Ratio For Progression-free Survival Research Articles

Treatment of Stage I-II A Non-Bulky Hodgkin's Lymphoma (HL): An Individual Patient-Data Comparison of German Hodgkin Study Group (GHSG) HD10 and HD11 Combined-Modality Therapy (CMT) and NCIC Clinical Trials Group (NCIC CTG) HD.6 ABVD Alone

AbstractAbstract 548 Background:Excellent results are seen in HL patients with stage I-IIA disease treated with CMT that includes involved field radiation therapy (IFRT), as per GHSG HD10 [Engert NEJM 2010] and HD11 [Eich JCO 2010] or with ABVD alone, as per NCIC CTG/ECOG HD.6 [Meyer NEJM 2012]. Comparing these reports is complicated by differences in eligibility, staging, endpoints and follow-up duration. Our objectives were to use individual patient data from these 3 trials to compare outcomes after standardizing patient eligibility. Methods:Potentially eligible patients were those treated with 2 cycles of ABVD/20 Gy IFRT on GHSG HD10, 4 cycles of ABVD/30 Gy IFRT on GHSG HD11 and 4–6 cycles of ABVD alone on NCIC CTG HD.6. To be included in analysis, patients were required to be eligible for GHSG HD10 or HD11 and NCIC CTG HD.6. Eligibility of HD10/11 patients for HD.6 was determined by the GHSG by applying HD.6 protocol criteria. Anonymized individual patient data of eligible patients was forwarded to NCIC CTG along with reasons for ineligibility of other patients. Eligibility of HD.6 patients for HD10/11 was determined by NCIC CTG by applying HD10/11 protocol criteria with listing of reasons for ineligibility. Eligibility questions were resolved through consensus. Patients meeting mutually inclusive eligibility criteria were stratified by a propensity score (PSc) based on age, gender, stage, ESR and number of disease sites. Outcomes were based on Revised Response Criteria for Malignant Lymphoma [Cheson JCO 2007]; no trial incorporated PET scanning. The primary outcome measure was progression-free survival (PFS), which includes disease progression and death from any cause as events. Secondary outcomes included overall survival (OS) and time to progression (TTP), which includes disease progression and death from HL as events. A priori subsets for analysis included eligibility for HD10 vs. HD11 and CR/CRu status after 2 cycles of ABVD among those eligible for both HD10 and HD.6. Cox models stratified by PSc were used to obtain hazard ratios (HR) for PFS, OS and TTP; HRs are expressed as GHSG HD10/11 relative to NCIC CTG HD.6. Results:Of 655 patients eligible for selected arms of HD10/HD11, 406 were eligible when applying the inclusion criteria for HD.6 (HD10 = 254; HD11 = 152). Most common reasons for ineligibility were B symptoms (n=127) and large mediastinal mass (n=80). Of 196 HD.6 patients, 182 were eligible for HD10 (n=110) or HD11 (n=71; 1 patient not assignable). Median follow-up for both HD10 and HD11 was 91 months and for HD.6 was 134 months. Results that include all eligible patients are shown in table; TTP was superior in GHSG trials.EndpointGHSG HD10/11NCIC CTG HD.6HR95% CI8-yr PFS89%86%0.710.42-1.188-yr OS95%95%1.090.49-2.408-yr TTP93%87%0.440.24-0.78In the HD10/HD.6 subset, 8-yr PFS was 87% vs 82% (HR=0.58; 95% CI=0.32–1.05) and OS was 96% vs 94% (HR=0.65; 95% CI=0.25–1.72). Among those with CR/CRu after 2 cycles of ABVD, 8-yr PFS was 87% vs 95% (HR=2.8; 95% CI=0.64–12.5) and OS was 96% vs 100%. Among those without CR/CRu after 2 cycles of ABVD, 8-yr PFS was 88% vs 74% (HR=0.35; 95% CI=0.16–0.79) and OS was 95% vs 91% (HR=0.42; 95% CI=0.12–1.44). In the HD11/HD.6 subset, 8-yr PFS was 91% vs 91% (HR=1.15; 95% CI=0.45–2.97) and OS was 95% vs 97% (HR=2.03; 95% CI=0.53–7.79). Among 406 HD10/11 patients, there have been 19 deaths; 7 were attributed to HL or immediate treatment toxicity and 12 to other causes. Among 182 HD.6 patients, there have been 10 deaths; 5 were attributed to HL or immediate treatment toxicity and 5 to other causes. Conclusions:In this non-randomized cohort comparison, TTP was superior and PFS trended to being superior in patients treated with CMT on HD10/11. No differences in OS are evident; longer follow-up is needed to assess trade-offs between disease control and risks of late treatment effects. The role of IFRT in attaining long-term disease control appears to be especially important in those who do not attain CR/CRu status after 2 cycles of ABVD. As outcomes of those eligible for HD10/HD.6 and treated with 4–6 cycles of ABVD alone were excellent if CR/CRu was attained after 2 cycles of ABVD, these data support more recent strategies evaluating response-adapted approaches for use of IFRT. Disclosures:Borchmann:Millenium The Takeda Oncology Company: Research Funding; Takeda Pharma GmbH: Travel Grants, Travel Grants Other. Horning:Genentech: Employment; Roche: Equity Ownership. Engert:Millenium The Takeda Oncology Company: Honoraria. Meyer:Lilly: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen Canada: Research Funding; Ariad Pharma: Research Funding; Astex Therapeutics: Research Funding; AstraZeneca: Research Funding; Bristol-Myers Squibb: Research Funding; GlaxoSmithKline: Research Funding; Janssen Ortho: Research Funding; Novartis: Research Funding; Oncothyreon: Research Funding; Pfizer: Research Funding; Roche: Research Funding; Sanofi-Aventis: Research Funding; Schering Canada: Research Funding.

WS13-2 - Correlation between Overall Survival and Other End Points in Clinical Trials of Second-Line of Chemotherapy for Patients with Advanced Gastric Cancer

ABSTRACT Background The correlation between progression-free survival (PFS) or time to progression (TTP) and overall survival (OS) has been evaluated in patients with advanced gastric cancer (AGC) who received first-line chemotherapy (Shitara, K et al. Invest New Drug 2011; Shitara K and Burzykowski T, et al, ASCO 2011). However, no corresponding analysis had been done in patients who underwent second-line chemotherapy for AGC. Methods We evaluated the potential of PFS, TTP, response rate (RR), or disease control rate (DCR) to act as surrogates for OS in phase II and III trials of second-line chemotherapy for AGC by comprehensive literature-based analysis. Correlations between each end point and OS were evaluated by Spearman rank correlation coefficient (r). Subgroup analyses were also conducted. Results Fifty-six trials, including four randomized studies, were selected for analysis and covered a total of 61 treatment arms and 3038 patients; 34 studies were conducted in Asia, 20 studies in Non-Asian countries, and two studies in both regions. Median PFS/TTP and OS showed a moderate correlation with r of 0.51 (95% CI, 0.31–0.73). Correlation tended to be higher in PFS (r = 0.62) than TTP (r = 0.29) and higher in non-Asian trials (r = 0.73) than Asian trials (r = 0.32). Correlation between PFS/TTP and OS among the trials in which eligibility required failure to previous fluorouracil and cisplatin also showed low correlation (r = 0.48). The RR and DCR also did not show high correlation with OS (r = 0.30; 95% CI 0.04–0.56; r = 0.53; 95% CI 0.31–0.75). The hazard ratio (HR) of PFS and OS in each arms of the four randomized studies showed a low correlation with an r of 0.10. Conclusion Our results indicate that PFS/TTP, RR, and DCR did not correlate sufficiently with OS to be used as surrogate end points in patients with AGC who underwent second-line chemotherapy. Further research is needed based on individual patient data from ongoing randomized trials.

Body mass index and bioelectrical impedance phase angle as potentially modifiable nutritional markers are independent risk factors for outcome in allogeneic hematopoietic cell transplantation

Beside many risk factors in patients considered for alloHCT, only body mass index (BMI) as a broad marker of nutritional status has prognostic value in these patients. This is the first prospective study to investigate the validity of further nutritional markers: adjusted BMI, normalized for gender and age; Subjective Global Assessment questionnaire and standardized phase angle, normalized for gender, age and BMI in 105 patients as independent risk factors for outcomes [overall survival (OS), non-relapse mortality (NRM), relapse mortality (RM), progression-free survival (PFS)] until 2years after alloHCT. In Cox proportional-hazards regression models, we included a variety of accepted risk factors. The two most influential pre-transplant risk factors identified and associated with similarly increased hazard ratios (HR) for OS, RM, and PFS were a low-standardized phase angle (HR = 1.97, P = 0.043; HR = 3.18, P = 0.017, and HR = 1.91, P = 0.039) and advanced disease. Under- and overweight according BMI percentiles (≤10th; ≥90th) revealed associations with increased risk of NRM (HR = 2.90, P = 0.018; HR = 3.02, P = 0.062), although only low BMI was weakly associated with OS (HR = 1.82, P = 0.09). In conclusion, our results demonstrate that pre-transplant phase angle is an independent predictor for 2-year outcomes in these patients. Further investigation is necessary to demonstrate whether the theoretically modifiable phase angle can be increased by physical training combined with nutritional support, and if this improves outcome after alloHCT.

1204P - Phase III Study Comparing Second- and Third-Generation Regimens with Concurrent Thoracic Radiotherapy in Unresectable Stage III Non-Small Cell Lung Cancer: An Additional Analysis by the Histological Type in the WJTOG0105 Study

ABSTRACT Background The WJTOG0105 study was conducted to compare third-generation regimen (irinotecan/carboplatin [IC], paclitaxel/carboplatin [PC]) and second-generation regimen (mitomycin/vindesine/cisplatin [MVP]) with concurrent thoracic radiotherapy (TRT) in patients with unresectable stage III non-small-cell lung cancer (J Clin Oncol. 2010; 28: 3739-45). We conducted an additional analysis by the histological type (Squamous [Sq] vs. Non-squamous [Non-sq]) to closely examine differences of efficacy between more frequent radiosensitizing doses and systemic doses of chemotherapy. Materials and methods Patients received the following treatments: MVP, mitomycin (8 mg/m2 on day 1, 29), vindesine (3 mg/m2 on day 1, 8, 29, 36), and cisplatin (80 mg/m2 on day 1, 29) with concurrent TRT (60 Gy), followed by 2 courses of MVP; IC, weekly irinotecan (20 mg/m2)/carboplatin (AUC 2) for 6 weeks with concurrent TRT (60 Gy), followed by 2 courses of irinotecan (50 mg/m2)/carboplatin (AUC 5); PC, weekly paclitaxel (40 mg/m2)/carboplatin (AUC 2) for 6 weeks with concurrent TRT (60 Gy), followed by 2 courses of paclitaxel (200 mg/m2)/carboplatin (AUC 5). Overall survival (OS), progression free survival (PFS), and patterns of initial failure were compared by the histological type. Results The median OS and PFS were 20.3, 9.0 months in Sq and 20.5, 8.1 months in Non-sq. The Hazard ratio (HR) for OS and PFS in Non-sq were 0.996 (P = 0.973) and 1.199 (P = 0.079). Although there was no statistically significant difference between Sq and Non-sq, the out-field recurrence rate in Non-sq (51.1%) was higher than Sq (26.1%) and the PFS in Sq tended to be longer than Non-sq. The efficacy of PC was compared with MVP in each histological type. For Sq, the median OS and PFS were 22.0, 10.4 months in PC and 19.7, 9.3 months in MVP. The HR for OS and PFS in PC were 0.957 (P = 0.822) and 0.871 (P = 0.459). For Non-sq, the median OS and PFS were 21.3, 8.1 months in PC and 21.8, 7.6 months in MVP. The HR for OS and PFS in PC were 1.083 (P = 0.662) and 0.996 (P = 0.984). Therefore no statistically significant difference was found between PC and MVP in each histological type. Furthermore, the patterns of initial failure were similar between PC and MVP. Conclusion Weekly PC with concurrent TRT showed similar efficacy to MVP with concurrent TRT, with no relation to the histological type. Disclosure All authors have declared no conflicts of interest.

54IN - Antiangiogenics in Ovarian Cancer: Where are We Now?

Vascular endothelial growth factor (VEGF) is often over expressed in ovarian cancer (OVCA), promoting ascites and effusions. Preclinical studies of inhibition of VEGF and its receptors (VEGFR) show activity in OVCA xenografts. Clinical interest in evaluating VEGF (R) inhibition was triggered when the Gynecologic Oncology Group demonstrated single agent activity of the VEGF targeted antibody, bevacizumab (BEV) in recurrent OVCA. Since that time, BEV and small molecular VEGFR inhibitors have been studied in numerous phase II and III trials in OVCA. Randomized BEV trials are the most mature with results reported in first line (GOG218, ICON7), platinum sensitive recurrent disease (OCEANS trial) and platinum resistant recurrent disease (AURELIA trial) settings. All trials gave concurrent chemotherapy + BEV with some providing maintenance BEV after chemotherapy. All have shown a biological effect of the addition of BEV with higher response rates and longer progression free survival (PFS) in BEV arms. To date, no trial has shown overall survival (OS) improvement, although mature analyses for OS are awaited. Quality of life data have not suggested a benefit with BEV and toxicity is greater. Results of phase III trials of VEGFR inhibitors cedarinib, pazopanib and nintedanib are awaited. The BEV results lead to several important questions: 1) in the absence of significant OS improvement to date, is there sufficient patient benefit from PFS increases to warrant incorporation of BEV into ovarian cancer treatment? And when over the course of the disease should the agent be given? 2) Is the use of BEV cost effective and affordable? 3) Which patient subset is benefiting most? Subgroup analysis of the ICON7 study, suggests that patients with greater bulk disease (Stage III> 1 cm residual and Stage IV) seem to derive more PFS benefit. Indeed in this subgroup, overall survival also was improved. However, in the GOG0218 trial, the hazard ratio for PFS was observed to be better in patients with < 1 cm residual. Some have suggested VEGF A plasma levels may be predictive of BEV benefit, but no results from the BEV OVCA trials are yet published. In summary, clinical results to date show significant PFS improvements from BEV in 4 trials, but it is unclear if this will translate into improved OS and how best and in whom BEV should be used in OVCA management. Disclosure: The author has declared no conflicts of interest.

Results from AMBER, a randomized phase 2 study of bevacizumab and bortezomib versus bortezomib in relapsed or refractory multiple myeloma

Newer systemic therapies have significantly advanced the treatment of multiple myeloma, but additional agents are needed. Bortezomib is a proteasome inhibitor with efficacy in relapsed/refractory multiple myeloma that inhibits tumor angiogenesis, a process that has been implicated in multiple myeloma pathogenesis. In AMBER("A Randomized, Blinded, Placebo-Controlled, Multicenter, Phase II Study of Bevacizumab in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma"), patients with relapsed or refractory multiple myeloma were randomized to receive bortezomib (1.3 mg/m(2) on days 1, 4, 8, and 11 of each 21-day cycle) and either placebo or bevacizumab (15 mg/kg on day 1 of each cycle) for up to 8 cycles. At completion, patients in the bortezomib-plus-bevacizumab arm could continue bevacizumab until they developed progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). The stratified hazard ratio of PFS for the bevacizumab-containing arm (n = 49) relative to the bortezomib monotherapy arm (n = 53) was 0.743 (95% confidence interval [CI], 0.43-1.28; P = .2804); the median PFS was 6.2 months (95% CI, 4.4-8.5 months) and 5.1 months (95% CI, 4.2-7.2 months), respectively; the overall response rates were 51% and 43.4% (P = .4029), respectively; and the median response duration was 6.9 months (95% CI, 4.73-11.83 months) and 6.0 months (95% CI, 4.86-8.31 months), respectively. Frequent adverse events occurred at similar rates across treatment arms, but hypertension, fatigue, and neuralgia occurred more frequently in the bevacizumab-containing arm. The addition of bevacizumab to bortezomib in unselected patients with pretreated multiple myeloma did not result in significant improvements in efficacy outcomes. The combination was well tolerated, and no new safety concerns for either agent were identified.

Attenuation of treatment effect due to measurement variability in assessment of progression‐free survival

For normally distributed data analyzed with linear models, it is well known that measurement error on an independent variable leads to attenuation of the effect of the independent variable on the dependent variable. However, for time-to-event variables such as progression-free survival (PFS), the effect of the measurement variability in the underlying measurements defining the event is less well understood. We conducted a simulation study to evaluate the impact of measurement variability in tumor assessment on the treatment effect hazard ratio for PFS and on the median PFS time, for different tumor assessment frequencies. Our results show that scan measurement variability can cause attenuation of the treatment effect (i.e. the hazard ratio is closer to one) and that the extent of attenuation may be increased with more frequent scan assessments. This attenuation leads to inflation of the type II error. Therefore, scan measurement variability should be minimized as far as possible in order to reveal a treatment effect that is closest to the truth. In disease settings where the measurement variability is shown to be large, consideration may be given to inflating the sample size of the study to maintain statistical power.

Randomized phase III trial of regorafenib in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib (IM) and sunitinib (SU): GRID trial.

LBA10008 Background: Oral multikinase inhibitor regorafenib (REG) demonstrated substantial activity in a phase II trial in pts with GIST after failure of both IM and SU (J Clin Oncol. 2011; 29:606s; abstr 10007). This phase III, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of REG for this unmet clinical need. Methods: Eligible pts had metastatic and/or unresectable GIST, objective failure of both prior IM and SU (progressive disease [PD] on, or intolerance to, IM and PD on SU), ≥1 measurable lesion, ECOG performance status 0 or 1. Pts were randomized 2:1 to receive best supportive care plus either REG 160 mg po once daily (3 wks on/1 wk off) or placebo (PL). The primary endpoint was progression-free survival (PFS) (modified RECIST 1.1, independent central review). Secondary endpoints included overall survival (OS), disease control rate (DCR, defined as rate of partial response [PR] plus stable disease [SD] lasting for ≥12 wks), response rate and duration, safety and correlative genotype analyses. At time of PD, pts were eligible for unblinding and crossover to open-label REG. Results: Between Jan and Aug of 2011, 234 pts were screened; 199 were randomized (REG: 133, PL: 66). Pts were stratified at randomization according to number of prior systemic therapies and geographical region. Baseline characteristics were balanced between the two arms. The primary endpoint was met: median PFS was 4.8 months for REG vs. 0.9 months for PL. Hazard ratio for PFS was 0.27 (95% CI, 0.18-0.39), p&lt;0.0001. PFS rates at 3 and 6 months were 60% and 38% for REG vs. 11% and 0% for PL. DCR was 53% (REG) vs. 9% (PL).The HR for OS was 0.77 (p=0.20) with 85% PL pts having crossed over to REG. The most common &gt; grade 3 treatment-emergent AEs in the REG arm during double-blind study were hypertension (28%), hand-foot skin reaction (21%), and diarrhea (8%). Conclusions: This randomized trial demonstrated that REG significantly improved PFS and DCR in pts with advanced GIST after failure of at least prior IM and SU. REG was well tolerated, with AEs as expected for this class and manageable with dose modifications.

Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma.

LBA8500^ Background: Dabrafenib, a selective BRAF inhibitor, has shown activity with a manageable safety profile in phase I/II studies in patients (pts) with BRAFV600E-mutated metastatic melanoma (MM). This phase III trial (NCT01227889) compared progression-free survival (PFS) in pts with advanced MM treated either with dabrafenib or dacarbazine (DTIC). Methods: Pts with previously untreated, unresectable stage III or IV BRAFV600E-mutated melanoma were randomized (3:1) and stratified by stage to dabrafenib (150 mg po bid) or DTIC (1000 mg/m2, IV, q3w). Primary endpoint was investigator-assessed PFS. Primary analysis for PFS was planned after 102 events. Pts on the DTIC arm were allowed to cross over once progression was confirmed by independent review (IR). Secondary endpoints included PFS by IR, overall survival (OS), response rate (RR), duration of response, safety and pharmacokinetics. Results: 250 pts were enrolled at 93 centers globally from February to September 2011. 187 were randomized to dabrafenib and 63 to DTIC. 141pts were on study treatment at the data cut-off at December 19, 2011 (dabrafenib n = 127; DTIC n = 14), including 21/28 DTIC pts crossed over to dabrafenib. Median age was 52 years, 31% of pts were ECOG &gt;1, 66% M1c, 33% LDH &gt; ULN. Demographics were well balanced between the two arms. At the time of the primary analysis, there were 118 events (77 dabrafenib and 41 DTIC). The hazard ratio for PFS was 0.30 (95% CI: 0.18–0.53; p &lt; 0.0001). Median PFS was 5.1 months for dabrafenib and 2.7 for DTIC. OS data were immature, with 30 deaths reported. Confirmed RR was 53% for dabrafenib and 19% for DTIC. Benefits in PFS and RR were observed in all subgroups evaluated. Common adverse events (AEs) on the dabrafenib arm were hyperkeratosis (37%), headache (32%), pyrexia (28%), arthralgia (27%), skin papillomas (24%). Serious AEs (&gt; 1%) on the dabrafenib arm included pyrexia (4%), squamous cell carcinomas (6%), and new primary melanomas (2%). Conclusions: Dabrafenib demonstrated a significant improvement in PFS and ORR over DTIC with an acceptable safety profile.

Correlation between overall survival and other endpoints in clinical trials of second-line chemotherapy for patients with advanced gastric cancer.

4067 Background: The correlation between progression-free survival (PFS) or time to progression (TTP) and overall survival (OS) has been evaluated in patients with advanced gastric cancer (AGC) who received first-line chemotherapy (Shitara, K et al. Invest New Drug 2011; Shitara K and Burzykowski T, et al, ASCO 2011). However, no corresponding analysis had been done in patients who underwent second-line chemotherapy for AGC. Methods: We evaluated the potential of PFS, TTP, response rate (RR), or disease control rate (DCR) to act as surrogates for OS in phase II and III trials of second-line chemotherapy for AGC by comprehensive literature-based analysis. Correlations between each endpoint and OS were evaluated by Spearman rank correlation coefficient (ρ). Subgroup analyses by trial region or type of failure to previous chemotherapy were also conducted. Results: Fifty-six trials, including four randomized studies, were selected for analysis and covered a total of 61 treatment arms and 3,038 patients; 34 studies were conducted in Asia, 20 studies in Non-Asian countries, and two studies in both regions. Median PFS were similar in Asian and Non-Asian trials (3.0 vs. 3.3 months). In contrast, median OS tended to be longer in Asian vs. Non-Asian trials (8.0 vs. 6.0 months; p&lt;0.01). Median PFS/TTP and OS showed a moderate correlation with ρ of 0.51 (95% CI, 0.31-0.73). Correlation tended to be higher in PFS (ρ = 0.62) than TTP (ρ = 0.29) and higher in non-Asian trials (ρ = 0.73) than Asian trials (ρ = 0.32). Correlation between PFS/TTP and OS among the trials in which eligibility required failure to previous fluorouracil and cisplatin also showed low correlation (ρ = 0.48). The RR and DCR also did not show high correlation with OS (ρ = 0.30 for RR; 95% CI 0.04-0.56; ρ = 0.53 for DCR; 95% CI 0.31-0.75). The hazard ratio (HR) of PFS and OS in each arms of the four randomized studies showed a low correlation with ρ of 0.10. Conclusions: Our results indicate that PFS/TTP, RR, and DCR did not correlate sufficiently with OS to be used as surrogate endpoints in patients with AGC who underwent second-line chemotherapy. Further research is needed based on individual patient data from ongoing randomized trials.

A randomized double-blind trial of carboplatin plus paclitaxel (CP) with daily oral cediranib (CED), an inhibitor of vascular endothelial growth factor receptors, or placebo (PLA) in patients (pts) with previously untreated advanced non-small cell lung cancer (NSCLC): NCIC Clinical Trials Group study BR29.

7511 Background: In NCIC CTG study BR24, CED 30 mg/d + CP increased objective response rate (RR) and progression-free survival (PFS), but there were concerns regarding toxicity in some pts. BR29 tested a lower dose of CED 20 mg/d limiting accrual to pts without significant weight loss/hypoalbuminemia. Methods: Consenting, eligible adult pts with advanced incurable NSCLC of any histology were randomized to receive CED 20 mg/d or PLA with up to 6 cycles of C (AUC = 6) P (200 mg/m2); non-progressing pts continued CED/PLA after CP until progression, unacceptable toxicity or pt request. The primary endpoint was overall survival (OS). An interim analysis (IA) for PFS was planned after 170 events in the first 260 pts; the study would continue if the hazard ratio (HR) for PFS was &lt; 0.7. Accrual continued until the required number of events was reached then held pending IA. Results: The trial was halted when the IA (n=260) revealed a HR for PFS of 0.89 (95% CI 0.66-1.20). A final analysis including all 306 randomized pts (median age 62, male 55%, PS 0 26%, PS 1 74%, adenocarcinoma 64%, squamous 13%, other histology 23%. RR was significantly higher with CED (52% vs 34 %, p = 0.001). For CED/PLA, respectively, median OS and PFS were 12.2/12.1 [HR: 0.95 (0.69-1.30, p=0.74)] and 5.5/5.5 months [HR: 0.91 (0.71-1.18, p=0.5)]. Grade &gt;3 hypertension (15% vs 3%, p=0.0002), anorexia (7% vs 1%, p=0.02) and diarrhea (16% vs 1%, p&lt;0.0001) were all significantly increased with CED; there were 2 deaths possibly-related to CED [1 each hemorrhage, leukoencephalopathy (prior radiation)]. Conclusions: Adding a lower dose of CED to CP increased RR and toxicity, but not PFS or OS.

Efficacy and tolerability of FOLFOX6 as first-line treatment for advanced gastric and esophagogastric junction cancers (AGC): A single-center experience.

e14705 Background: There are a number of options for first line treatment for AGC. We sought to review the efficacy and tolerability of FOLFOX (F) in AGC, and compare outcomes with anthracycline-based (A) ctx-treated patients (pts). Methods: Pts with AGC treated with F and A (EOX and ECF) were identified from institutional database. Pt. demographics, disease characteristics and treatment details were extracted from medical charts and pharmacy database. Progression-free survival (PFS) and overall survival (OS) were calculated from commencement of ctx to radiographic evidence of progression and death, respectively, estimated with the Kaplan-Meier method. Comparisons were made via log-rank method. Other descriptive statistics calculated via t-test or chi-square methods as appropriate. Results: Between July 05 and December 11, 27 pts were treated with F. Twenty-one (77.8%) were male and median age was 68yrs (range: 42 – 77). ECOG performance status was 0 -1 in 24 pts (88.9%) and 2 in 3 (11.1%). Median Charlson score prior to metastatic disease was 2 (range: 0 – 3). Three had relapsed disease and another three had locally-advanced disease. Sites of metastatic disease were liver (12), peritoneum (12), non-regional nodes (2) and lungs (2). Median number of cycles of F was 5 (range: 1 - 12), 51.8% of pts completed ≥10 cycles, while the rest discontinued treatment due to disease progression (33%) and toxicities (14.8%). 21 pts (77.8%) required dose reduction and 17 (63%) experienced treatment delay. Fourteen (51.8%), 6 and 2 pts had 2nd, 3rd and 4th line of ctx, respectively. Median PFS was 7.2 mos and median OS is 9.7 mos. Sixteen pts were treated with A. Pts were significantly younger (p=0.002) but other characteristics were similar. Median PFS with A was 6.6 mos and median OS was 9.2 mos. The hazard ratio (F vs A) for PFS was 1.11 (95% CI 0.56 to 2.18, p = 0.77) and for OS was 0.73 (95% CI 0.36 to 1.51, p = 0.40). Conclusions: Despite an older pts cohort with co-morbidities, high percentage of treatment delays and dose reductions, our data suggest that significant percentage of pts were able to complete ≥10 cycles of F and subsequent therapies. Outcomes are comparable to our A cohort and published data.

A single-institution phase II trial of radiation (RT), temozolomide (TMZ), erlotinib, and bevacizumab for initial treatment of glioblastoma (GBM).

2026 Background: Standard treatment for GBM includes surgery followed by RT and TMZ, rarely a curative treatment. Both the EGFR and VEGF pathways are frequently overactive in GBM; we previously added erlotinib, an EGFR inhibitor, to RT and TMZ, with modest improvement in survival. The present study combined bevacizumab, a VEGF inhibitor, and erlotinib with RT and TMZ, with the goal of improving overall survival (OS). Methods: Treatment consisted of fractionated RT to 60 Gy with daily TMZ at 75 mg/m2/d and erlotinib 150-200 mg/d (or 500-600 mg/d for patients on enzyme-inducing antiepileptic drugs [EIAEDs]). Bevacizumab was given at 10 mg/kg every 2 wks, starting ≥ 4 wks after surgery. After RT, adjuvant TMZ was given at 200 mg/m2/d x 5d per 28d cycle, with unchanged erlotinib and bevacizumab doses. Treatment was continued until progression or for 12 mo, with an option to continue for up to 24 mo. OS and progression-free survival (PFS) from initial diagnosis were compared against institutional historical controls (recent prior up-front clinical trials including RT and TMZ). Results: 59 pts were enrolled; 12 were receiving EIAEDs. Median age was 54 yrs; median KPS was 90. 33% underwent gross total resection and 53% subtotal resection. 16 pts had tumors with methylated MGMT (mMGMT), 26 with unmethylated MGMT (umMGMT), and 17 with unknown status. The most frequent related grade 3/4 AEs were lymphopenia (68%) thrombocytopenia (24%), neutropenia (10%), diarrhea (14%), weight loss (14%), and fatigue (12%). 1 pt died of aspergillosis. Median OS and PFS were 19.8 mo and 13.5 mo, respectively, vs. 18 mo and 8.6 mo for the historical control. The hazard ratio (adj for age, KPS, and extent of surgery) for PFS was 0.7 (95% CI 0.49-0.99, p=0.04). Median OS in pts with mMGMT was 20.9 mo, vs. 17.5 mo in pts with umMGMT; median PFS was 14 mo vs. 12.4 mo, respectively. Conclusions: The combination of bevacizumab, erlotinib, TMZ, and RT showed improved PFS but not OS vs. historical controls. Though the numbers were small, PFS and OS for pts with umMGMT were not significantly different from pts with mMGMT, suggesting that this combination may be more effective than standard therapy alone for pts with unMGMT tumors.

Comparative effectiveness of front-line agents in the treatment of metastatic clear cell renal cell carcinoma.

e15045 Background: Based on improved clinical outcomes in randomized controlled clinical trials (RCT) the FDA has approved 4 drugs in the front line treatment of good to intermediate risk metastatic clear cell renal cell carcinoma (RCC). However, there is little if any comparative data to help choose the most effective drug among these agents. Methods: We performed an indirect comparative effectiveness analysis of the pivotal RCTs (Escudier JCO 2009 and 2010, Rini JCO 2010, Motzer JCO 2009, Sternberg JCO 2010, MRCRCC Lancet 1999, Steineck Acta Oncologica 1990, Pyrhonen JCO 1999, Kriegmair Urology 1995) evaluating outcomes with sunitinib (SU), sorafenib (SO), bevacizumab plus interferon alpha (B+I), pazopanib (P), interferon alone (I) and other controls. Progression-free-survival (PFS) was the main endpoint. Other endpoints included response rate (RR) and overall survival (OS). Estimates, confidence intervals, and p-values from analyses that are stratified by risk factors were used throughout if available. A linear mixed effects model with a random effect for each study and known error variances was fit by restricted maximum likelihood and used to obtain indirect estimates. Results: The indirect estimate of the hazard ratio (95% confidence interval; p-value) for PFS for SU vs. B+I is 0.813 (0.624-1.059; p=0.125); for B+I vs. SO is 0.753 (0.497-1.141; p=0.181); for P vs. B+I is 0.963 (0.612-1.518; p=0.874); for SU vs. SO is 0.613 (0.392-0.956; p=0.0311); for SU vs. P is 0.844 (0.521-1.366; p=0.49; for P vs. SO is 0.726 (0.407-1.295; p=0.278)(Figure 1). SU, P, B+I had better PFS than I alone and than other controls, while SO did not. SU had statistically significantly better RR when compared to P, SO and B+I with HR of 0.254, 0.215 and 0.419 (all p&lt;0.05). OS data was not available to compare all agents and may be confounded by cross-over in the trials. Conclusions: Based on PFS, SU, B+I and P are adequate front line options in the treatment of advanced clear cell RCC. As SU had better RR it may be a preferred option for patients with symptoms or large disease burden. SO should not be considered an optimal front line treatment.

Carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in partially platinum-sensitive ovarian cancer patients: results from a subset analysis of the CALYPSO phase III trial

To perform a subset analysis of patients with partially platinum-sensitive recurrent ovarian cancer (ROC) who received either CD [carboplatin-pegylated liposomal doxorubicin (PLD)] or CP (carboplatin-paclitaxel) in the CALYPSO trial. CALYPSO, an international phase III, non-inferiority trial, enrolled women with ROC that relapsed >6 months following first- or second-line therapy. Patients were randomized to CD or CP. Patients with a treatment-free interval of >6 and ≤ 12 months were evaluated for progression-free survival (PFS), the primary end point of CALYPSO trial, and safety. A total of 344 partially platinum-sensitive patients were included (N = 161, CD and N = 183, CP). The hazard ratio for PFS was 0.73 (95% confidence interval: 0.58-0.90; P = 0.004 for superiority) in favor of CD. Median PFS times were 9.4 months (CD) and 8.8 months (CP). Toxicities more common with CP versus CD included grade 3/4 neutropenia (50% versus 39%; P = 0.015), grade 2 alopecia (86% versus 9%; P < 0.001), neuropathy and hypersensitivity reactions. Hand-foot syndrome was more common with CD; however, grade 3/4 reactions were low (one patient in each arm). Carboplatin-PLD has a more favorable risk-benefit profile than CP in patients with partially platinum-sensitive ROC and should be considered an effective treatment option for these patients.

The initial change in tumor size predicts response and survival in patients with metastatic colorectal cancer treated with combination chemotherapy

To determine whether the change in tumor diameters at the first follow-up computed tomography (CT) examination after baseline examination (first change) correlates with outcome in patients with metastatic colorectal cancer (mCRC) treated with combination chemotherapy. The first change was analyzed in a multicenter randomized phase III trial (Nordic VI, N = 567) comparing first-line irinotecan with either bolus or infused 5-fluorouracil. Cox proportional hazards multiple regression model and Kaplan-Meier survival analyses after correction for guarantee-time bias were carried out to evaluate correlations between first change, objective response according to RECIST 1.0, progression-free survival (PFS), and overall survival (OS). The hazard ratios for PFS and OS decreased along with first change. A decrease between 10% and <30%, albeit RECIST does not regard this as a partial response, was a positive prognostic factor for PFS and OS. Patients who had new lesions or unequivocal progression of nonmeasurable lesions had a worse prognosis than those with only an increase in size of >20%. The change in tumor size at the first follow-up CT is strongly prognostic for PFS and OS in mCRC.

Genetic Variants of NBS1 Predict Clinical Outcome of Platinum-based Chemotherapy in Advanced Non-small Cell Lung Cancer in Chinese

NBS1 plays a key role in the repair of DNA double-strand break (DSB). We conducted this study to investigate the effect of two critical polymorphisms (rs1805794 and rs13312840) in NBS1 on treatment response and prognosis of advanced non-small cell lung cancer (NSCLC) patients with platinum-based chemotherapy. Using TaqMan methods, we genotyped the two polymorphisms in 147 NSCLC patients. Odds ratios (ORs) and their 95% confidential intervals (CIs) were calculated as a measure of difference in the response rate of platinum-based chemotherapy using logistic regression analysis. The Kaplan-Meier and log-rank tests were used to assess the differences in progression-free survival (PFS) and overall survival (OS). Cox proportional hazards model was applied to assess the hazard ratios (HRs) for PFS and OS. Neither of the two polymorphisms was significantly associated with treatment response of platinum-based chemotherapy. However, patients carrying the rs1805794 CC variant genotype had a significantly improved PFS compared to those with GG genotype (16.0 vs. 8.0 months, P = 0.040). Multivariable cox regression analysis further showed that rs1805974 was a significantly favorable prognostic factor for PFS [CC/CG vs. GG: Adjusted HR = 0.62, 95% CI: 0.39-0.99; CC vs. CG/GG: Adjusted HR = 0.56, 95% CI: 0.32-0.97). Similarly, rs13312840 with a small sample size also showed a significant association with PFS (CC vs. CT/TT: Adjusted HR = 25.62, 95% CI: 1.53-428.39). Our findings suggest that NBS1 polymorphisms may be genetic biomarkers for NSCLC prognosis especially PFS with platinum-based chemotherapy in the Chinese population.

Apparent diffusion coefficient histogram analysis stratifies progression-free and overall survival in patients with recurrent GBM treated with bevacizumab: a multi-center study

We have tested the predictive value of apparent diffusion coefficient (ADC) histogram analysis in stratifying progression-free survival (PFS) and overall survival (OS) in bevacizumab-treated patients with recurrent glioblastoma multiforme (GBM) from the multi-center BRAIN study. Available MRI's from patients enrolled in the BRAIN study (n = 97) were examined by generating ADC histograms from areas of enhancing tumor on T1 weighted post-contrast images fitted to a two normal distribution mixture curve. ADC classifiers including the mean ADC from the lower curve (ADC-L) and the mean lower curve proportion (LCP) were tested for their ability to stratify PFS and OS by using Cox proportional hazard ratios and the Kaplan-Meier method with log-rank test. Mean ADC-L was 1,209 × 10(-6)mm(2)/s ± 224 (SD), and mean LCP was 0.71 ± 0.23 (SD). Low ADC-L was associated with worse outcome. The hazard ratios for 6-month PFS, overall PFS, and OS in patients with less versus greater than mean ADC-L were 3.1 (95 % confidence interval: 1.6, 6.1; P = 0.001), 2.3 (95 % CI: 1.3, 4.0; P = 0.002), and 2.4 (95 % CI: 1.4, 4.2; P = 0.002), respectively. In patients with ADC-L <1,209 and LCP >0.71 versus ADC-L >1,209 and LCP <0.71, there was a 2.28-fold reduction in the median time to progression, and a 1.42-fold decrease in the median OS. The predictive value of ADC histogram analysis, in which low ADC-L was associated with poor outcome, was confirmed in bevacizumab-treated patients with recurrent GBM in a post hoc analysis from the multi-center (BRAIN) study.

Second-line bevacizumab-containing therapy in patients with triple-negative breast cancer: subgroup analysis of the RIBBON-2 trial

Patients with metastatic triple-negative breast cancer (TNBC) typically have a poor prognosis and limited treatment options. To determine the impact of combining bevacizumab with second-line chemotherapy in patients with metastatic TNBC, we performed an exploratory subgroup analysis of the randomized phase 3 RIBBON-2 trial. RIBBON-2 enrolled patients with metastatic breast cancer that had progressed on first-line non-bevacizumab-containing chemotherapy. After selection of chemotherapy (taxane, gemcitabine, capecitabine, or vinorelbine), patients were randomized 2:1 to receive chemotherapy with either bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks) or placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Of 684 patients treated in RIBBON-2, 159 (23%) had TNBC. Baseline characteristics were reasonably balanced in the two treatment groups. The majority received taxane chemotherapy. The hazard ratio (HR) for PFS was 0.494 [95% confidence interval (CI) 0.33-0.74; P = 0.0006]. Median PFS was 6.0 months with bevacizumab-chemotherapy versus 2.7 months with chemotherapy alone. Median OS was 17.9 versus 12.6 months, respectively (HR 0.624, 95% CI 0.39-1.007; P = 0.0534). ORR was 41 versus 18%, respectively (P = 0.0078). The safety profile was consistent with the overall study population and previous phase 3 trials of bevacizumab. Patients with metastatic TNBC derived significant PFS and response benefits from the combination of bevacizumab with second-line chemotherapy. Despite the small sample size and immature data, there was a trend toward improved OS.

Randomized phase II study of first-line carboplatin-paclitaxel with or without bevacizumab in Japanese patients with advanced non-squamous non-small-cell lung cancer

PurposeThis multicenter, randomized, open-label, phase II study (JO19907) compared the efficacy and safety of first-line carboplatin-paclitaxel (CP) alone with bevacizumab-CP in Japanese patients with advanced non-squamous non-small-cell lung cancer (NSCLC). MethodsChemonaïve patients with stage IIIB, IV or recurrent non-squamous NSCLC were eligible for participation. Patients were randomly assigned in a 2:1 ratio to receive bevacizumab-CP or CP alone. Chemotherapy was repeated for up to 6 cycles or until disease progression or unacceptable toxicity. Bevacizumab recipients who completed ≥3 cycles of chemotherapy could continue bevacizumab as monotherapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). ResultsAfter confirming the tolerability of bevacizumab-CP in a small number of patients, 180 patients were recruited, of whom 121 were assigned to bevacizumab-CP and 59 to CP alone. Hazard ratio (HR) for PFS was 0.61 with bevacizumab-CP versus CP alone (p=0.0090; median 6.9 versus 5.9 months). Objective response rate was significantly higher with bevacizumab-CP than with CP alone (60.7% versus 31.0%; p=0.0013). Median overall survival was >22 months in both treatment groups (HR 0.99; p=0.9526). No new safety signals were detected. ConclusionStudy JO19907 met its primary endpoint, demonstrating that the addition of bevacizumab to first-line CP significantly improves PFS in Japanese patients with advanced non-squamous NSCLC. This prolonged PFS by bevacizumab did not translate into OS benefit with the extremely longer underlying survival compared to historical data. No new safety signals were identified in this population. (Japan Pharmaceutical Information Center [JAPIC] registration number: CTI-060338).