A weighted-adjusted indirect comparison of everolimus (EVE) versus axitinib (AXI) in second-line metastatic renal cell carcinoma (mRCC) patients who previously failed sunitinib therapy.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 491-491
Author(s):  
Steven A. Sherman ◽  
Xufang Wang ◽  
Billy Amzal ◽  
Roman Casciano ◽  
Haitao Gao ◽  
...  
Keyword(s):  
Indirect Comparison ◽  
Progression Free Survival ◽  
Similar Efficacy ◽  
Phase Iii ◽  
Second Line ◽  
Two Phase ◽  
Phase Iii Clinical Trials ◽  
Kaplan Meier ◽  
Adjusted Indirect Comparison ◽  
Baseline Characteristics

491 Background: Both EVE and AXI have been approved for second-line treatment of mRCC after VEGFR-TKI therapy failure. No head-to-head clinical trial has compared clinical outcomes between EVE and AXI in this setting. This study aims to compare progression free survival (PFS) from two phase III clinical trials among mRCC patients with SUN as their only prior antineoplastic therapy and subsequently treated with EVE in the RECORD-1 trial vs. AXI in the AXIS trial, after adjusting for cross-trial differences. Methods: A weighted-adjusted indirect comparison using patient-level data from RECORD-1 and summary data from the AXIS trial publication was performed to align baseline characteristics from both trials and compare PFS (central review). A subset of N=43 second-line SUN -refractory mRCC patients treated with EVE were identified in RECORD-1 to correspond to a similar subset of patients (N=194) treated with AXI in AXIS. Logistic regression was used to identify factors predicting PFS in RECORD-1. The RECORD-1 subset was weighted to align the distributions of these key factors (i.e., MSKCC risk, gender, and time on prior SUN) with the AXIS subset. Weights were calculated for each patient using the following equation: Wi = [Pi (AAXIS)/Pi (ARECORD-1)] * [Pi (BAXIS)/Pi (BRECORD-1)] * [Pi (CAXIS)/Pi (CRECORD-1)], where A=Gender, B=MSKCC risk, and C=time on prior SUN. A weighted median PFS estimate with 95% bootstrap confidence interval (CI) and corresponding Kaplan-Meier (KM) curve were derived for EVE patients. Results: After weighting, the three key baseline characteristics were mostly comparable between the two studies, with the exception of MSKCC where a higher proportion of poor risk patients was evident in RECORD-1 (42%) vs. AXIS (33%). A median PFS of 5.1 months (95% CI: 3.6-10.7) was observed for weighted EVE patients compared to 4.8 months (95% CI: 4.5-6.4) reported in AXIS. Conclusions: The PFS estimates suggest similar efficacy between EVE and AXI in SUN-refractory mRCC patients. Further research is needed to confirm these results, which should be interpreted as those from an observational study.

Efficacy of Daratumumab Based Regimens Compared to Standard of Care for Transplant Ineligible Newly Diagnosed Multiple Myeloma in Phase III Clinical Trials: A Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Zahoor Ahmed ◽  
Karun Neupane ◽  
Rabia Ashraf ◽  
Amna Khan ◽  
Moazzam Shahzad ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Standard Care ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Control Group ◽  
Two Phase ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Phase Iii Clinical Trials

Introduction: Daratumumab (Dara) is a human anti-CD38 monoclonal antibody approved for multiple myeloma (MM) treatment. Dara has a promising efficacy and a favorable safety profile in newly diagnosed MM (NDMM) patients. This study is focused on the efficacy and safety of Dara when added to the standard care regimen in transplant ineligible NDMM in phase III clinical trials. Methods: We performed a comprehensive database search on four major databases (PubMed, Embase, Cochrane, and Clinicaltrials.gov). Our search strategy included MeSH (Medical Subject Headings) terms and key words for multiple myeloma and Dara including trade names and generic names from date of inception to May 2020. Initial search revealed 587 articles. After excluding review articles, duplicates, and non-relevant articles, two phase III clinical trials were included which reported overall response rate (ORR), and progression free survival (PFS) of transplant ineligible NDMM patients with Dara addition to standard care regimen. Odds ratios (OR) of ORR were computed and hazard ratios (HR) of PFS (along with 95% confidence intervals; CI) were extracted to compute a pooled HR using a fixed effect model in RevMan v.5.4. Results: A total of 1453 transplant ineligible NDMM patients were enrolled and evaluated in two phase III randomized clinical trials. Seven hundred and eighteen patients were in Dara group and 735 patients were in control group. Bahlis et al. (2019) studied Dara + lenolidamide (R) and dexamethasone (d) vs Rd in NDMM pts (n=737) in MAIA phase III trial. Similarly, Mateos et al. (2018) reported the role of Dara + bortezomib (V) + melphalan (M), and prednisone (P) vs VMP in NDMM pts (n=706) in a phase III trial (Alcyone). A pooled analysis of these phase III trials showed ORR (OR: 3.26, 95% CI 2.36-4.49; p < 0.00001, I2 = 0%), and progression free survival (PFS) (HR: 0.53, 95% CI 0.43-0.65; p < 0.00001, I2 = 0%). Achievement of minimal residual disease (MRD) negative status was significant in Dara based regimen as compared to control group (OR: 4.49, 95% CI 3.31-6.37; p < 0.00001, I2 = 0%). Dara addition to standard care regimen (Rd and VMP) decreased the risk of progression/death to 42% (HR: 0.58, 95% CI 0.48-0.70; p < 0.00001, I2 = 0%). The addition of Dara increased the risk of neutropenia (OR: 1.41, 95% CI 1.07-1.85; p < 0.02, I2 = 44%), and pneumonia (OR: 2.25, 95% CI 1.54-3.29; p < 0.0001, I2 = 37%) vs control group. However, decreased risk of anemia (OR: 0.64, 95% CI 0.49-0.85: p < 0.002, I2=30%) was observed in Dara group vs control group (Figure 1). Conclusion: Addition of Dara to the standard care regimen for transplant ineligible NDMM achieved the surrogate end points with improved efficacy and MRD negative status with manageable toxicity. However, data from more randomized controlled trials is needed. Table Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

First-line sunitinib versus pazopanib in metastatic renal cell carcinoma (mRCC): Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 544-544 ◽  
Author(s):  
Jose Manuel Ruiz Morales ◽  
J Connor Wells ◽  
Frede Donskov ◽  
Georg A. Bjarnason ◽  
Jae-Lyun Lee ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Progression Free Survival ◽  
Similar Efficacy ◽  
Phase Iii ◽  
Line Treatment ◽  
Second Line ◽  
First Line

544 Background: Sunitinib (SU) and Pazopanib (PZ) have been compared head-to-head in the first-line phase III COMPARZ study in metastatic renal cell carcinoma (mRCC). We compared SU versus PZ, to confirm outcomes and subsequent second-line therapy efficacy in a population-based setting. Methods: We used the IMDC to assess overall survival (OS), progression-free survival (PFS), response rate (RR) and performed proportional hazard regression adjusting for IMDC prognostic groups. Second-line OS2 and PFS2 were also evaluated. Results: We obtained data from 3,606 patients with mRCC treated with either first line SU (n=3226) or PZ (n=380) with an overall median follow-up of 43.5 months (m) (CI95% 41.4 – 46.4). IMDC risk group distribution for favorable prognosis was 440 (17.3%) for SU vs 72 (25%) for PZ, intermediate prognosis 1414 (55.6%) for SU vs 153 (53%) for PZ, poor prognosis 689 (27.1%) for SU vs 62 (22%) for PZ, p= 0.0027. We found no difference between SU vs. PZ for OS (20.1 [CI95% 18.76-21.42] vs. 23.68 m [CI95% 19.54 - 28.81] p=0.19), PFS (7.22 [CI95% 6.76 - 7.78] vs. 6.83 m [CI95% 5.58 - 8.27] p=0.49). The RR was similar in both groups (Table 1). Adjusted HR for OS and PFS were 0.952 (CI95% 0.788 – 1.150 p=0.61) and 1.052 (CI95% 0.908 – 1.220 p = 0.49), respectively. We also found no difference in any second-line treatment between either post-SU vs. post-PZ groups for OS2 (12.88 [CI95% 11.89 – 14.19] vs. 12.91 m [CI95% 10.3 – 19.1] p=0.47) and PFS2 (3.67 [CI95% 3.38 – 3.87] vs. 4.53 m [CI95% 3.08 – 5.35] p=0.4). There was no statistical difference in OS2 and PFS2 if everolimus was used after SU or PZ (p = 0.33 and p = 0.41, respectively) or if axitinib was used after SU or PZ (p = 0.73 and p = 0.72, respectively). Conclusions: We confirmed in real world practice, that SU and PZ have similar efficacy in the first-line setting for mRCC and do not affect outcomes with subsequent second-line treatment. [Table: see text]

Indirect Comparisons to Assess the Relative Efficacy of Carfilzomib + Lenalidomide + Dexamethasone Versus Panobinostat + Bortezomib + Dexamethasone and Bortezomib + Dexamethasone: A Matching Adjusted Indirect Comparison

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5622-5622
Author(s):  
Michael Rael ◽  
Agnes Benedict ◽  
Jack Ishak ◽  
Sarah Cadarette ◽  
Marco Campioni ◽  
...  
Keyword(s):  
Indirect Comparison ◽  
Phase Iii ◽  
Novel Treatments ◽  
Prior Therapy ◽  
Hazard Ratios ◽  
Phase Iii Study ◽  
Adjusted Indirect Comparison ◽  
Equity Ownership ◽  
Baseline Characteristics ◽  
Indirect Comparisons

Abstract Background: Several novel treatments have recently been approved for the treatment of relapsed multiple myeloma (RMM). In the absence of head-to-head comparisons between these novel treatments, clinicians and payers must rely on statistical indirect comparisons. The objective of this analysis is to derive measures of relative effectiveness for carfilzomib + lenalidomide + dexamethasone (KRd) against bortezomib + dexamethasone (Vd), and the recently approved combination of panobinostat + bortezomib + dexamethasone (PVd) in patients with RMM who have been treated with at least one prior therapy. Methods: A matching-adjusted indirect comparison (MAIC) (Signorovitch, 2010) for progression-free survival (PFS) and overall survival (OS) was conducted between the KRd arm of the phase III study ASPIRE (Stewart et al., 2015) versus the PVd and Vd arms of the phase III study PANORAMA 1 (San-Miguel et al., 2014). The MAIC utilized patient level data from ASPIRE, and adjusted for reported patient population differences. An MAIC uses a propensity score type equation to assign case weights to the KRd patients so that their weighted baseline characteristics match the baseline of the PVd or Vd population. This re-weighting process attempts to answer the question: What would the outcomes be if KRd had been administered to a population matching the characteristics of the PVd or Vd arms? Adjustments were made for age, gender, ECOG status, history of autologous stem cell transplant, disease duration, number of prior regimens, ISS stage, prior bortezomib use, and creatinine clearance rate. Cox PH models were fitted to estimate hazard ratios (HRs) for PFS and OS. Weibull survival curves best fit the adjusted survival data and were used to estimate median survival times. A simulated treatment comparison (STC) (Ishak et al., 2015), which adjusts for reported patient population differences using regression equations, was conducted as a cross validation. Results: The KRd arm in ASPIRE included 396 patients and the PVd and Vd arms in PANORAMA 1 included 387 and 381 patients, respectively. After successfully matching, the effective sample size of the KRd population was 131 for the PVd comparison and 138 for the Vd comparison. See Figure 1 for the MAIC adjusted PFS and OS Kaplan-Meier curves. Hazard ratios (95% CIs) from the Cox models for PFS and OS outcomes were 0.317 (0.228, 0.44) and 0.582 (0.394, 0.86) for KRd vs PVd, respectively and 0.208 (0.153, 0.283) and 0.472 (0.324, 0.688) for KRd vs Vd, respectively. Corresponding hazard ratios from the STC were similar and validate the MAIC results. Estimates of median PFS and OS in months were 29.5 and 65.2 for KRd compared to 12.0 and 40.9 for PVd, respectively. Corresponding estimates were 29.7 and 57.3 for KRd compared to 8.2 and 33.0 for Vd. Figure 1. Conclusion: This MAIC analysis suggests that KRd provides a consistent and statistically significant PFS and OS benefit relative to PVd and Vd in RMM patients who have been treated with at least one prior therapy. Beyond the patient characteristics available from PANORAMA 1, other variables that may potentially influence outcomes were not adjusted for in the analysis. This analysis did not compare KRd to PVd in patients who have received at least 2 prior regimens including bortezmib and an IMiD (panobinostat's FDA-approved indication) due to lack of published data on the baseline characteristics of this patient subset studied in PANORAMA 1. Disclosures Rael: Onyx: Consultancy; Evidera: Employment. Benedict:Onyx: Consultancy; Evidera: Employment. Ishak:Onyx: Consultancy; Evidera: Employment. Cadarette:Evidera: Employment; Onyx: Consultancy. Campioni:Amgen: Employment, Equity Ownership. Panjabi:Onyx Pharmaceuticals Inc., An Amgen Subsidiary: Employment, Equity Ownership.

scholarly journals Efficacy of next treatment received after nivolumab progression in patients with advanced nonsmall cell lung cancer

2018 ◽  
Vol 4 (2) ◽  
pp. 00120-2017 ◽  
Author(s):  
Adrien Costantini ◽  
Jennifer Corny ◽  
Vincent Fallet ◽  
Sophie Renet ◽  
Sylvie Friard ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Lung Cancer ◽  
Performance Status ◽  
Progression Free Survival ◽  
Nonsmall Cell Lung Cancer ◽  
Similar Efficacy ◽  
Phase Iii ◽  
Second Line ◽  
Phase Iii Trials

Nivolumab for the treatment of advanced nonsmall cell lung cancer (NSCLC) evaluated in phase III trials showed 50% progression at first evaluation, but better overall survival (OS), suggesting regained efficacy of treatments given thereafter. We aimed to evaluate the efficacy of nivolumab and of next treatment received after nivolumab progression in patients with advanced NSCLC.Our multicentre retrospective study included all patients receiving nivolumab between January and December 2015. The primary end-point was progression-free survival (PFS) of treatment given after nivolumab.The 303 patients had the following characteristics: median age 63 years, 69% males, 92% smokers, 67% performance status 0–1 and 61% adenocarcinoma. Nivolumab was given as second-line treatment in 40% of patients. With 13.7 months of median follow-up, nivolumab PFS and OS were 2.6 and 11.3 months, respectively. At the cut-off analysis 18% were controlled under nivolumab, 14% were deceased and 5% were lost to follow-up under nivolumab. Among the 191 (63%) patients eligible for post-nivolumab (PN) treatment, 115 (38%) received further treatment and were characterised by better performance status (p=0.028) and by receiving more injections of nivolumab (p=0.001). Global PN-OS and PN-PFS were 5.2 and 2.8 months, respectively. Drugs most frequently used after nivolumab were gemcitabine (23%), docetaxel (22%) and erlotinib (16%), with median PFS of 2.8, 2.7 and 2.0 months, respectively.Nivolumab produced similar efficacy as in phase III trials, although patients received nivolumab later and had worse performance status. 38% received treatment after nivolumab progression with efficacy comparable to historical second-line trials.

Magnitude of progression-free survival (PFS) improvement and treatment (Tx) duration in metastatic colorectal cancer (mCRC) for bevacizumab (BV) in combination with oxaliplatin-containing regimens: An analysis of two phase III studies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4073-4073 ◽  
Author(s):  
B. J. Giantonio ◽  
N. J. Meropol ◽  
P. J. Catalano ◽  
V. Ng ◽  
R. Oliver ◽  
...  
Keyword(s):  
Cox Regression ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Two Phase ◽  
Free Survival ◽  
Kaplan Meier ◽  
Hazard Ratios ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Phase Iii Studies

4073 Background: In trials of BV with FOLFOX (fluorouracil, leucovorin, oxaliplatin) for mCRC, variability in the magnitude of PFS improvement has been reported [HR=0.61 in E3200 vs HR= 0.83 (FOLFOX or CAPOX (capecitabine and oxaliplatin)) in NO16966]. We propose that differences in rates of treatment discontinuation (D/C) for adverse events (AE) between these studies may have resulted in differences in the observed benefits associated with BV. We explored Tx duration (proportion of patients on Tx) and Tx D/C data at median PFS for the BV containing arms of each study. Methods: ECOG study E3200 randomized previously treated patients with mCRC to FOLFOX ± BV (10 mg/kg). NO16966 employed a 2x2 design that randomized previously untreated patients with mCRC to CAPOX vs FOLFOX and to BV (5 mg/kg) or placebo. In both trials, study Tx was defined as any component of the prescribed regimen. PFS was estimated from Kaplan-Meier curves, and hazard ratios (HR) for PFS were estimated by Cox regression. Results: Median PFS for the BV containing arm of the study: 30 weeks for E3200; 42 weeks for NO16966 Conclusion: These data suggest possible differences between the two studies in Tx duration and Tx D/C patterns with a greater proportion of patients on NO16966 discontinuing Tx for any AE. Duration of study Tx might have affected both the incidence of AEs and the magnitude of PFS benefit observed for the addition of bevacizumab to oxaliplatin-based chemotherapy in these studies. Attention to Tx duration and Non-PD Tx D/C in future clinical trials will be important when considering PFS as a primary efficacy endpoint. [Table: see text] No significant financial relationships to disclose.

Five-year survival outcomes with durvalumab after chemoradiotherapy in unresectable stage III NSCLC: An update from the PACIFIC trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8511-8511
Author(s):  
David R. Spigel ◽  
Corinne Faivre-Finn ◽  
Jhanelle Elaine Gray ◽  
David Vicente ◽  
David Planchard ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
Stage Iii ◽  
Smoking History ◽  
Kaplan Meier ◽  
Unresectable Stage ◽  
The Pacific ◽  
Patient Reported ◽  
Stage Iii Nsclc

8511 Background: In the placebo-controlled Phase III PACIFIC trial of patients with unresectable Stage III NSCLC whose disease had not progressed after platinum-based concurrent chemoradiotherapy (cCRT), durvalumab improved overall survival (OS) (stratified hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.53–0.87; p=0.0025; data cutoff [DCO] Mar 22, 2018) and progression-free survival (PFS) (stratified HR 0.52, 95% CI 0.42–0.65; p<0.0001; DCO Feb 13, 2017) based on the DCOs used for the primary analyses, and the degree of benefit remained consistent in subsequent updates. Durvalumab was associated with a manageable safety profile, and did not detrimentally affect patient-reported outcomes, compared with placebo. These findings established consolidation durvalumab after CRT (the ‘PACIFIC regimen’) as the standard of care in this setting. We report updated, exploratory analyses of OS and PFS, assessed approximately 5 years after the last patient was randomized. Methods: Patients with WHO PS 0/1 (and any tumor PD-L1 status) whose disease did not progress after cCRT (≥2 overlapping cycles) were randomized (2:1) 1–42 days following cCRT (total prescription radiotherapy dose typically 60–66 Gy in 30–33 fractions) to receive 12 months’ durvalumab (10 mg/kg IV every 2 weeks) or placebo, stratified by age (<65 vs ≥65 years), sex, and smoking history (current/former smoker vs never smoked). The primary endpoints were OS and PFS (blinded independent central review; RECIST v1.1) in the intent-to-treat (ITT) population. HRs and 95% CIs were estimated using stratified log-rank tests in the ITT population. Medians and OS/PFS rates at 60 months were estimated with the Kaplan–Meier method. Results: Overall, 709/713 randomized patients received treatment in either the durvalumab (n/N=473/476) or placebo (n/N=236/237) arms. The last patient had completed study treatment in May 2017. As of Jan 11, 2021 (median follow-up duration of 34.2 months in all patients; range, 0.2–74.7 months), updated OS (stratified HR 0.72, 95% CI 0.59–0.89; median 47.5 vs 29.1 months) and PFS (stratified HR 0.55, 95% CI 0.45–0.68; median 16.9 vs 5.6 months) remained consistent with the results from the primary analyses. The 60-month OS rates were 42.9% and 33.4% with durvalumab and placebo, respectively, and 60-month PFS rates were 33.1% and 19.0%, respectively. Updated treatment effect estimates for patient subgroups will be presented. Conclusions: These updated survival analyses, based on 5-year data from PACIFIC, demonstrate robust and sustained OS plus durable PFS benefit with the PACIFIC regimen. An estimated 42.9% of patients randomized to durvalumab remain alive at 5 years and approximately a third remain both alive and free of disease progression. Clinical trial information: NCT02125461.

Ziv-aflibercept: A novel angiogenesis inhibitor for the treatment of metastatic colorectal cancer

2013 ◽  
Vol 70 (21) ◽  
pp. 1887-1896 ◽  
Author(s):  
Clement Chung ◽  
Nisha Pherwani
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Performance Status ◽  
Angiogenesis Inhibitor ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Second Line ◽  
Patient Response ◽  
Line Setting

Abstract Purpose The pharmacology, pharmacokinetics, clinical efficacy, safety, and administration of ziv-aflibercept in combination therapy for metastatic colorectal cancer (mCRC) are reviewed. Summary Ziv-aflibercept (Zaltrap, Regeneron Pharmaceuticals and sanofi-aventis) is a novel recombinant fusion protein that targets the angiogenesis signaling pathway of tumor cells by blocking vascular endothelial growth factor (VEGF) receptors that play a key role in tumor growth and metastasis; it is a more potent VEGF blocker than bevacizumab. Ziv-aflibercept is approved by the Food and Drug Administration for use in combination with fluorouracil, irinotecan, and leucovorin (the FOLFIRI regimen) for second-line treatment of patients with mCRC who have disease progression during first-line oxaliplatin-based chemotherapy. A Phase III trial demonstrated that relative to FOLFIRI therapy alone, the use of ziv-aflibercept was associated with significantly improved patient response, overall survival, and progression-free survival in patients with good performance status at baseline, including some who had received prior bevacizumab therapy. The most common grade 3 or 4 adverse effects associated with ziv-aflibercept use in clinical studies were neutropenia, hypertension, and diarrhea; the U.S. product labeling warns of potential hemorrhage and other treatment-related risks. Conclusion Current clinical data are insufficient to directly compare ziv-aflibercept and bevacizumab when used with standard combination chemotherapy as first- or second-line regimens for mCRC. The role of ziv-aflibercept is currently limited to the second-line setting in combination with irinotecan-based regimens in mCRC patients who have not received irinotecan previously. The role of ziv-aflibercept in chemotherapy for other tumor types is yet to be determined.

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