Unstratified Log-rank Test Research Articles

Exploratory analysis of left- versus right-sided colorectal carcinoma in RAISE: A randomized, double-blind, phase 3 trial of ramucirumab (RAM) + FOLFIRI versus placebo (PBO) + FOLFIRI.

668 Background: Ramucirumab is a human IgG1 monoclonal antibody antagonist of VEGFR-2. Overall survival (OS) and progression-free survival (PFS) in 2nd line FOLFIRI based treatment for metastatic colorectal cancer (mCRC) were improved with RAM therapy versus PBO in the RAISE trial. Recent work suggests mCRC primary tumor location is both prognostic and predictive; with improved OS and therapy-specific sensitivity observed in left (L)- vs right (R)-sided tumors. Given these findings, the RAISE trial data was subjected to post-hoc analysis to determine if sidedness influenced RAM efficacy. Methods: Primary tumor site was obtained. L-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum, while R-CRC included transverse, ascending colon and cecum. OS/PFS in L and R subgroups were analyzed via Kaplan-Meier method and unstratified log-rank test (treatments within subgroup), unstratified Cox proportional hazards model (estimate hazard ratio [HR] and 95% CI), and Wald test (treatment-by-subgroup interaction). Results: Tumor location was available for 1012/1072 (94%) patients, 699 L- and 313 R-CRC. Baseline characteristics were balanced between arms. RAM treatment enhanced L-CRC median OS by 2.5 mo (median 14.5 vs 12.0 mo) with a HR (95% CI) = 0.807 (0.675, 0.965), P = 0.019; compared to a 1.1 mo increase in median OS in R-CRC vs PBO (12.7 vs 11.6) with a HR (95% CI) = 0.971 (0.750, 1.258), P = 0.823; and, RAM enhanced L-CRC median PFS by 1.6 mo (6.0 vs 4.4 mo) and HR (95% CI) = 0.776 (0.664, 0.906), P = 0.001 compared to a 1.1 mo increase in median PFS R-CRC vs PBO (5.6 vs 4.5) with a HR (95% CI) = 0.855 (0.674, 1.084), P = 0.197. The treatment-by-subgroup interaction for both OS and PFS was not significant ( P = 0.276, 0.578, respectively). Conclusions: Despite L-CRC patients having longer OS/PFS and a seemingly stronger RAM treatment effect than R-CRC, the non-significant interaction test cannot verify sidedness as being predictive of RAM efficacy. The current study confirms ramucirumab benefits mCRC patients regardless primary tumor location. Clinical trial information: NCT01183780.

Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial

In the PALOMA-3 study, palbociclib plus fulvestrant demonstrated improved progression-free survival compared with fulvestrant plus placebo in hormone receptor-positive, HER2- endocrine-resistant metastatic breast cancer (MBC). This analysis compared patient-reported outcomes (PROs) between the two treatment groups. Patients were randomized 2 : 1 to receive palbociclib 125 mg/day orally for 3 weeks followed by 1 week off (n = 347) plus fulvestrant (500 mg i.m. per standard of care) or placebo plus fulvestrant (n = 174). PROs were assessed on day 1 of cycles 1-4 and of every other subsequent cycle starting with cycle 6 using the EORTC QLQ-C30 and its breast cancer module, QLQ-BR23. High scores (range 0-100) could indicate better functioning/quality of life (QoL) or worse symptom severity. Repeated-measures mixed-effect analyses were carried out to compare on-treatment overall scores and changes from baseline between treatment groups while controlling for baseline. Between-group comparisons of time to deterioration in global QoL and pain were made using an unstratified log-rank test and Cox proportional hazards model. Questionnaire completion rates were high at baseline and during treatment (from baseline to cycle 14, ≥95.8% in each group completed ≥1 question on the EORTC QLQ-C30). On treatment, estimated overall global QoL scores significantly favored the palbociclib plus fulvestrant group [66.1, 95% confidence interval (CI) 64.5-67.7 versus 63.0, 95% CI 60.6-65.3; P = 0.0313]. Significantly greater improvement from baseline in pain was also observed in this group (-3.3, 95% CI -5.1 to -1.5 versus 2.0, 95% CI -0.6 to 4.6; P = 0.0011). No significant differences were observed for other QLQ-BR23 functioning domains, breast or arm symptoms. Treatment with palbociclib plus fulvestrant significantly delayed deterioration in global QoL (P < 0.025) and pain (P < 0.001) compared with fulvestrant alone. Palbociclib plus fulvestrant allowed patients to maintain good QoL in the endocrine resistance setting while experiencing substantially delayed disease progression. NCT01942135.

Abstract 5235: Circulating tumor DNA as a prognostic marker in colorectal cancer: Preliminary results of a prospective trial

Abstract Circulating tumor DNA has been suggested to be a prognostic factor in different types of tumors. In order to investigate this role, we prospectively enrolled 250 patients with stage II and stage III colorectal cancer (NCT01198743). Plasma samples were collected before surgery (D0) and 5 days later (D5), then every 4 months during the 3 years of follow-up. The end of follow-up will be May 2017. The primary tumors were characterized for KRAS, NRAS, BRAF, PIK3CA, APC and TP53 mutation by sequencing. The circulating DNA was assessed by picoliter digital droplet PCR (dPCR) using the Raindrop instrument (Raindance technologies) with Taqman probes for the 7 most frequent mutations of KRAS and for the BRAF V600E mutation. The survival without recurrence curves were estimated with the Kaplan- Meier method. Differences between groups of patients were analyzed using unstratified log-rank tests. For comparisons of baseline characteristics, categorical outcomes were analyzed with χ2 tests and continuous outcomes were compared with standard parametric or nonparametric tests. Continuous variables are presented as the mean (SD) and median interquartile rang. We present here the results of tumor circulating DNA for the first 56 patients with KRAS or a BRAF mutated tumors. The mean age was 65.3±11 years [37-84], the gender ratio M/F was 0.9. The tumor location was proximal or distal in 55% and 45% respectively. TNM classification showed 49% and 51% of stage II and stage III respectively. The tumors were found mutated for BRAF in 9 cases (16%) and mutated for KRAS in 47 cases (84%). Finally 54% of the patients received an adjuvant chemotherapy. Tumor circulating DNA was found in 12 patients out of the 56 tested patients (23%). A mutation identical to that found in the tumor was identified at D0 or D5 after surgery before any chemotherapy treatment in the plasma of 12 patients (21.4%). For the patients with circulating tumor DNA, the mutated allele frequency in the plasma range from 0.2‰ to 1.4% (median 2.4‰). The detection of circulating tumor DNA was more frequent in patients with recurrence or death from the disease during the follow-up than those without at the time of diagnosis (45.4% versus 15.6%, p = 0.03). Patients without circulating tumor DNA before or 5 days after surgery have a significant better survival without recurrence than those with circulating tumor DNA detectable in univariate analysis (HR: 7.3 CI95% [1.7-31.5] p = 0.006). After adjustment on tumor stage this result remains significant (HR: 6.9 CI95% [1.5-32.9] p = 0.01) During the follow-up DNA was detected in 36.7% of patients who recurred or died from the disease as compared to 2.2% of those who do not (P = 0.004). These preliminary results showed a strong prognostic impact of circulating tumor DNA at the time of surgery and need to be confirmed in the whole series of 250 patients and with the complete follow-up of 5 years. Citation Format: Pierre Laurent-Puig, Olivier Bouché, Ralph Niarra, Pascaline Aucouturier, Leonor Benhaim, Bruno Landi, Anne Berger, Thierry Lecomte, Corinne Normand, Delphine Le Corre, Audrey Didelot, Karine Mallet, Karla Perez Toralla, Thevy Hor, Zakaria El Harrak, Gilles Chatellier, Brian Hutchison, Darren Link, Valerie Taly. Circulating tumor DNA as a prognostic marker in colorectal cancer: Preliminary results of a prospective trial. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5235. doi:10.1158/1538-7445.AM2015-5235

Genotype correlations with blood pressure and efficacy outcomes from the randomized phase III AXIS trial of second-line axitinib versus sorafenib in metastatic renal cell carcinoma.

4528 Background: In the AXIS trial, axitinib significantly increased progression-free survival (PFS) vs sorafenib in patients with previously treated metastatic renal cell carcinoma (mRCC). Final analyses of association between select germline single nucleotide polymorphisms (SNPs) and outcomes in AXIS are reported. Methods: DNA samples from blood were genotyped by TaqMan allelic discrimination. Logistic/Cox regression analyses evaluated association between 15 SNPs in 4 genes (VEGF-A, VEGFR1, VEGFR2, HIF1α) and blood pressure (BP; grade ≥3 hypertension, diastolic BP >90 mmHg or increase ≥15 mmHg from baseline) and efficacy (overall survival [OS], independently-assessed objective response rate [ORR] and PFS) endpoints. Kaplan-Meier PFS/OS estimates were compared with 2-sided unstratified log-rank tests. Multivariate analyses assessed SNPs and baseline characteristics as potential predictors of PFS/OS. Results: Genotype samples were available for 305/714 (43%) patients: 159 received axitinib, 146 sorafenib....

Impact of crizotinib on patient-reported symptoms and quality of life (QOL) compared with single-agent chemotherapy in a phase III study of advanced ALK+ non-small cell lung cancer (NSCLC).

8108 Background: PROFILE 1007 compared the efficacy and safety of the ALK inhibitor crizotinib (N=172) with that of standard-of-care chemotherapy (pemetrexed [PEM; N=99] or docetaxel [DOC; N=72]) in patients with advanced ALK+ NSCLC. The primary endpoint was progression-free survival. The main objective of our present post-hoc analyses was to compare patient-reported outcomes in the crizotinib arm with those of the DOC and PEM subgroups in the chemotherapy arm. Methods: Patient-reported outcomes were assessed at baseline, on day 1 of each cycle, and at the end of treatment using EORTC QLQ-C30 and lung cancer module QLQ-LC13. Higher scores (range 0−100) indicate higher symptom severity or better functioning/QOL. Time to deterioration (TTD) was defined as time from randomization to the earliest time with a ≥10-point increase from baseline for pain in chest, dyspnea, or cough and was compared between groups using an unstratified log-rank test. Repeated measures mixed-effects analyses were performed to compare change from baseline scores, with no adjustment for multiple comparisons. Results: Completion rates at baseline were ≥90% in each group and scores were well balanced. Crizotinib treatment was associated with a significantly longer TTD compared with PEM (median, 5.6 vs. 1.9 mo; HR, 0.66; 95% CI, 0.48−0.92; P=0.013) or DOC (median, 5.6 vs. 0.9 mo; HR, 0.37; 95% CI, 0.26−0.54; P&lt;0.0001). A significantly greater improvement from baseline was observed with crizotinib compared with either the PEM or DOC subgroups for global QOL (P&lt;0.01), cough (P&lt;0.001), dyspnea (P&lt;0.0001), pain in arm or shoulder (P&lt;0.0001), pain in chest (P&lt;0.0001), pain in other parts (P&lt;0.01), fatigue (P&lt;0.05), insomnia (P&lt;0.05), and pain (P&lt;0.0001). A significantly greater improvement was also observed with crizotinib compared with DOC for functioning (P&lt;0.05), alopecia (P&lt;0.0001), and hemoptysis (P&lt;0.0001). Conclusions: Crizotinib treatment showed a significantly greater improvement from baseline in key patient-reported lung cancer symptoms and global QOL compared with DOC and PEM, in addition to improved efficacy previously reported. Clinical trial information: NCT00932893.

Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial

Bevacizumab plus fluoropyrimidine-based chemotherapy is standard treatment for first-line and bevacizumab-naive second-line metastatic colorectal cancer. We assessed continued use of bevacizumab plus standard second-line chemotherapy in patients with metastatic colorectal cancer progressing after standard first-line bevacizumab-based treatment. In an open-label, phase 3 study in 220 centres in Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, the Netherlands, Norway, Portugal, Saudi Arabia, Spain, Sweden, and Switzerland, patients (aged ≥18 years) with unresectable, histologically confirmed metastatic colorectal cancer progressing up to 3 months after discontinuing first-line bevacizumab plus chemotherapy were randomly assigned in a 1:1 ratio to second-line chemotherapy with or without bevacizumab 2·5 mg/kg per week equivalent (either 5 mg/kg every 2 weeks or 7·5 mg/kg every 3 weeks, intravenously). The choice between oxaliplatin-based or irinotecan-based second-line chemotherapy depended on the first-line regimen (switch of chemotherapy). A combination of a permuted block design and the Pocock and Simon minimisation algorithm was used for the randomisation. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00700102. Between Feb 1, 2006, and June 9, 2010, 409 (50%) patients were assigned to bevacizumab plus chemotherapy and 411 (50%) to chemotherapy alone. Median follow-up was 11·1 months (IQR 6·4-15·6) in the bevacizumab plus chemotherapy group and 9·6 months (5·4-13·9) in the chemotherapy alone group. Median overall survival was 11·2 months (95% CI 10·4-12·2) for bevacizumab plus chemotherapy and 9·8 months (8·9-10·7) for chemotherapy alone (hazard ratio 0·81, 95% CI 0·69-0·94; unstratified log-rank test p=0·0062). Grade 3-5 bleeding or haemorrhage (eight [2%] vs one [<1%]), gastrointestinal perforation (seven [2%] vs three [<1%]), and venous thromboembolisms (19 [5%] vs 12 [3%]) were more common in the bevacizumab plus chemotherapy group than in the chemotherapy alone group. The most frequently reported grade 3-5 adverse events were neutropenia (65 [16%] in the bevacizumab and chemotherapy group vs 52 [13%] in the chemotherapy alone group), diarrhoea (40 [10%] vs 34 [8%], respectively), and asthenia (23 [6%] vs 17 [4%], respectively). Treatment-related deaths were reported for four patients in the bevacizumab plus chemotherapy group and three in the chemotherapy alone group. Maintenance of VEGF inhibition with bevacizumab plus standard second-line chemotherapy beyond disease progression has clinical benefits in patients with metastatic colorectal cancer. This approach is also being investigated in other tumour types, including metastatic breast and non-small cell lung cancers. F Hoffmann-La Roche.

LBA17 - A Randomized Phase III Study Evaluating the Continuation of Bevacizumab (BV) Beyond Progression in Metastatic Colorectal Cancer (MCRC) Patients (PTS) Who Received BV as Part of First-Line Treatment: Results of the Bebyp Trial by the Gruppo Oncologico Nord Ovest (GONO)

ABSTRACT Introduction Retrospective data suggested that the continuation of BV with second line chemotherapy (CT) beyond the progression to a first line treatment with BV was associated with improved survival. Methods This phase III study randomized pts with unresectable mCRC treated with BV plus first line CT (fluoropyrimidine, FOLFIRI, FOLFOX or FOLFOXIRI) to receive a second line CT with FOLFOX or FOLFIRI (depending on first-line chemotherapy) alone (arm A) or in combination with BV at 5 mg/Kg i.v. every 2 weeks (arm B). Pts were stratified according to center, PS (0 vs 1-2), disease free interval from the last administration of first line CT (≤3 months vs >3 months), second line regimen. The primary endpoint was progression-free survival (PFS). To detect a HR for PFS of 0.70 the trial was designed to randomize 262 pts. Considering that the AIO/AMG ML18147 trial with a similar design demonstrated an improved overall survival (OS) with BV beyond progression, the accrual was stopped on May 11th 2012. Results A total of 185 pts were randomized and 184 pts were included in the ITT analysis (1 pt randomized in error). Pts characteristics (arm A/arm B): number 92/92, gender M75%-F25%/M57%-F43%, median age 66 (38-75) years/62 (38-75) years, PS = 0 82%/82%, multiple site of disease 76%/77%, liver-only disease 15%/13%. The study met its primary endpoint. After a median follow up of 18 months the number of events for PFS was 172 (93%); median PFS was 4.97 months for arm A and 6.77 months for arm B (HR = 0.65; 95% CI 0.48–0.89; unstratified log-rank test, p = 0.0062). Adjusted analysis for PFS taking into account stratification factors, age and sex confirmed the increased PFS for arm B (HR = 0.70; 95% CI 0.50–0.97; p = 0.032). The response rate was 18% for CT and 21% for BEV + CT (p = 0.71). The OS data are still immature with a number of events of 52 in arm A and 46 in arm B. The adverse event profile was consistent with previously reported data for BEV + CT. Conclusions This study demonstrates an increased PFS by continuing BV in second-line. Updated results will be presented. Disclosure A. Falcone: Research grant from Amgen, Merck and Roche. All other authors have declared no conflicts of interest.

Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: Results of a randomized phase III intergroup study (TML study).

CRA3503 Background: BEV in combination with fluoropyrimidine-based CT is standard treatment for mCRC in the first-line (1L) and BEV-naïve second-line (2L) settings. This is the first randomized study evaluating the benefit of continuing BEV in combination with standard CT as 2L treatment for patients with mCRC who progressed after receiving a standard BEV-containing regimen in the 1L setting. Methods: Patients with unresectable, histologically confirmed mCRC who progressed within 3 months after discontinuation of 1L BEV + CT were randomised to 2L fluoropyrimidine-based CT ± BEV (2.5 mg/kg/wk equivalent). Choice of oxaliplatin- or irinotecan-based 2L CT was dependent on the regimen used in 1L (crossover) and included as a stratification variable. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), response rate and safety. Results: 820 patients were randomized from February 2006 to June 2010 (409 to BEV + CT and 411 to CT alone). Baseline patient and disease characteristics were well balanced between arms. The study met its primary endpoint; median OS was 11.2 months for BEV + CT and 9.8 months for CT (HR=0.81; 95% CI 0.69–0.94; unstratified log-rank test, p=0.0062). Median PFS was 5.7 months for BEV + CT and 4.1 months for CT (HR=0.68; 95% CI 0.59–0.78; unstratified log-rank test, p&lt;0.0001). The response rate was 5.4% for BEV + CT and 3.9% for CT (unstratified Chi-Square Test, p=0.3113). The adverse event profile was consistent with previously reported data for BEV + CT. Compared with historical data from BEV treatment in 1L or 2L mCRC, BEV-related adverse events were not increased when continuing BEV beyond progression. Conclusions: This is the first randomized study to prospectively investigate the impact of continuing BEV treatment in 2L mCRC for patients who progressed after receiving a BEV-containing regimen in 1L. Our findings demonstrate that BEV + CT (crossed over from 1L regimen) continued beyond progression significantly prolongs OS and PFS in 2L mCRC. Additional analysis (including biomarker evaluation) is ongoing.

O-0020 Bevacizumab + Chemotherapy Beyond First Progression in Metastatic Colorectal Cancer Patients Previously Treated with Bevacizumab-Based Therapy: TML Study Subgroup Findings

ABSTRACT Introduction Bevacizumab in combination with fluoropyrimidine-based chemotherapy is a standard treatment for patients with metastatic colorectal cancer (mCRC) in the first-line and bevacizumab-naive second-line settings. This is the first randomised study evaluating the benefit of continuing bevacizumab in combination with standard chemotherapy as second-line treatment for patients with mCRC who progressed after receiving a standard bevacizumab-containing regimen in the first-line setting. Here we report the main study findings and those from planned subgroup analyses. Methods Patients with unresectable, histologically confirmed mCRC who progressed within 3 months after discontinuation of first-line bevacizumab + chemotherapy were randomised to second-line fluoropyrimidine-based chemotherapy ± bevacizumab (2.5 mg/kg/wk equivalent). Choice of oxaliplatin- or irinotecan-based second-line chemotherapy was dependent on the first-line regimen used (crossover); the type of chemotherapy partner was included in the stratification variables. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), response rate and safety. Subgroups analysed included gender, age, ECOG PS, duration of first-line PFS (≤9 months vs >9 months), first-line chemotherapy (oxaliplatin- vs irinotecan-based), time since last bevacizumab treatment (≤42 days vs >42 days), liver-only metastases (no vs yes) and number of organs with metastases (≤1 vs >1). Results The intent-to-treat (ITT) population comprised 409 patients who received bevacizumab + chemotherapy and 411 who were treated with chemotherapy alone. Demographics and baseline disease characteristics of the patients randomised between February 2006 and June 2010 were well balanced between treatment arms. The primary endpoint (improvement in OS) was met; median OS was 11.2 months for bevacizumab + chemotherapy vs 9.8 months for chemotherapy alone (hazard ratio [HR] = 0.81; 95% CI, 0.69–0.94; unstratified log-rank test, p = 0.0062). Median PFS was 5.7 months for bevacizumab + chemotherapy vs 4.1 months for chemotherapy alone (HR = 0.68; 95% CI, 0.59–0.78; unstratified log-rank test, p Conclusion This is the first randomised study to prospectively investigate the impact of continuing bevacizumab treatment in the second-line setting for patients who progressed after receiving a bevacizumab-containing regimen as first-line treatment for mCRC. Our findings demonstrate that bevacizumab + chemotherapy (crossed over from the first-line regimen) continued beyond progression significantly prolongs OS and PFS in the second-line mCRC setting. In the planned subgroup analysis for OS, findings were generally consistent with the overall population. Download : Download full-size image Figure 2 . Subgroup analysis. overall survival in the ITT population (n=820).

Lintuzumab and Low-Dose Cytarabine Compared to Placebo and Low-Dose Cytarabine in Patients with Untreated Acute Myeloid Leukemia (AML) 60 Years and Older: Results of a Randomized, Double-Blinded Phase 2b Study,

Abstract 3613 Background:Older adults with AML who decline intensive induction chemotherapy lack effective therapeutic options, as evidenced by a median overall survival (OS) of ∼5 months with low-dose cytarabine treatment (Burnett 2007). Leukemic blast cells express CD33 in most patients with AML. While antitumor activity has been previously demonstrated by CD33-directed agents, none of these are currently available. Lintuzumab (SGN-33) is a humanized antibody directed to CD33 that was studied in patients with myeloid malignancies and demonstrated tolerability with modest monotherapy activity. To determine if the addition of lintuzumab to low-dose cytarabine could prolong survival in older patients with untreated AML, a randomized, placebo-controlled, double-blinded phase 2b study was conducted (ClinicalTrials.gov #NCT00528333). Methods:The study was conducted at 72 international sites between November 2007 and August 2010. Patients were >60 years of age with centrally confirmed, previously untreated AML; the minimum blast percentage required was 20% with ≥50% CD33 expression. Maximum allowed WBC at baseline was 30,000/μL. All patients declined treatment with intensive induction chemotherapy. Cytarabine 20 mg was administered SC twice daily on Days 1–10 of each 28-day cycle (12 cycles maximum). Patients were randomized to additionally receive either lintuzumab 600 mg or placebo IV: in Cycle 1 on Days 1, 8, 15, and 22, and on Days 1 and 15 of subsequent cycles. Patients were stratified according to age, ECOG performance status (PS), and history of antecedent hematologic disorder (AHD). Cytogenetic risk was determined at baseline according to Fröling 2006. The primary endpoint of the study was OS, determined using an unstratified log rank test. Secondary endpoints included peripheral blood count recovery, transfusion requirements, infection rates, and quality of life. As patients choosing less-intensive therapy often incorporate quality of life into their treatment decision, follow-up bone marrow biopsies were not required in the study. Results:211 patients were randomized in the study (107 lintuzumab arm, 104 placebo arm). The study arms appeared balanced; overall, the median patient age was 70 years (range 60–90), 53% were female, and baseline ECOG PS was 0/1 (55%) or 2 (45%). Baseline blast percentages were ≥30% in 74% of patients and 23% had a history of AHD. A median of 95% CD33 expression was documented at baseline in either bone marrow or peripheral blood. Median number of treatment cycles was 4 in the lintuzumab arm and 3 in the placebo arm. At the time of the analysis, 24 patients were alive and the maximum follow-up was 32 months. The estimated median OS for the lintuzumab + low-dose cytarabine arm was 4.7 months compared with 5.1 months for the placebo + low-dose cytarabine arm with a hazard ratio (lintuzumab to placebo) of 0.96, indicating that lintuzumab was not associated with a treatment effect (P value 0.76, 95% CI [0.72, 1.28]). Rates of infections or fevers of unknown origin requiring hospitalization or IV antibiotics did not differ between the study arms. Overall, 28% of patients were observed to have no peripheral blasts, ANC >1.0 x109/L, platelets >100 × 109/L, and no transfusions for at least 1 week. The median OS among all patients was 5.0 months, which was significantly impacted by cytogenetic risk (8.7 months for standard-risk compared with 4.5 months for high-risk; P value 0.0024). The incidence of adverse events (AEs) was comparable between the treatment groups, with the exception of infusion-related reactions which occurred more frequently in the lintuzumab arm. The most common ≥ Grade 3 non-hematologic AEs in the study were pneumonia (12%) and sepsis (8%). Conclusions:In this randomized, placebo-controlled, double-blinded phase 2b trial, the combination of lintuzumab and low-dose cytarabine did not improve OS compared with placebo and low-dose cytarabine. While lintuzumab was not effective, CD33 remains a compelling target for AML because it is widely expressed by malignant cells and appears to be absent from pluripotent hematopoietic stem cells. This was the largest study to date of patients treated with low-dose cytarabine; the median OS across both treatment arms was 5 months. A similar outcome was observed in the subgroup of patients with high-risk cytogenetics, confirming that low-dose cytarabine remains a valid comparator in trials of older patients with AML. Disclosures:Lancet:Seattle Genetics, Inc.: Research Funding. Off Label Use: Lintuzumab is an investigational monoclonal antibody directed against CD33. Sekeres:Celgene Corp.: Membership on an entity's Board of Directors or advisory committees; Celgene Corp.: Honoraria; Seattle Genetics, Inc.: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Wood:Seattle Genetics, Inc.: Research Funding. Grove:Seattle Genetics, Inc.: Equity Ownership; Seattle Genetics, Inc.: Employment. Sandalic:Seattle Genetics, Inc.: Equity Ownership; Seattle Genetics, Inc.: Employment. Sievers:Seattle Genetics: Employment, Equity Ownership. Jurcic:Seattle Genetics, Inc.: Consultancy; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics, Inc.: Research Funding.

Final survival results of the randomized phase III study of trabectedin with pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer.

5046 Background: Trabectedin (T) in combination with pegylated liposomal doxorubicin (PLD) was demonstrated to improve progression-free survival (PFS) and overall response rate (ORR) in comparison to PLD alone as a second-line treatment of recurrent ovarian cancer (J Clin Oncol 28:3107-14, 2010). We report the protocol defined final analysis of overall survival (OS). Methods: Women ≥18 years, stratified by performance status (0-1 vs 2) and platinum-free interval (PFI) <6 vs > 6 months(m), were randomly assigned to receive an IV infusion of PLD 30 mg/m2 followed by a 3-hour infusion of T 1.1 mg/m2 every 3 weeks or PLD 50 mg/m2 every 4 weeks. The primary endpoint was PFS by independent radiology assessment and secondary endpoints included OS and ORR. Results: The final OS analysis was performed on 12 Nov 2010. The median follow-up was 47.4m. Among the 672 randomized subjects, 522 (77.7%) deaths were observed (258 in the T+PLD arm and 264 in the PLD arm). The median OS for T+PLD and PLD arms was 22.2 and 18.9m, respectively (HR= 0.86; 95%CI: 0.72, 1.02; p=0.0835 [unstratified log-rank test]). There was an unanticipated imbalance in the PFI between the two arms favoring the PLD arm (mean PFI: PLD=13.3m, T+D=10.6m. To provide a better estimate of the true treatment effect of adding T to PLD, a multivariate analysis adjusted for key prognostic factors (including PFI) was performed which demonstrated a significant improvement in OS in subjects treated with the combination (HR=0.82; 95%CI: 0.69,0.98; p=0.0285). Consistent improvement in OS was seen across all PFI subgroups, which was more pronounced in 6-12PFI subgroup (Table). Conclusions: T+PLD combination showed an improvement in OS in recurrent ovarian cancer compared with PLD alone. Randomized trials of T+PLD versus platinum combinations are indicated. Subgroup analysis by PFI. Subgroup by PFI (m) Median PLD (m) Median T+PLD (m) HR (95%CI) 0-6 12.3 14.2 0.94 (0.71, 1.25) 6-12 16.4 22.4 0.64 (0.47, 0.86) >12 31.7 36.5 0.83 (0.59, 1.16)

Long-term results from EORTC24971/TAX323: Comparing TPF to PF in patients with unresectable squamous cell carcinoma of the head and neck (SCCHN).

5530 Background: At a median follow-up (FU) of 32.5 months, the original EORTC24971/TAX323 study showed that compared with standard cisplatin/infusional fluorouracil (PF), induction chemotherapy (ICT) with the addition of docetaxel (TPF) prior to radiotherapy significantly improved progression-free survival (PFS) and overall survival (OS) with less toxicity and an improved quality of life in patients with unresectable SCCHN (NEJM 2007; 357: 1695; BJC 2010; 103: 1173). The present report describes survival data after a median FU of 8.6 years and long-term side effects (feeding tube dependency, tracheostomy, gastrostomy and second malignancies). Methods: Data were collected in a long-term FU form and analyzed in the intent-to-treatment population, using a Cox PH model adjusted for treatment, tumor site, T&N stage and performance status. The two treatment arms were also compared with an unstratified logrank test at a 2-sided 5% significance level. The clinical database was locked on January 10, 2011. Results: FU forms were obtained from 308 (86%) of the 358 randomized patients (156 TPF, 152 PF). PFS remained significantly better with TPF compared with PF (hazard ratio [HR] unadjusted 0.71 (95% CI, 0.57-0.89), p=0.003, medians of 12.7 vs 8.6 months, and 5-years PFS 22.9% vs 13.5%, mainly due to less locoregional progression). A similar picture was observed for OS (HR unadjusted 0.74 (95% CI, 0.59-0.94), p=0.011, medians of 18.8 vs 14.5 months, 5-years OS 27.5 vs 18.6%). These data were confirmed in the Cox PH model. Long-term side effects in TPF/ PF arms were: tracheostomy 13/9 ; feeding tube dependency 6/10; gastrostomy 19/19; second malignancy 14/6 (of which lung 42.9%/50%; H&N 42.9%/33.3%, and GI 14.3%/16.7%). Conclusions: This long-term update supports the conclusions of the final analysis that TPF is superior to PF as ICT for patients with unresectable SCCHN.

Everolimus versus placebo in Japanese patients with advanced pancreatic neuroendocrine tumors (pNET): Japanese subgroup analysis of RADIANT-3.

289 Background: Everolimus demonstrated a statistically and clinically significant improvement in PFS over placebo in a multi-national, randomized, placebo-controlled, phase III trial in patients with advanced low- or intermediate-grade pNET with disease progression within the prior 12 months (RADIANT-3) (Ann Oncol [2010] 21[suppl 6]: NP doi:10.1093/annonc/mdq340). Forty patients were enrolled from Japanese sites and randomized (n=23: everolimus; n=17: placebo) in that study. The purpose of this report is to investigate the efficacy and safety in the Japanese subgroup. Methods: Subgroup analysis for the Japanese patients was performed comparing the efficacy and safety between everolimus 10mg/d orally plus best supportive care (BSC) and matching placebo plus BSC. The primary efficacy endpoint was progression-free survival (PFS). The safety was evaluated based on the incidence of adverse events (AEs). Results: Treatment with everolimus resulted in a significant prolongation by 16.62 months in median PFS (19.45 months for everolimus, 2.83 months for placebo), with 81% reduction in the hazard ratio of progression/death (HR 0.19 [95% CI: 0.08, 0.48]; one-sided unstratified log-rank test: p&lt;.001). The most common AE was stomatitis (73.9% everolimus vs 23.5% placebo); mostly grade 1/2. Grade 3/4 AEs occurred in 69.5% of the everolimus arm and 29.4% of the placebo arm, and amongst the most frequent included (% in everolimus vs % in placebo): neutropenia (17.4% vs 3%); anemia (8.7% vs 0%); pneumonitis (8.7% vs 0%); leukopenia (8.7% vs 0%). The remainder of grade 3/4 AEs was less than 3%. Median duration of exposure to everolimus was 57 weeks vs 47 weeks on placebo. Treatment discontinuation for AEs was 17% in the everolimus arm vs 0% in the placebo arm. Conclusions: Everolimus demonstrated a clinically meaningful improvement in PFS over placebo in Japanese patients. Everolimus was well tolerated in Japanese patients, and no new safety concerns were noted. This result suggests that everolimus can be a standard treatment for Japanese patients with advanced pNET. [Table: see text]

Combining stratified and unstratified log‐rank tests in paired survival data

The log-rank test is the most widely used nonparametric method for testing treatment differences in survival between two treatment groups due to its efficiency under the proportional hazards model. Most previous work on the log-rank test has assumed that the samples from the two treatment groups are independent. This assumption is not always true. In multi-center clinical trials, survival times of patients in the same medical center may be correlated due to factors specific to each center. For such data, we can construct both stratified and unstratified log-rank tests. These two tests turn out to have very different powers for correlated samples. An appropriate linear combination of these two tests may give a more powerful test than either of the individual test. Under a bivariate frailty model, we obtain closed-form asymptotic local alternative distributions and the correlation coefficient between these two tests. Based on these results we construct an optimal linear combination of the two test statistics to maximize the local power. Simulation studies with Hougaard's model confirm our construction. We also study the robustness of the combined test by simulations.

Sunitinib (SU) in combination with docetaxel (D) versus D alone for the first-line treatment of advanced breast cancer (ABC).

LBA1010 Background: Taxane-based chemotherapy (CT) improves progression-free survival (PFS) in patients (pts) with newly diagnosed HER2-negative metastatic BC (MBC). SU, an oral multitargeted tyrosine kinase inhibitor (MTKI), demonstrated antitumor activity in combination with D in a phase I/II study in pts with MBC. A randomized, open-label, multicenter phase III trial in pts with newly diagnosed ABC tested the hypothesis that addition of a MTKI to D improves PFS vs. D alone. Methods: Eligible pts (female; ≥18 yrs) had an ECOG PS ≤1, and newly diagnosed HER2-negative MBC or ABC. If (neo)adjuvant therapy included a taxane, relapse must have occurred ≥12 mos after CT. Pts were randomized (1:1) to treatment (tx) with D 75 mg/m2 iv on day 1 and SU 37.5 mg/day po from day 2–15 q3w (Schedule 2/1; Arm A), or to D 100 mg/m2 iv 1-hr infusion q3w (Arm B) that could be given until progression. If D was discontinued in Arm A for reasons other than progressive disease (PD), single-agent SU 37.5 mg daily was permitted until PD. Median, independently assessed, PFS (primary endpoint) was compared between tx arms using stratified and unstratified log-rank tests. Overall objective response rate (ORR), overall survival (OS), pt-reported outcomes, and safety were secondary endpoints. Results: As of the data cutoff (February 1, 2010), the ITT population comprised 593 pts (SU+D, n=296; D, n=297). The trial did not meet its primary endpoint of prolonging PFS based on the independent radiologic assessment or in prolonging OS. Baseline characteristics were well balanced. Median relative dose intensity (RDI) was 94.2% and 92.4% for SU+D, and 92.6% for D arms, respectively. Median PFS was 8.6 mos (95% CI 8.2–10.3) in the SU+D arm vs 8.3 mos (95% CI 7.7–9.6) for the D arm (HR 0.922). Median OS was 24.8 mos (95% CI 21.5–33.1) in SU+D arm vs 25.5 mos (95% CI 22.8–27.8) for D arm (HR 1.207). ORR was significantly better for SU+D (51%) vs. D (39%) (p=0.0018). Frequent all causality grade 3/4 adverse events (≥10%) were neutropenia (46%), hand–foot syndrome (17%), and fatigue (12%) in the SU+D arm and neutropenia (44%) in the D arm. Conclusions: Based on these data, SU+D is not a recommended treatment option for patients with newly diagnosed ABC. Strategies using antiangiogenic TKIs that increase RR but not OS may need to be revisited. [Table: see text]

Phase III trial of sunitinib (SU) in combination with capecitabine (C) versus C in previously treated advanced breast cancer (ABC).

LBA1011 Background: Recent trials support combining an antiangiogenic agent with chemotherapy (CT) in pretreated patients (pts) with metastatic BC (MBC). SU, an oral multitargeted tyrosine kinase inhibitor demonstrated single-agent activity (11% ORR) in heavily pretreated pts with MBC. Antitumor activity with SU+C was reported in pts with advanced solid tumors. This multicenter, randomized, phase III trial (SUN 1099) compared the efficacy and safety of SU + C vs. C in pts with ABC. Methods: Eligibility criteria were: age ≥18 yrs, ECOG PS ≤1, measurable HER2-positive (FISH+, CISH+ or IHC3+) or -negative ABC, no brain metastases, prior treatment (tx) with an anthracycline and taxane in the (neo)adjuvant or metastatic setting, and ≤2 prior CT regimens for advanced disease. Prior C tx was not permitted. Pts were randomized (1:1) to combination tx with C 2,000 mg/m2/d po days 1–14 every q3w + SU 37.5 mg/d po daily, or to C 2,500 mg/m2/d days 1–14 q3w. Pts with progressive disease per RECIST on the C arm were offered single-agent SU (37.5 mg/d). Endpoints included PFS (primary), ORR, OS, QoL, and safety. Stratified and unstratified log-rank tests compared PFS between arms. Results: At the data cutoff (December 15, 2009), the ITT population comprised 442 pts: 221 in each arm with baseline characteristics well balanced between arms. The trial did not meet its primary endpoint of prolonging PFS based on the independent radiologic assessment nor secondary endpoint of longer OS (final analysis March 10, 2010). Median PFS was 5.5 mos (95% CI 4.5–6.0) in the SU+C arm vs. 5.9 mos (95% CI 5.4–7.6) in the C arm (HR 1.224). Median OS was 16.4 mos (95% CI 13.6–18.4) for the SU+C arm and 16.5 mos (95% CI 14.2–18.6) for the C arm (HR 0.995). ORR was 18.6% for the SU+C arm and 16.3% for the C arm. The most common all causality grade 3/4 AEs (≥10%) were neutropenia (32%), hand–foot syndrome (HFS; 16%), thrombocytopenia (17%), asthenia (12%), fatigue (10%) in the SU+C arm and HFS (24%) and diarrhea (10%) in the C arm. Intended drug delivery for each arm was &gt;80%. Discontinuations due to an AE were more frequent in the SU+C arm vs. the C arm. Discontinuations by drug in the SU+C arm: SU 39%, C 42%, SU and C 33%; in the C arm: 18%. Conclusions: Data from this randomized phase III trial do not support use of SU+C for therapy of patients with ABC. [Table: see text]

Updated safety and efficacy results of the phase III trial of sunitinib (SU) versus placebo (PBO) for treatment of pancreatic neuroendocrine tumors (NET).

4000 Background: SU has shown activity against pancreatic NET in preclinical and phase I/II studies, leading to its investigation in this double-blind, PBO-controlled trial (NCT00428597). Methods: Eligible pts had advanced, well- differentiated pancreatic endocrine tumors and disease progression in the past 12 months, and were randomized (1:1) to SU 37.5 mg/day continuous daily dosing (CDD) or PBO, each with best supportive care. Primary endpoint: progression-free survival (PFS). Target enrolment: 340 pts to detect 50% improvement in PFS (90% power, 2-sided unstratified log-rank test). Results: This trial ended early based on recommendations of the independent Data Monitoring Committee, which noted more serious adverse events (AEs) and deaths in the PBO arm and differences in efficacy. 171 pts were randomized to SU (n = 86) or PBO (n = 85) from Jun 2007 to Apr 2009. At baseline, 49% of pts had functioning tumors, Ki-67 index was ≤ 5% in 60% of evaluable pts, and 95% had distant metastases. Most pts had un...

Power Loss of Stratified Log-Rank Test in Homogeneous Samples

We study the loss of power of the stratified log-rank test (SLRT) compared to the unstratified log-rank test (ULRT) in the case of a large number of strata with relatively a small number of stratum sizes in terms of the asymptotic distributions of test statistics under local alternatives. The SLRT tends to lose information due to overstratification. It is better to test the homogeneity among strata before using the stratified log-rank test.

Dasatinib or high‐dose imatinib for chronic‐phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily

In patients with chronic-phase chronic myeloid leukemia (CP-CML), imatinib resistance is of increasing importance. Imatinib dose escalation was the main treatment option before dasatinib, which has 325-fold more potent inhibition than imatinib against unmutated Bcr-Abl in vitro. Data with a minimum of 2 years of follow-up were available for the current study of dasatinib and high-dose imatinib in CP-CML resistant to imatinib at daily doses from 400 mg to 600 mg. A phase 2, open-label study was initiated of 150 patients with imatinib-resistant CP-CML who were randomized (2:1) to receive either dasatinib 70 mg twice daily (n=101) or high-dose imatinib 800 mg (400 mg twice daily; n=49). At a minimum follow-up of 2 years, dasatinib demonstrated higher rates of complete hematologic response (93% vs 82%; P=.034), major cytogenetic response (MCyR) (53% vs 33%; P=.017), and complete cytogenetic response (44% vs 18%; P=.0025). At 18 months, the MCyR was maintained in 90% of patients on the dasatinib arm and in 74% of patients on the high-dose imatinib arm. Major molecular response rates also were more frequent with dasatinib than with high-dose imatinib (29% vs 12%; P=.028). The estimated progression-free survival also favored dasatinib (unstratified log-rank test; P=.0012). After 2 years of follow-up, dasatinib demonstrated durable responses and improved response and progression-free survival rates relative to high-dose imatinib.

Prognostic factors for overall survival with sunitinib as first-line therapy in patients with metastatic renal cell carcinoma (mRCC)

5042 Background: Sunitinib demonstrated superior progression-free survival (PFS; the primary endpoint) over interferon-alfa (IFN-α) as first-line mRCC therapy (NEJM 2007;356:115). Median overall survival (OS) with sunitinib compared to IFN-α was: 26.4 vs. 21.8 months (HR=0.821; P=0.051 by unstratified log-rank test; Proc ASCO 2008;26, May 20 suppl; abstr 5024). An analysis of prognostic factors for OS was performed on data from this trial. Methods: 750 treatment-naïve mRCC patients were randomized 1:1 to receive sunitinib or IFN-α. By Cox proportional hazards model, selected pretreatment variables were evaluated univariately and in a multivariate model for each treatment arm. Multivariate models for each treatment arm were based on a stepwise algorithm with a type I error of 0.25 for entry and 0.15 for elimination. Further elimination was applied to identify variables significant at P&lt;0.05. Results: In multivariate analysis of sunitinib patients, factors associated with longer OS include: interval from diagnosis to treatment ≥1 yr, ECOG PS of 0, lower corrected calcium, absence of bone metastases, lower lactic dehydrogenase (LDH), and higher hemoglobin (Hgb) ( table ). For the IFN-α treatment arm, male gender, absence of bone or lymph node metastases, lower LDH, higher Hgb, lower corrected calcium, higher neutrophil count, and interval from diagnosis to treatment ≥1 yr were associated with longer OS. Conclusions: For patients in the sunitinib treatment arm, prognostic factors identified were similar to the factors previously identified in the MSKCC risk groups (J Clin Oncol 2002;20:289). Additional prognostic factors were identified for the IFN-α arm. Further studies are warranted to independently validate these findings as well as to identify tumor-specific prognostic factors. [Table: see text] [Table: see text]