Quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) of nivolumab plus cabozantinib (N+C) versus sunitinib (SUN) in treatment-naïve, advanced/metastatic renal cell carcinoma (aRCC): A post-hoc analysis of CheckMate 9ER (CM 9ER) data.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6567-6567
Author(s):  
David Cella ◽  
Robert J. Motzer ◽  
Jessica May ◽  
Joel Wallace ◽  
Florence Marteau ◽  
...  
Keyword(s):  
Treatment Options ◽  
Minimal Important Difference ◽  
Progression Free Survival ◽  
Good Health ◽  
Geographic Region ◽  
Sensitivity Analyses ◽  
Relative Gain ◽  
Subgroup Analyses ◽  
Treatment Naïve ◽  
Clinical Benefits

6567 Background: In CM 9ER (ClinicalTrial.gov identifier NCT03141177), N+C demonstrated significant progression-free survival gains (median: 17.0 vs. 8.3 months [mos]; hazard ratio [HR]: 0.52; P <.0001) and overall survival (OS) benefits (median: not reached vs. 29.5 mos; HR: 0.66; P <.001) vs. SUN as a first-line treatment for aRCC (Motzer et al. ASCO-GU 2021). To more fully understand the clinical benefits and risks associated with N+C vs. SUN from a patient perspective, we applied the Q-TWiST method to CM 9ER data to assess the quality-adjusted survival of these two treatment options, after a minimum follow-up of 16 mos (Sept DBL 2020). Methods: OS was partitioned into 3 states: time with any grade 3 or 4 adverse events (TOX), time without symptoms of disease or toxicity (TWiST), and time after progression (REL). The Q-TWiST is a metric that combines the quantity and quality (i.e., “utility”) of time spent in each of the 3 states TWiST, TOX, and REL. Sensitivity analyses estimated Q-TWiST across varying values of TOX and REL utilities. Subgroup analyses were conducted based on geographic region, programmed cell death-ligand 1 status, and International Metastatic RCC Database Consortium risk score. Based on minimal important difference norms (Revicki et al, Qual Life Res, 2006), a relative gain in Q-TWiST (i.e., Q-TWiST gains divided by OS in SUN) of ≥ 10% and ≥ 15% were qualified as “clinically important” and “clearly clinically important” gains, respectively. Non-parametric bootstrapping was used to generate 95% confidence intervals (CI). Results: In the intent-to-treat (ITT) population (N = 651), the Q-TWiST gain in the N+C arm was 4.0 mos (95% CI: 2.4, 5.7) vs. SUN arm, resulting in a relative gain of 16.9%. N+C patients had significantly longer TWiST (4.7 mos [95% CI: 2.9, 6.7]) and TOX (0.5 mos [95% CI: 0.1, 0.9]), but significantly shorter REL (-2.0 mos [95% CI: -4.1, -0.1]) than did SUN patients. Sensitivity analyses were consistent with the main analysis—the Q-TWiST benefit was robust across different ranges of U(TOX) and U(REL), with minimum and maximum Q-TWiST gains of 2.7 mos (11.7% relative gain) and 5.2 mos (22.2% relative gain), respectively. Subgroup analyses were consistent with the ITT population, with all results demonstrating ≥10% (“clinically important”) gains favoring N+C. Conclusions: In CM 9ER, N+C resulted in a statistically significant and “clearly clinically important” (i.e., ≥ 15%) longer quality-adjusted survival vs SUN. Most gains were driven by added time in relatively good health (i.e., TWiST). These Q-TWiST results may help inform both aRCC patients and their clinicians to assess more comprehensively the clinical benefits and risks of N+C and SUN in making critical treatment decisions. Clinical trial information: NCT03141177.

scholarly journals Effectiveness of Lomustine Combined With Bevacizumab in Glioblastoma: A Meta-Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Xing Ren ◽  
Di Ai ◽  
Tong Li ◽  
Lei Xia ◽  
Lingzhi Sun
Keyword(s):  
Clinical Trials ◽  
Meta Analysis ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Cochrane Library ◽  
Control Group ◽  
Subgroup Analyses ◽  
Group A ◽  
Group 2 ◽  
The Cochrane Library

Introduction: Despite surgical and chemotherapeutical treatment options, the prognosis for glioblastoma (GBM) remains poor. Some studies have found that using lomustine plus bevacizumab to treat GBM can prolong overall survival (OS) and progression-free survival (PFS). The aim of this study was to explore the efficacy of the two drugs in combination treatment of GBM using a meta-analysis of the existing literature to help settle the ongoing debate.Materials and Methods: PubMed, EMBASE, and the Cochrane Library were searched for the effectiveness of lomustine plus bevacizumab in GBM literature, updated on June 6, 2020. The main outcomes analyzed included PFS and OS; the effects of this drug combination on the 6-month PFS, which represents the percentage of patients who had PFS for 6 months, were also analyzed. All the data were pooled: OS and PFS with the mean difference (MD) and 6-month PFS with the risk ratio (RR). Because there were different control groups and dose groups, two subgroup analyses were run to ensure they were comparable. All statistical analyses were performed using the Review Manager Version 5.3 software.Results: Six clinical trials were identified which included 1,095 patients (treatment group: 516; control group: 579). The group treated with lomustine and bevacizumab showed an improvement in OS (MD =1.37; 95% CI, 0.49–2.25; p = 0.002), PFS (MD = 0.23; 95% CI, 0.13–0.34; p &lt; 0.00001), and 6-month PFS (RR = 2.29; 95% CI, 1.43–3.65; p = 0.0005). Two subgroup analyses of the main outcome, OS, show that the results of Control group A (p = 0.01) and Dose group 2 (p = 0.003) are significantly different from those of the other control or dose groups.Conclusion: This study shows that lomustine and bevacizumab can effectively increase OS, PFS, and 6-month PFS in patients with GBM. The encouraging results of the lomustine and bevacizumab combination therapy for GBM should be studied in more clinical trials in the future.

scholarly journals Osimertinib Rechallenge With Bevacizumab vs. Chemotherapy Plus Bevacizumab in EGFR-Mutant NSCLC Patients With Osimertinib Resistance

2022 ◽  
Vol 12 ◽  
Author(s):  
Qingli Cui ◽  
Yanhui Hu ◽  
Qingan Cui ◽  
Daoyuan Wu ◽  
Yuefeng Mao ◽  
...  
Keyword(s):  
Growth Factor ◽  
Kinase Inhibitor ◽  
Treatment Options ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Vegf Inhibitors ◽  
Clinical Benefits ◽  
Grade 3 ◽  
Egfr Mutant

At present, treatment options for osimertinib resistance are very limited. Dual inhibition of the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) significantly improved the progression-free survival (PFS) of advanced EGFR-mutant non–small cell lung cancer (NSCLC). After EGFR-tyrosine kinase inhibitor (TKI) resistance, EGFR-TKI continuation combined with VEGF inhibitors still had clinical benefits. It is unclear whether the addition of bevacizumab after osimertinib progresses will prolong the duration of the osimertinib benefit. We screened 1289 patients with NSCLC and finally included 96 patients to evaluate osimertinib combined with bevacizumab (osi + bev) versus chemotherapy combined with bevacizumab (che + bev) for patients with acquired resistance to osimertinib. The overall response rate (ORR) for osi + bev and chem + bev was 15.8% (6 of 38) and 20.7% (12 of 58), respectively. The median PFS for osi + bev and che + bev was 7.0 and 4.9 months (HR 0.415 95%CI: 0.252–0.687 p = 0.001). The median OS for osi + bev and che + bev was 12.6 and 7.1 months (HR 0.430 95%CI: 0.266–0.696 p = 0.001). Multivariate analyses showed that no brain metastases and osi + bev treatment after osimertinib resistance correlated with longer PFS (p = 0.044, p = 0.001), while the median PFS of osimertinib less than 6 months (p = 0.021) had a detrimental effect on sequent treatment. Only osi + bev treatment was identified as an independent predictor of OS (p = 0.001). The most common adverse events (AEs) of grade ≥3 were hypertension (13.2%) and diarrhea (10.5%) in the osi + bevacizumab group. Neutropenia (24.1%) and thrombocytopenia (19%) were the most common grade ≥3 AEs in the che + bev group. The overall incidence of serious AEs (grade ≥3) was significantly higher in the chemotherapy plus bevacizumab group. Our study has shown the superiority of osi + bev compared to che + bev after the failure of osimertinib, making it a preferred option for patients with acquired resistance to osimertinib.

ALPINE: Phase III zanubrutinib (BGB-3111) versus ibrutinib in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS7572-TPS7572 ◽  
Author(s):  
Peter Hillmen ◽  
Jennifer R. Brown ◽  
John C. Byrd ◽  
Barbara Eichhorst ◽  
Nicole Lamanna ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Complete Response ◽  
Geographic Region ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Open Label ◽  
Duration Of Response ◽  
Treatment Naïve ◽  
Independent Review ◽  
Ecog Ps

TPS7572 Background: Inhibition of Bruton tyrosine kinase (BTK) has emerged as a strategy for targeting B-cell malignancies including CLL/SLL. Zanubrutinib, an investigational inhibitor of BTK, was specifically engineered to optimize selectivity, half-life and solubility in an effort to decrease toxicities and better penetrate tumor tissue. Early clinical data suggested that zanubrutinib treatment in patients with treatment-naïve (TN; n = 16) or R/R (n = 50) CLL/SLL induced deep responses: 94% overall response rate (ORR), including 6% and 2% complete response rates in TN and R/R CLL/SLL, respectively (ICML 2017). This study is designed to evaluate whether zanubrutinib monotherapy exhibits non-inferior and potentially superior efficacy based on the ORR vs ibrutinib monotherapy in patients with R/R CLL/SLL. Methods: This ongoing phase 3, randomized, open-label, global study (NCT03734016, BGB-3111-305) is comparing the efficacy and safety of zanubrutinib vs ibrutinib in adult patients with R/R CLL/SLL. Approximately 400 patients will be randomized, 1:1 to each arm and stratified by age (< 65 vs ≥ 65 years), refractory status (yes vs no), geographic region, and del(17p)/ TP53 mutation status (present vs absent). Key inclusion criteria include R/R CLL/SLL requiring treatment per iwCLL criteria, ECOG PS 0-2, and adequate hematologic function. The primary endpoint is ORR as determined by an independent review committee according to iwCLL guidelines, with modification for treatment-related lymphocytosis for patients with CLL and per 2014 Lugano Classification for patients with SLL. The study is powered to test the non-inferiority and superiority of the ORR for zanubrutinib vs ibrutinib. Secondary endpoints include progression-free survival, safety, duration of response, and overall survival. Recruitment is ongoing. Clinical trial information: NCT03734016.

scholarly journals Systematic Review of Molecular Biomarkers Predictive of Resistance to CDK4/6 Inhibition in Metastatic Breast Cancer

2022 ◽  
Author(s):  
Uzma S. Asghar ◽  
Ruhi Kanani ◽  
Rebecca Roylance ◽  
Sibylle Mittnacht
Keyword(s):  
Treatment Options ◽  
Acquired Resistance ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Circulating Tumor Dna ◽  
Systemic Review ◽  
Breast Cancers ◽  
Liquid Biopsies ◽  
Metastatic Setting ◽  
Clinical Benefits

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have revolutionized the treatment of hormone-positive metastatic breast cancers (mBCs). They are currently established as standard therapies in combination with endocrine therapy as first- and second-line systemic treatment options for both endocrine-sensitive and endocrine-resistant mBC populations. In the first-line metastatic setting, the median progression-free survival for the three currently approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, with aromatase inhibitors is greater than 2 years (palbociclib 27.6 months; ribociclib 25.3 months; and abemaciclib 28.18 months). Although CDK4/6 inhibitors have significant clinical benefits and enable physicians to delay starting chemotherapy, they are expensive and can be associated with drug toxicities. Here, we have performed a systemic review of the reported molecular markers predictive of drug response including intrinsic and acquired resistance for CDK4/6 inhibition in mBC. The rapidly emerging molecular landscape is captured through next-generation sequencing of breast cancers (DNA with or without RNA), liquid biopsies (circulating tumor DNA), and protein analyses. Individual molecular candidates with robust and reliable evidence are discussed in more depth.

scholarly journals Comparative efficacy of dabrafenib + trametinib versus treatment options for metastatic melanoma in first-line settings

2021 ◽  
Author(s):  
Jing Wu ◽  
Jaydeep Das ◽  
Manik Kalra ◽  
Barbara Ratto
Keyword(s):  
Metastatic Melanoma ◽  
Survival Data ◽  
Meta Analysis ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Comparable Efficacy ◽  
First Line ◽  
Eligibility Criteria ◽  
Term Survival ◽  
Treatment Naïve

Aim: The objective was to systematically review the literature and assess the relative efficacy of agents approved in first-line settings via network meta-analysis. Materials & methods: A literature review was conducted via searching different medical databases. The eligibility criteria included Phase II or III randomized controlled trials that had enrolled treatment-naive adult patients with advanced/metastatic melanoma. Results: The network meta-analysis results suggested that dabrafenib + trametinib significantly prolongs the survival outcomes compared with the monotherapies and had comparable efficacy profile compared with encorafenib + binimetinib and cobimetinib + vemurafenib. In comparison with immunotherapies, the results varied for progression-free survival and overall survival. Conclusion: Long-term survival data of dabrafenib + trametinib establishes the combination as one of the preferred treatment options for previously untreated melanoma patients.

scholarly journals Molecular and Cellular Mechanisms of Metformin in Cervical Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2545
Author(s):  
Ya-Hui Chen ◽  
Po-Hui Wang ◽  
Pei-Ni Chen ◽  
Shun-Fa Yang ◽  
Yi-Hsuan Hsiao
Keyword(s):  
Cervical Cancer ◽  
Potential Role ◽  
Treatment Options ◽  
Cellular Mechanisms ◽  
Anticancer Effects ◽  
Clinical Benefits ◽  
Underlying Mechanisms

Cervical cancer is one of the major gynecologic malignancies worldwide. Treatment options include chemotherapy, surgical resection, radiotherapy, or a combination of these treatments; however, relapse and recurrence may occur, and the outcome may not be favorable. Metformin is an established, safe, well-tolerated drug used in the treatment of type 2 diabetes; it can be safely combined with other antidiabetic agents. Diabetes, possibly associated with an increased site-specific cancer risk, may relate to the progression or initiation of specific types of cancer. The potential effects of metformin in terms of cancer prevention and therapy have been widely studied, and a number of studies have indicated its potential role in cancer treatment. The most frequently proposed mechanism underlying the diabetes–cancer association is insulin resistance, which leads to secondary hyperinsulinemia; furthermore, insulin may exert mitogenic effects through the insulin-like growth factor 1 (IGF-1) receptor, and hyperglycemia may worsen carcinogenesis through the induction of oxidative stress. Evidence has suggested clinical benefits of metformin in the treatment of gynecologic cancers. Combining current anticancer drugs with metformin may increase their efficacy and diminish adverse drug reactions. Accumulating evidence is indicating that metformin exerts anticancer effects alone or in combination with other agents in cervical cancer in vitro and in vivo. Metformin might thus serve as an adjunct therapeutic agent for cervical cancer. Here, we reviewed the potential anticancer effects of metformin against cervical cancer and discussed possible underlying mechanisms.

scholarly journals Association of UCP1 and UCP2 variants with diabetic retinopathy susceptibility in type-2 diabetes mellitus patients: a meta-analysis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xujia Liu ◽  
Zehua Jiang ◽  
Guihua Zhang ◽  
Tsz Kin Ng ◽  
Zhenggen Wu
Keyword(s):  
Diabetes Mellitus ◽  
Diabetic Retinopathy ◽  
Fixed Effects ◽  
Literature Search ◽  
Meta Analysis ◽  
Sensitivity Analyses ◽  
Fixed Effects Models ◽  
Type 2 Dm ◽  
Subgroup Analyses

Abstract Background Genetic association of uncoupling proteins (UCPs) variants with the susceptibility of diabetic retinopathy (DR) in diabetes mellitus (DM) patients has been reported but with controversy. Here we aimed to conduct a meta-analysis to confirm the association of different UCPs variants with DR. Methods Three databases (Medline Ovid, Embase Ovid and CENTRAL) were applied in the literature search. Five genetic models, including allelic, homozygous, heterozygous, dominant and recessive models, were evaluated. Odds ratios (OR) were estimated under the random or fixed-effects models. Subgroup analyses, publication bias and sensitivity analyses were also conducted. Results Eleven studies on 2 UCPs variants (UCP1 rs1800592 and UCP2 rs659366) were included. Our meta-analysis showed that UCP1 rs1800592 was not associated with DR in type-2 DM patients, and UCP2 rs659366 also showed no association with DR. In the subgroup analyses on the stage of DR, allele G of UCP1 rs1800592 significantly increased the susceptibility of proliferative diabetic retinopathy (PDR) in type-2 DM patients in the allelic (OR = 1.26, P = 0.03) and homozygous models (OR = 1.60, P = 0.04). Subgroup analysis on ethnicity did not found any significant association of rs1800592 and rs659366 with DR. Conclusion Our meta-analysis confirmed the association of UCP1 rs1800592 variant with PDR in patients with type-2 DM, suggesting its potential as a genetic marker for PDR prediction in population screening.

scholarly journals Bevacizumab plus capecitabine as later-line treatment for patients with metastatic colorectal cancer refractory to irinotecan, oxaliplatin, and fluoropyrimidines

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yeong Hak Bang ◽  
Jeong Eun Kim ◽  
Ji Sung Lee ◽  
Sun Young Kim ◽  
Kyu-Pyo Kim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Median Overall Survival ◽  
Treatment Options ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Line Treatment ◽  
Free Survival ◽  
Medical Need ◽  
Significant Disease

AbstractThere is an unmet medical need for later-line treatment options for patients with metastatic colorectal cancer (mCRC). Considering that, beyond progression, co-treatment with bevacizumab and cytotoxic chemotherapy showed less toxicity and a significant disease control rate, we aimed to evaluate the efficacy of capecitabine and bevacizumab. This single-center retrospective study included 157 patients between May 2011 and February 2018, who received bevacizumab plus capecitabine as later-line chemotherapy after progressing with irinotecan, oxaliplatin, and fluoropyrimidines. The study treatment consisted of bevacizumab 7.5 mg/kg on day 1 and capecitabine 1,250 mg/m2 orally (PO) twice daily on day 1 to 14, repeated every 3 weeks. The primary endpoint was progression-free survival (PFS). The median PFS was 4.6 months (95% confidence interval [CI] 3.9–5.3). The median overall survival (OS) was 9.7 months (95% CI 8.3–11.1). The overall response rate was 14% (22/157). Patients who had not received prior targeted agents showed better survival outcomes in the multivariable analysis of OS (hazard ratio [HR] = 0.59, 95% CI 0.43–0.82, P = 0.002) and PFS (HR = 0.61, 95% CI 0.43–0.85, P = 0.004). Bevacizumab plus capecitabine could be a considerably efficacious option for patients with mCRC refractory to prior standard treatments.

scholarly journals Immunotherapy in Adrenocortical Carcinoma: Predictors of Response, Efficacy, Safety, and Mechanisms of Resistance

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 304
Author(s):  
Marta Araujo-Castro ◽  
Eider Pascual-Corrales ◽  
Javier Molina-Cerrillo ◽  
Teresa Alonso-Gordoa
Keyword(s):  
Adrenocortical Carcinoma ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Mechanisms Of Resistance ◽  
Response Efficacy ◽  
Predictors Of Response ◽  
Primary Endpoints ◽  
Tumor Mutational Burden

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options in the advanced stages. Immunotherapy offers hope for altering the orthodox management of cancer, and its role in advanced ACC has been investigated in different studies. With the aim clarifying the role of immunotherapy in ACC we performed a comprehensive review about this topic focusing on the predictors of response, efficacy, safety, and the mechanisms of resistance. Five clinical trials with four immune checkpoint inhibitors (pembrolizumab, avelumab, nivolumab, and ipilimumab) have investigated the role of immunotherapy in advanced ACC. Despite, the different primary endpoints used in these studies, the reported rates of overall response rate and progression free survival were generally poor. Three main potential markers of response to immunotherapy in ACC have been described: Expression of PD-1 and PD-L1, microsatellite instability and tumor mutational burden. However, none of them has been validated in prospective studies. Several mechanisms of ACC immunoevasion may be responsible of immunotherapy failure, and a greater knowledge of these mechanisms might lead to the development of new strategies to overcome the immunotherapy resistance. In conclusion, although currently the role of immunotherapy is limited, the identification of immunological markers of response and the implementation of strategies to avoid immunotherapy resistance could improve the efficacy of this therapy.

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