The impact of transmitted drug resistance on the natural history of HIV infection and response to first-line therapy

1039 Background: A phase III randomized double-blind multicenter trial compared lapatinib plus letrozole (L+Let) with letrozole plus placebo (Let), as first-line therapy for hormone receptor positive (HR+) MBC. Median PFS, the primary endpoint of the study, in patients who were HER2+ was significantly prolonged for L+Let compared with Let (8.2 vs 3 months, Hazard Ratio (95% CI)=0.71(0.53,0.96), p=0.019). This analysis focuses on the impact of treatments on QOL in the HER2+ subgroup. Methods: QOL outcomes included the Functional Assessment of Cancer Therapy-Breast (FACT-B) total, FACT-general (FACT-G), and trial outcome index (TOI) scores assessed at screening, every 12 weeks and at withdrawal. Higher scores indicate better QOL. Changes from baseline were analyzed using analysis of covariance. In a responder analysis, patients achieving minimally important differences in QOL scores (QOL responders) were compared with Fisher's exact test. Results: Among 1,286 patients, 219 were identified as HER2+ (L+Let n=111; Let n=108). Baseline QOL scores were comparable in the two arms. In this population, mean changes in subscale and total QOL scores were generally stable over time in both treatment arms for patients who stayed on study. For example, on the FACT-B, the average change from baseline in both groups was positive at all scheduled visits through Week 48 and the maximum difference between arms was 2.6 points (CI: -5.8, 11). There were no significant differences between the two treatment arms in percentage of QOL responders (Table). Conclusions: The addition of lapatinib to letrozole significantly increases PFS while maintaining QOL when compared with letrozole alone thus confirming the clinical benefit of the combination therapy in the HR+, HER2+ MBC patient population. This combination provides an effective option in this patient population by maintaining QOL and delaying the need for chemotherapy and its accompanying side effects. [Table: see text] [Table: see text]

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Progress and Challenges of Integrated Drug Efficacy Surveillance for Uncomplicated Malaria in Thailand

10.21203/rs.3.rs-343048/v1 ◽

2021 ◽

Author(s):

Prayuth Sudathip ◽

Aungkana Saejeng ◽

Nardlada Khantikul ◽

Thannikar Thongrad ◽

Suravadee Kitchakarn ◽

...

Keyword(s):

System Integration ◽

Treatment Guidelines ◽

Drug Efficacy ◽

Fiscal Year ◽

Efficacy Rate ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Kaplan Meier ◽

History Of

Abstract BackgroundIntegrated drug efficacy surveillance (iDES) was formally introduced nationally across Thailand in fiscal year 2018 (FY2018), building on a history of drug efficacy monitoring and interventions. According to the National Malaria Elimination Strategy for Thailand 2017–2026, diagnosis is microscopically confirmed, treatment is prescribed, and patients are followed up four times to ensure cure.MethodsRoutine patient data were extracted from the malaria information system for FY2018–FY2020. Treatment failure of first-line therapy was defined as confirmed parasite reappearance within 42 days for Plasmodium falciparum and 28 days for Plasmodium vivax. The primary outcome was the crude drug efficacy rate, estimated using Kaplan–Meier methods, at day 42 for P. falciparum treated with dihydroartemisinin-piperaquine plus primaquine, and day 28 for P. vivax treated with chloroquine plus primaquine; day 60 and day 90 efficacy were secondary outcomes for P. vivax.ResultsThe proportion of patients with outcomes recorded at day 42 for P. falciparum malaria and at day 28 for P. vivax malaria has been increasing, with FY2020 follow-up rates of 61.5% and 57.2%, respectively. For P. falciparum malaria, day 42 efficacy in FY2018 was 92.4% (n = 249), in FY2019 93.3% (n = 379), and in FY2020 98.0% (n = 167). P. falciparum recurrences occurred disproportionally in Sisaket Province, with day 42 efficacy rates of 75.9% in FY2018 (n = 59) and 49.4% in FY2019 (n = 49), leading to an update in first-line therapy to pyronaridine-artesunate at the provincial level, rolled out in FY2020. For P. vivax malaria, day 28 efficacy was 98.5% in FY2018 (n = 2,048), 99.1% in FY2019 (n = 2,206), and 99.9% in FY2020 (n = 2,448), and day 90 efficacy was 94.8%, 96.3%, and 97.1%, respectively.ConclusionsIn Thailand, iDES provided operationally relevant data on drug efficacy, enabling the rapid amendment of treatment guidelines to improve patient outcomes and reduce the potential for the spread of drug-resistant parasites. A strong case-based surveillance system, integration with other health system processes, supporting biomarker collection and molecular analyses, and cross-border collaboration may maximize the potential of iDES in countries moving towards elimination.

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Implications for the future of the HIV epidemic if drug resistance against dolutegravir cannot occur in first-line therapy

Journal of the International AIDS Society ◽

10.7448/ias.18.1.20824 ◽

2015 ◽

Vol 18 (1) ◽

pp. 20824 ◽

Cited By ~ 11

Author(s):

Mark A Wainberg ◽

Thibault Mesplede

Keyword(s):

Drug Resistance ◽

First Line ◽

First Line Therapy ◽

Hiv Epidemic ◽

Line Therapy ◽

The Future

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A randomized second line trial in patients with gemcitabine refractory advanced pancreatic cancer - CONKO 003

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.4517 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 4517-4517 ◽

Cited By ~ 8

Author(s):

H. Riess ◽

U. Pelzer ◽

J. Stieler ◽

I. Schwaner ◽

G. Heil ◽

...

Keyword(s):

Pancreatic Cancer ◽

Side Effects ◽

Disease Progression ◽

Advanced Pancreatic Cancer ◽

Phase Iii ◽

Second Line ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

The Impact

4517 Objective: For nearly ten years gemcitabine (G) was standard first line therapy for patients (pts) with advanced pancreatic cancer (APC). There is no consensus about second line therapy after disease progression while receiving G, but 5-FU-based regimens are considered. Results about randomized second line studies in APC are very rare. Our phase II study (ASCO 2002) showed activity of the OFF (oxaliplatin/folinic Acid (FA)/5-fluorouracil (FU) [24h] ) regimen in 23 pts. To examine the impact and the side effects of oxaliplatin we initiated a multicenter phase III study to compare OFF and FF in pts with G refractory APC. Methods: Pts with CT/ MRT confirmed failure with G in first line therapy, Karnofsky Performance Status (KPS) >60%, controlled pain, adequate hematological, renal and liver functions were eligible. Pts were stratified according to duration of first line therapy, KPS and tumor stage. We randomized pts to outpatient treatment with FF (FU 2g/m2 (24h)/ FA 200 mg/m2 (30min) on d1, d8, d15 and d22) or OFF (FF+Oxaliplatin 85mg/m2, d8, d22). In both arms the next cycle started on day 43. Pts were followed with regular staging every 3 months or at any signs of disease progression. Results: Until now we randomized 161 of 165 (planned) pts between 02/2004 and 01/2007. So we expect to present first results (side effects, progression free survival, overall survival) at the meeting. No significant financial relationships to disclose.

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IMPACT study: A phase II-III clinical study with the immunomodulator MGN1703 in patients with advanced colorectal carcincoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.633 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 633-633 ◽

Cited By ~ 2

Author(s):

Marina Tschaika ◽

Hans-Joachim Schmoll ◽

Jorge Riera-Knorrenschild ◽

Dieter Nitsche ◽

Jorg Trojan ◽

...

Keyword(s):

Clinical Study ◽

Adverse Events ◽

Disease Control ◽

Phase Ii ◽

Impact Study ◽

Efficacy And Safety ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

The Impact

633 Background: The synthetic DNA-based immunomodulator MGN1703 acts as an agonist of toll-like receptor 9. Based on promising data from a phase I study in patients with metastatic solid tumors including those with CRC, a phase II-III study was initiated in patients with advanced CRC having disease control after first-line therapy. The objective of the study is to assess efficacy and safety of the MGN1703 treatment in comparison to placebo. Methods: The IMPACT study is designed as a randomized double-blind placebo-controlled phase II-III study, which is conducted in patients with advanced CRC showing disease control after first-line therapy with standard chemotherapy regimen. The treatment is administered subcutaneously twice weekly in a ratio 2:1 (60 mg MGN1703 or placebo). The study is conducted in Germany, Austria, France, UK, Czech Republic and Russia, and 129 patients will be recruited into the study. The efficacy and safety of the study treatment will be evaluated based on extensive immunological tests, radiological assessment, safety laboratory results and assessments of the quality of life. The study treatment will be continued until tumor progression, intolerable toxicity, exclusion criteria or withdrawal of consent. Results: The majority of adverse events were assessed as not drug-related by the investigator. The remaining AEs include mild night sweat (not assessable), mild fever (at three occasions, possible related), and mild arthralgia (certain related) in one patient each. Three SAE have been reported so far of which one was assessed as probably drug-related – atypical pneumonia. Only in single patients local reactions such as mild redness and swelling at injection site were reported. No laboratory or clinical signs of autoimmunity or dose-limiting toxicities were reported, so far. Conclusions: With these preliminary safety results of the ongoing clinical study in patients with advanced CRC it could be shown that ttreatment with MGN1703 at the dosage of 60 mg is well tolerated and safe. Reported adverse events assessed as possibly drug-related belong to expected study drug reactions known for immune modulating drugs. These events were not accompanied by any signs of autoimmunity.

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Objective response rate and progression-free survival as surrogate endpoints for overall survival and the impact of crossover and unbalanced post-progression treatments: A systematic review and meta-analysis in first-line therapy of advanced non-small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.9049 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 9049-9049

Author(s):

Boris Pfeiffer ◽

Mahmoud Hashim ◽

Monica Duran ◽

Maarten Postma ◽

Bart Heeg

Keyword(s):

Response Rate ◽

Objective Response ◽

Progression Free Survival ◽

Absolute Difference ◽

Surrogate Endpoints ◽

First Line ◽

Free Survival ◽

First Line Therapy ◽

Line Therapy ◽

The Impact

9049 Background: Correlations between overall survival (OS) and objective response rate (ORR) or progression-free survival (PFS) are poor. We aimed to evaluate the impact of crossover and unbalanced subsequent treatments on ORR and PFS as surrogate endpoints for OS in patients with advanced NSCLC receiving first-line therapy. Methods: A systematic literature review of randomized clinical trials of systemic treatment for patients with stage IIIB/IV NSCLC receiving first-line therapy was performed. Weighted (by trial size) linear regression models were fitted with the absolute difference in ORR or median PFS as an independent variable and the absolute difference in median OS as a dependent variable. The analysis was repeated in predefined subsets based on crossover and balance of post-progression therapies. Surrogate threshold effect (STE) was estimated using prediction intervals. Results: 317 trials (78,644 patients) fulfilled the eligibility criteria. In all treatment arms, the mean ORR, median PFS, and median OS were 28.2% (standard deviation (SD) = 12.4%), 5.1 months (SD = 2.1), and 10.4 months (SD = 2.5), respectively. ORR and PFS had weak (R = 0.351; 95% CI: 0.251-0.443) and (R = 0.397; 95% CI: 0.267-0.512) associations with OS, respectively. However, within phase III trials that did not allow crossover and reported balanced post-progression treatments, both ORR and PFS had stronger associations with OS (ORR and OS: R = 0.601, 95% CI: 0.399-0.747; PFS and OS: R = 0.695, 95% CI: 0.446-0.844). STE estimation indicated that trials that show statistically significant treatment effect size of ≥43% ORR or ≥3.2 median PFS months can be expected to show significant OS benefit with sufficient certainty. Conclusions: Surrogacy of ORR and PFS for OS might be better estimated in trials that do not allow crossover and report balanced post-progression treatments. Presented STE calculation can be used to estimate the expected effect on OS when either ORR or PFS are used as primary endpoints.

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