Survival with novel hormonal therapies in patients with nonmetastatic castration-resistant prostate cancer: indirect comparison of three randomized phase-III trials.

INTRODUCTION: In recent years, new treatments have been approved for nonmetastatic castration-resistant prostate cancer (M0CRPC). Because direct comparisons between these treatments are not available to guide treatment decisions, indirect comparisons can be of interest. METHODS: Our analysis evaluated second-generation hormone treatments proposed for M0CRPC. We searched multiple databases for articles published between 2010 and 2022. Phase-III clinical trials that studied these agents in M0CRPC patients were eligible. Among these, we included trials reporting overall survival (OS) through Kaplan-Meier curves. We performed the reconstruction of individual patient data from Kaplan-Meier graphs, according to the Shiny method, to indirectly compare the efficacy of the different agents. Indirect comparisons included testing for equivalence according to FDA criteria. Confidence intervals (CI) were 95% in all analyses except equivalence testing, where 90%CIs were used. RESULTS: Three studies met these inclusion criteria. Apalutamide (hazard ratio [HR]: 0.75, 95% confidence interval [CI] 0.64-0.88), darolutamide (HR 0.70, 95%CI 0.58-0.84), and enzalutamide (HR 0.77, 95%CI 0.65-0.90) were all significantly more effective than the placebo. Our results showed no difference in OS between any of these three agents, and in testing for equivalence, our estimates of HR met the 0.75-1.33 level. CONCLUSIONS: While the Shiny method has confirmed its validity in reconstructing individual patient data, our indirect comparisons based on mature OS demonstrated similar efficacy and substantial equivalence among these three second-generation androgen receptor inhibitors.

Evaluation of maintenance treatment with PARP inhibitors in ovarian carcinoma patients responding to platinum therapy: Use of restricted mean survival time as an index of efficacy.

BACKGROUND: Maintenance therapy using poly (ADP-ribose) polymerase inhibitors (PARPIs) is an important therapeutic option in advanced ovarian cancer after platinum-based chemotherapy. MATERIALS AND METHODS: We evaluated randomized studies (n = 5) describing the effect of maintenance therapy with PARPIs; they were obtained mainly by searching PubMed. Patient data for the analysis were derived from progression-free survival curves. Restricted mean survival time (RMST) and 95% confidence interval were estimated for individual arms of each trial. RESULTS: The three PARPIs used (olaparib, niraparib, rucaparib) all showed a higher effectiveness than placebo. The gains in progression-free survival were 6 - 8 months. CONCLUSION: Maintenance therapy studies provide evidence that olaparib, niraparib, rucaparib are effective treatments for advanced ovarian cancer.

Toward a common understanding of competencies for health technology assessment: enhancing educational and training programs around the globe.

BACKGROUND: Depending on the health system context and the demands of relevant stakeholders in countries, the need, organizational structure, and prerequisites for enabling capacity building and development in health technology assessment (HTA) will vary. Core competencies are instrumental in this and include essential knowledge, skills, and attitudes (KSAs). They provide building blocks for delivering high-quality and effective practices of HTA. We aimed to systematically explore and develop an overview of the core competencies necessary for HTA. METHODS: This study was conducted during 2016-19 using different methods in a structured manner. We drew concepts of KSAs from various literature sources, surveyed universities and HTA professionals, and conducted expert workshops to arrive at a common understanding of the required competencies. RESULTS: The terminology for KSAs defining competencies in HTA programs has been clarified. In addition, a list of competencies offered through different educational and training programs has been created. The surveys provided clarity on a common understanding of KSAs among HTA stakeholders. Thereafter, a set of competencies was described and classified according to the HTA domains. CONCLUSIONS: Our study shows that there is diversity in HTA programs offered by educational institutions. The content of the programs varies due to differences between countries regarding the level of HTA development and the need for HTA, including the understanding of what HTA is. The preparation of a competency checklist or a "menu" of options mirroring the diversity of HTA will ensure that the specific needs of the HTA community will be covered.

Trastuzumab biosimilar in metastatic breast cancer: Evaluating equivalence with originator using network meta-analysis
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OBJECTIVE: The European Medicines Agency (EMA) and the Food and Drug Administration (FDA) have recently approved four different trastuzumab biosimilars, marketed by different pharmaceutical companies. Biosimilars, unlike their originators, are typically supported by less clinical data about safety and efficacy. The objective of our analysis was to demonstrate that one of the approved trastuzumab biosimilars (MYL-1401O) is as effective as its originator in terms of hazard ratio (HR) of progression-free survival (PFS). MATERIALS AND METHODS: We carried out a network meta-analysis to compare the HR values for biosimilar, originator, and standard of care (SOC). Our analysis included a preliminary pairwise meta-analysis. The pooled HR for all pairwise comparisons was the output of the analysis (fixed-effect inverse variance method), along with 95% confidence intervals (CIs). The indirect comparison between biosimilar and SOC was performed using a network meta-analysis software. RESULTS: We estimated an HR of 0.59 (95% CI: 0.52 - 0.66) for the comparison between PFS values of originator and SOC, 0.97 (95% CI: 0.74 - 1.28) for biosimilar vs. originator, and 0.61 (95% CI: 0.44 - 0.83) for biosimilar vs. SOC. Our network meta-analysis increased the overall number of evaluated patients from 458 to 1,955. CONCLUSION: According to the network meta-analysis, MYL-1401O biosimilar is as effective as its originator in terms of HR of PFS.
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CAPACITY BUILDING IN AGENCIES FOR EFFICIENT AND EFFECTIVE HEALTH TECHNOLOGY ASSESSMENT.

OBJECTIVES: Health technology assessment (HTA) yields information that can be ideally used to address deficiencies in health systems and to create a wider understanding of the impact of different policy considerations around technology reimbursement and use. The structure of HTA programs varies across different jurisdictions according to decision-maker needs. Moreover, conducting HTA requires specialized skills. Effective decision making should include multiple criteria (medical, economic, technical, ethical, social, legal, and cultural) and requires multi-disciplinary teams of experts working together to produce these assessments. A workshop explored the multi-disciplinary skills and competencies required to build an effective and efficient HTA team, with a focus on low- and middle-income settings. METHODS: This proceeding summarizes main points from a workshop on capacity building, drawing on presentations and group discussions among attendees including different points of view. RESULTS AND CONCLUSIONS: The workshop and thus this study would have benefited from a larger variety of stakeholders. Therefore, the conclusions arising from the workshop are not the opinion of a representative sample of HTA professionals. Nonetheless, organizations and speakers were carefully selected to provide a valuable approach to this theme. Thus, these proceedings highlight some of the gaps and needs in the education and training programs offered worldwide and calls for further investigation.

Efficacy of deprescribing on health outcomes: An umbrella review of systematic reviews with meta-analysis of randomized controlled trials.

BACKGROUND: Deprescribing is an important intervention across different settings in medicine, but the literature supporting such a practice is still conflicting. Therefore, we aimed to capture the breadth of outcomes reported and assess the strength of evidence of the use of deprescribing for health outcomes. METHODS: Umbrella review of systematic reviews of the use of deprescribing searching in Medline, Scopus, and Web of Science until 01 November 2023. The grading of evidence was carried out using the GRADE for intervention studies, whilst data regarding systematic reviews were reported as narrative findings. RESULTS: Among 456 papers, 12 systematic reviews (six with meta-analysis) for a total of 231 RCTs and 44,193 patients were included. In any setting, deprescribing was able to significantly reduce the number of total and of potentially inappropriate medications (PIMs) in older patients (low certainty of evidence) and to reduce the proportion of participants potentially having several or PIMs (moderate certainty of evidence). In community, supported by a high certainty of evidence, deprescribing was not more effective than standard care in decreasing injurious falls, any falls or number of fallers. In nursing home, deprescribing was associated with a significantly lower PIMs than standard care (very low certainty of evidence). In end-of-life situations, deprescribing significantly reduced mortality rate of approximately 41% (high certainty of evidence). CONCLUSIONS: Deprescribing is a promising intervention across different settings and situations, but a notable gap in the literature concerning its effects on substantial outcomes still exists.

A real-world retrospective, observational study of first-line pembrolizumab plus chemotherapy for metastatic non-squamous non-small cell lung cancer with PD-L1 tumor proportion score < 50% (PEMBROREAL).

Introduction: The phase III Keynote-189 trial established a first-line treatment combining pembrolizumab with pemetrexed and platinum as a standard treatment for patients with stage IV non-small cell lung cancer (NSCLC) without known EGFR and ALK driver mutations and independent of programmed cell death ligand 1 (PD-L1) expression. However, in Italy, eligibility for the National Health Service payment program is limited to patients with PD-L1 <50%. The PEMBROREAL study assesses the real-world effectiveness and safety of pembrolizumab in patients eligible for the National Health Service payment program. Methods: PEMBROREAL is a retrospective, observational study on patients with NSCLC who started pembrolizumab combined with pemetrexed and platinum within the reimbursability time window, considered as December 2019 to December 2020. The primary endpoints were to assess progression-free survival (PFS) and overall survival (OS; using the Kaplan-Meier method), response to therapy, and tolerability. Results: Until February 2022, 279 patients (median follow-up: 19.7 months) have been observed. The median PFS was 8.0 months (95% confidence interval: 6.5-9.2). OS was not reached, but we can estimate a 12- to 24-month survival rate for the combined treatment: 66.1% and 52.5%, respectively. PD-L1 expression and Eastern Cooperative Group (ECOG) Performance Status were both associated with PFS and OS. Overall, only 44.4% of patients reported an adverse event, whereas toxicity led to a 5.4% discontinuation rate. Conclusion: The results of the PEMBROREAL study have shown that the combined treatment of pembrolizumab with pemetrexed and platinum is effective for metastatic non-squamous NSCLC, even for patients with PD-L1 levels below 50%, despite the differences in patient demographics and pathological features compared to the Keynote-189 study. The adverse events reported during the study were more typical of chemotherapy treatment rather than immunotherapy, and physicians were able to manage them easily.

Real-World Safety and Outcome of First-Line Pembrolizumab Monotherapy for Metastatic NSCLC with PDL-1 Expression ≥ 50%: A National Italian Multicentric Cohort ("PEMBROREAL" Study).

Results from the phase III Keynote-024 clinical trial established pembrolizumab monotherapy as the first-line standard of care for patients with metastatic NSCLC who have PD-L1 expression ≥ 50%, EGFR, and ALK wild-type tumors. However, given the differences between patients treated in routine clinical practice and those treated in a clinical trial, real-world data are needed to confirm the treatment benefit in standard practice. Given the lack of data on large cohorts of patients with long follow-ups, we designed an observational retrospective study of patients with metastatic NSCLC who were treated with pembrolizumab, starting from its reimbursement eligibility until December 2020. The primary endpoints were PFS and OS, determined using the Kaplan-Meier method. Response and safety were also evaluated. We followed 880 patients (median follow-up: 35.1 months) until February 2022. Median PFS and OS were 8.6 months (95% CI: 7.6-10.0) and 25.5 months (95% CI: 21.8-31.6), respectively. We also found that ECOG PS, PD-L1 expression, and habitual smoking were prognostic factors for PFS, while age, sex, ECOG PS, habitual smoking and histology had an impact on OS. Multivariable analysis confirms the prognostic role of PD-L1 for PFS and of ECOG for both PFS and OS. 39.9% of patients reported an adverse event, but only 6.3% of patients discontinued therapy due to toxicity. Our results suggest a long-term benefit of pembrolizumab in the first-line setting, as well as a safety profile consistent with the results of Keynote-024. Many collected variables appear to influence clinical outcome, but results from these exploratory unadjusted analyses should be interpreted with caution.

Adjuvant Nivolumab in Esophageal or Gastroesophageal Junction Cancer: the Improvement in Progression-Free Survival Is Small.

Esophageal cancer is the seventh most common cancer globally, accounting more than a half million deaths per year. Despite several therapeutic options in neoadjuvant setting, including chemoradiotherapy and surgery, no adjuvant treatment has been established for patients at high risk of recurrence. Even so, findings from the recently published CheckMate 577 trial seem to suggest an important clinical impact, in terms of disease-free progression, for the use of adjuvant nivolumab, a PDL-1 inhibitor, in resected esophageal cancer or gastroesophageal junction cancer. The authors reported a benefit for the treatment arm of 22.4 months compared with 11.0 in the placebo group. Although median is commonly used as an endpoint in survival studies, it can be influenced by the timing of a few events in the descending portion of the Kaplan-Meier curve. Restricted mean survival time (RMST) considers the entire time-course of the curve and does not assume that event risks are constant over the follow-up. This may be helpful to a more realistic interpretation of survival outcomes. In this letter, we re-analyzed the study curves of the CheckMate 577 trial by application of RMST. While confirming the disease-free progression benefits for nivolumab compared with placebo (28.54 months for the treatment arms versus 22.70 for the controls), our analysis allows us to interpret the survival benefit in a more conservative manner.

Tislelizumab plus chemotherapy vs. pembrolizumab plus chemotherapy for the first-line treatment of advanced non-small cell lung cancer: systematic review and indirect comparison of randomized trials.

BACKGROUND: Pembrolizumab (PEM) and tislelizumab (TIS), in combination with chemotherapy, have demonstrated significant clinical benefits in first-line treatment of advanced non-small cell lung cancer (NSCLC). However, no head-to-head clinical trial has yet compared these two treatments. METHODS: We conducted a literature search of randomized trials, in which TIS plus chemotherapy or PEM plus chemotherapy were studied for the first-line treatment of NSCLC. Randomized design and the endpoint of progression-free survival (PFS) were the inclusion criteria for our analysis. Adjusted indirect comparison between TIS and PEM was performed by application of the IPDfromKM-Shiny method. This method is based on the reconstruction of individual patient data from Kaplan-Meier curves. Outcomes in terms of PFS were expressed as hazard ratio (HR) with 95% and 90% confidence interval (CI). RESULTS: Data were extracted from five randomized trials involving nearly 2,000 participants. In comparing PEM plus chemotherapy (n=748) or TIS plus chemotherapy (n=462) vs. chemotherapy alone (n=782), the Shiny method found a significant advantage in terms of PFS (HR =0.5856, 95% CI: 0.4986-0.6876 for TIS; HR =0.5573, 95% CI: 0.4969-0.6251 for PEM), thus confirming the results of the original trials. The indirect comparison of PEM plus chemotherapy vs. TIS plus chemotherapy showed a substantial equivalence between these two regimens (HR =0.952; 95% CI: 0.775-1.168; 90% CI: 0.801-1.130) suggesting an acceptable degree of equivalence according to regulatory criteria. Medians were 8.89 months for PEM combination, 7.97 months for TIS combination, and 5.69 for the controls. CONCLUSIONS: The PFS of TIS combined with chemotherapy was similar to that of PEM combined with chemotherapy. Based on the HR with 90% CI, these two agents met an equivalence criterion for PEM vs. TIS ranging from -19.9% to +13.0%.

Low-Intensity and Chemo-Free Treatments in Ph+ ALL: Progression-Free Survival Based on Indirect Comparisons.

In Philadelphia chromosome-positive B-cell (Ph+) acute lymphoblastic leukemia (LLA), growing evidence has accumulated regarding the efficacy of low-intensity and chemo-free regimens. Our objective was to analyze all recent trials evaluating these treatments and to compare them in terms of efficacy. We applied the Shiny method, an artificial intelligence technique, to analyze Kaplan-Meier curves and reconstruct patient-level data. Reconstructed patient data were then evaluated through standard survival statistics and subjected to indirect head-to-head treatment comparisons. The endpoint was progression-free survival (PFS). Based on 432 reconstructed patients, eight trials were analyzed. The survival data from these trials were pooled into three types of treatments: (i) treatments based on tyrosine kinase inhibitors (TKIs) combined with reduced-intensity chemotherapy (denoted as TKICHE); (ii) TKIs associated with steroids with no chemotherapy (TKISTE); (iii) chemotherapy-free combinations of blinatumomab plus TKIs (TKIBLI). According to the Shiny method, the three PFS curves were reported in a single Kaplan-Meier graph and subjected to survival statistics. In terms of PFS, TKIBLI ranked first, TKICHE second, and TKISTE third; the differences between these three regimens were statistically significant. This multi-treatment Kaplan-Meier graph, generated through the Shiny method, summarized the current evidence on these treatments in both qualitative and quantitative terms.

Immune checkpoint inhibitors as first line in advanced melanoma: Evaluating progression-free survival based on reconstructed individual patient data.

BACKGROUND: In patients with advanced melanoma, immune-checkpoint inhibitors (ICIs) represent the mainstay for first line treatment. Recently, relatlimab+nivolumab was proposed as a new combination therapy. This review was aimed at summarizing the current data of effectiveness for ICIs. Progression-free survival (PFS) was the endpoint of our analysis. METHODS: After a standard literature search, Phase II/III studies comparing different ICI regimens in previously untreated advanced melanoma patients were analyzed. Patient-level data were reconstructed from Kaplan-Meier curves by application of the IPDfromKM method. These reconstructed datasets were used to perform indirect comparisons between treatments. Standard statistical testing was used, including hazard ratio and medians. A secondary analysis employed the restricted mean survival time. RESULTS: Six trials were included in our analysis. Information on PFS from these trials was pooled according to the following treatments: nivolumab or pembrolizumab as monotherapy, or in combination with ipilimumab, and relatlimab + nivolumab. Pembrolizumab+ipilimumab showed significantly better PFS compared with the other treatments; nivolumab+ipilimumab ranked second; the other treatments showed a similar survival pattern. CONCLUSIONS: The picture of comparative effectiveness resulting from our analysis is complex. The IPDfromKM method is advantageous because it accounts for the length of follow-up but loses the balance between treatment group and controls determined by randomization. Based on indirect comparisons, the combination of pembrolizumab+ipilimumab showed a particularly high efficacy, and so deserves further investigation. While the effect of between-trial differences in inclusion criteria plays an important role, our results do not support the proposal of relatlimab+nivolumab as a new standard of care.

Progression-Free and Overall Survival of First-Line Treatments for Advanced Renal Cell Carcinoma: Indirect Comparison of Six Combination Regimens.

BACKGROUND: Recently, numerous combination therapies based on immune checkpoint inhibitors (ICI) and vascular endothelial growth factor (VEGF) inhibitors have been proposed as first-line treatments for advanced renal cell carcinoma (aRCC). Our study aimed to compare the efficacy of these combination regimens by the application of an innovative method that reconstructs individual patient data. METHODS: Six phase III studies describing different combination regimens for aRCC were selected. Individual patient data were reconstructed from Kaplan-Meier (KM) curves through the "Shiny method". Overall survival (OS) and progression-free survival (PFS) were compared among combination treatments and sunitinib. Results were summarized as multi-treatment KM curves. Standard statistical testing was used, including hazard ratio and likelihood ratio tests for heterogeneity. RESULTS: In the overall population of aRCC patients, pembrolizumab + lenvatinib showed the longest median PFS and was expected to determine the longest OS. Pembrolizumab + axitinib, nivolumab + cabozantinib and nivolumab + ipilimumab were similar in terms of PFS, but pembrolizumab + axitinib also demonstrated a better OS. Our subgroup analysis showed that sunitinib is still a valuable option, whereas, in intermediate-poor risk patients, pembrolizumab + axitinib and nivolumab + ipilimumab significantly improve OS compared to sunitinib. CONCLUSION: The Shiny method allowed us to perform all head-to-head indirect comparisons between these agents in a context in which "real" comparative trials have not been performed.

Hospital Pharmacy Response to Covid-19 Pandemic in Italy: What We Learned From the First Outbreak Wave.

BACKGROUND: When COVID-19 pandemic started, Italian hospital pharmacists faced multiple challenges and change their work practices. OBJECTIVES: The aim of this study was to describe the impact of COVID-19 emergency on pharmaceutical care provided by pharmacists during the first wave of the pandemic. Issues related to pharmacist's involvement in the pandemic management were: changes in activities, support received by authorities and pharmacists' own perceived role in the Health System. METHODS: A cross-sectional study based on a web survey was conducted between May and June 2020 collecting information from pharmacists, members of Italian Society of Clinical Pharmacy and Therapeutics. 113 (11.4%) completed the questionnaire. The cohort was divided in 2 arms: pharmacists who worked in severely COVID-19 affected areas (High Spread Regions) and those employed in less affected areas (Low Spread Regions). RESULTS: The changes in pharmacy work settings reflected the increase of logistics area and non-sterile clinical galenic, and reduction of clinical tasks. The most demanding challenge was referred to shortages of medical devices and drugs, 61/113 pharmacists reported difficulty in obtaining products compliant to quality standards. National Institutions and Regional Governments provided a greater perceived support. More than 50% of participants felt that their role did not change if compared to other health professionals. CONCLUSIONS: Despite some limitations related to their clinical activity, pharmacists played a crucial role in supplying personal protective equipment, medical devices and medications to improve health outcomes during this emergency. The results may guide pharmacists in future actions to improve the management of the pandemic.

Survival in Patients with Relapsed-Refractory Multiple Myeloma: Indirect Comparison of Six New Treatments.

In recent years, new treatments have been studied for relapsed-refractory multiple myeloma (RRMM), including two CAR-T products and a variety of non-CAR-T agents. Since direct comparisons between these innovative treatments are not available, indirect comparisons can be of interest. Reconstruction of individual patient data from Kaplan-Meier graphs (e.g., according to the Shiny method) has been the subject of numerous reports that have fully validated their performance. In the present systematic review, we evaluated six treatments proposed for RRMM, including two CAR-T products (ciltacabtagene autoleucel and idecabtagene vicleucel) and four treatments not based on a CAR-T (melflufen plus dexamethasone, isatuximab plus dexamethasone, selinexor, and belantamab). The endpoint was overall survival (OS). Our results showed statistically significant differences in OS across these treatments. In particular, ciltacabtagene autoleucel showed better OS than idecabtagene vicleucel. As regards non-CAR-T treatments, the ranking in OS was headed by isatuximab plus dexamethasone, followed by belantamab, selinexor, and melflufen plus dexamethasone. In conclusion, while the Shiny method has confirmed its validity in reconstructing individual patient data, our indirect comparisons have offered some original clues to interpret the results of OS published in these studies.

Application of the IPDfromKM-Shiny Method to Compare the Efficacy of Novel Treatments Aimed at the Same Disease Condition: A Report of 14 Analyses.

In the area of evidence-based medicine, the IPDfromKM-Shiny method is an innovative method of survival analysis, midway between artificial intelligence and advanced statistics. Its main characteristic is that an original software investigates the Kaplan-Meier graphs of trials so that individual-patient data are reconstructed. These reconstructed patients represent a new form of original clinical material. The typical objective of investigations based on this method is to analyze the available evidence, especially in oncology, to perform indirect comparisons, and determine the place in therapy of individual agents. This review examined the most recent applications of the IPDfromKM-Shiny method, in which a new web-based software-published in 2021-was used. Reported here are 14 analyses, mostly focused on oncological treatments. Indirect comparisons were based on overall survival or progression free survival. Each of these analyses provided original information to compare treatments with one another and select the most appropriate depending on patient characteristics. These analyses can also be useful to assess equivalence from a regulatory viewpoint. All investigations stressed the importance of heterogeneity to better interpret the evidence generated by IPDfromKM-Shiny investigations. In conclusion, these investigations showed that the reconstruction of individual patient data through this online tool is a promising new method for analyzing trials based on survival endpoints. This new approach deserves further investigation, particularly in the area of indirect comparisons.