Relation of overall survival, progression free survival, post progression survival and response rate in four randomized Japanese phase III trials comparing various combinations of S-1 therapy for first-line treatment of advanced gastric cancer

588 Background: Bevacizumab (BV) is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor. Used in combination with chemotherapy, BV has been shown to improve survival in both first- and second-line treatment for metastatic colorectal cancer (mCRC). However, it was reported that addition of BV to FOLFOX conferred only little survival benefit (Saltz et al. JCO2008). The aim of this study was to assess the efficacy of addition of BV to FOLFOX in first-line treatment for patients with mCRC. Methods: Bevacizumab was approved for mCRC in July 2007 in Japan. This study was conducted at a single institution and comprised 217 consecutive patients receiving first-line treatment for mCRC between 2005 and 2009. The primary objective was to compare survival benefit in patients treated with FOLFOX4 (FF) between 2005 and 2007 with that in patients receiving FOLFOX4+BV 5 mg/kg (FF+BV) between 2007 and 2009. Results: Total number of patients in the FF and FF+BV groups was 132 and 85, respectively. Characteristics of patients were as follows (FF vs. FF+B): median age, 62 yrs (range 28-76 yrs) vs. 60 yrs (range16-74 yrs); ECOG PS0, 98.8% vs. 81.8%; and median follow-up time, 20.8 months vs. 24.4 months. Median progression-free survival (PFS) in the FF and FF+BV groups was 10 months (95% CI, 8.7-11.3) and 17 months (95% CI, 10.2-14.1), while median overall survival (OS) was 21 months (95% CI, 17.9-24.1) and not reached, respectively. Response rate was 46% (95% CI, 37- 54) in FF, and 62% (95% CI, 51-73) in FF+BV. Addition of BV to FOLFOX4 significantly improved PFS (p=0.002) and OS (p<0.001). Conclusions: The additive effect of BV for first-line FOLFOX was reconfirmed. These data indicate potential survival benefits from the addition of BV to FOLFOX in first-line treatment of mCRC. In addition, PFS may be a sensitive indicator of outcome prior to post-treatment. No significant financial relationships to disclose.

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Combined analysis of three randomized phase III trials comparing S-1 monotherapy and S-1 combination therapy for first-line treatment of advanced gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.49 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 49-49

Author(s):

Madoka Takeuchi ◽

Wataru Ichikawa ◽

Kohei Shitara ◽

Yu Sunakawa ◽

Koji Oba ◽

...

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

Combination Therapy ◽

Advanced Gastric Cancer ◽

Progression Free Survival ◽

Phase Iii ◽

First Line ◽

Free Survival ◽

First Line Therapy ◽

Phase Iii Trials

49 Background: S-1 is the gold standard for first line therapy of advanced gastric cancer in Asia. There have been multiple meta-analyses published researching and comparing the efficacy and safety of S-1 monotherapy versus combination1,2. However there has been no analysis using actual trial data. Methods: Actual data from three randomized Phase III trials were combined to compare the efficacy of S-1 Monotherapy and S-1 combination therapy. The START trial, comparing S-1 and combination S-1 with docetaxel, SPIRITS, comparing S-1 and combination S-1 with cisplatin and TOP-002, comparing S-1 and S-1 combination with irinotecan, were merged and combined. For this analysis, the three S-1 arms were combined (n = 642) and the different S-1 combination therapy were combined (n = 617) creating two new treatment arms. The primary efficacy outcome of overall survival, progression free survival and subset analysis of overall survival stratified by baseline characteristics were performed. Results: A total of 1248 patients, including 210 Korean patients from the START were used in the analysis. The median overall survival days for S-1 combination and monotherapy was 382 [209, 648] and 321 [177, 597] and median progression free survival days for S-1 combination and monotherapy was 153 [81, 267] and 122 [61, 204]. Both overall survival (p = 0.0088 HR = 0.85 (0.76,0.96)) and progression free survival ( p = < 0.001 HR = 0.75 (0.67,0.85)) was significantly longer in the combination therapy arm compared to the monotherapy arm. Conclusions:Although there are limitations, the analysis re-confirms that S-1 combination therapy shows to be more efficacious compared to S-1 monotherapy for advanced gastric cancer patients. It must be noted that heterogeneity of the S-1 arm was not carefully considered when combining the S-1 data for the trials. In addition, the results are limited to the Asian (Japanese and Korean) population.

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A phase I dose escalation study of eryaspase in combination with modified FOLFIRINOX in locally advanced and metastatic pancreatic ductal adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.tps453 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. TPS453-TPS453

Author(s):

Marcus Smith Noel ◽

Philip Agop Philip ◽

Mohamedtaki Abdulaziz Tejani ◽

John Marshall ◽

Aiwu Ruth He ◽

...

Keyword(s):

Overall Survival ◽

Phase I ◽

Pancreatic Adenocarcinoma ◽

Locally Advanced ◽

Progression Free Survival ◽

Phase Iii ◽

Line Treatment ◽

First Line ◽

Free Survival ◽

First Line Treatment

TPS453 Background: FOLFIRINOX remains the standard of care for the first line treatment of patients with locally advanced and metastatic pancreatic adenocarcinoma, however the prognosis remains poor, thus novel treatment options are indicated. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. A randomized phase IIb study in patients with advanced pancreatic cancer whose disease progressed following first-line treatment (NCT02195180) was previously conducted. Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression free survival (PFS). The safety profile of eryaspase was acceptable. A second line pivotal randomized phase III trial (Trybeca-1) is currently enrolling (NCT03665441). We design this phase I study to determine the safety of mFOLFIRINOX combined with Eryaspase in the first line of treatment. Methods: Patients with locally or metastatic biopsy proven pancreatic adenocarcinoma will be treated with the combination of mFOLFIRINOX plus Eryaspase. This will be a standard 3+3 design with 4 possible doing levels. mFOLFIRINOX dosing will include 5-Fluorouracil 2400 mg/m2 over 46 hours, Oxaliplatin 85 mg/m2, Irinotecan 150 mg/m2 plus Eryaspase 75 Units/kg at dose level 0. Eryaspase will be dose escalated up to 100 Units/kg. The study will enroll at three academic centers. Key eligibility criteria include performance status 0 or 1; locally advanced or metastatic tumor disease; adequate organ function. The primary objective is to determine the maximum tolerated dose and safety of this novel combination. Key secondary objectives include objective response rate, progression-free survival, overall survival, pharmacokinetics, pharmacodynamics, and biomarker research. A data safety monitoring committee will review data every 3 months. Clinical trial information: 04292743.

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Erlotinib and bevacizumab versus cisplatin, gemcitabine and bevacizumab in unselected nonsquamous nonsmall cell lung cancer

European Respiratory Journal ◽

10.1183/09031936.00229014 ◽

2015 ◽

Vol 46 (1) ◽

pp. 219-229 ◽

Cited By ~ 11

Author(s):

Michael Thomas ◽

Jürgen Fischer ◽

Stefan Andreas ◽

Cornelius Kortsik ◽

Christian Grah ◽

...

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Cell Lung Cancer ◽

Response Rate ◽

Progression Free Survival ◽

Nonsmall Cell Lung Cancer ◽

Line Treatment ◽

First Line ◽

Free Survival ◽

First Line Treatment

Erlotinib with bevacizumab showed promising activity in recurrent nonsquamous (NS) nonsmall cell lung cancer (NSCLC). The INNOVATIONS study was designed to assess in first-line treatment of unselected cisplatin-eligible patients this combination compared to cisplatin, gemcitabine and bevacizumab.Stage IIIB/IV patients with NS-NSCLC were randomised on erlotinib (150 mg daily) and bevacizumab (15 mg·kg−1 on day 1, every 3 weeks) (EB) until progression, or cisplatin (80 mg·m−2 on day 1, every 3 weeks) and gemcitabine (1250 mg·m−2 on days 1 and 8, every 3 weeks) up to six cycles and bevacizumab (15 mg·kg−1 on day 1, every 3 weeks) (PGB) until progression.224 patients were randomised (EB n=111, PGB n=113). The response rate (12% versus 36%; p<0.0001), progression-free survival (median 3.5 versus 6.9 months; hazard ratio (HR) 1.85, 95% CI 1.39–2.45; p<0.0001) and overall survival (median 12.6 versus 17.8 months; HR 1.41, 95% CI 1.01–1.97; p=0.04) clearly favoured PGB. In patients with epidermal growth factor receptor mutations (n=32), response rate, progression-free survival and overall survival were not superior with EB.Platinum-based combination chemotherapy remains the standard of care in first-line treatment of unselected NS-NSCLC. Molecular targeted approaches strongly mandate appropriate testing and patient selection.

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Bevacizumab in Combination With Chemotherapy As First-Line Therapy in Advanced Gastric Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase III Study

Journal of Clinical Oncology ◽

10.1200/jco.2011.36.2236 ◽

2011 ◽

Vol 29 (30) ◽

pp. 3968-3976 ◽

Cited By ~ 711

Author(s):

Atsushi Ohtsu ◽

Manish A. Shah ◽

Eric Van Cutsem ◽

Sun Young Rha ◽

Akira Sawaki ◽

...

Keyword(s):

Gastric Cancer ◽

Advanced Gastric Cancer ◽

Overall Response Rate ◽

Response Rate ◽

Progression Free Survival ◽

Line Treatment ◽

First Line ◽

Free Survival ◽

Overall Response ◽

First Line Treatment

Purpose The Avastin in Gastric Cancer (AVAGAST) trial was a multinational, randomized, placebo-controlled trial designed to evaluate the efficacy of adding bevacizumab to capecitabine-cisplatin in the first-line treatment of advanced gastric cancer. Patients and Methods Patients received bevacizumab 7.5 mg/kg or placebo followed by cisplatin 80 mg/m2 on day 1 plus capecitabine 1,000 mg/m2 twice daily for 14 days every 3 weeks. Fluorouracil was permitted in patients unable to take oral medications. Cisplatin was given for six cycles; capecitabine and bevacizumab were administered until disease progression or unacceptable toxicity. The primary end point was overall survival (OS). Log-rank test was used to test the OS difference. Results In all, 774 patients were enrolled; 387 were assigned to each treatment group (intention-to-treat population), and 517 deaths were observed. Median OS was 12.1 months with bevacizumab plus fluoropyrimidine-cisplatin and 10.1 months with placebo plus fluoropyrimidine-cisplatin (hazard ratio 0.87; 95% CI, 0.73 to 1.03; P = .1002). Both median progression-free survival (6.7 v 5.3 months; hazard ratio, 0.80; 95% CI, 0.68 to 0.93; P = .0037) and overall response rate (46.0% v 37.4%; P = .0315) were significantly improved with bevacizumab versus placebo. Preplanned subgroup analyses revealed regional differences in efficacy outcomes. The most common grade 3 to 5 adverse events were neutropenia (35%, bevacizumab plus fluoropyrimidine-cisplatin; 37%, placebo plus fluoropyrimidine-cisplatin), anemia (10% v 14%), and decreased appetite (8% v 11%). No new bevacizumab-related safety signals were identified. Conclusion Although AVAGAST did not reach its primary objective, adding bevacizumab to chemotherapy was associated with significant increases in progression-free survival and overall response rate in the first-line treatment of advanced gastric cancer.

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Phase II study of S-1 plus docetaxel as first-line treatment for elderly patients with advanced gastric cancer (OGSG0902).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.129 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 129-129

Author(s):

Jin Matsuyama ◽

Hiroshi Imamura ◽

Ryohei Kawabata ◽

Tomono Kawase ◽

Kazuyuki Okada ◽

...

Keyword(s):

Gastric Cancer ◽

Elderly Patients ◽

Survival Time ◽

Advanced Gastric Cancer ◽

Response Rate ◽

Progression Free Survival ◽

Line Treatment ◽

First Line ◽

Free Survival ◽

First Line Treatment

129 Background: There is not enough evidence for the treatment of elderly patients with advanced gastric cancer. S-1 plus CDDP is one of the standard treatment for advanced gastric cancer in japan, but the efficacy remains insufficient due to the drug toxicity such as renal function disorders. The efficacy and safety of S-1 plus docetaxel as first-line treatment for elderly patients with unresectable advanced or recurrent gastric cancer were investigated. Methods: 75 years or older patients with unresectable advanced or recurrent gastric cancer were enrolled. Docetaxel was administered i.v. (40mg/m2) on day 1, while S-1 was administered orally (80mg/m2/day, b.i.d.) for 14 days followed by a 7-day rest. This schedule was repeated every 3 weeks. The primary endpoint was response rate (RR) of S-1 plus docetaxel; secondary endpoints were safety, progression free survival (PFS), time to treatment failure (TTF) and overall survival (OS). Sample size was set to be 30, which was determined to reject the response rate of 20% under the expectation of 40% with the power of 90% and two-sided alpha of 5%. Results: 31 patients were enrolled and assessable for efficacy. The response rate was 45.2% (95%CI 27.3-64.0, p = 0.001), and disease control rate was 77.4%. The median progression-free survival time was 5.8 months, the 1-year survival rate was 58.1%, and the median survival time was 16.1months. In 31 patients assessed for safety, the major grade 3/4 toxic effects were neutropenia (58%), febrile neutropenia (13%), anemia (10%), anorexia (10%), and fatigue (6%). Conclusions: These findings indicate that S-1 plus docetaxel as first-line treatment for elderly patients is feasible and shows promising efficacy against advanced gastric cancer. Clinical trial information: UMIN000002785.

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Optimal duration of therapy in the first line treatment of metastatic colorectal cancer: single center experience

Vojnosanitetski pregled ◽

10.2298/vsp200924053j ◽

2021 ◽

pp. 53-53

Author(s):

Sasa Jungic ◽

Biljana Tubic ◽

Jelena Berendika ◽

Zdenka Gojkovic ◽

Ivanka Rakita ◽

...

Keyword(s):

Overall Survival ◽

Overall Response Rate ◽

Response Rate ◽

Progression Free Survival ◽

Line Treatment ◽

Drug Reactions ◽

First Line ◽

Free Survival ◽

Patient Groups ◽

First Line Treatment

Background / Aim. FOLFOX (5fluorouracil, folinic acid, oxaliplatin)/CapOx (capecitabine, oxaliplatin) plus bevacizumab and FOLFIRI (5 fluorouracil, folinic acid, irinotecan) plus bevacizumab are a standard treatment options for a first line treatment of metastatic colorectal carcinoma (mCRC). The aim of this study was to compare overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) in the groups of patients with mCRC who were treated in the first line with FOLFIRI/bev versus FOLFOX/bev. At the same time, it was compared the safety profile in observed groups of patients and investigated optimal treatment duration and characteristics of patients who had the best treatment outcomes. Methods. In a retrospective-prospective study, patients with mCRC were treated with a chemotherapy protocols for the first line in combination with bevacizumab (FOLFOX/bev, respectively, FOLFIRI/bev). Treatment efficacy was evaluated on the basis of overall response rate (ORR), progression-free survival (PFS) and overall survival (OS), and the safety of treatment was evaluated by monitoring adverse drug reactions. Results. ORR was 70% in the FOLFIRI/bev group and 50% in the FOLFOX/bev group. Median PFS for FOLFIRI/bev (n = 30) and for FOLFOX/bev (n = 30) was 15.6 months and 12.1 months respectively (HR, 0.85; 95% confidence interval (CI) 0.47-1.53; P = 0.5591). Median OS for FOLFIRI/bev and for FOLFOX/bev was 24.7 months and 19.9 months respectively (HR, 0.67; 95% confidence interval (CI) 0.37-1.23; P = 0.1552). In both patient groups, the patients who received more than 9 cycles of induction therapy had better treatment response in comparison with patients who received less than 9 cycles of therapy. In FOLFOX/bev group PFS was 16.9 versus 9.7 months and OS was 22.1 versus 17.6 months respectively. In FOLFIRI/bev group PFS was 9 months for patients who received less than 9 cycles of therapy versus 18.8 months for patients who received more than 9 cycles, OS was 18.0 versus 27.7 respectively. The adverse drug reactions grade 3 and 4 were 7% in the FOLFIRI/bev group versus 27% in the FOLFOX/bev group. Conclusion. Patients who received FOLFIRI/bev had better ORR (70 % versus 50 %), PFS (15.6 versus 12.1 months) and OS (24.7 versus 19.9 months). In both patient groups, better treatment response had the patients who received induction therapy for 4-6 months (more than 9 cycles of therapy).

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