Final overall survival (OS) analysis with modeling of crossover impact in the phase III GRID trial of regorafenib vs placebo in advanced gastrointestinal stromal tumors (GIST).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 156-156 ◽  
Author(s):  
George D. Demetri ◽  
Peter Reichardt ◽  
Yoon-Koo Kang ◽  
Jean-Yves Blay ◽  
Heikki Joensuu ◽  
...  
Keyword(s):  
Failure Time ◽  
Cox Model ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Positive Trend ◽  
Structural Failure ◽  
Free Survival ◽  
Hazard Ratios ◽  
Background Grid ◽  
The Impact

156 Background: GRID showed that regorafenib (REG) improves progression-free survival (PFS; primary endpoint) vs placebo (PBO) in patients (pts) with advanced GIST after failure of at least imatinib and sunitinib (HR 0.27; 1-sided p < 0.0001). An interim OS analysis at the time of the primary PFS analysis showed a positive trend (HR 0.77; p = 0.199) despite 85% of PBO pts crossing over to REG. An exploratory analysis modeling the impact of crossover on OS suggested a benefit for REG. We present exploratory analyses of OS comparing crossover correction results at different times, including at the planned final OS analysis. Methods: Data cut-off dates for OS analyses were 26 Jan 2012 (final PFS analysis), 31 Jan 2014, and 8 Jun 2015 (final OS analysis). The impact of crossover on OS was modeled using 2 randomization-based methods: rank preserving structural failure time (RPSFT) and iterative parameter estimation (IPE), both considered best choice among correction analytics. Hazard ratios (HRs) and 95% CIs were derived using the Cox model. Results: Pts were randomized (2:1) to REG (n = 133) or PBO (n = 66). Data maturity in terms of deaths of randomized pts was 23%, 70%, and 81%. At data cut-off for the final OS analysis, a total of 162 deaths occurred: REG 109 (82%) and PBO 53 (80%); 7 pts remained on treatment. Compared to the 2012 OS analysis, continued crossover treatment further diluted the treatment effect, evidenced by the increasing HR in the ITT analysis at later times (Table). Conclusions: IPE correction provides more stable estimated median times and HRs than RPSFT. These exploratory analyses modeling the impact of crossover to active drug suggest that REG has a greater OS benefit than noted in the ITT analysis. Such sensitivity analytics are needed to understand fully the benefits of active drugs in crossover trials. Clinical trial information: NCT01271712. [Table: see text]

The occurrence of grade 4 adverse events and survival outcomes in patients with nonsquamous non-small cell lung cancer receiving bevacizumab with chemotherapy in the phase III PointBreak and AVAiL studies.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19022-e19022
Author(s):  
Liza Cosca Villaruz ◽  
Mark A. Socinski ◽  
Jyoti D. Patel ◽  
Larry Leon ◽  
Sebastien Hazard ◽  
...  
Keyword(s):  
Cox Model ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Free Survival ◽  
End Point ◽  
Kaplan Meier ◽  
Hazard Ratios ◽  
Post Hoc ◽  
Unacceptable Toxicity ◽  
Clinical Trial Information

e19022 Background: Progression-free survival (PFS) is a key trial end point for clinical practice, as it relates to a change of treatment line. Grade 4 progression-free survival (G4PFS; defined as time from treatment start to the earlier of progressive disease [PD], onset of a G4 adverse event [AE], or death from any cause) is a composite end point incorporating a measure of tolerability to PFS. This post hoc analysis evaluates G4PFS and the effect of G4 AEs on PFS and overall survival (OS) in patients (pts) enrolled in PointBreak (PB) and AVAiL. Methods: Pts in PB were randomized to bevacizumab (BEV) 15 mg/kg q3w with carboplatin and paclitaxel (CP) or pemetrexed (CPem) for ≤4 cycles. Eligible pts received either BEV or BEV + Pem q3w until PD or unacceptable toxicity. Pts in AVAiL received cisplatin and gemcitabine for ≤6 cycles and either placebo or BEV (7.5 or 15 mg/kg) q3w until PD. AEs were graded via NCI-CTCAE v3.0. Kaplan-Meier and Cox model methods were used to estimate medians and hazard ratios (HRs) for PFS, G4PFS, and OS. PFS and OS were also compared in each arm for pts with occurrence of a G4 AE before week 12 of treatment vs those without. Results: Of those receiving BEV, ~30% of AVAiL pts and 38% of PB pts had a G4 AE. Uncomplicated neutropenia was the most common G4 AE in the CP + BEV arm of PB (26%) and in the BEV arms of AVAiL (11%). PFS, G4PFS, and outcomes by G4 AE occurrence are shown (Table). Conclusions: In both the PB and AVAiL trials, median G4PFS was numerically shorter than median PFS. G4 AE occurrence, however, did not affect subsequent PFS or OS in either trial. Clinical trial information: NCT00762034 and NCT00806923. [Table: see text]

An updated overall survival analysis with correction for protocol-planned crossover of the international, phase III, randomized, placebo-controlled trial of regorafenib in advanced gastrointestinal stromal tumors after failure of imatinib and sunitinib (GRID).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 110-110 ◽  
Author(s):  
George D. Demetri ◽  
Peter Reichardt ◽  
Yoon-Koo Kang ◽  
Jean-Yves Blay ◽  
Heikki Joensuu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Failure Time ◽  
Cox Model ◽  
Controlled Trial ◽  
Progression Free Survival ◽  
High Rate ◽  
Phase Iii ◽  
Primary Analysis ◽  
Significant Difference ◽  
The Impact

110 Background: The GRID study showed that regorafenib improves progression-free survival compared with placebo in patients with advanced GIST after failure of at least imatinib and sunitinib (HR 0.27; 1-sided p<0.0001; Demetri 2013). At the time of the primary analysis, no significant difference in the secondary endpoint of overall survival (OS) was observed (HR 0.77; p=0.199), but this result may have been confounded by the high rate of crossover to regorafenib (85%) of placebo patients at progression. We conducted exploratory analyses of updated OS data to assess the effect of correcting for this protocol-planned crossover. Methods: The data cut-off for this updated OS analysis was 31 January 2014 (2 years after the primary analysis). OS was corrected using two randomization-based methods: rank preserving structural failure time (RPSFT) and iterative parameter estimation (IPE); both methods are considered as best choice among all correction analytics. Hazard ratios and 95% CI were derived using the Cox model. Results: A total of 139 deaths had occurred at the time of data cut-off: 91 events (68.4% of patients) in the regorafenib group and 48 (72.7%) in the placebo group. A total of 22 patients remained on regorafenib treatment (median duration 2.1 years, range 0.9–2.4). The updated hazard ratio for OS favored regorafenib (0.85, 95% CI: 0.60 - 1.21; p=0.18). Median OS was estimated as 17.4 months in both groups, with crossover from placebo. The corrected HRs for OS are less than the uncorrected HR (Table). Conclusions: The updated analysis of OS in the GRID trial is consistent with the primary analysis. An exploratory analysis correcting for the impact of cross-over on OS suggests a survival benefit for regorafenib in GIST. Clinical trial information: NCT01271712. [Table: see text]

scholarly journals Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater

2019 ◽  
Vol 37 (7) ◽  
pp. 537-546 ◽  
Author(s):  
Martin Reck ◽  
Delvys Rodríguez–Abreu ◽  
Andrew G. Robinson ◽  
Rina Hui ◽  
Tibor Csőszi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Failure Time ◽  
Progression Free Survival ◽  
Small Cell ◽  
Structural Failure ◽  
Small Cell Lung ◽  
Free Survival ◽  
Inverse Probability ◽  
Platinum Based Chemotherapy

Purpose In the randomized, open-label, phase III KEYNOTE-024 study, pembrolizumab significantly improved progression-free survival and overall survival (OS) compared with platinum-based chemotherapy in patients with previously untreated advanced non–small-cell lung cancer (NSCLC) with a programmed death ligand 1 tumor proportion score of 50% or greater and without EGFR/ALK aberrations. We report an updated OS and tolerability analysis, including analyses adjusting for potential bias introduced by crossover from chemotherapy to pembrolizumab. Patients and Methods Patients were randomly assigned to pembrolizumab 200 mg every 3 weeks (for up to 2 years) or investigator’s choice of platinum-based chemotherapy (four to six cycles). Patients assigned to chemotherapy could cross over to pembrolizumab upon meeting eligibility criteria. The primary end point was progression-free survival; OS was an important key secondary end point. Crossover adjustment analysis was done using the following three methods: simplified two-stage method, rank-preserving structural failure time, and inverse probability of censoring weighting. Results Three hundred five patients were randomly assigned (pembrolizumab, n = 154; chemotherapy, n = 151). At data cutoff (July 10, 2017; median follow-up, 25.2 months), 73 patients in the pembrolizumab arm and 96 in the chemotherapy arm had died. Median OS was 30.0 months (95% CI, 18.3 months to not reached) with pembrolizumab and 14.2 months (95% CI, 9.8 to 19.0 months) with chemotherapy (hazard ratio, 0.63; 95% CI, 0.47 to 0.86). Eighty-two patients assigned to chemotherapy crossed over on study to receive pembrolizumab. When adjusted for crossover using the two-stage method, the hazard ratio for OS for pembrolizumab versus chemotherapy was 0.49 (95% CI, 0.34 to 0.69); results using rank-preserving structural failure time and inverse probability of censoring weighting were similar. Treatment-related grade 3 to 5 adverse events were less frequent with pembrolizumab compared with chemotherapy (31.2% v 53.3%, respectively). Conclusion With prolonged follow-up, first-line pembrolizumab monotherapy continues to demonstrate an OS benefit over chemotherapy in patients with previously untreated, advanced NSCLC without EGFR/ALK aberrations, despite crossover from the control arm to pembrolizumab as subsequent therapy.

Project Switch: Docetaxel as a potential synthetic control in metastatic non-small cell lung cancer (mNSCLC) trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9105-9105 ◽  
Author(s):  
Michael E. Menefee ◽  
Yutao Gong ◽  
Pallavi Shruti Mishra-Kalyani ◽  
Rajeshwari Sridhara ◽  
Bindu Kanapuru ◽  
...  
Keyword(s):  
Randomized Trials ◽  
Progression Free Survival ◽  
Experimental Therapy ◽  
Synthetic Control ◽  
Small Cell Lung ◽  
Free Survival ◽  
Kaplan Meier ◽  
Hazard Ratios ◽  
Real World Evidence ◽  
The Impact

9105 Background: Docetaxel is a common comparator arm to test novel therapies in post-platinum mNSCLC trials. The advent of Real World Evidence (RWE) has renewed interest in the use of synthetic control arms (control arms from previously conducted randomized trials) to improve accrual to trials and increase patient access of promising experimental agents. We reviewed legacy second-line (2L) mNSCLC trials to assess the impact of switching docetaxel control arms from one trial to another and compare to an experimental regimen. Methods: We identified 5 contemporary 2L trials that enrolled 2013 patients receiving an experimental therapy vs. docetaxel: 5 immunoncology head-to-head trials (one with 2 arms) and one anti-VEGF add-on trial. Kaplan-Meier curves of overall survival (OS) and progression-free survival (PFS) were produced for docetaxel controls. We calculated OS and PFS hazard ratios and 95% confidence intervals for each synthetic trial. A pooled doc arm was also compared with each experimental agent. Results: See Table. Conclusions: Both individual and pooled docetaxel switching of control arms approximated the original OS HR and 95% CI. Methods such as bootstrapped sampling and propensity score matching will be performed in an effort to more closely approximate the original trial characteristics. [Table: see text]

scholarly journals Impact of Informative Censoring on the Kaplan-Meier Estimate of Progression-Free Survival in Phase II Clinical Trials

2014 ◽  
Vol 32 (27) ◽  
pp. 3068-3074 ◽  
Author(s):  
Federico Campigotto ◽  
Edie Weller
Keyword(s):  
Treatment Failure ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Informative Censoring ◽  
Phase Iii ◽  
Inadequate Response ◽  
Phase Ii Trials ◽  
Free Survival ◽  
Kaplan Meier ◽  
The Impact

Informative censoring in a progression-free survival (PFS) analysis arises when patients are censored for initiation of an effective anticancer treatment before the protocol-defined progression, and these patients are at a different risk for treatment failure than those who continue on therapy. This may cause bias in the estimated PFS when using the Kaplan-Meier method for analysis. Although there are several articles that discuss this issue from a theoretical perspective or in randomized phase III studies, there are little data to demonstrate the magnitude of the bias on the estimated quantities from a phase II trial. This article describes the issues by using two oncology phase II trials as examples, evaluates the impact of the bias using simulations, and provides recommendations. The two trials were selected because they demonstrate two different reasons for censoring. Simulations show that the magnitude of the bias depends primarily on the proportion of patients who are informatively censored and secondarily on the hazard ratio between the group of patients who remain on study and the group of patients who are informatively censored. Recommendations include using an alternative end point, which includes inadequate response and initial signs of clinical progression as treatment failure, and a competing risk analysis for studies in which competing events preclude or modify the probability of observing the primary event of interest. If informative censoring cannot be avoided, then all patients should be observed until progression, and sensitivity analyses should be used as appropriate.

POLO: Radiologic assessment of the impact of maintenance olaparib in patients (pts) with metastatic pancreatic cancer (mPaC).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 412-412
Author(s):  
Lawrence Howard Schwartz ◽  
Hedy L. Kindler ◽  
Pascal Hammel ◽  
Michele Reni ◽  
Eric Van Cutsem ◽  
...  
Keyword(s):  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Complete Response ◽  
Pancreatic Disease ◽  
Phase Iii ◽  
Sensitivity Analyses ◽  
Primary Analysis ◽  
Free Survival ◽  
Radiologic Assessment ◽  
The Impact

412 Background: The phase III POLO study (NCT02184195) demonstrated a benefit of maintenance olaparib over placebo in the radiologically assessed primary endpoint of progression-free survival (PFS) in pts with mPaC (median 7.4 vs 3.8 months [mo]; 12-mo rate 34% vs 15%). The impact of radiologic assessment of pancreatic lesions, which is considered challenging, was explored. Methods: Tumors were assessed using Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review (BICR) in pts with mPaC treated with maintenance olaparib or placebo. PFS was analyzed in subsets of pts based on various event criteria. Results: All 154 randomized pts had mPaC prior to chemotherapy, of whom 122 had disease in the pancreas at POLO baseline (BL); 34% (53/154) had pancreas-only target lesions (TL), 26% (40/154) also had ≥1 TL outside of the pancreas, and in 19% (29/154) pancreatic disease was recorded as non-TL. Sensitivity analyses were consistent with the primary PFS analysis (Table), including when all pancreas lesion assessments were discounted (median PFS 7.4 vs 4.7 mo; 12-mo rate 38% vs 22%). Of 53 pts with pancreas-only TLs at BL, 34 had disease progression (PD); in 20 pts this was not solely based on TL measurements (16 had new lesions; 4 had multiple-cause PD). Confirmed objective responses occurred during study maintenance treatment in 20% of olaparib pts (18/92) and 10% of placebo pts (6/62). In pts with pancreas-only TLs at BL there were 7 responses in the olaparib arm (1 complete response [CR], 6 partial responses [PR]) and 2 (2 PR) in the placebo arm. In pts who had ≥1 TL outside of the pancreas at BL there were 11 (1 CR, 10 PR) and 4 (4 PR) responses, respectively. Responses were generally durable irrespective of TL location. Conclusions: The significant PFS benefit with maintenance olaparib over placebo shown in the primary analysis was consistent across all sensitivity analyses and was not impacted by radiologic assessment of pancreatic TLs. Taken together, these findings suggest that contrary to historically held belief, primary pancreas TLs may be appropriate for inclusion as sites of RECIST-evaluable disease and for assessment of treatment outcome. Clinical trial information: NCT02184195. [Table: see text]

Impact of Chromosomal Abnormalities Del(13), T(4;14), and Del(17p) and Prior Treatment on Outcomes in Patients with Relapsed or Refractory Multiple Myeloma Treated with Lenalidomide

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3685-3685 ◽  
Author(s):  
Herve Avet Loiseau ◽  
Jean Soulier ◽  
Jean-Paul Fermand ◽  
Thierry Facon ◽  
Michel Attal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Plasma Cells ◽  
Chromosomal Abnormalities ◽  
Progression Free Survival ◽  
Median Number ◽  
Phase Iii ◽  
Free Survival ◽  
The Impact

Abstract The chromosomal abnormalities of del(13), t(4;14), and del(17p) are associated with poor progression-free survival (PFS) and shorter overall survival (OS) in newly diagnosed multiple myeloma (MM) treated with traditional chemotherapy. In patients with relapsed or refractory MM, a recent study demonstrated that lenalidomide (Revlimid®) can overcome poor prognosis conferred by del13q and t(4;14) but not del17p13 (Bahlis et al 2007). Here, we performed a retrospective analysis of medical records obtained from 49 clinical centers participating in the French Autorisation Temporaire d’Utilisation program. Patients with relapsed or refractory MM received dexamethasone 40 mg orally (days 1–4; 9–12 and 17–20 for 4 cycles, then days 1–4 beginning with cycle 5) and lenalidomide 25 mg orally on days 1–21 of a 28 day cycle. CD138-purified plasma cells were analyzed with fluorescent in-situ hybridization (FISH) for del(13), t(4;14), and del(17p) at diagnosis. Response and disease progression endpoints were evaluated using the European Group for Blood and Marrow Transplantation criteria. A multivariate analysis was performed to assess the impact of the following 7 variables on outcomes: any chromosomal change, prior bortezomib use, prior thalidomide use, prior transplant, progression on thalidomide, age, and number of lines of previous therapy. In total, 207 patients were included in the analysis; the median number of treatment cycles was 5 (range, 1–22). Most patients in the current study had received prior thalidomide (87%) or bortezomib (81%). The overall response rate (ORR) was 59%, including 7% complete response and 14% very good partial response. Median progression-free survival (PFS) and overall survival (OS) were 9.6 months and 15.1 months, respectively. These values are comparable to the recently published phase III trials (Weber et al., 2007; Dimopoulos et al., 2007), despite the higher median number of prior therapies in this analysis (5 vs. 3). Overall, 41% of patients had del(13), 14% had t(4;14) and 5% had del(17p). The ORR was significantly lower, and PFS and OS significantly shorter, in patients with del(13) compared with patients without del(13) (ORR: 43% vs. 71%, P<0.001; PFS: 5.0 months vs. 12.5 months, P<0.0001; OS: 10.4 months vs. 17.4 months, P=0.001). A similar pattern was observed in patients with t(4;14) versus patients without t(4:14) (ORR 39% vs. 62%, p=0.04; PFS 5.5 months vs. 10.6 months, p<0.01; OS 9.4 months vs. 15.4 months, p=0.005). Multivariate analysis identified hemoglobin (<10 g/dL), progression on thalidomide, and del(13) as independent predictors of reduced PFS (Table). There was a trend towards reduced PFS with prior bortezomib use and number of prior therapies. Age, sex, prior transplant, prior thalidomide use, and t(4;14) did not affect PFS. The results from the analysis indicate that del(13), progression on thalidomide, and hemoglobin levels ≥10 g/dL have a significant impact on outcomes in heavily pre-treated patients with relapsed or refractory MM. Randomized trials are needed to further assess these findings.

Impact of the prior chemotherapy with two different fluoropyrimidines on the efficacy of CapeIRI or FOLFIRI in metastatic colorectal cancer: An exploratory analysis of the phase III AXEPT trial.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 711-711
Author(s):  
Tae Won Kim ◽  
Kei Muro ◽  
Rui-hua Xu ◽  
Young Suk Park ◽  
Wei Wang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Progression Free Survival ◽  
Exploratory Analysis ◽  
Phase Iii ◽  
Free Survival ◽  
Prior Chemotherapy ◽  
Oral Fluoropyrimidine ◽  
Significant Difference ◽  
Phase Iii Study ◽  
The Impact

711 Background: Modified CapeIRI (irinotecan 200 mg/m2 on day 1, capecitabine 1600 mg/m2 on days 1–14 every 3 weeks) with or without bevacizumab (± BV) has shown non-inferiority of overall survival compared with FOLFIRI ± BV based on the phase III study, AXEPT, as second-line chemotherapy for patients with mCRC. In this exploratory analysis of the AXEPT trial, we evaluated the impact of the prior chemotherapy with two different fluoropyrimidine backbones (fluorouracil and leucovorin vs oral fluoropyrimidine) on the efficacy of CapeIRI and FOLFIRI. Methods: Patients were randomized to receive standard FOLFIRI ± bevacizumab or modified CapeIRI ± bevacizumab after failure to fluoropyrimidine-based chemotherapy in the AXEPT study. Prior fluoropyrimidine backbones were categorized into oral fluoropyrimidine-based (eg, capecitabine or S-1) regimen (oral 5-FU group) and fluorouracil and leucovorin-based regimen (infusional 5-FU group). Assessed endpoints included overall survival, progression-free survival, response rate, and safety. Results: Prior fluoropyrimidine backbone was available for 642 patients among all 650 randomized patients (oral 5-FU group in 291, and infusional 5-FU group in 351). Median overall survival was 17.0 and 16.7 months for FOLFIRI ± BV and CapeIRI ± BV in the prior oral 5-FU group, and 14.9 and 16.7 months for FOLFIRI ± BV and CapeIRI ± BV in the prior infusional 5-FU group. Median progression-free survival was 7.9 and 8.6 months for FOLFIRI ± BV and CapeIRI ± BV in the prior oral 5-FU group, and 6.8 and 8.3 months for FOLFIRI ± BV and CapeIRI ± BV in the prior infusional 5-FU group. Conclusions: There was no significant difference in the efficacy of CapeIRI or FOLFIRI regardless of prior fluoropyrimidine backbones. Therefore, CapeIRI ± BV could also be effective for patients after failure of oral fluoropyrimidine-based chemotherapy (eg, CapeOX ± BV). Clinical trial information: NCT01996306. [Table: see text]

POLO: Radiologic assessment of the impact of maintenance olaparib in patients (pts) with metastatic pancreatic cancer (mPaC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16800-e16800
Author(s):  
Lawrence Howard Schwartz ◽  
Hedy L. Kindler ◽  
Pascal Hammel ◽  
Michele Reni ◽  
Eric Van Cutsem ◽  
...  
Keyword(s):  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Complete Response ◽  
Pancreatic Disease ◽  
Phase Iii ◽  
Sensitivity Analyses ◽  
Primary Analysis ◽  
Free Survival ◽  
Radiologic Assessment ◽  
The Impact

e16800 Background: The Phase III POLO study (NCT02184195) demonstrated a benefit of maintenance olaparib over placebo in the radiologically assessed primary endpoint of progression-free survival (PFS) in pts with mPaC (median 7.4 vs 3.8 months [mo]; 12-mo rate 34% vs 15%). The impact of radiologic assessment of pancreatic lesions, which is considered challenging, was explored. Methods: Tumors were assessed using Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review (BICR) in pts with mPaC treated with maintenance olaparib or placebo. PFS was analyzed in subsets of pts based on various event criteria. Results: All 154 randomized pts had mPaC prior to chemotherapy, of whom 122 had disease in the pancreas at POLO baseline (BL); 34% (53/154) had pancreas-only target lesions (TL), 26% (40/154) also had ≥1 TL outside of the pancreas, and in 19% (29/154) pancreatic disease was recorded as non-TL. Sensitivity analyses were consistent with the primary PFS analysis (Table), including when all pancreas lesion assessments were discounted (median PFS 7.4 vs 4.7 mo; 12-mo rate 38% vs 22%). Of 53 pts with pancreas-only TLs at BL, 34 had disease progression (PD); in 20 pts this was not solely based on TL measurements (16 had new lesions; 4 had multiple-cause PD). Confirmed objective responses occurred during study maintenance treatment in 20% of olaparib pts (18/92) and 10% of placebo pts (6/62). In pts with pancreas-only TLs at BL there were 7 responses in the olaparib arm (1 complete response [CR], 6 partial responses [PR]) and 2 (2 PR) in the placebo arm. In pts who had ≥1 TL outside of the pancreas at BL there were 11 (1 CR, 10 PR) and 4 (4 PR) responses, respectively. Responses were generally durable irrespective of TL location. Conclusions: The significant PFS benefit with maintenance olaparib over placebo shown in the primary analysis was consistent across all sensitivity analyses and was not impacted by radiologic assessment of pancreatic TLs. Taken together, these findings suggest that contrary to historically held belief, primary pancreas TLs may be appropriate for inclusion as sites of RECIST-evaluable disease and for assessment of treatment outcome. Clinical trial information: NCT02184195 . [Table: see text]

scholarly journals The impact of ignoring Interval censoring in progression-free survival in cancer trials: a systematic review

2021 ◽  
Vol 2 (2) ◽  
Author(s):  
Xiawen Zhang ◽  
Eleanor Pullenayegum ◽  
Kelvin Kar-Wing Chan
Keyword(s):  
Systematic Review ◽  
Treatment Effect ◽  
Progression Free Survival ◽  
Interval Censoring ◽  
Limits Of Agreement ◽  
Free Survival ◽  
Kaplan Meier ◽  
Hazard Ratios ◽  
Mean Differences ◽  
The Impact

Introduction & Objective: From statistical literature, the bias in treatment effect from ignoring interval censoring in Progression-free survival (PFS) is demonstrated. However, the impact on estimators caused by interval censoring is not carefully took account and investigated by researchers in practice. The objective of this study is to examine the impact of accounting for interval censoring in practice among RCTs used to support FDA approvals anti-cancer drugs between the years 2005 and 2019 that used PFS as an endpoint. Methods: In this systematic review, the differences of hazard ratios between two methods: considering and ignoring interval censoring, are visualized by Kaplan-Meier survival curves and estimated from a Cox proportional hazard model of 87 RCTs. With assumption that these differences and mean differences (bias) follow a normal distribution, limits of agreement of differences and confidence interval of bias are used to represent agreement of two methods. Results: Limits of agreement of difference range from -0.044 to 0.0615, while confidence intervals for the bias range from 0.0026 to 0.0145, which does not include zero, resulting in estimated treatment effect differs for two methods. Conclusion: In general, bias caused by interval censoring in treatment effect exists with large sample studies. Focusing on individual clinical trials, limits of agreement can provide more information for researchers to make decision on how to account for interval censoring.

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