prolongs the QT interval and sudden deaths have been reported; these risks and appropriate risk minimization strategies are described in a boxed warning on the labeling. CONCLUSIONS: On October 29, 2007, the U.S. FDA granted accelerated approval to nilotinib (Tasigna) for use in the treatment of CP and AP Philadelphia chromosome positive CML in adult patients resistant to or intolerant of prior therapy that included imatinib.

Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate.

PURPOSE: On June 28, 2006, the U.S. Food and Drug Administration approved dasatinib (Sprycel; Bristol-Myers Squibb), a new small-molecule inhibitor of multiple tyrosine kinases, for the treatment of adults with chronic phase, accelerated phase, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) with resistance or intolerance to prior therapy including imatinib. This summary reviews the database supporting this approval. EXPERIMENTAL DESIGN: Four single-arm multicenter studies supported the efficacy and safety of dasatinib. The primary efficacy end point in chronic phase CML was major cytogenetic response. The primary end point in accelerated phase, myeloid phase, and lymphoid blast phase CML, and Ph(+) ALL was major hematologic response. RESULTS: The four studies combined enrolled 445 patients. In patients with chronic phase CML, the major cytogenetic response rate was 45% with a complete cytogenetic response rate of 33%. Major hematologic response rates in patients with accelerated phase CML, myeloid CML, lymphoid blast CML, and Ph(+) ALL were 59%, 32%, 31%, and 42%, respectively. Median response durations in chronic phase, accelerated phase, and myeloid phase CML had not been reached. The median durations of major hematologic response were 3.7 months in lymphoid blast CML and 4.8 months in Ph(+) ALL. Common toxicities with dasatinib included myelosuppression, bleeding, and fluid retention. CONCLUSIONS: This report describes the Food and Drug Administration review supporting the approval of dasatinib for CML and Ph(+) ALL based on the rates and durability of cytogenetic and hematologic responses.