Second-line and third-line therapy for autoimmune hepatitis: A position statement from the European Reference Network on Hepatological Diseases and the International Autoimmune Hepatitis Group

PURPOSE: A large, randomized study comparing the efficacy and safety of topotecan versus paclitaxel in patients with relapsed epithelial ovarian cancer showed that these two compounds have similar activity. In this study, a number of patients crossed over to the alternative drug as third-line therapy, ie, from paclitaxel to topotecan and vice versa. We therefore were able to assess the degree of non–cross-resistance between these two compounds. PATIENTS AND METHODS: Patients who had progressed after one platinum-based regimen were randomized to either topotecan (1.5 mg/m2/d) × 5 every 21 days (n = 112) or paclitaxel (175 mg/m2 over 3 hours) every 21 days (n = 114). A total of 110 patients received cross-over therapy with the alternative drug (61 topotecan, 49 paclitaxel) as third-line therapy. RESULTS: Response rates to third-line cross-over therapy were 13.1% (8 of 61 topotecan) and 10.2% (5 of 49 paclitaxel; P = .638). Seven patients who responded to third-line topotecan and four patients who responded to paclitaxel had failed to respond to their second-line treatment. Median time to progression (from the start of third-line therapy) was 9 weeks in both groups, and median survival was 40 and 48 weeks for patients who were receiving topotecan or paclitaxel, respectively. The principal toxicity was myelosuppression; grade 4 neutropenia was more frequent with topotecan (81.4% of patients) than with paclitaxel (22.9% of patients). CONCLUSION: Topotecan and paclitaxel have similar activity as second-line therapies with regard to response rates and progression-free and overall survival. We demonstrated that the two drugs have a degree of non–cross-resistance. Thus, there is a good rationale for incorporating these drugs into future first-line regimens.

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Efficacy and safety of regorafenib as beyond second-line therapy in patients with metastatic colorectal cancer: an adjusted indirect meta-analysis and systematic review

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920940932 ◽

2020 ◽

Vol 12 ◽

pp. 175883592094093

Author(s):

Yinying Wu ◽

Yangwei Fan ◽

Danfeng Dong ◽

Xuyuan Dong ◽

Yuan Hu ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Meta Analysis ◽

Objective Response ◽

Cochrane Library ◽

Second Line ◽

Efficacy And Safety ◽

Line Therapy ◽

Third Line Therapy ◽

Third Line

Background: The evidence base for optimum third-line therapy for metastatic colorectal cancer (mCRC) is not conclusive. Recent studies have demonstrated the efficacy of regorafenib as third-line therapy in mCRC. This indirect meta-analysis compared the efficacy and safety of regorafenib with other available third-line therapies for mCRC. Methods: A literature search for randomized controlled trials (RCTs) was conducted in PubMed, Embase, and Cochrane Library for studies evaluating the efficacy and safety of fruquintinib, regorafenib, TAS-102, and nintedanib as third-line therapies in patients with mCRC. Overall survival (OS) and progression-free survival (PFS) were the primary outcomes, while objective response rate (ORR) and safety were the secondary outcomes. Hazard ratio (HR) and relative risk (RR) with their respective 95% confidence interval (CI) were used for analysis of survival, clinical response, and safety data. An adjusted indirect meta-analysis with placebo as the common comparator was performed. Results: We identified eight RCTs comparing regorafenib (two studies), fruquintinib (two studies), TAS-102 (three studies), and nintedanib (one study) against placebo. The OS with regorafenib was significantly better when compared with nintedanib (HR = 0.66; 95% CI: 0.45, 0.95, p = 0.02) but was similar to that of fruquintinib (HR = 1.01; 95% CI: 0.67, 1.52, p = 0.94) and TAS-102 (HR = 0.97; 95% CI: 0.68, 1.38, p = 0.88). The PFS and ORR for regorafenib were slightly better than those of TAS-102 (PFS: HR = 0.86, 95% CI: 0.54, 1.37, p = 0.5; ORR: RR = 1.13, 95% CI: 0.11, 11.05, p = 0.92) and nintedanib (PFS: HR = 0.68, 95% CI: 0.42, 1.10, p = 0.12; ORR: not reported) but were lower than those for fruquintinib (PFS: HR = 1.53, 95% CI: 0.93, 2.52, p = 0.08; ORR: RR = 0.68269, 95% CI: 0.045, 10.32, p = 0.79). Safety analysis showed that the RR of adverse events (AEs) was lesser in patients treated with regorafenib in comparison with that in patients treated with fruquintinib, but was similar to that in patients treated with nintedanib and TAS-102. Conclusion: Regorafenib has efficacy similar to that of TAS-102 and better safety when compared with fruquintinib. Considering the mechanism of action of regorafenib, which targets multiple factors in the angiogenic pathway, it could be an ideal option for treatment in the beyond second-line setting.

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Comparasion Between Nilotinib and Dasatinib as Second-Line Therapy for Patients with Chronic Myeloid Leukemia: A Single Center Retrospective Study.

Blood ◽

10.1182/blood.v116.21.3440.3440 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3440-3440

Author(s):

Clarisse Lobo ◽

Carla Boquimpani ◽

Tania Silva Madeira ◽

Patricia Wendling ◽

Claudia Maximo ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Second Generation ◽

Randomized Clinical Trials ◽

Molecular Response ◽

Second Line ◽

Second Line Therapy ◽

Line Therapy ◽

Third Line Therapy ◽

Third Line

Abstract Abstract 3440 Nilotinib and dasatinib are second-generation tyrosine kinase inhibitors (TKI) used in patients with chronic myeloid leukemia (CML) resistant or intolerant to imatinib. There are no randomized clinical trials comparing these drugs in this context. The aim of this study was to compare, retrospectively, the hematological, cytogenetic and molecular response in patients submitted to these second-generation TKI at Hemorio, a public brazilian institution. A total of 114 patients were analyzed, 63 received nilotinib and 51 dasatinib as second-line therapy (55.3% and 44.7%, respectively). The following variables were equally distributed between these two groups (nilotinib vs. dasatinib, respectively): male sex (54% vs. 60.8%, p=0.46), median age at diagnosis (46 vs. 45 years, p=0.76), median time in months using imatinib before the switch (45.2 vs. 44.1, p=0.96), resistance to imatinib (98.4% vs. 98%, p=0.88), presence of the mutation T315I (3.2% vs. 3.9%, p=0.09), patients in chronic phase before the switch (85.7% vs. 86.3%, p=0.93). Use of another second generation TKI, as a third-line therapy, was necessary in 30 out of the 114 patients analyzed (26.1%) because of lack of response. This modification was slightly more frequent in the group initially submitted to nilotinib (31.7% vs. 19.6%, p=0.21). Patients who used a third-line therapy were excluded from response and survival analyzes. Response rates after the second-generation TKI were similar between these two groups (nilotinib vs. dasatinib): complete hematological response until three months (77.8% vs. 87.3%, p=0.24), complete cytogenetic response until six months (21.6% vs. 22.2%, p=0.95) and 12 months (32.4% vs. 33.3%, p=0.94) and major molecular response reached before 12 months (32.7% vs. 21.6%, p=0.25). Two-year overall survival (OS) and progression free-survival (PFS) were similar between these two groups (nilotinib vs. dasatinib, respectively): 92.2% vs. 87.8% (p=0.38) for OS and 87.8% vs. 83.7% (p=0.14) for PFS. Although not statistically significant, two-year OS was inferior in the group of patients who needed a third-line therapy (70.5% vs. 95.6%, p=0.70). Our results suggest that the response and survival rates are similar between nilotinib and dasatinib as second-line therapy for patients with imatinib resistant or intolerant CML. Also, they suggest an inferior prognosis for patients who need a third-line therapy. In this way, the choice between these two TKI for second-line therapy should be guided by the clinical characteristics and the mutation status of the patient. Disclosures: Lobo: NOVARTIS: Research Funding.

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Diffuse Large B-Cell Lymphoma (DLBCL) Patients Failing Second-Line R-DHAP Or R-ICE Chemotherapy Included In The Coral Study

Blood ◽

10.1182/blood.v122.21.764.764 ◽

2013 ◽

Vol 122 (21) ◽

pp. 764-764 ◽

Cited By ~ 4

Author(s):

Eric Van Den Neste ◽

Christian Gisselbrecht ◽

Norbert Schmitz ◽

Nicolas Mounier ◽

Devinder S Gill ◽

...

Keyword(s):

Research Funding ◽

B Cell Lymphoma ◽

Salvage Chemotherapy ◽

New Drugs ◽

High Dose ◽

Second Line ◽

Line Therapy ◽

Significant Difference ◽

Third Line Therapy ◽

Third Line

Abstract Introduction and Methods Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation (ASCT) is the standard of care for relapsing/refractory DLBCL. In the CORAL study, there was no difference between two randomized second line regimens (R-DHAP or R-ICE) and only half of the patients (pts) eventually underwent per protocol ASCT (Gisselbrecht et al, JCO 2010 & 2012). Because outcome data are limited in DLBCL pts failing second-line strategy, 145 pts included in the CORAL study who failed R-DHAP or R-ICE and could not proceed to scheduled ASCT were herein reviewed. Results Median age was 56y (range 20-67, 31% > 60y), M/F ratio 91/54, IPI 0-1 in 30%, 2-3 in 56%, and 4-5 in 14%. Third-line therapy consisted of ICE-type (19%), DHAP-type (19%), gemcitabine-containing (16%), CHOP-like (8%), dexaBEAM (8%), and miscellaneous (31%) regimens with or without rituximab according to centre policy. Overall response rate to third-line chemotherapy was 43%, with 21% complete response (CR), 8% CR unconfirmed (CRu), and 14% PR. CR/CRu and PR rates among pts treated with ICE-type, DHAP-type, gemcitabine-containing, or CHOP-like regimens were 23 and 23%, 35 and 8%, 9 and 4%, 25 and 25%, respectively. Among the 145 patients, 64 (44%) could eventually be transplanted (ASCT 56, allogeneic SCT 8). Median overall survival (OS), calculated from time of second failure until death, was 5.9 months (95% CI 4.6-7.5; min: 0.0-max: 68.8 months; median follow-up: 32.8 months) and was not influenced by the type of third-line regimen (p=.49). OS was statistically different (p<.0001) according to IPI at CORAL failure: IPI 0-2: 11.1 months (1-y OS 42.9%), IPI > 2: 3.7 months (1-y OS 7.7%, HR 3.021). OS in pts achieving CR/CRu, PR, or no response after third-line regimen was 63.6 m (1-y OS 72.1%, p<.0001), 12.8 m (1-y OS 53.5%, p=.04), and 4.4 months (1-y OS 9.2%), respectively. Median OS of pts who could eventually be transplanted was 11.1 months (1-y OS 41.6%), as compared to a median OS of 5.0 months in those who were not transplanted (1-y OS 19.2%) with a HR of 2.182 (1.41-3.38, p<.0001, Figure 1). Median OS of pts transplanted in CR after third-line regimen was not reached as compared to those in PR (11.8 months) or those with no response (4.4 months, p<.0001). There was no statistically-significant difference in median OS between ASCT and alloSCT, taking into account the low numbers. In multivariate Cox analysis, IPI at relapse (HR 2.409) and transplantation (HR 0.381) independently predicted for OS. Conclusions Outcome of DLBCL pts failing second-line R-DHAP or R-ICE is overall poor. However, response to third-line therapy occurs, and 44% of the pts can be further transplanted. Long-term disease control can be observed, especially in pts achieving CR after third-line. This approach (salvage chemotherapy aiming at achieving response followed by transplantation) should then be encouraged in these patients, although there is obviously an urgent need for new drugs improving salvage efficacy. Disclosures: Gisselbrecht: Roche: Consultancy, Research Funding; Baxter: Research Funding; Chugai Pharma: Research Funding. Trneny:Roche: Honoraria, Research Funding. Radford:Roche: Consultancy. Shpilberg:Roche: Consultancy, Honoraria, Research Funding. Dührsen:Roche Pharma: Honoraria, Research Funding. Moskowitz:Genentech: Consultancy, Research Funding. Glass:Roche: Honoraria, Research Funding.

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Third-line therapy in metastatic renal cell carcinoma: Results from the International mRCC Database Consortium.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.7_suppl.430 ◽

2015 ◽

Vol 33 (7_suppl) ◽

pp. 430-430 ◽

Cited By ~ 2

Author(s):

Daniel Yick Chin Heng ◽

Connor Wells ◽

Frede Donskov ◽

Brian I. Rini ◽

Jae-Lyun Lee ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Targeted Therapy ◽

Cell Carcinoma ◽

Renal Cell ◽

Second Line ◽

Second Line Therapy ◽

Therapy Initiation ◽

Line Therapy ◽

Third Line Therapy ◽

Third Line

430 Background: Third-line targeted therapy efficacy in metastatic renal cell carcinoma (mRCC) is not well characterized and many funding bodies do not provide reimbursement for it. Methods: The International mRCC Database Consortium (IMDC) consists of consecutive patient series from 25 cancer centers. It was queried for specific sequences of targeted therapy and third-line therapy. Kaplan Meier estimates were used for survival. Cox proportional hazards models were used to adjust hazard ratios for confounders. Patients that stopped second-line therapy were divided into two groups: those that went onto third-line therapy and those did not. Results: 4,050 patients were treated with first-line targeted therapy, of which 2,011 (49.6%) had second-line therapy and 879 (21.7%) had third-line targeted therapy. The most common third-line therapies were everolimus 25%, sorafenib 14%, sunitinib 13%, temsirolimus 11%, pazopanib 10%, and axitinib 6%. IMDC prognostic groups at third-line therapy initiation were 6% favorable risk, 67% intermediate risk, and 27% poor risk. Overall response rate for third-line therapy was 10.5% and 50.9% had stable disease in those patients that were evaluable. Median PFS was 5.1 months (95% CI, 4.5-5.7) and median OS from third-line therapy initiation was 12.0 months (95% CI, 10.7-12.9). Patients stopping second-line therapy that move on to third-line therapy vs. those that do not receive third line therapy have a median OS from stopping second-line therapy of 13.1 vs. 2.3 mons (p<0.0001). When adjusted for second-line IMDC prognostic criteria and KPS at second-line treatment cessation, patients who do receive third-line therapy have a HR of death of 0.41 (95% CI, 0.32-0.52; p<0.0001) compared to those that do not receive third-line therapy. This may be in part due to patient selection. To further limit bias, when excluding patients that live less than 3 months after second-line therapy cessation, the adjusted HR was similar. Conclusions: Third-line targeted therapy has demonstrated activity and is prevalent in use. Further studies are required to determine appropriate sequencing.

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Safety and tolerability profile of raltitrexed in Chinese patients with locally advanced or recurrent and metastatic colorectal cancer: A phase IV trial.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.571 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 571-571

Author(s):

Shukui Qin ◽

Jin Li ◽

Yunpeng Liu ◽

Yin Chen ◽

Nong Xu ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Locally Advanced ◽

Chinese Patients ◽

Tolerability Profile ◽

Second Line ◽

Line Therapy ◽

Third Line Therapy ◽

Third Line ◽

Phase Iv

571 Background: The clinical benefit and safety profile associated with raltitrexed in patients with advanced colorectal cancer (CRC) were established. However, safety information of raltitrexed in Chinese patients is rare. We aimed to assess the safety of raltitrexed monotherapy in Chinese patients with advanced CRC. Methods: This single-arm, open-label, multi-center, phase IV trial was conducted in 13 hospitals across China between March 2011 and July 2014. Patients with locally advanced or recurrent and metastatic colorectal cancer (mCRC) received raltitrexed (3mg/m2) as a 15-min infusion on day 1, every 21 days. Treatment was continued until disease progression or unacceptable toxicity. The primary objective was safety and the secondary objectives were disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results: A total of 215 patients were enrolled, and the safety was assessed in 205 patients. 92 patients had 394 Adverse events (AEs) during the study. A majority (94.4%) of AEs was grade 1/2 and only 5.3% was grade 3/4. Most AEs were either resolved spontaneously or treated successfully with standard medical interventions. Severe AEs were reported by 5.8% (12/205) of patients. The most commonly reported AEs were increase of transaminases, leukopenia, nausea and vomiting. Serum transaminase elevation, an important safety concern associated with raltitrexed therapy, were transient, self-limiting and manageable. No deaths were reported during the study. The DCR in second-line and third-line therapy by raltitrexed reached 49.5% and 37.4%, respectively. The median PFS in second-line and third-line therapy was 1.43 months and 1.47 months, respectively. The median OS was 13.6 months and 8.9 months, respectively. Conclusions: Raltitrexed monotherapy is a safe, well-tolerated and convenient therapy option for Chinese patients. The treatment-associated toxicity is manageable and does not lead to discontinuation of treatment in oncology practice.

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

Journal of Clinical Oncology ◽

10.1200/jco.2008.20.4552 ◽

2009 ◽

Vol 27 (17) ◽

pp. 2848-2854 ◽

Cited By ~ 42

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.

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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 ◽

10.1136/bmjopen-2018-022293 ◽

2019 ◽

Vol 9 (3) ◽

pp. e022293 ◽

Cited By ~ 4

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.

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