R WE ready for reimbursement? A round up of developments in real-world evidence relating to HTA: part 5

In the latest update we focus on recent publications which have provided insights into the importance of focusing on the development and consideration of a body of real-world evidence, and an approach to evaluating the complex area of treatment sequencing.

Spatial structure governs the mode of tumour evolution

Characterizing the mode—the way, manner or pattern—of evolution in tumours is important for clinical forecasting and optimizing cancer treatment. Sequencing studies have inferred various modes, including branching, punctuated and neutral evolution, but it is unclear why a particular pattern predominates in any given tumour. Here we propose that tumour architecture is key to explaining the variety of observed genetic patterns. We examine this hypothesis using spatially explicit population genetics models and demonstrate that, within biologically relevant parameter ranges, different spatial structures can generate four tumour evolutionary modes: rapid clonal expansion, progressive diversification, branching evolution and effectively almost neutral evolution. Quantitative indices for describing and classifying these evolutionary modes are presented. Using these indices, we show that our model predictions are consistent with empirical observations for cancer types with corresponding spatial structures. The manner of cell dispersal and the range of cell–cell interactions are found to be essential factors in accurately characterizing, forecasting and controlling tumour evolution.

OP179 Quantitative Evidence Synthesis Methods For Assessing The Effectiveness Of Treatment Sequences For Clinical And Economic Decision-Making: Methodology Review

IntroductionThe sequential use of alternative treatments for chronic conditions represents a complex, dynamic intervention pathway; previous treatment and patient characteristics affect both choice and effectiveness of subsequent treatments. Evidence synthesis methods that produce the least biased estimates of treatment-sequencing effects are required to inform reliable clinical and policy decision-making. A comprehensive review was conducted to establish what existing methods are available, outline the assumptions they make, and identify their shortcomings.MethodsThe review encompassed both meta-analytic techniques and decision-analytic modelling, any disease condition, and any type of treatment sequence, but not diagnostic tests, screening, or treatment monitoring. It focused on the estimation of clinical effectiveness and did not consider the impact of treatment sequencing on the estimation of costs or utility values.ResultsThe review included ninety-one studies. Treatment-sequencing is usually dealt with at the decision-modelling stage and is rarely addressed using evidence synthesis methodology for clinical effectiveness. Most meta-analyses are of discrete treatments, sometimes stratified by line of therapy. Prospective sequencing trials are scarce. In their absence, there is no single best way to evaluate treatment sequences, rather there is a range of approaches, each of which has advantages and disadvantages and is influenced by the evidence available and the decision problem. Due to the scarcity of data on sequential treatments, modelling studies generally apply simplifying assumptions to data on discrete treatments. A taxonomy for all possible assumptions was developed, providing a unique resource to aid the critique of decision-analytic models.ConclusionsThe evolution of network meta-analysis in HTA demonstrates that clinical and policy decision-making should account for the multiple treatments available for many chronic conditions. However, treatment-sequencing has yet to be accounted for within clinical evaluations. Economic modelling is often based on the simplifying assumption of treatment independence. This can lead to misrepresentation of the true level of uncertainty, potential bias in estimating the effectiveness and cost effectiveness of treatments and, eventually, the wrong decision.

A Retrospective Database Analysis of Treatment Pathways in US Medicare Patients with Multiple Myeloma and Prior Exposure to Daratumumab, an Immunomodulatory Agent, and a Proteasome Inhibitor

Introduction: Recentreal-world data for multiple myeloma (MM) treatment patterns and outcomes are limited, particularly for patients with refractory or relapsed MM. As the MM treatment landscape evolves, it is important to understand how new treatments are integrated into patient treatment patterns. The aim of this study was to examine patient demographics, clinical characteristics, treatment patterns, and survival among Medicare patients with MM following exposure to daratumumab (DAR), an immunomodulatory agent, and a proteasome inhibitor (PI). Methods: This was a retrospective database analysis utilizing the Centers for Medicare and Medicaid Services claims data during the study period of January 1, 2016, through December 31, 2018. The start of the study period was chosen to align with DAR market entry in the United States (FDA approval November 2015). Medicare patients, diagnosed with MM, and with existing claims for DAR, an immunomodulatory agent, and a PI (tri-exposure) were eligible for inclusion. Index tri-exposure was achieved once a patient had been exposed to all 3 MM treatments, regardless of their sequence. The index date was the first observed claim for any MM regimen (index line of therapy [LOT]) following tri-exposure. Patients were required to have ≥6 months of continuous enrollment prior to the index date (baseline period). Therapies given after the index LOT were defined as post-index therapy. Patient data were assessed until health plan disenrollment, death, or end of study period, whichever occurred first. Results: There were 1336 Medicare patients with MM who met the inclusion criteria. Of these patients, the mean age (standard deviation [SD]) at the index date was 71 (8.5) years and 705 (52.8%) were male. The Southern United States showed the largest representation of patients in this population (n=471, 35.3%). The top baseline comorbidities included respiratory infections (98.3%), osteoarthritis (86.8%), anemia (86.9%), hypertension (78.1%), dyslipidemia (66.5%), chronic pain/fibromyalgia (51.9%), acute or chronic kidney disease (44.5%), cardiac arrhythmia (45.81%), and neutropenia (47.98%). The mean (SD) number of days from the index date until the end of index LOT was 48.7 days (12.0). Among 949 patients (71.0%) who had post-index therapy, the mean (SD) time from the last observed claim for index LOT to the beginning of the post-index therapy and duration of post-index therapy was 51.8 (44.2) days and 57.8 (16.0) days, respectively. The median (range) duration of follow-up time from the index date was 223 (3─886) days. During the study follow-up period, 571 patients (42.7%) died, and the median (range) number of days from the index date until death was 173 (3─873) days. While there was variation in treatment sequencing leading to tri-exposure, the most frequent tri-exposure sequence was an immunomodulatory agent < PI < DAR (33.2% [See Table for overview of treatment sequencing]). Among patients who received index LOT following tri-exposure, 49.4% had triplet therapy and 29.8% had doublet therapy. The most common index LOT regimens were triplet: DAR/pomalidomide/dexamethasone (DEX; 7.6%), elotuzumab/lenalidomide/DEX (5.2%), and DAR/bortezomib/DEX (4.9%). The most common post-index LOT regimens were triplet (39.9%): DAR/pomalidomide (6.1%), carfilzomib/cyclophosphamide/DEX (3.7%), DAR/bortezomib/DEX (3.5%), and DAR/lenalidomide/DEX (3.5%). During follow-up, 52.8% of patients were retreated with DAR, 79% with PI, and 77.3% with immunomodulatory drugs. Conclusions: This study suggests wide variation in treatment sequencing and regimens after tri-exposure to DAR, an immunomodulatory agent, and a PI. Triplet regimens were predominant treatment after the tri-exposure and following the index LOT. Retreatment with the same agents was common. Among those who died, survival was often less than 1 year following tri-exposure. These results highlight the need for new treatment options in triple-class refractory MM settings. Funding: GSK (Study 213462) Figure 1 Figure 1. Disclosures Boytsov: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Cyhaniuk: STATinMED Research: Current Employment. Leung: STATinMED Research: Current Employment. Wang: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Hogea: GlaxoSmithKline, paid employee: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Mudumby: STATinMED Research: Current Employment.

601 Sequencing immunotherapy before lymphatic ablation unleashes cDC1-dependent antitumor immunity in HNSCC

BackgroundDespite the proven efficacy of immune checkpoint inhibitor (ICI) therapy in the recurrent/metastatic setting for head and neck squamous cell carcinoma (HNSCC), clinical trials of ICI combined with curative-intent therapies have yielded equivocal results [1–4]. Collectively, this highlights gaps in our understanding of rational immune oncology (IO) treatment sequencing and suggests that the efficacy ICI may be disrupted by standard therapies, which necessarily compromise regional lymphatics.MethodsWe employ a preclinical model of tobacco-signature HNSCC to identify sequences of therapy that maximize durable response. By mapping the cervical lymphatic basins in the mouse, we define patterns of active antitumor immunosurveillance. Additionally, we establish tumors with distinct patterns of regional lymphatic drainage and develop a murine neck dissection (ND) model.ResultsWe find that cervical lymphatic ablation, with ND or stereotactic body radiation therapy, in tumor bearing animals abolishes the response to ICI therapy, significantly impacting overall survival. Examination of the tumor immune microenvironment following ND reveals dramatic changes with a ten-fold increase in CD45 cells and exclusion of cytotoxic and antigen-specific lymphocytes. By examining the lymphatics removed at the time of ND, we find that conventional type I dendritic cells (cDC1s) and type I interferon (IFN-I) signaling are significantly increased, suggesting that these effectors are lost after curative-intent therapy. Depleting IFN-I or cDC1s blocks the response to ICI similar to lymphatic ablation. We find that successful primary response to ICI leads to durable immunity, conferred by systemically distributed memory T cells, not impaired by delayed ND. Lastly, we discover a rational IO treatment sequence by delivering neoadjuvant ICI followed by ND. Neoadjuvant ICI leads to complete tumor response, accumulation of nodal cDC1, and durable immunity. Surprisingly, the incidence of nodal metastasis at early timepoints reveals a similar burden of nodal disease between control and ICI-treated animals that decreases at late timepoints only with ICI treatment (44% vs 15%, n=25, p=0.033). This suggests that ICI also drives active immunosurveillance in regional, tumor-draining lymphatics, challenging the landmark findings from the definitive clinical trial demonstrating the benefit of elective versus therapeutic neck dissection for oral SCC patients with clinically negative necks.ConclusionsThis work demonstrates the necessity of preserving tumor-draining lymphatics during the tumor response to ICI therapy in HNSCC. Overall, we define rational IO treatment sequences to achieve optimal primary tumor response, durable antitumor immunity and immunosurveillance of regional metastatic disease. These findings can inform future clinical trials investigating combination IO therapy and treatment sequencing.ReferencesHarrington, K. J. et al. Nivolumab versus standard, single-agent therapy of investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial. Lancet Oncology 18, 1104–1115 (2017).Burtness, B. et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet (London, England) 394, 1915–1928 (2019).Lee, N. Y. et al. Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol 22, 450–462 (2021).D’Cruz, A. K. et al. Elective versus Therapeutic Neck Dissection in Node-Negative Oral Cancer. New England Journal of Medicine 373, 521–529 (2015).

Thymic tumours and their special features

Thymic tumours are rare thoracic malignancies, that may be aggressive and difficult to treat. The pillars of the management include pathological review, consideration of differential diagnoses, staging and multidisciplinary discussion. Assessment of resectability is key to drive the treatment sequencing. Association with autoimmune diseases, especially myasthenia gravis, is observed, which impacts the oncological management. Networks are being built at the national and international levels. This article provides an overview of the most recent findings in the diagnosis, staging, histology, and management strategies of thymic tumours.

Laparoscopic Heated Intraperitoneal Chemotherapy in the Treatment of Carcinomatosis of Gastric Adenocarcinoma Origin

The use of heated intraperitoneal chemotherapy (HIPEC) in conjunction with cytoreductive surgery has been gaining increasing traction in treating gastric adenocarcinoma with metastasis to the peritoneum in recent years. The addition of laparoscopic HIPEC (LS-HIPEC) to these treatment algorithms has increased the flexibility and adaptability of HIPEC integrating into treatment sequencing, allowing for iterative protocols of LS-HIPEC prior to cytoreduction as neoadjuvant treatment, as well as in the palliation of patients with unresectable disease and uncontrolled ascites. As the use of HIPEC in gastric adenocarcinoma continues to be refined, LS-HIPEC algorithms should continue to be considered and utilized both in curative treatment algorithms as well as in patients in the palliative setting. Given that LS-HIPEC remains a relatively nascent treatment modality, we advocate for its use in the setting of a clinical trial when feasible.