scholarly journals Late-line treatment in metastatic gastric cancer: today and tomorrow

2019 ◽  
Vol 11 ◽  
pp. 175883591986752 ◽  
Author(s):  
Elizabeth C. Smyth ◽  
Markus Moehler
Keyword(s):  
Gastric Cancer ◽  
Asian Population ◽  
Phase Iii ◽  
Response To Treatment ◽  
Evidence Based ◽  
Line Treatment ◽  
Second Line ◽  
Specific Patient ◽  
Line Therapy ◽  
Third Line

Survival for patients with unresectable advanced or recurrent gastric cancer (GC) remains poor and the historical lack of evidence-based therapeutic options after second-line therapy is reflected in current clinical guidelines for this condition. Despite uncertainty about optimal therapeutic strategies, further treatment is appropriate for some patients after failure of second line and may prolong survival. This approach has been reported in clinical trials and is becoming more common in real-world clinical settings. Several prognostic factors may increase the likelihood that a patient will be eligible for treatment in the third-line setting, including geographic location, status at diagnosis and response to treatment. There has been little progress over the last decade until the results from two large phase III randomized controlled trials completed in the last year: the ATTRACTION-2 trial with the programmed cell death-1 (PD-1) inhibitor, nivolumab, in an Asian population; and the TAGS trial with the oral chemotherapy trifluridine/tipiracil in a global population. Both ATTRACTION-2 and TAGS reported positive results in third-line treatment in advanced GC in specific patient groups. A further recently reported study, KEYNOTE-059, which was a single-arm phase II trial of the PD-1 inhibitor pembrolizumab in a mainly non-Asian population, has provided evidence supporting the use of this immunotherapy in patients with advanced GC. As further third-line options become available, more GC patients are expected to benefit from an individualized evidence-based approach to later-line therapy, with a common goal of extending survival and improving outcomes for their refractory disease.

scholarly journals HIV-1 Drug Resistance and Third-Line Therapy Outcomes in Patients Failing Second-Line Therapy in Zimbabwe

2018 ◽  
Vol 5 (2) ◽  
Author(s):  
Cleophas Chimbetete ◽  
David Katzenstein ◽  
Tinei Shamu ◽  
Adrian Spoerri ◽  
Janne Estill ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Line Treatment ◽  
Second Line ◽  
Resistance Mutations ◽  
Reverse Transcriptase Inhibitors ◽  
Cd4 Cell Count ◽  
Line Therapy ◽  
Third Line ◽  
Cd4 Cell ◽  
Third Line Treatment

Abstract Objectives To analyze the patterns and risk factors of HIV drug resistance mutations among patients failing second-line treatment and to describe early treatment responses to recommended third-line antiretroviral therapy (ART) in a national referral HIV clinic in Zimbabwe. Methods Patients on boosted protease inhibitor (PI) regimens for more than 6 months with treatment failure confirmed by 2 viral load (VL) tests >1000 copies/mL were genotyped, and susceptibility to available antiretroviral drugs was estimated by the Stanford HIVdb program. Risk factors for major PI resistance were assessed by logistic regression. Third-line treatment was provided as Darunavir/r, Raltegravir, or Dolutegravir and Zidovudine, Abacavir Lamivudine, or Tenofovir. Results Genotypes were performed on 86 patients who had good adherence to treatment. The median duration of first- and second-line ART was 3.8 years (interquartile range [IQR], 2.3–5.1) and 2.6 years (IQR, 1.6–4.9), respectively. The median HIV viral load and CD4 cell count were 65 210 copies/mL (IQR, 8728–208 920 copies/mL) and 201 cells/mm3 (IQR, 49–333 cells/mm3). Major PI resistance-associated mutations (RAMs) were demonstrated in 44 (51%) non-nucleoside reverse transcriptase inhibitor RAMs in 72 patients (83%) and nucleoside reverse transcriptase inhibitors RAMs in 62 patients (72%). PI resistance was associated with age >24 years (P = .003) and CD4 cell count <200 cells/mm3 (P = .007). In multivariable analysis, only age >24 years was significantly associated (adjusted odds ratio, 4.75; 95% confidence interval, 1.69–13.38; P = .003) with major PI mutations. Third-line DRV/r- and InSTI-based therapy achieved virologic suppression in 29/36 patients (81%) after 6 months. Conclusions The prevelance of PI mutations was high. Adolescents and young adults had a lower risk of acquiring major PI resistance mutations, possibly due to poor adherence to ART. Third-line treatment with a regimen of Darunavir/r, Raltegravir/Dolutegravir, and optimized nucleoside reverse transcriptase inhibitors was effective.

A randomized, open-label, phase III study of lapatinib in combination with weekly paclitaxel versus weekly paclitaxel alone in the second-line treatment of HER2 amplified advanced gastric cancer (AGC) in Asian population: Tytan study.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 11-11 ◽  
Author(s):  
Yung-Jue Bang
Keyword(s):  
Randomized Study ◽  
Asian Population ◽  
Phase Iii ◽  
Weekly Paclitaxel ◽  
Line Treatment ◽  
Second Line ◽  
Her2 Positive ◽  
Open Label ◽  
Significant Prolongation ◽  
The Difference

11 Background: The use of trastuzumab has been established as the standard first-line treatment of HER2 positive (+) AGC. However, the role of anti-HER2 agents in the second-line treatment of HER2+ AGC has not been clearly established yet. TyTAN is the first randomized study to compare the efficacy and safety of adding lapatinib (L) to paclitaxel (P) vs P alone in the second-line treatment of HER2+ AGC. Methods: Eligibility required patients (pts) with AGC, amplification of HER2 by fluorescence in situ hybridization (FISH), and one prior regimen containing fluoropyrimidines and/or cisplatin. Pts were randomized 1:1 to L (1500mg QD) and P (80mg/m2, Day 1, 8, 15 q4w) or P alone. The treatments were given until disease progression or unacceptable toxicity. Stratification variables were prior trastuzumab treatment and gastrectomy status. Primary endpoint was overall survival (OS). Results: From March 2008 to June 2011, 1923 pts were screened and 430 pts were HER2+ AGC. 261 out of 430 pts were enrolled. All pts were from Asian countries: Japan (100), China (95), Korea (46), and Taiwan (20). Median OS was 11.0 months for L+P and 8.9 months for P alone in the intent-to-treat (ITT) population (HR 0.84; p=0.2088). In a pre-planned subgroup analysis, median OS in HER2 immunohistochemistry (IHC) 3+ subgroup was 14.0 months for L+P and 7.6 months for P alone (HR 0.59; p=0.0176). The endpoints in efficacy and AEs of special interest for L+P are summarized below (Table). Conclusions: Although OS was prolonged in L+P arm by 2 months, the difference was not statistically significant. HER2 IHC 3+ subgroup demonstrated statistically significant prolongation of OS by adding L. Clinical trial information: NCT00486954. [Table: see text]

Association of UGT1A1 gene polymorphism with the safety and efficacy of irinotecan monotherapy for advanced gastric cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 16-16 ◽  
Author(s):  
Toshifumi Yamaguchi ◽  
Satoru Iwasa ◽  
Hirokazu Shoji ◽  
Yoshitaka Honma ◽  
Atsuo Takashima ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Initial Dose ◽  
Uridine Diphosphate ◽  
Second Line ◽  
Safety And Efficacy ◽  
Line Therapy ◽  
Third Line ◽  
Grade 3 ◽  
Ugt1a1 Genotype

16 Background: The uridine diphosphate glucuronosyltransferase (UGT) 1A1, which transforms SN-38 into SN-38 glucuronide, is a key enzyme involved in the metabolism of irinotecan. Previous studies showed that UGT1A1 genotype is related to the toxicity of irinotecan-based chemotherapy in metastatic colorectal cancer. The purpose of this study was to investigate the relationship between UGT1A1genotype and safety and efficacy of irinotecan monotherapy in patients with advanced gastric cancer. Methods: We reviewed the data of 208 patients who were tested for UGT1A1 genotype and treated with irinotecan-based chemotherapy for advanced gastric cancer from 2009 to 2014. We evaluated the efficacy and safety of irinotecan monotherapy in the three groups with wild-type (WT), single heterozygosity (SH), and homozygosity/double heterozygosity (Homo-DH) classified by the genotypes for UGT1A1*28 or UGT1A1*6. Results: A total of 117 patients received irinotecan monotherapy: 40 patients in second-line, 74 in third-line, and 3 in forth-line therapy. The UGT1A1genotype was WT in 62 patients (53.0%), SH in 41 (35.0%), and Homo-DH in 14 (12.0%). Patients’ characteristics were similar among the three groups. The initial dose of irinotecan was reduced in 10 patients (16%) with the WT genotype, in 11 (27%) with SH, and in 10 (71%) with Homo-DH. Grade 3-4 neutropenia, diarrhea, and febrile neutropenia occurred in 13/22/64%, 6/5/21%, and 2/7/50% of WT/SH/Homo-DH patients. Median time to treatment failure of second-line and third-line therapies were 2.4/2.8/3.3 months and 2.4/2.3/1.3 months in WT/SH/Homo-DH patients. Median overall survival of second-line and third-line therapy were 7.9/9.9/4.6 months and 6.9/6.3/2.8 months in WT/SH/Homo-DH patients. Conclusions: Patients with UGT1A1 Homo-DH displayed high frequency of grade 3-4 toxicities, although the initial dose of irinotecan was reduced in some patients. UGT1A1 polymorphism may be related to the efficacy of irinotecan monotherapy in second- and third-line treatments for advanced gastric cancer.

Efficacy and safety of paclitaxel/ramucirumab as the second-line chemotherapy in Japanese patients with advanced gastric cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15540-e15540
Author(s):  
Tetsuya Kusumoto ◽  
Akinori Egashira ◽  
Hideto Sonoda ◽  
Kenkichi Hashimoto ◽  
Hideo Uehara ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Japanese Patients ◽  
Phase Iii ◽  
Weekly Dose ◽  
Line Treatment ◽  
Second Line ◽  
Efficacy And Safety ◽  
Second Line Chemotherapy ◽  
Line Chemotherapy

e15540 Background: Second-line chemotherapy can now be considered as a proven treatment option for metastatic or locally advanced gastric cancer (AGC). Two global randomized phase III trials (REGARD and RAINBOW) showed that survival benefit was significantly observed in patients treated with ramucirumab (RAM) alone and in combination with weekly doses of PTX, compared with placebo, respectively. The purpose of the study is to evaluate the efficacy and safety of weekly dose of PTX combined with RAM practically as the second-line treatment in Japanese patients with AGC refractory to an S-1-containing chemotherapy regimen. Methods: We conducted a retrospective review of the data of 18 patients with AGC who received more than 2 cycles of PTX/RAM combined chemotherapy as the second-line regimen following S-1-based treatment. The objective response rate (ORR), adverse events, progression-free survival (PFS) and overall survival (OS) were analyzed and compared with PTX monotherapy group. Results: Median number of courses were 5 for the PTX/RAM group and the discontinuation of treatment except for disease progression was found in 2 cases (33.3%). The rates of hematological toxicities of higher than grade 3 were 33.3% in the PTX/RAM group, which were higher than those found in the PTX groups. The tumor responses of the PTX/RAM group were 22% for the ORR and 78% for the DCR, compared with 21% and 48% in the PTX group, respectively. The dose intensities of PTX were 72.4% in the former group. The survival data showed that the MST after second-line exposure was 290 days and the median PFS was 131 days in the PTX/RAM group, compared with 159 days and 90 days in the PTX group, which were not significantly different. Conclusions: PTX/RAM might be one of the best regimens for Japanese patients with AGC as the second-line treatment following S-1-containing chemotherapy.

scholarly journals Phase III Noninferiority Trial Comparing Irinotecan With Oxaliplatin, Fluorouracil, and Leucovorin in Patients With Advanced Colorectal Carcinoma Previously Treated With Fluorouracil: N9841

2009 ◽  
Vol 27 (17) ◽  
pp. 2848-2854 ◽  
Author(s):  
George P. Kim ◽  
Daniel J. Sargent ◽  
Michelle R. Mahoney ◽  
Kendrith M. Rowland ◽  
Philip A. Philip ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Phase Iii ◽  
Second Line ◽  
Line Therapy ◽  
Third Line Therapy ◽  
Advanced Colorectal Carcinoma ◽  
Previously Treated ◽  
Third Line ◽  
Grade 3 ◽  
Experienced Treatment

Purpose The primary goal of this multicenter phase III trial was to determine whether overall survival (OS) of fluorouracil (FU) -refractory patients was noninferior when treated with second-line infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4; arm B) versus irinotecan (arm A). Cross-over to the other treatment on disease progression was mandated. Patients and Methods Patients who experienced treatment failure with one prior FU-based therapy and had not received prior irinotecan or oxaliplatin, either for metastatic disease or within 6 months of adjuvant FU therapy, were randomly assigned to arm A (irinotecan 350 or 300 mg/m2 every 3 weeks) or arm B (FOLFOX4). Results A total of 491 patients were randomly assigned (arm A, n = 245; arm B, n = 246); 288 (59%) had experienced treatment failure with FU for metastatic colorectal cancer. Two hundred twenty-seven patients (46%) received protocol-mandated third-line therapy (arm A, 43%; arm B, 57%). Median survival was 13.8 months (95% CI, 12.2 to 15.0 months) for initial treatment with FOLFOX4 and 14.3 months (95% CI, 12.0 to 15.9 months) for irinotecan (P = .38; hazard ratio = 0.92; 95% CI, 0.8 to 1.1). Response rates (RR; 28% v 15.5%; P = .0009) and time to progression (TTP; 6.2 v 4.4 months; P = .0009) were significantly superior with FOLFOX4. In the nonrandom subset of patients who crossed over, RR and TTP improvements with FOLFOX4 continued into third-line treatment. Irinotecan therapy was associated with more grade 3 nausea, vomiting, diarrhea, and febrile neutropenia; FOLFOX4 was associated with more neutropenia and paresthesias. Conclusion In patients who experienced treatment failure with front-line FU therapy, OS does not significantly differ whether second-line therapy begins with irinotecan or FOLFOX4. FOLFOX4 produces higher RR and longer TTP. Both arms had notable OS in patients who experienced treatment failure with first-line FU therapy.

scholarly journals Effects of removing reimbursement restrictions on targeted therapy accessibility for non-small cell lung cancer treatment in Taiwan: an interrupted time series study

BMJ Open ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. e022293 ◽  
Author(s):  
Jason C Hsu ◽  
Chen-Fang Wei ◽  
Szu-Chun Yang
Keyword(s):  
Lung Cancer ◽  
Targeted Therapies ◽  
Interrupted Time Series ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Third Line Therapy ◽  
Third Line

InterventionsTargeted therapies have been proven to provide clinical benefits to patients with metastatic non-small cell lung cancer (NSCLC). Gefitinib was initially approved and reimbursed as a third-line therapy for patients with advanced NSCLC by the Taiwan National Health Insurance (NHI) in 2004; subsequently it became a second-line therapy (in 2007) and further a first-line therapy (in 2011) for patients with epidermal growth factor receptor mutation-positive advanced NSCLC. Another targeted therapy, erlotinib, was initially approved as a third-line therapy in 2007, and it became a second-line therapy in 2008.ObjectivesThis study is aimed towards an exploration of the impacts of the Taiwan NHI reimbursement policies (removing reimbursement restrictions) related to accessibility of targeted therapies.SettingWe retrieved 2004–2013 claims data for all patients with lung cancer diagnoses from the NHI Research Database.Design and outcome measuresUsing an interrupted time series design and segmented regression, we estimated changes in the monthly prescribing rate by patient number and market shares by cost following each modification of the reimbursement policy for gefitinib and erlotinib for NSCLC treatment.ResultsTotally 92 220 patients with NSCLC were identified. The prescribing rate of the targeted therapies increased by 15.58%, decreased by 10.98% and increased by 6.31% following the introduction of gefitinib as a second-line treatment in 2007, erlotinib as a second-line treatment in 2008 and gefitinib as as first line treatment in 2011, respectively. The average time to prescription reduced by 65.84% and 41.59% following coverage of erlotinib by insurance and gefitinib/erlotinib as second-line treatments in 2007–2008 and following gefitinib as the first-line treatment in 2011.ConclusionsThe changes in reimbursement policies had a significant impact on the accessibility of targeted therapies for NSCLC treatment. Removing reimbursement restrictions can significantly increase the level and the speed of drug accessibility.

A phase Ib study of anlotinib plus TQB2450 as second-line therapy for advanced biliary tract adenocarcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4075-4075
Author(s):  
Yongkun Sun ◽  
Aiping Zhou ◽  
Wen Zhang ◽  
Zhichao Jiang ◽  
Wang Qu
Keyword(s):  
Biliary Tract ◽  
Dose Group ◽  
Checkpoint Inhibitors ◽  
Response To Treatment ◽  
10Mg Dose ◽  
Line Treatment ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy ◽  
10Mg Group

4075 Background: Although with modest efficacy, mFOLFOX is recommended as standard second-line chemotherapy for advanced biliary tract adenocarcinoma. Several clinical trials are exploring the combination treatment of anti-angiogenic drugs and immune checkpoint inhibitors. Anlotinib is an oral small molecule inhibitor of receptor tyrosine kinases, with inhibitory effects on tumor angiogenesis and growth. Anlotinib plus TQB2450,an anti-PD-L1 mAb, have shown anti-tumor activity in preclinical study and here we investigate the efficacy and safety of different dosage of this regimen as second-line treatment for advanced biliary tract adenocarcinoma. Methods: Patients with advanced biliary tract adenocarcinoma who had progressed after first-line treatment received anlotinib (once daily for 2 weeks on/1 week off) plus TQB2450 (1200mg once) every three weeks. The planned anlotinib dose levels to be explored were 10mg (starting) and 12mg daily. Dose expansion was performed after the determination of the maximum tolerable dose. Response to treatment was evaluated using the RECIST 1.1 criteria, supplemented by iRECIST. The primary endpoints were MTD, ORR, and the secondary endpoints were PFS, OS and safety. Results: Both 10mg and 12mg of anlotinib were tolerable after the initial safety observation of different doses from May 2019 to April 2020. 34 patients (8 cases of gallbladder cancer [GBC], 22 of intrahepatic cholangiocarcinoma [ICC] and 4 of extrahepatic cholangiocarcinoma [ECC]) were enrolled, 22 patients in the 10mg dose group and 12 in the 12mg dose group. The median age was 57 (37-72) years and 55.9% (19) of the patients were female. At the analysis cut-off date of 31 December 2020, the median follow-up duration was 14.9 months. Of the 34 patients, 4 patients had partial response (PR, 2 cases in the 10mg group and 2 in the 12mg group), including 2 cases with GBC and 2 with ICC, 17 had stable disease (SD, shrinkage, 12 in the 10mg group and 5 in the 12mg group) and 5 SD (enlargement, 4 in the 10mg group and 1 in the 12mg group), 7 had progression disease (PD, 5 in the 10mg group and 2 in the 12mg group) and 1 patient of ECC could not be evaluated. In the overall population, the median PFS (mPFS) was 5.95 (95%CI: 3.78-11.50) months. The mPFS was 5.29 (95%CI: 3.45-10.32) months in 10mg group and 12.98 (95%CI: 1.38-NR) in 12mg group. The median OS was not reached and the 12-month OS rate was 64.71% (60.87% in the 10mg group and 72.73% in the 12mg group). Grade 3 or higher toxicities were observed in 8 patients, with elevated transaminase (n = 4, 11.8%), elevated bilirubin (n = 3, 8.8%), fatigue (n = 1, 2.9%), hypertension (n = 1, 2.9%) and prolonged QTc (n = 1, 2.9%). Conclusions: Anlotinib plus TQB2450 as second-line therapy for advanced biliary tract adenocarcinoma was well tolerated and showed promising efficacy. No unexpected adverse events were observed in both drugs. This regimen is worthy of further exploration. Clinical trial information: NCT03825705.

Sign in / Sign up

Export Citation Format

Share Document