A Comparison of Response Patterns for Progression-Free Survival and Overall Survival Following Treatment for Cancer With PD-1 Inhibitors

Gyawali, Bishal; Hey, Spencer Phillips; Kesselheim, Aaron S.

doi:10.1001/jamanetworkopen.2018.0416

Cited by 53 publications

(55 citation statements)

References 33 publications

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“…34 A previous pooled meta-analysis evaluated correlation between PFS and OS outcomes for patients who received PD-1 inhibitors and showed that, using a random-effects meta-analysis, the protective effects of treatment were greater for OS than for PFS, and there was no significant correlation between OS and PFS in terms of medians and gains in medians. 35 Our meta-analysis supports this observation, suggesting that OS should be included as a primary endpoint in future phase 3 trials of immunotherapy agents. It is important to recognize that inter-and intra-tumor heterogeneity of the immune-microenvironment may affect the results of immunotherapy combinations in each tumor type.…”

Section: Discussionsupporting

confidence: 78%

Efficacy and safety of anticancer drug combinations: a meta-analysis of randomized trials with a focus on immunotherapeutics and gene-targeted compounds

et al. 2020

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Hundreds of trials are being conducted to evaluate combination of newer targeted drugs as well as immunotherapy. Our aim was to compare efficacy and safety of combination versus single non-cytotoxic anticancer agents. We searched PubMed (01/01/2001 to 03/06/2018) (and, for immunotherapy, ASCO and ESMO abstracts (2016 through March 2018)) for randomized clinical trials that compared a single non-cytotoxic agent (targeted, hormonal, or immunotherapy) versus a combination with another noncytotoxic partner. Efficacy and safety endpoints were evaluated in a meta-analysis using a linear mixedeffects model (guidelines per PRISMA Report).We included 95 randomized comparisons (single vs. combination non-cytotoxic therapies) (59.4%, phase II; 41.6%, phase III trials) (29,175 patients (solid tumors)). Combinations most frequently included a hormonal agent and a targeted small molecule (23%). Compared to single non-cytotoxic agents, adding another non-cytotoxic drug increased response rate (odds ratio [OR]=1.61, 95%CI 1.40-1.84)and prolonged progression-free survival (hazard ratio [HR] =0.75, 95%CI 0.69-0.81)and overall survival (HR=0.87, 95%CI 0.81-0.94) (all p<0.001), which was most pronounced for the association between immunotherapy combinations and longer survival. Combinations also significantlyincreased the risk of high-grade toxicities (OR=2.42, 95%CI 1.98-2.97) (most notably for immunotherapy and small molecule inhibitors) and mortality at least possibly therapy related (OR: 1.33, 95%CI 1.15-1.53) (both p<0.001) (absolute mortality = 0.90% (single agent) versus 1.31% (combinations)) compared to single agents. In conclusion, combinations of non-cytotoxic drugs versus monotherapy in randomized cancer clinical trials attenuated safety, but increased efficacy, with the balance tilting in favor of combination therapy, based on the prolongation in survival.

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Section: Discussionsupporting

confidence: 78%

Efficacy and safety of anticancer drug combinations: a meta-analysis of randomized trials with a focus on immunotherapeutics and gene-targeted compounds

et al. 2020

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“…However, when used alone, it is not considered to be enough evidence of benefit to patients, which is exemplified by recent guidance from the American Society of Clinical Oncology [64]. For this reason, OS is recommended as a measure of effectiveness for new cancer medicines [65, 68], with a significant effect on OS necessarily entailing a significant effect on PFS [66]. …”

Section: Methodsmentioning

confidence: 99%

Comparative Effectiveness and Safety of Monoclonal Antibodies (Bevacizumab, Cetuximab, and Panitumumab) in Combination with Chemotherapy for Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis

Silva

Araújo

Lima³

et al. 2018

BioDrugs

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BackgroundThe last decade has seen the increasing use of biological medicines in combination with chemotherapy containing 5-fluorouracil/oxaliplatin or irinotecan for the treatment of metastatic colorectal cancer (mCRC). These combinations have resulted in increased progression-free survival (PFS) in patients with mCRC; however, there are remaining concerns over the extent of their effect on overall survival (OS). Published studies to date suggest no major differences between the three currently available monoclonal antibodies (MoAbs); however, there are differences in costs. In addition, there is rising litigation in Brazil in order to access these medicines as they are currently not reimbursed.ObjectiveThe aim was to investigate the comparative effectiveness and safety of three MoAbs (bevacizumab, cetuximab and panitumumab) associated with fluoropyrimidine-based chemotherapy regimens and compared to fluoropyrimidine-based chemotherapy alone in patients with mCRC, through an updated systematic review and meta-analysis of concurrent or non-concurrent observational cohort studies, to guide authorities and the judiciary.MethodA systematic review and meta-analysis was performed based on cohort studies published in databases up to November 2017. Effectiveness measures included OS, PFS, post-progression survival (PPS), Response Evaluation Criteria In Solid Tumors (RECIST), response rate, metastasectomy and safety. The methodological quality of the studies was also evaluated.ResultsA total of 21 observational cohort studies were included. There were statistically significant and clinically relevant benefits in patients treated with bevacizumab versus no bevacizumab mainly around OS, PFS, PPS and the metastasectomy rate, but not for the disease control rates. However, there was an increase in treatment-related toxicities and concerns with the heterogeneity of the studies.ConclusionThe results pointed to an advantage in favor of bevacizumab for OS, PFS, PPS, and metastasectomy. Although this advantage may be considered clinically modest, bevacizumab represents a hope for increased survival and a chance of metastasectomy for patients with mCRC. However, there are serious adverse events associated with its use, especially severe hypertension and gastrointestinal perforation, that need to be considered.Electronic supplementary materialThe online version of this article (10.1007/s40259-018-0322-1) contains supplementary material, which is available to authorized users.

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“… 11 Overestimations in the magnitude of treatment effects on PFS are also observed in ICI RCTs. 12 , 13 …”

Section: Introductionmentioning

confidence: 99%

Validation of Progression-Free Survival Rate at 6 Months and Objective Response for Estimating Overall Survival in Immune Checkpoint Inhibitor Trials

et al. 2020

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Key Points Question Can surrogate end points, such as progression-free survival, be used to estimate overall survival in immunotherapy trials? Findings This systematic review and meta-analysis using data from 60 published immunotherapy randomized clinical trials in advanced solid cancers found that 6-month progression-free survival in the immunotherapy arm estimated 12-month overall survival well using a statistical model that accounts for tumor type. Meaning These findings suggest that this model could assist with selecting immunotherapy agents for further testing in large randomized clinical trials and with regulatory approvals in rare cancers for which randomized trials are not feasible.

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A Comparison of Response Patterns for Progression-Free Survival and Overall Survival Following Treatment for Cancer With PD-1 Inhibitors

Cited by 53 publications

References 33 publications

Efficacy and safety of anticancer drug combinations: a meta-analysis of randomized trials with a focus on immunotherapeutics and gene-targeted compounds

Efficacy and safety of anticancer drug combinations: a meta-analysis of randomized trials with a focus on immunotherapeutics and gene-targeted compounds

Comparative Effectiveness and Safety of Monoclonal Antibodies (Bevacizumab, Cetuximab, and Panitumumab) in Combination with Chemotherapy for Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis

Validation of Progression-Free Survival Rate at 6 Months and Objective Response for Estimating Overall Survival in Immune Checkpoint Inhibitor Trials

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