Two decades of therapy in metastatic colorectal cancer (mCRC): An analysis to discern the contribution and progress made by chemotherapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14064-e14064
Author(s):  
Irfan Jawed ◽  
Julia Wilkerson ◽  
Austin G. Duffy ◽  
Antonio Tito Fojo
Keyword(s):  
Supportive Care ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Second Line ◽  
Phase Ii Trials ◽  
First Line ◽  
The Past ◽  
Large Phase ◽  
And Control ◽  
Over Time

e14064 Background: The past 20 years have seen progress in mCRC with more effective agents and better medical, surgical and supportive care. Methods: Systematic review of 101 phase III and large phase II trials in mCRC to quantify benefit over time with first-line and subsequent therapies. Outcomes in the experimental (EA) and control arms (CA) included progression-free survival (PFS), overall response rate (ORR), stable disease (SD), and overall survival (OS). Data were analyzed according to dates of publication and median enrollment. Results: Significant outcomes are reported; most had R2 values > 0.6. OS of EA improved 0.83 mos/yr. Importantly OS of CA improved 0.58 mos/yr likely reflecting subsequent use of experimental regimens in CA and improvement in mCRC care over time. Chemotherapy has contributed only partly to gains in OS since (1) only modest improvements of PFS (0.33 [EA] and 0.26 [CA] mos/yr) and we have shown OS gains are proportional to PFS gains indicating other factors are as or more important than chemotherapy; and (2) lack of OS improvement in 14 second/subsequent line trials. Furthermore, to assess the contribution of each drug/drug class to improvement in OS we performed linear regression with OS the dependent variable versus time publication. We found oxaliplatin, irinotecan and bevacizumab have contributed to progress; but not cetuximab/panitumumab likely explained by inclusion of pts with tumors harboring mutant ras in studies. Not surprisingly, capecitabine in place of 5-fluorouracil had no impact on progress made. As expected PFS correlates highly with OS, but importantly ORR had very high correlations with both PFS and OS. SD was an “adverse” outcome, OS decreasing as SD rates increase. Conclusions: OS of mCRC patients has improved gradually over the past two decades, with gains from chemotherapy and importantly gains from other factors, including lead-time bias, better loco-regional approaches and supportive care. Gains from first line therapies have been modest but consistent; gains from second line therapies have been disappointing. We believe future progress will be more fruitful if emphasis is given to improving second line therapies.

Twenty years of chemotherapy for colorectal cancer (CRC): Progress made, insights gleaned.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 596-596
Author(s):  
Irfan Jawed ◽  
Julia Wilkerson ◽  
Austin G. Duffy ◽  
Antonio Tito Fojo
Keyword(s):  
Supportive Care ◽  
Odds Ratio ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Negative Effects ◽  
Phase Ii Trials ◽  
Free Survival ◽  
Large Phase ◽  
And Control ◽  
Over Time

596 Background: The past 20 years have seen progress in CRC therapy with more effective agents and better medical, surgical and supportive care. Methods: We conducted a systematic review of 101 phase III and large phase II trials in CRC to quantify benefit over time with first-line and subsequent therapies. Outcomes examined in the experimental (EA) and control arms (CA) included progression-free survival (PFS), overall response rate (ORR), stable disease (SD), overall survival (OS) and post-treatment survival (PTS). Data were analyzed according to dates of publication and median enrollment. Results: Significant outcomes are reported; most had R2 values > 0.6. OS of EA improved 0.83 mos/yr. Importantly the OS of CA improved 0.58 mos/yr likely reflecting use of experimental therapies in CA in subsequent studies and improvement in CRC care over time as suggested by: (1) modest improvements of PFS: 0.33 [EA] and 0.26 [CA] mos/yr; (2) PTS gains of 0.48 [EA] and 0.29 [CA] mos/yr, accounting for majority of OS gains; and (3) lack of OS improvement in 14 second/subsequent line trials. Using logistic regression to examine all drugs as class predictors of increasing OS, oxaliplatin [OX], bevacizumab [BEV], and irinotecan [IRI] were significant in the EA, but only OX and BEV were significant in the CA. Capecitabine [CAP] and cetuximab/panitumumab [CET/PAN] were not significant in EA or CA, with CAP odds ratio towards null and CET/PAN odds ratio away from null. The lack of IRI effect in CA concurs with observation that only IRI regimens had worse OS in CA compared with EA. The CET/PAN results likely reflect lack of efficacy/harm in patients with WT KRAS tumors. As expected PFS and PTS correlate highly with OS, but importantly ORR had very high correlations with both PFS and OS. SD emerged as an “adverse” outcome, OS decreasing as SD rates increase. Conclusions: OS of CRC patients has improved gradually over past two decades, with gains from chemotherapy but also other factors, such as lead-time bias, more loco-regional approaches and improved supportive care. IRI performed better in EA than in CA. CET/PAN had negative effects in the entire population. In CRC, ORR correlates highly with OS, while SD portends a poor outcome.

Phase III Trial of Pemetrexed Plus Best Supportive Care Compared With Best Supportive Care in Previously Treated Patients With Advanced Malignant Pleural Mesothelioma

2008 ◽  
Vol 26 (10) ◽  
pp. 1698-1704 ◽  
Author(s):  
Jacek Jassem ◽  
Rodryg Ramlau ◽  
Armando Santoro ◽  
Wolfgang Schuette ◽  
Assad Chemaissani ◽  
...  
Keyword(s):  
Partial Response ◽  
Supportive Care ◽  
Malignant Pleural Mesothelioma ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Best Supportive Care ◽  
Phase Iii ◽  
Pleural Mesothelioma ◽  
Second Line ◽  
First Line

PurposeThis multicenter, phase III study compared overall survival (OS) of second-line pemetrexed plus best supportive care (BSC) versus BSC alone in patients with advanced malignant pleural mesothelioma (MPM). Secondary end points included response rate, progression-free survival (PFS), time to tumor progression (TTP), time to treatment failure (TTF), and toxicity.Patients and MethodsPatients with relapsed MPM after first-line chemotherapy were randomly assigned to receive pemetrexed 500 mg/m2plus BSC (P+BSC) every 21 days or BSC alone.ResultsThe study enrolled 243 patients (123 on P+BSC arm and 120 on BSC arm). Median OS time was not significantly different between the arms (8.4 months for P+BSC and 9.7 months for BSC; P = .74). Cox regression modeling suggested a trending survival benefit for patients who responded to first-line therapy. Time-to-event measures significantly favored P+BSC (median PFS, TTP, and TTF). Partial response was achieved in 18.7% and 1.7% of patients in P+BSC and BSC arms, respectively (P < .0001), and a disease control rate (partial response plus stable disease) was achieved in 59.3% and 19.2% of patients in P+BSC and BSC arms, respectively (P < .0001). Use of postdiscontinuation chemotherapy was significantly greater among BSC patients compared with P+BSC patients (51.7% v 28.5%, respectively; P = .0002), with more BSC patients receiving pemetrexed (18.3% v 3.3%, respectively; P = .0001). Postdiscontinuation therapy was initiated earlier for BSC than P+BSC patients (median time to initiation, 4.3 v 15.7 months, respectively; log-rank P < .0001). Chemotherapy was well tolerated, with expected modest (4% to 7%) grade 3 and 4 hematologic toxicities.ConclusionSecond-line pemetrexed elicited significant tumor response and delayed disease progression compared with BSC alone in patients with advanced MPM. Improvement in OS was not seen in this study, possibly because of the significant imbalance in postdiscontinuation chemotherapy between the arms.

Phase II study of sequential first-line pazopanib (PAZ) followed by everolimus (EVE) in patients (pts) with advanced or metastatic renal cell carcinoma (RCC) (CATChEz Study).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 648-648 ◽  
Author(s):  
Paul L. de Souza ◽  
Shirley Wong ◽  
Sanjeev Sewak ◽  
Dusan Kotasek ◽  
Bhumsuk Keam ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Phase Iii ◽  
Second Line ◽  
First Line ◽  
Free Survival ◽  
Anticancer Treatment ◽  
Secondary Endpoints ◽  
Prior Systemic Therapy ◽  
Grade 3 ◽  
Metastatic Rcc

648 Background: EVE following failure of sorafenib or sunitinib for RCC was first approved by the FDA in 2009. CATChEz (NCT01545817) was designed to test the activity of EVE following first-line PAZ in pts with advanced or metastatic RCC who had not received prior systemic therapy. Methods: From 2012 to 2016, pts received first-line PAZ followed by EVE until progressive disease (PD), death, unacceptable toxicity, consent withdrawal, or study termination. Pts with PD during or within 6 months of stopping PAZ were eligible for EVE. Pts off study treatment were evaluated for PD, survival, and updates on anticancer treatment every 8 weeks until death or end of study. The primary efficacy endpoint was median progression-free survival (mPFS) for the second-line EVE treatment period; secondary endpoints included other survival measures, and safety evaluations were for second-line EVE and grade 3/4 toxicities attributable to PAZ and EVE. Results: Of 74 pts who started first-line PAZ, 38 received ≥1 dose of second-line EVE. The primary endpoint of mPFS from the start of second-line EVE and the secondary endpoint of mPFS with first-line PAZ (Table) were consistent with previous reports; no unexpected adverse events (AEs) were reported. All pts had ≥1 treatment-emergent AE, 83.8% had grade ≥3 AEs, and 71.6% had serious AEs. Of 34 total deaths, 29 were due to PD and 5 were due to AEs (2 related to EVE [lower respiratory tract infection; pulmonary sepsis]; 3 unrelated to study treatment). Conclusions: Efficacy and safety outcomes were consistent with published phase III data. The CATChEz study supports sequential first-line use of PAZ followed by EVE for the treatment of pts with advanced or metastatic RCC. Clinical trial information: NCT01545817. [Table: see text]

Randomized phase III study of irinotecan (CPT-11) versus weekly paclitaxel (wPTX) for advanced gastric cancer (AGC) refractory to combination chemotherapy (CT) of fluoropyrimidine plus platinum (FP): WJOG4007 trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4002-4002 ◽  
Author(s):  
Shinya Ueda ◽  
Shuichi Hironaka ◽  
Hirofumi Yasui ◽  
Tomohiro Nishina ◽  
Masahiro Tsuda ◽  
...  
Keyword(s):  
Adverse Events ◽  
Progression Free Survival ◽  
Best Supportive Care ◽  
Phase Iii ◽  
Second Line ◽  
First Line ◽  
Standard Regimen ◽  
Phase Iii Trials ◽  
Phase Iii Study ◽  
Third Line

4002 Background: A combination CT of FP has been regarded as the standard first-line treatment for AGC. Although two randomized trials showed a survival benefit of second-line CT (CPT-11 or docetaxel) compared with best supportive care, no standard regimen has been established. In Japan, wPTX has been used more frequently than docetaxel as the second‑line CT. The objective of this study was to compare CPT-11 with wPTX in patients (pts) with AGC refractory to FP. Methods: Patients with AGC refractory to the first‑line FP regimen were randomized 1:1 to either CPT-11 (150 mg/m2, q2w) or wPTX (80 mg/m2, days 1, 8, 15, q4w). The primary endpoint was overall survival (OS) and secondary endpoints were progression‑free survival (PFS), overall response rate (ORR), adverse events and receiving rates of third-line CT. To demonstrate an increase in median OS from 5 months (wPTX) to 7.5 months (CPT-11) with 2-sided alpha 5% and 80% power, 220 pts were required. Results: Between Aug 2007 and Aug 2010, 223 pts were enrolled; 112 pts were randomized to CPT-11 and 111 pts to wPTX. Baseline characteristics were well balanced between arms. Median OS was 8.4 months for CPT-11 and 9.5 months for wPTX (HR 1.132; 95% CI, 0.86-1.49; p=0.38). Median PFS was 2.3 months for CPT-11 and 3.6 months for wPTX (HR 1.14; 95% CI, 0.88-1.49; p=0.33). The ORR was 13.6% (12/88) for CPT-11 and 20.9% (19/91) for wPTX (p=0.20). The most common grade 3/4 adverse events were neutropenia (39.1% for CPT-11 vs. 28.7% for wPTX), anemia (30.0% vs. 21.3%), anorexia (17.3% vs. 7.4%) and fatigue (12.7% vs. 6.5%). Four (4%) CPT-11 and three (3%) wPTX recipients died within 30 days after the last administration. Subsequent CT was performed in 80 pts (71%) for CPT-11 and 97 pts (89%) for wPTX. Seventy-five pts (67%) in the CPT-11 group and 87 pts (80%) in the wPTX group received the crossover CT. Conclusions: The WJOG4007 trial, the first phase III study comparing second-line CT regimens for AGC, did not demonstrate the superiority of CPT-11 over wPTX. Thus, wPTX can be adopted as a control arm of future phase III trials of second-line CT for AGC.

Phase III AXIS trial for second-line metastatic renal cell carcinoma (mRCC): Effect of prior first-line treatment duration and axitinib dose titration on axitinib efficacy.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 354-354 ◽  
Author(s):  
Brian I. Rini ◽  
Bernard J. Escudier ◽  
M Dror Michaelson ◽  
Sylvie Negrier ◽  
Martin Eric Gore ◽  
...  
Keyword(s):  
Treatment Duration ◽  
Kinase Inhibitors ◽  
Performance Status ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Dose Titration ◽  
Second Line ◽  
First Line ◽  
Sunitinib Treatment ◽  
Prior Therapy

354 Background: Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. In the phase 3 AXIS trial of axitinib vs sorafenib for second-line mRCC, axitinib significantly prolonged median progression-free survival (mPFS) (6.7 vs 4.7 months; hazard ratio 0.665; P<0.0001). Here, we evaluated the effect of prior sunitinib treatment duration and axitinib dose titration on subsequent axitinib efficacy. Methods: Eligible patients had clear-cell mRCC; measurable RECIST-defined progressive disease after 1 prior first-line systemic therapy; and Eastern Cooperative Oncology performance status (PS) 0/1. Patients were stratified by PS and prior therapy, and randomized 1:1 to either axitinib, at a starting dose of 5 mg twice daily (BID), or sorafenib, 400 mg BID. Patients without toxicity >grade 2 and BP <150/90 mmHg without antihypertensive medication for >2 weeks were eligible to increase axitinib dose to 7 mg BID and then to 10 mg BID. Results: The mPFS for patients receiving at least one total daily axitinib dose >10 mg (dose-titrated group; n=132) was 6.6 months [95% CI 4.7–8.3] and 8.3 months [95% CI 6.0–10.2] for patients receiving axitinib ≤10 mg (n=227). A total of 194 patients (53.7%) in the axitinib arm and 195 patients (53.9%) in the sorafenib arm had prior sunitinib treatment. The mPFS for patients with duration of prior sunitinib treatment ≥6 months and <6 months were 4.8 months [95% CI 4.5–6.5] and 4.6 months [95% CI 2.8–8.3] for axitinib patients; and 4.6 months [95% CI 2.9–4.9] and 2.9 months [95% CI 2.8–4.6), for sorafenib patients. The mPFS for duration of prior sunitinib ≥9 months and <9 months were 6.3 months [95% CI 4.6–6.7] and 4.5 months [95% CI 2.8–6.4] for axitinib patients; and 4.6 months [95% CI 2.8–4.9] and 2.9 months [95% CI 2.8–4.7]) for sorafenib patients. Conclusions: Duration of prior sunitinib ≥9 months may be associated with a longer PFS on second-line VEGFR tyrosine kinase inhibitors. Both axitinib dose-increased and non-increased patients had longer PFS compared with the sorafenib arm.

First-line sunitinib versus pazopanib in metastatic renal cell carcinoma (mRCC): Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 544-544 ◽  
Author(s):  
Jose Manuel Ruiz Morales ◽  
J Connor Wells ◽  
Frede Donskov ◽  
Georg A. Bjarnason ◽  
Jae-Lyun Lee ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Progression Free Survival ◽  
Similar Efficacy ◽  
Phase Iii ◽  
Line Treatment ◽  
Second Line ◽  
First Line

544 Background: Sunitinib (SU) and Pazopanib (PZ) have been compared head-to-head in the first-line phase III COMPARZ study in metastatic renal cell carcinoma (mRCC). We compared SU versus PZ, to confirm outcomes and subsequent second-line therapy efficacy in a population-based setting. Methods: We used the IMDC to assess overall survival (OS), progression-free survival (PFS), response rate (RR) and performed proportional hazard regression adjusting for IMDC prognostic groups. Second-line OS2 and PFS2 were also evaluated. Results: We obtained data from 3,606 patients with mRCC treated with either first line SU (n=3226) or PZ (n=380) with an overall median follow-up of 43.5 months (m) (CI95% 41.4 – 46.4). IMDC risk group distribution for favorable prognosis was 440 (17.3%) for SU vs 72 (25%) for PZ, intermediate prognosis 1414 (55.6%) for SU vs 153 (53%) for PZ, poor prognosis 689 (27.1%) for SU vs 62 (22%) for PZ, p= 0.0027. We found no difference between SU vs. PZ for OS (20.1 [CI95% 18.76-21.42] vs. 23.68 m [CI95% 19.54 - 28.81] p=0.19), PFS (7.22 [CI95% 6.76 - 7.78] vs. 6.83 m [CI95% 5.58 - 8.27] p=0.49). The RR was similar in both groups (Table 1). Adjusted HR for OS and PFS were 0.952 (CI95% 0.788 – 1.150 p=0.61) and 1.052 (CI95% 0.908 – 1.220 p = 0.49), respectively. We also found no difference in any second-line treatment between either post-SU vs. post-PZ groups for OS2 (12.88 [CI95% 11.89 – 14.19] vs. 12.91 m [CI95% 10.3 – 19.1] p=0.47) and PFS2 (3.67 [CI95% 3.38 – 3.87] vs. 4.53 m [CI95% 3.08 – 5.35] p=0.4). There was no statistical difference in OS2 and PFS2 if everolimus was used after SU or PZ (p = 0.33 and p = 0.41, respectively) or if axitinib was used after SU or PZ (p = 0.73 and p = 0.72, respectively). Conclusions: We confirmed in real world practice, that SU and PZ have similar efficacy in the first-line setting for mRCC and do not affect outcomes with subsequent second-line treatment. [Table: see text]

Impact of first-line platinum therapy on survival in patients with platinum-refractory advanced transitional cell carcinoma of the urothelium (TCCU) treated with vinflunine.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15007-e15007
Author(s):  
Ronan Fougeray ◽  
Toni K. Choueiri ◽  
Francesc Pons ◽  
Fabio Augusto Barros Schutz ◽  
Yacine Salhi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Supportive Care ◽  
Best Supportive Care ◽  
Phase Iii ◽  
Second Line ◽  
First Line ◽  
Line Therapy ◽  
Line Setting

e15007 Background: Standard first-line therapy of advanced TCCU is based on cisplatin-based combinations. In patients deemed unfit to receive CISPLATIN, carboplatin-based or non-platinum combinations are considered. A phase III trial comparing vinflunine (VFL) and best supportive care (BSC) with BSC alone for second-line treatment of advanced TCCU patients demonstrated a survival advantage for VFL+BSC. We studied the impact of the first-line platinum therapy on overall survival in second line setting. Methods: Eligible 357 patients of the phase III study were split in the two following subsets: CISPLATIN (Patients with prior CISPLATIN administration) and NO CISPLATIN (patients without prior CISPLATIN administration). Survival was measured from the date of random assignment. Overall Survival (OS) was calculated using Kaplan-Meier method, with log-rank comparisons. Multivariate Analysis of OS was analyzed with the Cox proportional hazards model, including prognostic factors for second-line setting previously identified (Bellmunt, 2010). Updated survival data in 11/2008 cut-off date was used. Results: CISPLATIN group represented 70.3% (n=251) and NO CISPLATIN 29,7% (n= 106). CISPLATIN group had less Liver involvement (25% vs 43%, p=0.0007) and better WHO-PS (>1: 66% vs 76%; p=0.0478). OS was higher in CISPLATIN group for all eligible patients (HR: 0.77; CI 95% 0.61-0.97; p=0.0294), for VFL+BSC arm (HR: 0.78; CI 95% 0.59-1.02; p=0.0693) and for BSC arm (HR: 0.68; CI 95% 0.42-1.08; p=0.0978). Multivariate analysis including prognostic factors (liver involvement, hemoglobin, PS) and prior platinum administration, did not show effect of CDDP on OS. VFL reduced the risk of death by 24% in CDDP-group (HR: 0.76; CI 95% 0.58-0.99; p=0.043) and by 35% in NO CDDP –group (HR: 0.65; CI 95% 0.41-1.04; p=0.0724). Conclusions: Differences in prognostic factors between CISPLATIN and NO CISPLATIN groups may explain the differences in OS in patients who undergo 2nd line therapy. The choice of Cisplatin or no Cisplatin chemotherapy in the first line did not impact subsequent benefit of vinflunine over best supportive care.

Second-line chemotherapy (CT) with or without bevacizumab (BV) in metastatic colorectal cancer (mCRC) patients (pts) who progressed to a first-line treatment containing BV: Updated results of the phase III “BEBYP” trial by the Gruppo Oncologico Nord Ovest (GONO).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3615-3615 ◽  
Author(s):  
Gianluca Masi ◽  
Fotios Loupakis ◽  
Lisa Salvatore ◽  
Chiara Cremolini ◽  
Lorenzo Fornaro ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Phase Iii ◽  
Second Line ◽  
First Line ◽  
Free Survival ◽  
Phase Iii Study ◽  
Reported Data ◽  
To Receive ◽  
Clinical Trial Information

3615 Background: Retrospective data suggested that the continuation of BV with second-line CT beyond progression (PD) in pts who received BV in first-line can improve the outcome. Recently, results of the AIO/AMG ML18147 study demonstrated an improved overall survival (OS) by continuing BV beyond PD. Methods: This phase III study randomized pts with measurable mCRC treated in first-line with BV plus fluoropyrimidine, FOLFIRI, FOLFOX or FOLFOXIRI, to receive in second-line mFOLFOX6 or FOLFIRI (depending on first-line CT) with or without BV. The primary end-point was progression free survival (PFS).To detect a HR for PFS of 0.70 with an α and β error of 0.05 and 0.20 respectively, the study required 249 events. Assuming an accrual time of 24 months (mos) and a follow up of 12 mos we planned to randomize 262 pts. Results: Considering the results of the AIO/AMG ML18147 trial, the study accrual was stopped prematurely. A total of 185 pts were randomized and 184 pts were included in the ITT analysis (1 pt randomized in error). Pts characteristics were (arm A/arm B): number 92/92, gender M75%-F25%/M57%-F43%, median age 66 (38-75)/62 (38-75) years, PS=0 82%/82%, multiple site of disease 76%/77%. At a median follow up of 18 mos the study met its primary endpoint by improving PFS in the BV arm. We updated results and at a median follow up of 22 mos the improvement in PFS for the experimental arm was confirmed with a median PFS of 5.2 mos for arm A and 6.7 mos for arm B (HR=0.66; 95% CI 0.49–0.90; unstratified p=0.0072). Subgroup analyses showed a consistent benefit in all subgroups including gender (F: HR=0.63; M: HR=0.72) and first-line PFS (≤10 mos: HR=0.57; >10 mos: HR=0.71). Response rates (RECIST) were 18% and 21% (p=0.71). Toxicity profile was consistent with previously reported data. The OS data are still immature, with 56 events in arm A and 54 in arm B and the median OS is 16.0 mos and 16.5 mos respectively (HR=0.83; 95% CI 0.57-1.22; unstratified p=0.34). Conclusions: This study demonstrates an improvement in PFS by continuing BV in second-line in pts who had received CT+BV in first-line. Clinical trial information: NCT00720512.

RAISE: A randomized, double-blind, multicenter phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab (RAM) or placebo (PBO) in patients (pts) with metastatic colorectal carcinoma (CRC) progressive during or following first-line combination therapy with bevacizumab (bev), oxaliplatin (ox), and a fluoropyrimidine (fp).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 512-512 ◽  
Author(s):  
Josep Tabernero ◽  
Allen Lee Cohn ◽  
Radka Obermannova ◽  
Gyorgy Bodoky ◽  
Rocio Garcia-Carbonero ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Statistical Significance ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Double Blind ◽  
Ecog Ps

512 Background: Angiogenesis is an important therapeutic target in CRC; VEGF plays a key role in angiogenesis. RAM is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. The RAISE study evaluated the efficacy and safety of adding RAM to standard second-line treatment FOLFIRI. Methods: Eligible pts with mCRC who progressed on or after first-line combination therapy with bev, ox, and fp, had an ECOG PS of 0 or 1, and adequate organ function were randomized 1:1 (stratified by region, KRAS mutation status, and time to progressive disease [PD] after beginning first-line treatment) to receive RAM (8 mg/kg IV) plus FOLFIRI or PBO plus FOLFIRI every 2 weeks until PD, unacceptable toxicity, or death. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Planned sample size of 1,050 pts ensured 85% power to demonstrate statistical significance at an overall two-sided alpha of 0.05, assuming a hazard ratio (HR) of 0.8. Results: Between Dec 2010 and Aug 2013, 1,072 eligible pts were randomized (RAM 536; PBO 536). Baseline pt characteristics were similar between treatment arms. The OS HR was 0.84 (95% CI: 0.73, 0.98; log-rank p=0.0219). Median OS was 13.3months (m) for RAM vs 11.7m for PBO. The PFS HR was 0.79 (95% CI: 0.70, 0.90; log-rank p = 0.0005). Median PFS with RAM was 5.7m and 4.5m for PBO. ORR was 13.4% RAM; 12.5% PBO (p = 0.6336). Subgroup results were consistent with the OS and PFS results. Grade ≥3 adverse events (AEs) occurring in >5% of pts in RAM+FOLFIRI were: neutropenia (RAM 38.4% vs PBO 23.3% ), hypertension (11.2% vs 2.8%), diarrhea (10.8% vs 9.7%), and fatigue (11.5% vs 7.8%). Conclusions: RAISE met its primary end-point, demonstrating a statistically significant improvement in OS for RAM and FOLFIRI vs PBO and FOLFIRI in second-line mCRC pts. Benefits were similar across important clinical subgroups and no unexpected AEs were identified. Clinical trial information: NCT01183780.

A phase II study of trifluridine/tipiracil, irinotecan, and bevacizumab in pretreated metastatic colorectal cancer (TABAsCO).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS275-TPS275
Author(s):  
Medhavi Gupta ◽  
Christos Fountzilas ◽  
Namrata Vijayvergia ◽  
Kristopher Attwood ◽  
Howard S. Hochster ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Excision Repair ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Phase Iii ◽  
Second Line ◽  
First Line ◽  
Oncology Research

TPS275 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related death in US. The majority of US patients (pts) receive first-line therapy (Rx) with FOLFOX [Folinic acid (FA), 5-fluorouracil (5-FU) and oxaliplatin (Ox)] + a biologic, making FOLFIRI [FA+ 5-FU+ irinotecan (Iri)] + bevacizumab (Bev) a common second-line Rx. This regimen has a median progression-free survival (PFS) of approximately 6 months (mo) and overall survival (OS) of 12 mo. Further gains are desperately needed. Trifluridine/tipiracil (FTD/TPI) is an oral combination Rx of a thymidine-based nucleoside analogue, FTD, and a phosphorylase inhibitor, TPI. FTD/TPI has a distinct mechanism of action from 5-FU and in preclinical models can overcome 5-FU resistance via DNA incorporation, base excision repair pathway and glycosylation responses to DNA damage. Further, there is an additive effect in combination with Iri. FTD/TPI was FDA approved for use in refractory metastatic CRC (mCRC) based on phase III RECOURSE trial. Phase I data showed combination of FTD/TPI, Iri and Bev to be safe, and an efficacy signal was seen in dose-expansion cohort (NCT01916447). A 12.5% response rate, 83.4 % disease control rate and PFS of 7.9 mo was achieved. As this study largely assessed refractory pts, one might expect a greater efficacy in Iri naïve pts. To test this hypothesis, we are conducting a multi-center phase II study of FTD/TPI, Iri and Bev as second-line Rx in mCRC pts. Methods: Eligible pts have mCRC and received first-line Ox based Rx. Rx to be given in 28-day cycles: Iri (180 mg/m2) and Bev (5 mg/kg) on D1 & 15, and FTD/TPI (25 mg/m2) twice daily on D2-6 & 16-20. Response assessment via CT/MRI to be done q8 wks (RECIST 1.1). Rx to continue until disease progression or unacceptable toxicity. The primary objective is to estimate PFS. Secondary objectives include ORR, OS, and safety. Final analysis to be done either 12 mo after enrollment of the final pt or once all pts have progression, whichever occurs earlier. A total of 40 pts to be accrued, and enrollment to start in January 2020. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Taiho Oncology, Inc.

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