A prospective, real-world, multinational study of febrile neutropenia (FN) occurrence in oncology patients receiving chemotherapy with intermediate risk of FN: a MASCC Neutropenia, Infection, and Myelosuppression Study Group initiative.

PURPOSE: Limited knowledge is available on the incidence of febrile neutropenia (FN) in intermediate-risk patients and the rationale for use of granulocyte colony-stimulating factor (G-CSF) in these patients. We aimed to estimate the rate at which patients associated with intermediate risk (10-20%) of FN would develop ≥ 1 episode of FN with a commonly used chemotherapy regimen in clinical practice. METHODS: This prospective, real-world, observational, multinational, multicenter study (December 2016-October 2019) recruited patients with solid tumors or Hodgkin's/non-Hodgkin's lymphoma. Patients receiving chemotherapy with intermediate risk of FN, but not G-CSF as primary prophylaxis were included and observed for the duration of the chemotherapy (≤ 6 cycles and ≤ 30 days after the last chemotherapy administration). RESULTS: In total, 364 patients (median age, 56 years) with 1601 cycles of chemotherapy were included in the analysis. The incidence of FN was 5% in cycle 1, 3% in cycles 2-3, and 1% in cycles 4-6. The rate of patients with ≥ 1 episode of FN was 9%, and 59% of FN events were reported during cycle 1. The rate of grade 4 neutropenia in cycle 1 was 11%, and 15% of patients experienced ≥ 1 episode of grade 4 neutropenia. CONCLUSIONS: Overall, the incidence of FN was low, with a high incidence in cycle 1 and a decrease in the subsequent cycles. These results provide the real FN risk for common chemotherapy regimens in patients generally excluded from clinical trials. Prophylactic G-CSF in intermediate-risk patients could be considered as per clinician's judgement.

Early access provision: Awareness, educational needs and opportunities to improve oncology patients' access to care.

Background: An unmet medical need exists for many oncology patients who cannot be treated satisfactorily by available therapeutic options. Early access provision (EAP) is endorsed by competent authorities to improve patient access to innovative medicinal products (InMPs). This paper determined awareness and understanding among practicing physicians of integrated EAP protocols, and of the procedures involved in EAP applications for oncology trials prior to marketing authorization. Methods: An on-line, fully anonymous survey reaching out to more than 3,258 physicians (including practicing oncologists) was initiated between November 2020 - January 2021. Participants were questioned about their knowledge and understanding of EAP and the decision processes involved, level of experience, interest for further educational activities and opportunities to improve the process, both in general and specifically during the COVID-19 pandemic. The frequency of EAP protocols for oncology InMPs was identified by a search of ClinicalTrials.gov and EU Clinical Trials registers. Results: Survey results (75% oncologists) indicated 75% of respondents were 'very comfortable' or 'comfortable' with using EAP for their patients, but only 54.5% correctly answered the specific knowledge-based question related to the EAP definition. For 56% of respondents, experience with EAP in daily practice was very limited. Two-thirds indicated an average or lower level of understanding about the application process and regulatory requirements involved (65.2% and 66.0%, respectively). Knowledge on data collection and serious adverse event reporting under EAP was lower at 57.8% and 50.5% of respondents, respectively. Awareness of physician responsibilities was high in 59.7% of respondents, but fewer understood roles and responsibilities of manufacturing companies (31.2%). Most indicated they would consider clinical efficacy and safety data from comparative phase III randomized controlled trials as of high importance to support their decision to apply for EAP (93.4% and 86.8%, respectively). During the COVID-19 pandemic, the majority of respondents highlighted the need to improve and adapt EAP with regard to the application process and documentation (83.8%), InMP supply and logistics (88.4), and safety reporting process (78.0%). Of identified oncology trials with a ClinicalTrials.gov protocol, only 149 (0.4%) included EAP, and 23 used the data to receive a marketing authorization during the period Jan 2015 to December 2020. Of oncology trials with a EudraCT protocol, only 21 (0.23%) included EAP, of which 6 were used to receive a conditional or full marketing authorisation over the same period. Conclusion: Use of EAP in daily practice remains limited. Challenges posed by the EAP process, together with a lack of education on this topic, might contribute to its under-utilization and influence access of oncology patients to care. Continuous educational efforts from different stakeholders are required to better inform and support practicing oncologists during the EAP application process and regulatory framework follow up. Education should also be provided on EAP roles and responsibilities, monitoring, and potential adaptations when faced with specific challenges, such as the current COVID-19 pandemic.

Medical Affairs and Innovative Medicinal Product Strategy Development.

Innovative medicinal products are required for progress in many therapeutic areas, and in particular, oncology. For these products to succeed, pharmaceutical companies must generate the relevant and robust clinical data required to meet the needs of regulators and healthcare providers. In addition, real-world and health economic evidence is increasingly required to support pricing and reimbursement for innovative medicinal products. To incorporate all of these requirements into the innovative medicinal product strategy early in development, the core principles of how product strategies are developed and applied must be revisited and end-to-end strategic planning implemented. This paper reviews the hurdles faced during development of the integrated strategy for innovative medicinal products, particularly in the oncology field, and examines which functions of a pharmaceutical company should play the greatest role in addressing patient and different stakeholders' needs. It will then illustrate how Medical Affairs activities are evolving to take on this strategic leadership role.

Value of Adaptive Trials and Surrogate Endpoints for Clinical Decision-Making in Rare Cancers.

Despite high-level endorsement, the number of adaptive Phase II/III trials in rare cancers needs to be improved, with better understanding of their value for clinical decisions in daily practice. This paper describes approaches to trial design in rare cancers, which has been supplemented by a search of ClinicalTrials.gov for adaptive trial designs in rare cancer. In addition, an online survey of 3,200 oncologists was conducted. Practicing physicians were questioned on the importance of different evidence levels, types of adaptive trial design, and categories of surrogate endpoints for clinical decision making. The results of the online survey revealed that evidence from Phase II/III trials with an adaptive design and relatively small sample size was considered high value in rare cancer by 97% of responders, similar to the randomized controlled trial rating (82%). Surrogate clinical endpoints were considered valuable alternatives to overall survival by 80% of oncologists. Preferred adaptive designs were futility analysis, interim analysis, adaptive sample size, and adaptive randomization. In conclusion, rare cancer oncologists rate evidence from adaptive clinical trials with as high a value and importance for clinical decision making processes as conventional randomized controlled trials. All stakeholders have a vested interest in advances in clinical trial designs to ensure efficient and timely development of innovative medicinal products to allow more patients faster access to the pivotal treatment.

CD95L and Anti-Tumor Immune Response: Current Understanding and New Evidence.

The ability of FasL/CD95L to induce apoptosis in various Fas/CD95-expressing cells has been described in the context of hematopoiesis or thymic elimination of self-reactive T cells and resolution of an acute immune response under physiological conditions. At the same time, non-apoptotic CD95 activation is widely described in cancer and shown to stimulate invasiveness of cancer cells, promote cancer progression as well as stemness of cancer cells. This paper puts emphasis on the evolving understanding of expression and the non-apoptotic activities of the CD95/CD95L signaling pathway on the function of tumor cells, tumor microenvironment and immune cells. The emerging evidence to support the role of CD95/CD95L signaling in the anti-tumor immune response will be presented in the context of various malignancies and the modalities of potential therapeutic interventions via selective CD95L inhibition in combination with traditional interventions such as RT, chemotherapy and immune checkpoint inhibitors.

Critical Factors Shaping Strategy Development of an Innovative Medicine in Oncology.

Innovative medicinal products are required to achieve progress in oncology; however, these are associated with high financial investments, extensive development times, and significant risk of potential failure in the pivotal clinical trials required for marketing authorization. With increasing budgetary constraints and requirements to demonstrate value, effective strategies to develop and commercialize innovative oncology products are more important than ever. Strategies that have proved successful in other industries require major revision for use in the oncology field, both during preclinical and clinical development as well as in the post approval value chain. This paper will examine how medicinal product strategy development differs from other industries. In particular, it will look at how the global trend toward value-based healthcare requires strategies that are based on an in-depth scientific understanding of the disease area and product-specific characteristics supported by clinical evidence. The findings are complemented by a review of the available literature and a survey of industry representatives.

Febrile neutropenia hospitalization due to pegfilgrastim on-body injector failure compared to single-injection pegfilgrastim and daily injections with reference and biosimilar filgrastim: US cost simulation for lung cancer and non-Hodgkin lymphoma.

Background: Guidelines recommend febrile neutropenia (FN) prophylaxis following myelotoxic chemotherapy with either daily injections of filgrastim (Neupogen®) or biosimilar filgrastim-sndz (Zarzio/Zarxio®), single-injection pegfilgrastim (Neulasta®), or pegfilgrastim administered through an on-body injector (PEG-OBI; Neulasta® Onpro®). PEG-OBI failure rates up to 6.9% have been reported, putting patients at incremental risk for FN and FN-related hospitalization. Our objective was to estimate, from a US payer perspective, the incremental costs of FN hospitalizations and the total incremental costs associated with PEG-OBI prophylaxis at varying device failure rates over assured FN prophylaxis with daily injections of filgrastim or filgrastim-sndz or a single injection of pegfilgrastim.Methods: Cost simulations comparing prophylaxis with PEG-OBI at failure rates of 1-10% versus assured prophylaxis in cycle 1 of chemotherapy were performed for panels of 10,000 patients with lung cancer treated with cyclophosphamide, doxorubicin, and etoposide (1 analysis) or non-Hodgkin lymphoma (NHL) treated with CHOP or CNOP (2 analyses). Daily injection scenarios were 4.3, 5, and 11 injections for lung cancer and 5, 6.5, and 11 for NHL. The analyses are from the US payer perspective.Results: For lung cancer, the total incremental cost of PEG-OBI prophylaxis at varying failure rates and durations ranged from $6,691,969‒$31,765,299 over filgrastim and $18,901,969‒$36,538,299 over filgrastim-sndz. For NHL, in scenario 1, the total incremental costs ranged from $6,794,984‒$30,361,345 over filgrastim and $19,004,984‒$35,911,345 over filgrastim-sndz; in scenario 2, the incremental costs ranged from $7,003,657‒$32,448,067 over filgrastim and $19,213,657‒$37,998,067 over filgrastim-sndz.Conclusions: In this simulation, the incremental costs of FN-related hospitalization due to PEG-OBI failure in cycle 1 compared to assured prophylaxis with reference pegfilgrastim, reference filgrastim, and biosimilar filgrastim-sndz varied depending upon the PEG-OBI failure rate and the alternative G-CSF prophylaxis option. Biosimilar filgrastim-sndz offers the greatest cost-efficiency.

Longitudinal analysis of quality of life following treatment with Asunercept plus reirradiation versus reirradiation in progressive glioblastoma patients.

PURPOSE: Glioblastoma is an aggressive malignant cancer of the central nervous system, with disease progression associated with deterioration of neurocognitive function and quality of life (QoL). As such, maintenance of QoL is an important treatment goal. This analysis presents time to deterioration (TtD) of QoL in patients with recurrent glioblastoma receiving Asunercept plus reirradiation (rRT) or rRT alone. METHODS: Data from patients with a baseline and ≥ 1 post-baseline QoL assessment were included in this analysis. TtD was defined as the time from randomisation to the first deterioration in the EORTC QLQ-C15, PAL EORTC QLQ-BN20 and Medical Research Council (MRC)-Neurological status. Deterioration was defined as a decrease of ≥ 10 points from baseline in the QLQ-C15 PAL overall QoL and functioning scales, an increase of ≥ 10 points from baseline in the QLQ-C15 PAL fatigue scale and the QLQ-BN20 total sum of score, and a rating of "Worse" in the MRC-Neurological status. Patients without a deterioration were censored at the last QoL assessment. Kaplan-Meier estimates were used to describe TtD and treatment groups (Asunercept + rRT or rRT alone) were compared using the log-rank test. RESULTS: Treatment with Asunercept + rRT was associated with significant improvement of TtD compared with rRT alone for QLQ-CL15 PAL overall QoL and physical functioning, and MRC Neurological Status (p ≤ 0.05). In the Asunercept + rRT group, QoL was maintained beyond progresison of disease (PoD). CONCLUSION: Treatment with Asunercept plus rRT significantly prolongs TtD and maintains QoL versus rRT alone in recurrent glioblastoma patients.

Asunercept as an innovative therapeutic approach for recurrent glioblastoma and other malignancies.

Glioblastoma is the most common and aggressive malignant tumor of the central nervous system. Despite the existing high unmet medical needs, the past few decades have seen no notable improvement in overall survival for glioblastoma patients. One active area of research to develop new therapeutic options for this disease is focusing on the CD95/Fas receptor and its ligand CD95L/FasL. It is now recognized that in addition to its role in programmed cell death, CD95/CD95L signaling is involved in a wide range of other apoptotic and non-apoptotic pathways directed toward T-effector cells and cells in the tumor microenvironment involved in tumor progression and invasiveness. Asunercept is a first-in-class recombinant glycosylated fusion protein, which has been designed to selectively bind to CD95L and therefore disrupt CD95/CD95L signaling. The current report provides a brief overview of the role of the CD95/CD95L signaling pathway in cancer pathogenesis and discusses how asunercept was designed to bind and neutralize CD95L and disrupt signaling thereby potentially improving outcomes in glioblastoma and other malignancies.

Extrapolation in Practice: Lessons from 10 Years with Biosimilar Filgrastim.

Biosimilar filgrastim (Sandoz) was approved in Europe in 2009 and, in 2015, was the first biosimilar approved in the USA. These authorizations were based on the "totality of evidence" concept, an approach that considers data from structural and functional characterization and comparability analysis and non-clinical and clinical studies. For biosimilar filgrastim, phase III confirmatory clinical studies were performed in the most sensitive population, patients with breast cancer undergoing myelosuppressive chemotherapy. In Europe and the USA, approval was granted for all indications of the reference biologic. Hence, stem cell mobilization and severe chronic neutropenia indications were approved on the basis of extrapolation, with no clinical data available at the time of market authorization in the EU. Although extrapolation is well-accepted in biologic development and regulatory contexts, it remains a misunderstood part of the biosimilarity concept in the medical community. Since approval, more than a decade of obtained clinical experience supports the totality of evidence and reassures clinicians regarding the efficacy and safety of biosimilar filgrastim. This includes real-world data from MONITOR-GCSF, a multicenter, prospective, observational study describing treatment patterns and clinical outcomes of patients with cancer (n = 1447) receiving biosimilar filgrastim for the prophylaxis of chemotherapy-induced neutropenia in solid tumors and hematological malignancies. Evidence is also available from unrelated healthy donors and those with severe chronic neutropenia. Together, the experience from a decade of use of biosimilar filgrastim includes over 24 million patient-days of exposure, which can help reassure oncologists that extrapolation is based on strong scientific evidence and works in practice.

Biosimilars in oncology: A decade of experience with granulocyte colony-stimulating factor and its implications for monoclonal antibodies.

Biosimilars offer the potential for improved sustainability of cancer care. In oncology, granulocyte colony-stimulating factor and erythropoiesis-stimulating agent biosimilars have been available for almost a decade, with biosimilars of monoclonal antibodies a more recent development. Sandoz biosimilar filgrastim was approved based on Phase III confirmatory studies conducted in patients with breast cancer experiencing chemotherapy-induced neutropenia, with other indications granted based on extrapolation. Despite the fact that extrapolation is a well-established scientific principle in regulation of biological medicines, it is a commonly misunderstood part of the biosimilar concept. Broad experience from almost a decade of use of Sandoz biosimilar filgrastim includes >21 million patient-days exposure and >9 years of real-world clinical evidence, indicates extrapolation successfully at work. Together, this can help reassure oncologists that extrapolation is based on sound scientific principles. Efforts to improve understanding of extrapolation are critical to ensure the acceptance of future oncology biosimilar monoclonal antibodies.

Meta-analysis comparing incidence of grade 3-4 neutropenia with ALK inhibitors and chemotherapy in patients with non-small-cell lung cancer.

Aim: This meta-analysis compared incidence of grade 3-4 neutropenia with ALK inhibitors versus chemotherapy in patients with non-small-cell lung cancer. Materials & methods: PubMed/MEDLINE was searched to identify Phase II and III randomized clinical trials published up to 25 October 2018. Summary incidence, relative risk and corresponding 95% CIs were calculated for grade 3-4 neutropenia. Results: Five randomized clinical trials were included. Relative risk (95% CI) of developing grade 3-4 neutropenia with ALK inhibitor versus chemotherapy was 0.27 (0.07-1.06). Probabilities of developing grade 3-4 neutropenia were 6.56 and 14.19%, respectively; no significant difference was found. Conclusion: In patients with non-small-cell lung cancer, incidence of grade 3-4 neutropenia with ALK-targeted therapy is not significantly different compared with chemotherapy.

Epoetin alfa for the treatment of myelodysplastic syndrome-related anemia: A review of clinical data, clinical guidelines, and treatment protocols.

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, leading to hematopoietic precursor cell apoptosis and peripheral blood cytopenias. Anemia is the most frequently experienced cytopenia and is the main cause of MDS symptoms, with fatigue and dyspnea contributing to reduced quality of life and increased morbidity. As MDS disease course and prognosis is influenced by disease factors, prognostic scoring systems have been developed for MDS to aid clinical and therapeutic decisions following diagnosis. Erythropoiesis- stimulating agents (ESAs) have been used for many years to treat anemia in patients with lower-risk MDS without chromosomal abnormalities. The use of ESAs is recommended by international clinical practice guidelines, due to the large body of evidence demonstrating their effectiveness in lower-risk MDS. In March 2017, the European Medicines Agency approved epoetin alfa for the treatment of anemia in lower-risk MDS patients, based on the results from a Phase 3 clinical trial and three European registry studies. The effectiveness of biosimilar epoetin alfa (Binocrit®, Sandoz) to correct anemia in lower-risk MDS patients has also been demonstrated in a retrospective, single-center, observational study. The recent approval of epoetin alfa by the EMA in this setting will provide clinicians with a welcome, approved treatment option for lower-risk MDS.

Treatment patterns and outcomes in patients with non-small cell lung cancer receiving biosimilar filgrastim for prophylaxis of chemotherapy-induced/febrile neutropaenia: Results from the MONITOR-GCSF study.

OBJECTIVE: Real-world evidence data on the use of granulocyte colony-stimulating factor (G-CSF) in patients with non-small cell lung cancer (NSCLC) are limited. MONITOR-GCSF is a pan-European, multicentre, prospective, non-interventional study designed to describe patient characteristics, treatment patterns and clinical outcomes in patients receiving biosimilar filgrastim in the prophylaxis of chemotherapy-induced neutropaenia (CIN) and febrile neutropaenia (FN). METHODS: In this subanalysis, patient characteristics, treatment patterns, and outcomes are described for 345 patients with stage 3 or 4 NSCLC, receiving up to six chemotherapy cycles. Patients were treated with biosimilar filgrastim as per their treating physician's best judgement. RESULTS: CIN (any grade) occurred in 13.6% of patients in Cycle 1 and in 36.5% of patients in all cycles. FN occurred in 1.4% of patients in Cycle 1 and in 5.2% of patients in all cycles. Grade 3-4 FN occurred in 1.2% of patients in Cycle 1 and in 3.8% of patients in all cycles. CONCLUSION: Results show that in real-life practice in patients with NSCLC, biosimilar filgrastim has similar effectiveness and safety to the known effectiveness and safety profile of reference filgrastim, supporting the use of biosimilar filgrastim for the real-world treatment of neutropaenia in patients with NSCLC.

Chemotherapy-induced neutropenia/febrile neutropenia prophylaxis with biosimilar filgrastim in solid tumors versus hematological malignancies: MONITOR-GCSF study.

AIM: This study aimed to report patterns of biosimilar filgrastim prophylaxis and outcomes of chemotherapy-induced neutropenia (CIN)/febrile neutropenia (FN) in patients with hematological malignancies or solid tumors. PATIENTS & METHODS: MONITOR-GCSF is a real-world study of 1447 cancer patients receiving CIN/FN prophylaxis with biosimilar filgrastim (solid tumors: 77.2%; hematological malignancies: 22.8%). RESULTS: Differences in prophylaxis intensity and day of initiation relative to guideline recommendations were observed. In hematology patients, higher rates of CIN and FN occurred at cycle level, and rate of FN was higher at patient level (9.1 vs 5.0% in solid tumor patients). CONCLUSION: Adequate GCSF support in hematology and solid tumor patients is important to prevent CIN/FN and related hospitalizations and chemotherapy disturbances.

Safety analysis of proposed pegfilgrastim biosimilar in Phase I and Phase III studies.

Aim: This analysis compares safety data for Sandoz proposed biosimilar (LA-EP2006) and reference pegfilgrastim from a Phase I pharmacokinetic/pharmacodynamic study in healthy volunteers (HVs) and two Phase III confirmatory studies in patients with breast cancer (BC; total n = 808). Patients & methods: Baseline characteristics were summarized, and event rates of bone pain and headache calculated. Results: HVs in the Phase I pharmacokinetic/pharmacodynamic study were generally younger, with lower mean body mass index, versus BC patients in PROTECT-1/-2. Bone pain was the most frequent adverse event with similar incidences with reference versus proposed biosimilar in all studies. Conclusion: No differences in adverse events were found between Sandoz proposed biosimilar and reference pegfilgrastim, notwithstanding some differences between HVs and BC patients.

The evolution of value with filgrastim in oncology.

The recombinant G-CSF filgrastim was first approved in 1991, and its value has been evolving ever since. Initial health technology assessments suggested low value due to high drug cost and no evidence for significant gain in overall survival. However, more recent meta-analyses of placebo-controlled randomized trial data show falling costs due to biosimilar competition and absolute overall survival gains of 3.2% (95% CI: 2.1-4.2%) from filgrastim support of cytotoxic chemotherapy. The launch of biosimilar alternatives merits a re-evaluation of decisions by health technology assessments and explains the first inclusion of filgrastim in the WHO Essential Drug List for cancer >20 years after its original approval in 1991, thus demonstrating the power of biosimilar medicines in transforming healthcare.

Outcomes of chemotherapy-induced (febrile) neutropenia prophylaxis with biosimilar filgrastim (Zarzio®) initiated "same-day" (< 24 h), "per-guidelines" (24-72 h), and "late" (> 72 h): findings from the MONITOR-GCSF study.

PURPOSE: Granulocyte colony-stimulating factors (G-CSFs) are indicated for prophylaxis or management of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN). Guidelines recommend G-CSF 24-72 h following chemotherapy; however, some evidence suggests that G-CSF initiated < 24 h may benefit some patients. METHODS: MONITOR-GCSF was a prospective, observational, multicenter, pan-European study of 1447 chemotherapy-treated patients receiving daily biosimilar (standard) filgrastim (Zarzio®/Zarxio®, filgrastim-sndz, Hexal AG, Sandoz Inc.). In this analysis, cycles were classified as same-day, per-guidelines, or late if G-CSF support was initiated < 24 h, 24-72 h, and > 72 h after chemotherapy. Outcomes included occurrence of CIN of any grade (CIN1/4), grade 3 or 4 (CIN3/4), grade 4 (CIN4), or FN: CIN/FN-related hospitalization or CIN/FN-related chemotherapy disturbance. RESULTS: A total of 5930 chemotherapy cycles from 1423 evaluable patients from MONITOR-GCSF had data for day of G-CSF initiation: 795 cycles (13.4%) classified as same-day, 3320 (56.0%) as per-guidelines, and 1815 (30.6%) as late. Groups did not differ as to CIN1/4 and FN episodes, or CIN/FN-related hospitalizations or chemotherapy disturbances. Patients in the same-day and per-guidelines groups had statistically similar odds of not experiencing any outcomes of interest in any given cycle. Patients in the late group had worse odds of experiencing CIN1/4, CIN3/4, and CIN4 episodes in any given cycle. Proportions of patients reporting clinical events of interest were generally similar. CONCLUSIONS: This real-world evidence indicates that CIN/FN prophylaxis initiated with biosimilar filgrastim within 24-72 h post-chemotherapy is effective and safe. Filgrastim administration on the day of chemotherapy may be appropriate in some patients.