Psoriasis is a common, chronic, immune-mediated inflammatory skin disease with increased epidermal proliferation. The objective of this review was to systematically identify the evidence and perform ...a network meta-analysis (NMA) to estimate the relative efficacy of secukinumab (SEC) against adalimumab (ADA) and infliximab (INF) for the treatment of moderate-to-severe plaque psoriasis.
A systematic literature review (SLR) was conducted according to a pre-specified protocol to identify relevant studies. Initially, the databases were searched from database inception till June 2013, and the SLR was updated in April 2020. The eligibility criteria included adult patients (≥18 years old) with moderate-to-severe plaque psoriasis, and the SLR included randomized controlled trials (RCTs). The comparators of interest were SEC, ADA, INF, and placebo (PLA), while outcomes of interest were Psoriasis Area and Severity Index (PASI) (50, 75, and 90) at weeks 12, 16, and 24. A Bayesian NMA for PASI was utilized with a framework that evaluated the probability of PASI responses in different categories of PASI thresholds within a single model.
A total of 23 RCTs that assessed the efficacy of SEC, ADA, and INF in patients with moderate-to-severe plaque psoriasis were identified. At 12 weeks, SEC was associated with a significantly better response compared with PLA and ADA for PASI 75 and 90, while response results were comparable against INF. At 12 weeks, risk ratio (95% confidence interval) derived from NMA for SEC vs. ADA and INF for PASI 75 was 1.35 (1.19, 1.57) and 1.01 (0.90, 1.18), respectively. At the 16-week and 24-week time interval, SEC was significantly better than PLA, ADA, and INF for PASI 75 and 90.
Efficacy of SEC in the treatment of patient populations with moderate-to-severe plaque psoriasis is well demonstrated through NMA.
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Background: The approval of newer agents in metastatic renal cell carcinoma (mRCC) has changed the treatment paradigm in first-line settings. The aim of this review was to ...compare pazopanib against current first-line treatments in RCC. Methods: A systematic review was conducted that assessed pazopanib against first-line agents in treatment naïve patients with mRCC. Relevant databases and conferences were searched to identify randomized controlled trials (RCTs) assessing treatment naïve adult patient (≥18 years). Frequentist mixed treatment comparison (MTC) method was applied for the pairwise comparisons among treatments for ITT population and favorable, intermediate, and poor risk subgroups. Results: Twenty-three RCTs met the eligibility criteria. The MTC results showed that pazopanib was comparable to sunitinib in terms of progression free survival (PFS) and overall survival (OS) in ITT population. Cabozantinib was significantly better compared to pazopanib for PFS; however, there was heterogeneity in the patient population. Pazopanib was comparable to nivolumab + ipilimumab when assessed for PFS in ITT population; although, favorable risk patients treated with pazopanib achieved significantly higher PFS compared to nivolumab + ipilimumab (HR: 0.46, 95% CI: 0.37, 0.57). Atezolizumab + bevacizumab and avelumab + axitinib were associated with significantly higher PFS compared to pazopanib. Cabozantinib and nivolumab + ipilimumab were associated with better OS compared to pazopanib. Conclusions: The newer agents i.e. cabozantinib and nivolumab + ipilimumab are approved for intermediate/poor risk patients. The results suggests that pazopanib is still a reliable option for treatment of patients in first-line settings, especially for favorable/intermediate risk patients.Table: see text
535
Background: DFS has been widely adopted as a clinically meaningful primary endpoint in EBC trials in place of OS, which needs extensive follow-up to observe sufficient events and fails to assess ...survival benefit early. However, a rigorous validation of DFS as a surrogate endpoint for OS is required for each given setting. The objective of this analysis was to evaluate DFS as surrogate for OS in the adjuvant treatment of HR+/HER2− EBC. Methods: A systematic literature review (SLR) was conducted using biomedical literature databases (ie, Embase, PubMed, and Medline from database inception to January 2023) and key conferences to identify published studies in EBC. The eligibility criteria for the SLR were RCTs that included ≥80% of adult pts with HR+/HER2− EBC and assessing different treatment options (ie, cyclin-dependent kinase 4/6 inhibitors CDK4/6i, endocrine therapies ET, and chemotherapies CT). Studies were considered for correlation analysis if hazard ratios (HRs) were reported for both DFS and OS. The analysis excluded observational studies and trials with immature OS data. Spearman rank correlation (r
s
) and weighted linear regression analyses (measured by coefficient of determination R
2
) were performed to evaluate the correlation between HRs for OS and DFS. Considering heterogeneity, multiple scenario analyses were conducted. Surrogate threshold effect (STE) was also estimated; STE is defined as the maximum value of the HR for DFS that needs to be observed in a trial to ensure the possibility of concluding that a significant effect on OS occurred. Correlation was also assessed using pt-level data from the FACE trial (letrozole vs anastrozole in postmenopausal pts with HR+/HER2− EBC) to validate findings of the trial-level analysis. Results: A total of 14 RCTs (N = 31,668) were included (CDK4/6, 2; ET, 7; CT, 5). Trial-level analysis showed that r
s
between OS and DFS was 0.81 (95% CI, 0.56-0.94), which when weighted by variance was 0.81. Regression analysis showed that 84% of the variability in OS was explained by DFS (R
2
= 0.84). A meta-regression model estimated an STE of 0.82 for HR of DFS, which can be leveraged to validate the surrogacy based on the DFS estimated from a future trial. Analysis of pt-level data from the FACE trial demonstrated a correlation between DFS and OS (r
s
= 0.75). Additionally, correlation coefficients estimated by the Pearson method and iterative imputation were 0.83 and 0.89, respectively. Conclusions: Both trial-level and pt-level analyses demonstrate a positive correlation between DFS and OS. These results support the use of DFS as a reliable surrogate endpoint for OS in HR+/HER2− EBC trials to give an early access to innovative therapies.
The objective was to systematically review the literature and assess the relative efficacy of agents approved in first-line settings via network meta-analysis.
A literature review was conducted via ...searching different medical databases. The eligibility criteria included Phase II or III randomized controlled trials that had enrolled treatment-naive adult patients with advanced/metastatic melanoma.
The network meta-analysis results suggested that dabrafenib + trametinib significantly prolongs the survival outcomes compared with the monotherapies and had comparable efficacy profile compared with encorafenib + binimetinib and cobimetinib + vemurafenib. In comparison with immunotherapies, the results varied for progression-free survival and overall survival.
Long-term survival data of dabrafenib + trametinib establishes the combination as one of the preferred treatment options for previously untreated melanoma patients.
To assess the cost-effectiveness of pazopanib versus sunitinib as a first-line treatment for patients with metastatic renal cell carcinoma (mRCC) from an Italian National Health Service perspective, ...considering the evolving Italian landscape in terms of new reimbursement agreements trend.
This analysis is an update of the previously published cost-effectiveness analysis to incorporate recent 2019 costs and additional changes regarding drug discounting. A partitioned-survival analysis model with three different health states (progression-free survival, post-progression survival, and dead) was utilized. Outcomes included progression-free life years, post-progression life years, overall life years, quality-adjusted life years (QALYs), and costs calculated for both treatments. Cost-effectiveness was assessed in terms of incremental costs per QALY gained and the net monetary benefit (NMB) of pazopanib versus sunitinib. In the base case analysis, a time horizon of 5 years was used and future costs and QALYs were discounted at a 3% annual discount rate. An impact of methodological and parameter uncertainly on base case results was evaluated using probabilistic and deterministic sensitivity analyses.
In the base case, pazopanib had higher QALYs (+0.060) at lower costs (−€5,857) versus sunitinib, hence it dominated sunitinib. At willingness-to-pay thresholds of €30,000 and €50,000 per QALY, the NMB with pazopanib were €7,647 and €8,841 per patient, respectively, versus sunitinib. The probability that pazopanib is cost-effective versus sunitinib was estimated to be 97.5% at a cost-effectiveness threshold of €20,000, 95.4% at a threshold of €30,000, and 90.2% at a threshold of €50,000 per QALY. Cost-effectiveness results were robust to changes in key parameter values and assumptions as demonstrated by deterministic sensitivity analyses.
Pazopanib is likely to represent a cost-effective treatment option compared with sunitinib as a first-line treatment for patients with metastatic RCC in Italy.
Introduction
Chronic spontaneous (previously known as idiopathic) urticaria (CSU) is a chronic skin disease with the potential for natural remission. The objectives of this targeted literature review ...were to identify evidence on the clinical course of CSU, including remission rates, and to estimate cumulative remission rates for different time points.
Methods
Electronic databases (MEDLINE, MEDLINE-In Process, Embase, Web of Science, BIOSIS Previews and the Cochrane Library) and relevant conference proceedings were searched to identify studies involving patients with CSU aged ≥ 12 years that provide data on remission rates and disease duration. Observational studies with patient follow-ups of ≥ 1 year or review articles were included. Data extracted from five selected studies were used to run Kaplan–Meier (KM) analyses and best-fit distributions to calculate remission rates per 4-week period and weighted averages.
Results
Ten publications were included in this review. The proportion of patients achieving remission within year 1 ranged from 21 to 47%, while reported remission rate estimates at year 5 were 34% and 45%. Based on calculated 4-weekly remission rates, cumulative remission estimates ranged from 9 to 38% at year 1, from 29 to 71% at year 5 and from 52 to 93% at year 20. Cumulative weighted average estimates for the proportion of patients remitting at years 1, 5 and 20 were 17%, 45% and 73%, respectively.
Conclusions
Published evidence suggests that CSU is a self-limiting condition with variable disease severity and duration, apparently dependent on multiple factors. However, data sources differed in terms of definitions of disease severity and remission, as well as in conclusions on influencing factors. Further studies and uniform definitions are required.
BackgroundAdoptive cell therapy demonstrated significant clinical benefit in patients with hematological malignancies but results in most solid tumors have been less encouraging so far.In the IMA203 ...trial we are treating advanced solid cancer patients utilizing TCR-engineered T cells (TCR-T) directed against an HLA-A*02-restricted peptide derived from the highly prevalent cancer testis antigen PRAME. This target was selected due to homogenous expression and exceptionally high target peptide density per tumor cell (assessed by quantitative mass spectrometry), two features we hypothesize to be critical determinants of anti-tumor activity in TCR-T trials.MethodsThis ongoing first-in-human, dose escalation, multi-indication trial enrolls HLA-A*02:01- and PRAME-positive recurrent and/or refractory solid cancer patients, who failed all available standard treatments. Eligible patients undergo leukapheresis and an autologous TCR-T product is manufactured. After lymphodepletion with fludarabine and cyclophosphamide, T cells are infused, followed by low-dose IL-2. The primary objective of the trial is to assess the safety and tolerability of IMA203. Secondary objectives are to evaluate the anti-tumor activity and pharmacodynamics using molecular and immunological methods.ResultsAs of August 15, 2021, 16 heavily pre-treated patients received IMA203 T cells across multiple escalating dose levels (DL). Absolute IMA203 doses infused ranged from 0.08 to 0.81x109 transduced CD8 T cells per patient, which to our knowledge did not lead to anti-tumor responses in other TCR-T trials. Treatment-emergent adverse events after IMA203 infusion were transient and manageable. Most common events were expected cytopenias (G1-4), CRS and ICANS (both G1-2) and 1 DLT in DL2 (reported earlier). All evaluable patients (N=12) achieved disease control (i.e. best overall response: stable disease SD or partial response PR) and 6 patients demonstrated PRs according to RECIST1.1 with 2 of these PRs being confirmed. While all 3 patients treated at DL1 (median dose: 0.11x109) experienced SD, a PR was observed in 6/9 patients treated beyond DL1 (median dose: 0.30x109). Responses were seen in patients with synovial sarcoma (N=3), malignant melanoma (N=2) and head and neck cancer (N=1). Robust engraftment of T cells was observed in all patients and tumor infiltration by TCR-modified T cells was demonstrated in patients with evaluable on-treatment biopsies.ConclusionsTo our knowledge IMA203 is the first TCR-T product candidate that induced frequent tumor responses across multiple solid cancers using transduced T cells at doses below 1 billion and has a manageable safety profile. The next step is to assess response rates at higher dose levels and durability of responses.Trial RegistrationNCT03686124Ethics ApprovalThe study was approved by the institutional review board/ethics committee as required for each participating site.
Abstract
T cell receptor (TCR)-based adoptive cell therapy represents an innovative and promising treatment for pts with solid cancers who continue to have a high unmet medical need. This ongoing ...trial (NCT03686124) evaluates IMA203, an autologous TCR-engineered T cell therapy (TCR-T) utilizing a novel, pairing-enhanced TCR with high affinity and specificity against an HLA-A*02:01-presented peptide derived from PRAME. PRAME is a multi-cancer target with a prevalence of 80-100% in cut. and uveal melanoma, sarcoma subtypes, uterine and ovarian cancer; it has a high prevalence in many other solid cancer types, such as lung, triple-negative breast and head and neck cancer, among others. Eligible pts have recurrent and/or refractory solid cancer, are ≥18 y, ECOG PS of 0-1 and have exhausted all available SOC treatments. PRAME expression is assessed by RT-qPCR analysis of archived or fresh tumor tissue. After lymphodepletion with Cy/Flu (500 mg/m2 and 30 mg/m2 IV x 4d), IMA203 is infused followed by low-dose IL-2 (1 mil IU SC daily x 5d, then twice daily x 5d). Herein, we present preliminary results from 38 pts treated across the phase 1a dose escalation (N=27) and phase 1b dose expansion cohort A at the provisional RP2D (N=11) (data cut-off April 04, 2023). Pts were heavily pre-treated with a median of 4 prior systemic therapies. At baseline, tumor burden was 113 mm (median sum of diameters of target lesions) and LDH >ULN in 63% of pts. Pts in phase 1a (dose level, DL, 1-4) received a median of 0.41x109, pts in phase 1b (DL4/5) a median of 3.94x109 IMA203 T cells. TEAEs were manageable with most common events being expected cytopenias (100%), CRS (92% G1-2, 3% G3) and ICANS (13% G1-2). 61% (11/18) of pts in phase 1a and phase 1b treated at DL4/5 above 1x109 IMA203 T cells showed an initial objective response according to RECIST1.1 at week 6 post infusion. 11 pts in phase 1b were infused with IMA203 T cells manufactured with an improved process leading to significantly increased TCR-T levels and persistence. In these pts IMA203 achieved an initial objective response rate (ORR) of 64% (7/11) at week 6 and a confirmed ORR of 67% (6/9) at month 3. Objective responses were observed across multiple tumor types, including PD1-refractory cut. melanoma, uveal melanoma, platinum-resistant ovarian cancer, synovial sarcoma and head and neck cancer. 5 of 7 responders in phase 1b had an ongoing response at 9 (N=2), 6 (N=1), 3 (N=1), and 1.5 months (N=1) post infusion. At a mFU of 8.5 months, mDOR was not reached (min 1.3+, max 8.8+ months). IMA203 T cells were detectable in all evaluable post treatment tumor tissues and degree of infiltration was associated with objective responses. Objective responses were observed at low, medium and high PRAME expression levels. In summary, IMA203 showed a manageable tolerability profile and, to our knowledge, is the first TCR-T product candidate achieving a high rate of objective responses independent of tumor type, thus providing a potential innovative treatment option for many solid cancer pts with PRAME-positive tumors.
Citation Format: Martin Wermke, Winfried Alsdorf, Dejka Araujo, Manik Chatterjee, Norbert Hilf, Tobias A.W. Holderried, Amir A. Jazaeri, Mamta Kalra, Andrea Mayer-Mokler, Regina Mendrzyk, Ali Mohamed, Sapna P. Patel, Ran Reshef, Arun Satelli, Harpreet Singh, Apostolia-Maria Tsimberidou, Steffen Walter, Toni Weinschenk, Cedrik M. Britten, Jason Luke. IMA203 TCR-T targeting PRAME demonstrates potent anti-tumor activity in patients with different types of metastatic solid tumors abstract. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR018.
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