PIK3CA mutation status and progression-free survival in advanced hormone receptor positive (HR+)/ human endocrine receptor negative (HER2–) metastatic breast cancer (mBC): A meta-analysis of published clinical trials.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1069-1069
Author(s):  
James Signorovitch ◽  
Fabrice Andre ◽  
Ruchuan Wang ◽  
Ines Lorenzo ◽  
Antonia Ridolfi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Pik3ca Mutation ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Significant Heterogeneity ◽  
Mutation Status ◽  
Free Survival ◽  
Hormone Receptor Positive

1069 Background: Approximately 40% of HR+/HER2- mBC patients harbor PIK3CA mutation. Associations between PIK3CA mutation status and clinical outcomes among patients with HR+/HER2- mBC have been heterogeneous across clinical trials. We synthesized available evidence from clinical trials to estimate the association between PIK3CA status and progression-free survival (PFS) using a meta-analysis adjusting for study design differences. Methods: Randomized clinical trials reporting PFS stratified by PIK3CA status in HR+/HER2- mBC were identified via a systematic literature review. Trial arms receiving PIK3CA targeted therapies were excluded. Median PFS, 6-, 12- and 18-month PFS rates, and data on trial design features were extracted. Associations between PIK3CA status and PFS were estimated adjusting for study follow-up duration, PIK3CA testing method (ctDNA vs tissue ) and study treatment using multi-level random effects meta-regression. Results: The analyzed data included 3,238 patients from 33 study arms across 11 trials ( PIK3CA mutated (MT): 1,386, wild type (WT): 1,852). PIK3CA mutation was overall associated with shorter median PFS (difference [95% CI] (months): -2.15 [-4.14, -0.15]) with substantial heterogeneity across studies ( I2 = 98.34%). The direction of this association was robust to adjustment for study treatment (-1.27 [-2.22, -0.32]). The association was stronger for ctDNA testing (-2.16 [-3.65, -0.66]; N (total patients): 1,876) than for tissue testing (-0.65 [-2.2, 0.91]; N: 998). Findings were similar for 6-month PFS rates (absolute rate difference -9.17% [-14.22, -4.12], N: 3,179; MT: 1,366, WT: 1,813). Associations were directionally consistent but not statistically significant at 12 months (N = 2,487; MT: 1,056, WT: 1,431) and 18 months (N = 1,745; MT: 811, WT: 934), potentially due to the decreasing precision towards the tails of the PFS curves and significant heterogeneity across studies. Conclusions: Pooling evidence across multiple studies, PIK3CA mutation was associated with shorter PFS, especially when ctDNA testing was used. These findings suggest a negative prognostic value of PIK3CA mutation in patients with HR+/HER2- mBC.

scholarly journals Upfront Therapy with Ibrutinib Results in a Longer Progression-Free Survival Independently of IGHV Mutational Status and Del(11q) in CLL Patients. Results of a Comprehensive Review and Meta-Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5469-5469
Author(s):  
Stefano Molica ◽  
Diana Giannarelli ◽  
Luciano Levato ◽  
Emili Montserrat
Keyword(s):  
Clinical Trials ◽  
Lower Risk ◽  
Selection Criteria ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Free Survival ◽  
Risk Of Progression ◽  
Upfront Therapy ◽  
11Q Deletion

Background: Recent studies have demonstrated a prolonged progression-free survival (PFS) in CLL patients receiving ibrutinib-based regimes as upfront therapy. These studies, however, are limited in number and heterogeneous regarding patients' selection criteria, treatment combinations and schedules. Because of this, we conducted a meta-analysis of randomized clinical trials using ibrutinib as upfront treatment to evaluate the strength of the evidence and patients' subgroups who benefit the most of such treatment. Materials & Methods: A systematic literature search was performed using PubMed to identify full length reports dealing with the randomized clinical trials (RCTs) of ibrutinib, used alone or in combination as upfront therapy of CLL prior to August 2nd, 2019. A complementary manual search of the ASH, EHA and ASCO conference proceedings was also performed. The search strategy used both Medical Subject Headings (MESH) terms and free text words to increase the sensitivity of the search. The electronic search yielded 4 full-text articles assessed for eligibility. Results: In total 4 RCTs (i.e., RESONATE2, ALLIANCE, ILLUMINATE, ECOG-ACRIN) including 1574 untreated CLL patients compared head-to-head an ibrutinib-based regimen to CT or CIT. Inclusion criteria were either age 65 years or older or coexisting conditions for 1045 patients and age younger than 70 years in absence of coexisting conditions for 529 patients. Among patients treated with an ibrutinib-based regimen, 318 received ibrutinib as single agent and 649 ibrutinib in association with anti-CD20 monoclonal antibodies (i.e., 536 ibrutinib + rituximab [R], 113 ibrutinib + obinotuzumab [Obino]). The CT or CIT control arms included 607 patients and consisted of chlorambucil (CLB)(n=133), CLB+Obino (n=116), bendamustine and R (BR) (n=183) and fludarabine, cyclophosphamide and R (FCR)(n=175). All four studies included in the quantitative meta-analysis had enough data to assess PFS. Results indicate that treatment with ibrutinib-based regimens improved PFS compared with CT or CIT. The pooled HR for PFS in ibrutinib-treated patients was 0.331 (95% confidence interval [CI]: 0.272-0.403; P=0.000). The I2 statistic for heterogeneity (i.e. 0%; P=0.50) and Q values (i.e. 3.35) indicated a high level of homogeneity of results across studies. Of note, data were robust with no evidence of obvious publication bias (i.e., Funnel plot analysis indicate several missing studies that would bring p-value up to >0.05=156). Overall survival (OS) was evaluated in 3 studies accounting for 1017 patients and revealed an HR of 0.289 (95% CI, 0.071-0.1175), with definite heterogeneity across studies (I2=82.7%; Q=11.6; P=0.003). Next, we evaluated the magnitude of improvement in PFS obtained with ibrutinib-based regimens in patients with high-risk genetic features such as 11q deletion and unmutated IGHV status. Data for PFS by 11q deletion status, restricted to 3 studies (n=206), revealed a significantly lower risk of progression for 11q deleted patients treated with ibrutinib-based regimens (HR,0.159; 95% CI: 0.077-0.327; I2 = 42%; P=0.18; Q = 3.46) (Fig 1A). Of note, a lower risk of progression was observed in both patients with unmutated (n=522) (HR, 0.178; 95% CI, 0.121-0.261; p=.000; I2=11%; Q=2.21;P=0.32)(Fig 1B) and mutated IGHV (n= 287)(HR, 0.270;95% CI, 0.149-0.489; I2=0%; P=0.38;Q=1.91)(Fig 1B) who received ibrutinib in upfront. Despite slight differences of the HR values between patients with mutated and unmutated IGHV, interaction analysis suggests that the magnitude of PFS improvement is comparable in both groups (HR, 1.50; 95% CI, 0.74-3.04; P=0.87). Conclusions This meta-analysis validates the notion that in comparison with CT or CIT ibrutinib-based regimens, given as upfront therapy, abrogate the negative impact of 11q deletion and unmutated IGHV on PFS. Even more, 11q deletion could be a favorable predictive biomarker for ibrutinib therapy. Because of design and selection criteria of studies included in this meta-analysis, some aspects such as the impact on response and its duration in patients with 17p deletion/TP53 mutations need further evaluation. Nonetheless, our results should inform updated algorithms of upfront CLL treatment. Figure 1 Disclosures Molica: Gilead, AbbVie, Jansen, Roche: Other: Advisory Board. Levato:Novartis: Honoraria; BMS: Honoraria; Incyte: Honoraria; Pfizer: Honoraria.

Systematic review and meta-analysis of post-progression outcomes in ER+/HER2- metastatic breast cancer after treatment with endocrine therapy and CDK 4/6 inhibitors within randomized clinical trials.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1059-1059
Author(s):  
Elisabetta Munzone ◽  
Eleonora Pagan ◽  
Vincenzo Bagnardi ◽  
Emilia Montagna ◽  
Giuseppe Cancello ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Metastatic Breast Cancer ◽  
Endocrine Therapy ◽  
Fixed Effects ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Progression Free Survival

1059 Background: CDK4/6 inhibitors combined with endocrine therapy (ET) deeply transformed the treatment landscape of HR+/HER2− advanced breast cancer. After progression with the combination, there are no established guidelines for an optimal sequencing of the various therapeutic options. Data from randomized clinical trials (RCT) suggest that subsequent progression free survival (PFS2) was not compromised by the use of these drugs and time to subsequent chemotherapy (TTC) may be delayed. Therefore, we performed a meta-analysis to evaluate the benefit of such treatments on PFS2 and on delaying the TTC. Methods: We conducted a systematic literature search using PubMed to select all available randomized clinical trials of CDK4/6-inhibitors and ET reporting PFS2 or TTC data in first- or second-line therapy of HR+/HER2- pre- or postmenopausal metastatic breast cancer. We also reviewed abstracts and presentations from all major conference proceedings. We calculated the pooled hazard ratios (HR) for PFS2 and TTC with 95% confidence intervals (CI) using fixed-effects models. The pooled HRs for PFS and OS were also calculated. I2 was used to quantify heterogeneity between studies’ results. Results: Seven studies (PALOMA 1-2-3, MONALEESA 3-7, MONARCH 2-3) were included in our analyses (n = 3912 patients). A clear PFS2 benefit was observed in patients who received CDK 4/6 inhibitors + ET (pooled HR = 0.67, 95% CI = 0.61 to 0.74, I2 = 0.0%) and also a delay in subsequent TTC (pooled HR = 0.63, 95% CI = 0.58 to 0.70, I2 = 0.0%). As previously reported, the benefit in terms of PFS (pooled HR = 0.54, 95% CI = 0.50 to 0.59, I2= 0%) and OS (pooled HR = 0.77, 95% CI = 0.68 to 0.86, I2= 0%) was also confirmed. Conclusions: CDK4/6-inhibitors plus ET compared with ET alone improve PFS2, and TTC. The delay of chemotherapy can spare the patients toxicities, potentially improving the quality of life. Thus, the observed benefit in PFS2 may postpone the onset of endocrine resistance and may offer an additional therapeutic advantage in this setting.

Duration of Chemotherapy for Metastatic Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

2011 ◽  
Vol 29 (16) ◽  
pp. 2144-2149 ◽  
Author(s):  
Alessandra Gennari ◽  
Martin Stockler ◽  
Matteo Puntoni ◽  
Mariapia Sormani ◽  
Oriana Nanni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Metastatic Breast Cancer ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Published Data ◽  
First Line ◽  
Line Chemotherapy

Purpose To evaluate the effect of different first-line chemotherapy durations in patients with metastatic breast cancer (MBC) on overall survival (OS) and progression-free survival (PFS). Methods We searched literature databases to identify randomized controlled trials that compared different chemotherapy durations in the first-line treatment of MBC. Only trials with unconfounded comparisons of additional cycles of chemotherapy were included. The main outcome measures for this analysis were OS and PFS. Published data from retrieved studies were analyzed according to standard meta-analytic techniques. Results We found 11 randomized clinical trials including 2,269 patients. Longer first-line chemotherapy duration resulted into a significantly improved OS (hazard ratio [HR], 0.91; 95% CI, 0.84 to 0.99; P = .046) and PFS (HR, 0.64; 95% CI, 0.55 to 0.76; P < .001). There were no differences in effects on either OS or PFS between subgroups defined by time of random assignment, study design, number of chemotherapy cycles in the control arm or concomitant endocrine therapy. Conclusion Longer first-line chemotherapy duration is associated with marginally longer OS and a substantially longer PFS.

scholarly journals A model for predicting effect of treatment on progression-free survival using MRD as a surrogate end point in CLL

Blood ◽  
2018 ◽  
Vol 131 (9) ◽  
pp. 955-962 ◽  
Author(s):  
Natalie Dimier ◽  
Paul Delmar ◽  
Carol Ward ◽  
Rodica Morariu-Zamfir ◽  
Günter Fingerle-Rowson ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Significant Relationship ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Free Survival ◽  
End Point ◽  
Key Points ◽  
Effect Of Treatment ◽  
Meta Regression

Key Points Meta-analysis of 3 randomized clinical trials shows a statistically significant relationship between treatment effects on PFS and MRD. Meta-regression model supports use of MRD as a primary end point in clinical trials of chemoimmunotherapy in CLL.

scholarly journals Clinical and Molecular Characteristics Associated with Survival in Advanced Melanoma Treated with Checkpoint Inhibitors

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Sunil Badami ◽  
Sunil Upadhaya ◽  
Ravi Kanth Velagapudi ◽  
Pushyami Mikkilineni ◽  
Ranju Kunwor ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Random Effect ◽  
Eastern Cooperative Oncology Group ◽  
Advanced Melanoma ◽  
Cochrane Library ◽  
Molecular Characteristics ◽  
Significant Heterogeneity

Background. We performed meta-analysis to gather more evidence regarding clinical-molecular subgroups associated with better overall survival (OS) in advanced melanoma treated with checkpoint inhibitors. Materials and Methods. We performed a systematic search of PubMed, Scopus, Cochrane Library, and clinical trial.gov. Randomized clinical trials that compared a checkpoint inhibitor (nivolumab or pembrolizumab) with investigator choice chemotherapy or ipilimumab were included in our study. Hazard ratios (HR) and confidence interval (CI) were calculated for progression-free survival (PFS) and OS for each subgroup using generic inverse model along with the random effect method. Results. A total of 6 clinical trials were eligible for the meta-analysis. OS was prolonged in wild BRAF subgroup (HR 0.65, 95% CI 0.49-0.85, p 0.002), Programmed cell death subgroup (PD-1+) (HR 0.57, 95% CI 0.41-0.80, p 0.001), and high lactate dehydrogenase (LDH) level subgroup (HR 0.60, 95% CI 0.38-0.95, p 0.03). Similarly, we found increased OS in eastern cooperative oncology group (ECOG) 1, males and age >65 years subgroups. Conclusions. Checkpoint inhibitors significantly increased OS in patients with wild BRAF, positive PD-1, and high LDH. However, results should be interpreted keeping in mind associated significant heterogeneity. The results of this study should help in designing future clinical trials.

Progression-Free Survival for Real-World Use of Palbociclib in Hormone Receptor-Positive Metastatic Breast Cancer

2020 ◽  
Vol 20 (1) ◽  
pp. 33-40 ◽  
Author(s):  
Jonathan Wilkie ◽  
M. Alexandra Schickli ◽  
Michael J. Berger ◽  
Maryam Lustberg ◽  
Raquel Reinbolt ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Real World ◽  
Hormone Receptor ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Free Survival ◽  
Hormone Receptor Positive
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