Pembrolizumab alone or with chemotherapy for metastatic non-small-cell lung cancer: A systematic review and network meta-analysis.

Pembrolizumab monotherapy has replaced chemotherapy as first-line treatment for patients with metastatic non-small-cell lung cancer with tumor programmed death-ligand 1 expression ≥ 50%. The benefit of chemotherapy combined with pembrolizumab, as compared to pembrolizumab monotherapy, remains uncertain. This systematic review and network meta-analysis aimed to compare these therapies through a network of randomized controlled trials. Endpoints evaluated were progression-free survival (PFS) and overall survival (OS) expressed as hazard ratio (HR) and restricted mean survival time (RMST) through reconstruction of individual patient data from Kaplan-Meier curves, and objective response rate and adverse events. Four trials were included. Through HR and RMST, combination therapy demonstrated longer PFS and similar OS as compared to pembrolizumab monotherapy. Combination therapy was associated with an increase in response rate and adverse events. Thus, combination therapy can be considered when rapid response or prevention of rapid progression is needed. Further evidence to directly compare these therapies is required.

Reassessing the Net Benefit of Cancer Drugs With Evolution of Evidence Using the ASCO Value Framework.

BACKGROUND: Regulatory approval of oncology drugs is often based on interim data or surrogate endpoints. However, clinically relevant data, such as long-term overall survival and quality of life (QoL), are often reported in subsequent publications. This study evaluated the ASCO-Value Framework (ASCO-VF) net health benefit (NHB) at the time of approval and over time as further evidence arose. METHODS: FDA-approved oncology drug indications from January 2006 to December 2016 were reviewed to identify clinical trials scorable using the ASCO-VF. Subsequent publications of clinical trials relevant for scoring were identified (until December 2019). Using ASCO-defined thresholds (≤40 for low and ≥45 for substantial benefit), we assessed changes in classification of benefit at 3 years postapproval. RESULTS: Fifty-five eligible indications were included. At FDA approval, 40.0% were substantial, 10.9% were intermediate, and 49.1% were low benefit. We then identified 90 subsequent publications relevant to scoring, including primary (28.9%) and secondary endpoint updates (47.8%), safety updates (31.1%), and QoL reporting (47.8%). There was a change from initial classification of benefit in 27.3% of trials (10.9% became substantial, 9.1% became low, and 7.3% became intermediate). These changes were mainly due to updated hazard ratios (36.4%), toxicities (56.4%), new tail-of-the-curve bonus (9.1%), palliation bonus (14.5%), or QoL bonus (18.2%). Overall, at 3 years postapproval, 40.0% were substantial, 9.1% were intermediate, and 50.9% were low benefit. CONCLUSIONS: Because there were changes in classification for more than one-quarter of indications, in either direction, reassessing the ASCO-VF NHB as more evidence becomes available may be beneficial to inform clinical shared decision-making. On average, there was no overall improvement in the ASCO-VF NHB with longer follow-up and evolution of evidence.

Assessment of Food and Drug Administration- and European Medicines Agency-Approved Systemic Oncology Therapies and Clinically Meaningful Improvements in Quality of Life: A Systematic Review.

Importance: For patients with cancer treated with palliative intent, quality of life (QOL) is a critical aspect of treatment decision-making, alongside survival. However, regulatory approval can be based solely on survival measures or antitumor activities, without QOL evidence. Objective: To investigate whether recently approved oncology therapies demonstrate clinically meaningful improvements in QOL. Evidence Review: This systematic review study identified oncology drug indications approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) from January 2006 to December 2017 and supporting clinical trials (QOL publications identified to October 2019). Indications were evaluated for the presence of published QOL evidence; QOL benefits according to the American Society of Clinical Oncology Value Framework version 2.0 (ASCO-VF) and European Society of Medical Oncology Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS) QOL bonus criteria; and clinically meaningful improvements in QOL beyond minimal clinically important differences. Hematology trials were not evaluated by ESMO-MCBS. Associations between QOL evidence and approval year were examined using logistic regression models. Findings: In total, 214 FDA-approved (77 [36%] hematological) and 170 EMA-approved (52 [31%] hematological) indications were included. QOL evidence was published for 40% and 58% of FDA- and EMA-approved indications, respectively. QOL bonus criterion for ASCO-VF and ESMO-MCBS was met in 13% and 17% of FDA-approved and 21% and 24% of EMA-approved indications, respectively. Clinically meaningful improvements in QOL beyond minimal clinically important differences were noted in 6% and 11% of FDA- and EMA-approved indications, respectively. Availability of published QOL evidence at the time of approval increased over time for EMA (odds ratio [OR], 1.13; P = .03), however not for FDA (OR, 1.10; P = .12). Over time, no increase in awarded QOL bonuses or clinically meaningful improvements in QOL were found. Conclusions and Relevance: The findings of this systematic review suggest that approved systemic oncology therapies often do not have published evidence to suggest QOL improvement, despite its recognized importance. Of indications with evidence of statistical improvement, few have demonstrated clinically meaningful improvements.

Evaluation of the impact of patient involvement in health technology assessments: A scoping review.

OBJECTIVES: While involving patients in health technology assessment (HTA) has become increasingly common and important around the world, little is known about the optimal methods of evaluating patients' involvement (PI) in HTA. This scoping review was undertaken to provide an overview of currently available methods for the evaluation of PI, specifically the impact of PI on HTA recommendations. METHODS: A literature search was conducted using nine databases as well as a grey literature search of the websites of 26 organizations related to the conduct, practice or research of HTA to identify articles, reports and abstracts related to the evaluation of PI impact in HTA. RESULTS: We identified 1,248 unique citations, six of which met our eligibility criteria. These six records (five articles, and one report) were all published after 2012. Four assessed the impact of patient experience submissions on final HTA recommendations; one evaluated the impact of direct involvement on HTA committees, and one assessed impact of multiple forms of involvement. Methods of evaluation included quantitative analyses of reimbursement decisions, qualitative interviews with those directly involved in an assessment, surveys of patient groups and committee members, and the review of HTA reports. CONCLUSIONS: Quantitative evaluation of PI based on associations with funding decisions may not be feasible or fully capture the relevant impact of PI in the assessment of health technologies. Rather, a combination of both qualitative and quantitative strategies may allow for the most comprehensive assessment of the impact of PI on HTA recommendations when possible.

Quantifying the Survival Benefits of Oncology Drugs With a Focus on Immunotherapy Using Restricted Mean Survival Time.

BACKGROUND: Restricted mean survival time (RMST) overcomes limitations of current measures of survival benefits because it directly captures information of the entire area under Kaplan-Meier survival curves. Using RMST difference (absolute survival benefit) and RMST ratio (relative survival benefit), we quantified the magnitude of survival benefits of recent oncology drugs and compared immunotherapies with nonimmunotherapies. METHODS: Kaplan-Meier curves were extracted from phase II/III randomized controlled trials used by the FDA for oncology drug approvals from January 2011 through November 2017 with overall survival (OS) or progression-free survival (PFS) as primary endpoints. RMST differences, ratios, and their 95% confidence intervals were meta-analyzed to estimate absolute and relative survival benefits of contemporary oncology drugs and to compare immunotherapies with nonimmunotherapies. Meta-regression was conducted to adjust for potential confounders. RESULTS: Ninety-four trials with a total of 51,639 patients were included. Overall absolute survival benefits (RMST differences) were 1.55 months for OS (95% CI, 1.32-1.77) and 2.99 months for PFS (95% CI, 2.65-3.33). Overall relative survival benefits (RMST ratios) were 1.11 for OS (95% CI, 1.09-1.13) and 1.42 for PFS (95% CI, 1.36-1.48). Immunotherapy absolute PFS benefit was less than that of nonimmunotherapy (1.56 vs 3.23 months), whereas immunotherapy absolute OS benefit was larger than that of nonimmunotherapy by 0.59 months (2.02 vs 1.43 months). Adjusted OS RMST difference was 0.91 months greater for immunotherapy than for nonimmunotherapy after adjusting for confounders. CONCLUSIONS: Absolute survival benefits of recent oncology drugs are modest. Survival benefits of immunotherapies are not dramatically superior to those of nonimmunotherapies. Routine reporting and use of RMST may help patients, physicians, and payers make more informed and responsible decisions regarding the care of patients with cancer.

Adjuvant treatment for resected pancreatic adenocarcinoma: A systematic review and network meta-analysis.

Adjuvant chemotherapy has significantly improved outcomes following surgical resection for pancreatic adenocarcinoma; however, the optimal adjuvant strategy remains unclear. This systematic review and network meta-analysis was conducted to provide indirect comparative evidence across adjuvant chemotherapies. Electronic searches of EMBASE, MEDLINE, Cochrane and ASCO databases were conducted to identify eligible randomized controlled trials (RCT). Direct pairwise meta-analysis was conducted for disease-free survival (DFS), overall-survival (OS) and adverse events (AE). Network meta-analysis of DFS and OS was conducted to evaluate indirect comparisons. Ten publications of eleven RCT met eligibility criteria. Indirect DFS comparison demonstrated superiority of mFOLFIRINOX versus gemcitabine-capecitabine, gemcitabine-erlotinib and gemcitabine-nab-paclitaxel. S-1 demonstrated a DFS benefit versus gemcitabine-capecitabine, gemcitabine-erlotinib, gemcitabine-nab-paclitaxel. OS benefits were demonstrated for mFOLFIRINOX verus gemcitabine-erlotinib and for S-1 versus gemcitabine-based combination with erlotinib, capecitabine and nab-paclitaxel. In conclusion, mFOLFIRINOX is the preferred approach for adjuvant therapy. For mFOLFIRINOX-ineligible patients no additional benefit is seen with gemcitabine-nab-paclitaxel.

Are Surrogate Endpoints Unbiased Metrics in Clinical Benefit Scores of the ASCO Value Framework?

BACKGROUND: Clinical benefit scores (CBS) are key elements of the ASCO Value Framework (ASCO-VF) and are weighted based on a hierarchy of efficacy endpoints: hazard ratio for death (HR OS), median overall survival (mOS), HR for disease progression (HR PFS), median progression-free survival (mPFS), and response rate (RR). When HR OS is unavailable, the other endpoints serve as "surrogates" to calculate CBS. CBS are computed from PFS or RR in 39.6% of randomized controlled trials. This study examined whether surrogate-derived CBS offer unbiased scoring compared with HR OS-derived CBS. METHODS: Using the ASCO-VF, CBS for advanced disease settings were computed for randomized controlled trials of oncology drug approvals by the FDA, European Medicines Agency, and Health Canada in January 2006 through December 2017. Mean differences of surrogate-derived CBS minus HR OS-derived CBS assessed the tendency of surrogate-derived CBS to overestimate or underestimate clinical benefit. Spearman's correlation evaluated the association between surrogate- and HR OS-derived CBS. Mean absolute error assessed the average difference between surrogate-derived CBS relative to HR OS-derived CBS. RESULTS: CBS derived from mOS, HR PFS, mPFS, and RR overestimated HR OS-derived CBS in 58%, 68%, 77%, and 55% of pairs and overall by an average of 5.62 (n=90), 6.86 (n=110), 29.81 (n=101), and 3.58 (n=108), respectively. Correlation coefficients were 0.80 (95% CI, 0.70-0.86), 0.38 (0.20-0.53), 0.20 (0.00-0.38), and 0.01 (-0.18 to 0.19) for mOS-, HR PFS-, mPFS-, and RR-derived CBS, respectively, and mean absolute errors were 11.32, 12.34, 40.40, and 18.63, respectively. CONCLUSIONS: Based on the ASCO-VF algorithm, HR PFS-, mPFS-, and RR-derived CBS are suboptimal surrogates, because they were shown to be biased and poorly correlated to HR OS-derived CBS. Despite lower weighting than OS in the ASCO-VF algorithm, PFS still overestimated CBS. Simple rescaling of surrogate endpoints may not improve their validity within the ASCO-VF given their poor correlations with HR OS-derived CBS.