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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.

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.

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.

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.

Background The long-acting granulocyte colony-stimulating factor (G-CSF) pegfilgrastim is widely used to prevent chemotherapy-induced neutropenia (CIN). Biosimilars could potentially improve sustainability of cancer care. Sandoz proposed biosimilar pegfilgrastim is under development and has been evaluated in Phase I and III studies.1,2 The current meta-analysis uses data from two Phase I studies in healthy volunteers (HVs) comparing pharmacokinetic (PK)/pharmacodynamic (PD) properties of Sandoz proposed biosimilar and EU-reference (Neulasta®) pegfilgrastim. Methods Data from two studies were included: a single-dose, double-blind, parallel-group study (study 1, data on file) and a single-dose, double-blind, crossover study (study 2),3 both in HVs randomized to receive proposed biosimilar or reference biologic (PK/PD analysis populations: study 1, n=93 per arm; study 2, n=169 per arm). Primary PK and PD parameters were AUC0–inf, AUC0–last, Cmax and ANC AUEC0–last, ANC Emax, respectively. For each parameter, geometric mean ratios and confidence intervals (CIs) for treatment comparisons (proposed biosimilar vs reference biologic) from the two studies were combined using meta-analytical techniques with a fixed-effects model. The 90% (PK) or 95% (PD) CIs were calculated and PK/PD biosimilarity was demonstrated if all CIs fell within equivalence margins of 80% to 125%. Non-baseline corrected PD parameters were used. Results The combined CIs of the geometric mean ratios for primary PK and PD parameters were all contained within the predefined equivalence margins. Safety, tolerability and immunogenicity were found to be similar between proposed biosimilar and EU-reference biologic in HVs (data not shown). Combined geometric mean with 90% (PK)/95% (PD) CICombined ratio with 90% (PK)/95% (PD) CI Proposed biosimilarEU-referenceProposed biosimilar vs EU-referencePK parametersAUC0–last (ng×h/mL)N93+16993+169 Geometric mean 90% CI6823 [6122, 7603]6034 [5404, 6738]1.1385 [1.0606, 1.2221]AUC0–inf (ng×h/mL)N92+168a93+168a Geometric mean 90% CI6973 [6268, 7757]6183 [5560, 6876]1.1335 [1.0570, 1.2156]Cmax (ng/mL)N93+16993+169 Geometric mean 90% CI196 [178, 216]180 [163, 198]1.0994 [1.0265, 1.1774]PD parametersAUEC0–last (109×h/L)N93+16993+169 Geometric mean 95% CI4986 [4855, 5121]4952 [4816, 5093]1.0119 [0.9959, 1.0281]Emax (109/L)N93+16993+169 Geometric mean 95% CI36.4 [35.3, 37.5]36.2 [35.1, 37.2]0.9981 [0.9790, 1.0175]AUC=area under serum-concentration curve; AUEC=area under effect curve; CI=confidence interval; Cmax=maximum observed serum concentration; Emax=maximum effect attributable to investigational medicinal product; PD=pharmacodynamic; PK=pharmacokinetic. aOne subject in study 2 had AUC0–inf extrapolated >20% and was excluded from AUC0–inf analysis Conclusions This meta-analysis of two Phase I studies supports PK/PD similarity of Sandoz proposed biosimilar to EU-reference pegfilgrastim. Also, no clinically meaningful differences in safety, tolerability and immunogenicity were found. Sandoz proposed biosimilar pegfilgrastim presents as a sustainable option to manage CIN in patients with cancer. References 1Blackwell et al. Oncologist 2016;21:789–94 2Harbeck et al. Future Oncol 2016;12:1359–67 3Nakov et al. Cancer Res 2018;78:P3-14-10 Citation Format: Nakov R, Wang J, Chen Y, Bellon A, Gattu S, Krendyukov A, Li Y. Meta-analysis of Phase I pharmacokinetic/pharmacodynamic results of proposed biosimilar pegfilgrastim [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-16-14.

BackgroundAn 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.MethodsAn 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.ResultsSurvey 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.ConclusionUse 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.

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.

David M Richards, Christian Merz, Christian Gieffers, Andriy Krendyukov Apogenix AG, Heidelberg, GermanyCorrespondence: Andriy Krendyukov Tel +49 6221 5860877Email andriy.krendyukov@apogenix.comAbstract: 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.Keywords: FasL/CD95L, anti-tumor immune response, immune checkpoint, tumor microenvironment, novel therapeutic target

Background CD95/CD95L signalling plays an important role in cancer cells resistant to CD95-mediated apoptosis and CD95L inhibition can overcome this mechanism. Several mechanisms related to apoptosis induction or dysfunction of effector T-cells via CD95L in the tumour microenvironment (TME) have also been investigated, with supporting evidence from preclinical melanoma models. Methods An autochthonous mouse model of melanoma (TiRP), genetically engineered to express P1A (defined MAGE-type antigen) mimics the T-cell suppressive effects of the TME through CD95L, which normal transplantation models cannot replicate. An advanced version of this murine melanoma TiRP model has been recently developed. This model can generate synchronized tumours in multiple mice in which treatments can be compared simultaneously while maintaining the advantages of the previous model regarding the role of CD95L in the TME interaction. This enhanced TiRP model was used to verify the effect of CD95L inhibition on apoptosis of tumour specific TILs using asunercept. Results In this novel synchronized in vivo melanoma model, asunercept decreased intra-tumour apoptosis among tumour-specific T cells by 67% vs controls (9% vs 28%, p = 0.04). This validates the immune-suppressive interaction between the TME and infiltrating tumour-specific T cells in this model. Furthermore, cross-species specific asunercept prevents T cell apoptosis triggered by the tumour microenvironment, highlighting a rationale for potential application of CD95L inhibition in immuno-oncology for other solid tumours. Conclusion Selective CD95L inhibition by asunercept might have potential clinical implications in different tumours beyond recurrent glioblastoma, including cutaneous melanoma. To date, asunercept has demonstrated clinical efficacy and safety in patients with recurrent glioblastoma and myelodysplastic syndromesand may warrant further investigation in clinical trials. Legal entity responsible for the study The authors. Funding Apogenix AG. Disclosure A. Krendyukov: Full / Part-time employment: Apogenix AG. N. Kneisel: Full / Part-time employment: Apogenix AG. J. Zhu: Research grant / Funding (self), Full / Part-time employment: Ludwig Institute for Cancer Research. C. Merz: Full / Part-time employment: Apogenix AG. D. Richards: Full / Part-time employment: Apogenix AG. C. Gieffers: Full / Part-time employment: Apogenix AG. B. van den Eynde: Research grant / Funding (self), Full / Part-time employment: Ludwig Institute for Cancer Research; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Officer / Board of Directors: iTeos Therapeutics.

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.

The use of supportive granulocyte colony-stimulating factor (G-CSF) to reduce the risk of neutropenic complications in high-risk cancer patients is consistently recommended by several clinical practice guidelines. However, in a previous meta-analysis, G-CSF prophylaxis was associated with an increased risk of secondary malignancies while reducing long-term mortality. We present here an updated systematic review and meta-analysis.A systematic literature search was carried out to identify randomized controlled trials of cancer patients receiving conventional-dose chemotherapy, assigned to primary G-CSF support or a control group without initial G-CSF, with at least 2 years of follow-up. Studies were categorized into one of the four groups, based on the chemotherapy regimen and study design. An updated meta-analysis was carried out; relative risk (RR) and 95% confidence intervals (CIs) for all-cause mortality and secondary malignancies were calculated.Of 2604 articles screened, 14 eligible studies were identified and combined with studies identified in the previous systematic literature searches. The updated meta-analysis included a total of 68 studies presenting 71 separate comparisons. Survival was significantly improved in patients receiving primary G-CSF support, compared with patients without primary G-CSF support (mortality RR=0.92; 95% CI 0.90-0.95; ARD=-3.3%; 95% CI -4.2--2.4; P 0.0001). The largest improvement in survival was observed with dose-dense chemotherapy regimens with G-CSF support, compared with controls receiving no G-CSF support (mortality RR=0.86; 95% CI 0.80-0.92; P 0.0001). Patients who received primary G-CSF support experienced a significantly higher risk of secondary malignancies, compared with controls (RR=1.85; 95% CI 1.19-2.88; ARD=0.47; 95% CI 0.21-0.73; P 0.01).Our findings demonstrate that overall survival is improved in patients receiving intensified chemotherapy with primary G-CSF support, compared with those receiving standard chemotherapy. Primary G-CSF support was also associated with a higher risk of developing secondary malignancies, including secondary acute myeloid leukemia and myelodysplastic syndrome.

High-quality, safe, and effective biosimilars have the potential to increase access to biological therapies worldwide and to reduce cancer care costs. The European Medicines Agency (EMA) was the first regulatory authority to establish legislative procedures for the approval of biosimilars when they published their guidelines on similar biological medicinal products in 2005. Biosimilar epoetins were first approved in 2007, and a wealth of data has been collected over the last decade. Two biosimilar epoetins (under five commercial names) have been approved by the EMA so far. The availability of epoetin biosimilars generated discussion among the oncology community regarding prescribing these products, their efficacy, and their safety. These agents are approved only if they are shown in extensive analytical and clinical testing to have comparable quality, safety, and efficacy to the reference medicine, and real-world studies provide further data that biosimilar epoetins are an effective and well-tolerated option for the treatment of chemotherapy-induced anemia in patients with cancer. Other countries have adopted similar regulatory pathways to those in Europe and have approved epoetin biosimilars. The now extensive European experience with biosimilar epoetins should reassure regulators from other territories.

Aims To assess real-world effectiveness and safety of intravenous (IV) HX575, a biosimilar epoetin-α, in hemodialysis (HD) patients. Materials and methods This prospective, observational, pharmacoepidemiological study of adult HD patients treated with IV HX575 for renal anemia for up to 24 months was conducted in 114 centers in 10 European countries. Of 2,086 enrolled subjects (safety sample), 2,023 had ≥ 1 follow-up visit (effectiveness sample). Results Most (59.3%) patients were male, median age was 68 years. At enrollment, most (82.5%) had been treated with an erythropoiesis-stimulating agent, and 73.0% had adequate iron stores. At baseline, mean (± standard deviation) baseline hemoglobin (Hb) was 11.09 (± 1.14) g/dL and HX575 dose 106.5 (± 78.7) international units (IU)/kg/week; at month 24, Hb was 11.25 (± 1.19) g/dL and HX575 dose 113.0 (± 102.5) IU/kg/week. Variations in mean HX575 dose and Hb over the study were not statistically significant. As to safety, 140 patients (6.7%) experienced ≥ 1 adverse event; of these, 19 events (16 patients; 0.8%) were related to HX575 treatment, 148 (108 patients; 5.2%) were reported as serious, including 12 events in 11 patients (0.5%) stated to be related. No cases of anti-epoetin antibodies or pure red cell aplasia were reported. Conclusions MONITOR-CKD5 confirmed the real-world effectiveness and safety profile of IV biosimilar HX575. HD patients treated for up to 24 months showed stable dosing patterns and Hb outcomes. The safety profile of HX575 is likewise comparable to reference epoetin-α. .

Background Granulocyte colony–stimulating factors (G-CSFs) are widely used to prevent neutropenia in cancer patients undergoing myelosuppressive chemotherapy. Several biosimilar medicines of G-CSF are now available, with their development involving a step-wise series of comparisons to demonstrate similarity to reference biologics. Randomised clinical trials (RCTs) are considered confirmatory, and for G-CSF biosimilars, patients with breast cancer (BC) undergoing myelosuppressive chemotherapy are the most sensitive population in which to confirm similarity. This meta-analysis aimed to compare the clinical efficacy and safety of approved or proposed G-CSF biosimilars (filgrastim or pegfilgrastim) with reference G-CSF in patients with BC. Methods A Medline literature search up to March 2017 identified RCTs comparing biosimilar G-CSF to reference in BC patients. The primary efficacy end-point was mean difference in duration of severe neutropenia (DSN). Secondary efficacy end-points were differences in depth of absolute neutrophil count (ANC) nadir, time to ANC recovery and incidence of febrile neutropenia. Safety analyses included calculation of risk ratios for bone pain events, myalgia events and serious adverse events. Random effect models were fitted to obtain the pooled estimates of the mean difference for continuous outcomes and the risk ratio for dichotomous outcomes and their corresponding 95% confidence intervals (CIs). Findings Eight eligible RCTs were included in this meta-analysis. Overall difference in DSN between reference and biosimilar medicines was not statistically significant (0·06 d [95% CI −0·05, 0·17]). The analysis of secondary efficacy end-points showed no significant differences between reference biologics and biosimilar medicines, as well as the analysis of bone pain events, myalgia events and serious adverse events. Interpretation This meta-analysis showed no significant differences in clinical efficacy and safety between biosimilar and reference G-CSF in BC patients.

Background: Early access provision (EAP) is endorsed by competent authorities to improve patient access to innovative medicinal products (InMPs). Despite efforts made by competent authorities to expedite development, review and approval of InMPs, there may still be lengthy delay before oncology patients can gain access to InMPs. Challenges practicing oncologists face when dealing with EAP, together with limited education and support, may influence access of oncology patients to care. Methods: EAP protocols for oncology InMPs were identified by a search of the ClinicalTrials.gov and EU Clinical Trials registers. On-line, fully anonymous survey reaching out to more than 3,000 physicians was conducted. Practicing oncologists were questioned about their understanding of EAP, level of experience, knowledge on roles and responsibilities, rationale for decision process, interest for further educational activities and opportunities to improve EAP. Results: During the period Jan 2015 to March 2021, of oncology trials only 149 (0.4%) and 21 (0.23%) included EAP protocols at ClinicalTrials.gov EudraCT registry respectively. Survey results found 75% of respondents were ‘very comfortable’ or ‘comfortable’ with using EAP, but only 54.5% correctly answered the specific knowledge-based question. EAP experience was limited in 56% of respondents. Two-thirds indicated an average or lower level of understanding about application process and regulatory requirements (65.2% and 66.0%, respectively). Knowledge on data collection and reporting under EAP was lower at 57.8% and 50.5% of respondents, respectively. During COVID-19 pandemic, the majority of respondents highlighted need to improve and adapt EAP with regard to application process (83.8%), InMP supply and logistics (88.4), and safety reporting process (78.0%). Conclusions: Challenges posed by the EAP process for InMP, together with a lack of education on this topic, might contribute to its under-utilization and influence early access of oncology patients to care. Continuous educational efforts from different stakeholders, specifically duting IMP clinical development stage, are required to better inform and support practicing oncologists dealing with EAP. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: A. Krendyukov: Financial Interests, Personal, Full or part-time Employment: Apogenix AG. S. Singhvi: Financial Interests, Personal, Full or part-time Employment: System Analytic. Y. Green-Morrison: Financial Interests, Personal, Full or part-time Employment: System Analytic. M. Zabransky: Financial Interests, Personal, Full or part-time Employment: Hexal AG.

Erythropoiesis-stimulating agents, such as recombinant human erythropoietin, are commonly used for the treatment of anemia in patients with chronic kidney disease (CKD). In 2007, HX575 (Binocrit®) became the first biosimilar epoetin alfa to be approved by the European Medicines Agency (EMA). The decision to approve a biosimilar is based on the totality of evidence obtained in a comprehensive comparability exercise that involves extensive analytical characterization, nonclinical studies and clinical studies. The development process for HX575 included extensive analytical characterization and comparison with the reference epoetin alfa. This was followed by a clinical development program, comprising Phase I pharmacokinetic/pharmacodynamic studies to show bioequivalence to the reference medicine and a confirmatory Phase III study to demonstrate therapeutic effectiveness in anemia related to CKD. In addition to the comparability exercises, extensive clinical experience over the last decade also confirms that HX575 provides an effective treatment for CKD-related anemia, with a favorable safety profile. Growing clinical experience with EMA-approved biosimilars, including HX575, should offer additional reassurance to health care professionals and patients that these agents are as effective and well tolerated as others in the therapeutic class.

Biosimilars are biological medicines that have been shown to be similar to a reference biological medicine that has already been approved for use. Development of biosimilars is based on a “totality of evidence” approach that involves a series of steps by which biosimilars must demonstrate similarity to a reference product in all aspects of the drug and eliminate any remaining uncertainties. Clinical studies are then considered confirmatory and are performed to show that there are no clinically meaningful differences compared with the reference product in a sensitive patient population. The recombinant human granulocyte colony-stimulating factor (G-CSF) biosimilar EP2006/Zarxio® (filgrastim-sdnz) became the first FDA-approved biosimilar in 2015. This review evaluates how clinical equivalence can be demonstrated with G-CSF biosimilars through the identification of “sensitive” study populations and endpoints. Patients with non-metastatic breast cancer treated in the (neo)adjuvant setting represent a potentially homogenous population, making this a suitable sensitive indication for assessing filgrastim and pegfilgrastim biosimilars compared with reference products. This review includes clinical trials of G-CSF biosimilars in breast cancer, focusing on key aspects of the trials that were necessary to accurately demonstrate clinical equivalence and enable extrapolation to relevant indications, based on guidelines and biostatistical principles.

Background Following the functional and physicochemical characterization of a proposed biosimilar, comparative clinical studies help to confirm biosimilarity by demonstrating similar safety and efficacy to the reference product in a sensitive patient population. Patients and methods LA-EP2006 is a proposed biosimilar that has been developed for pegfilgrastim, a long-acting form of granulocyte colony-stimulating factor for the prevention of neutropenia. The current analysis reports data pooled from two independent, multinational, prospective, randomized, controlled, double-blind phase III studies of similar design comparing the safety and efficacy of reference pegfilgrastim with LA-EP2006 in patients with breast cancer receiving myelotoxic (neo)adjuvant TAC (docetaxel, doxorubicin, and cyclophosphamide) chemotherapy and requiring granulocyte colony-stimulating factor. Results A total of 624 patients were randomized in the PROTECT-1 and PROTECT-2 studies (NCT01735175; NCT01516736) (LA-EP2006: n = 314; reference: n = 310). Baseline characteristics of patients were well balanced across treatment groups. The primary end point, mean duration of severe neutropenia in the first chemotherapy cycle was similar in both the LA-EP2006 and reference groups (1.05 ± 1.055 days versus 1.01 ± 0.958 days), with a treatment difference of − 0.04 days [95% confidence interval (CI): −0.19 to 0.11] that met the equivalence criteria (the 95% CI were within the defined margin of ±1 day). Secondary end points, such as the nadir of absolute neutrophil count and the incidence of febrile neutropenia, were also similar between LA-EP2006 and reference pegfilgrastim. The safety and tolerability profile of LA-EP2006 was similar to that observed with reference pegfilgrastim, and there were no reports of neutralizing antibodies. Conclusions This pooled analysis confirms, as a part of totality of evidence approach, that the proposed biosimilar pegfilgrastim LA-EP2006 has a comparable efficacy and safety profile to reference pegfilgrastim in patients with breast cancer receiving TAC chemotherapy. Clinical trial numbers NCT01735175 and NCT01516736.

Aim To assess the safety and immunogenicity of subcutaneous (SC) HX575 (epoetin-α) in dialysis- and nondialysis-dependent adult patients with chronic kidney disease (CKD). Methods Open-label, single-arm, multicenter study in patients (n = 416) from Germany, Italy, Poland, Romania, Russia, Turkey, and Ukraine. Results Mean (standard deviation (SD)) age was 52.3 (15.8) years, all patients were Caucasian, and similar proportions were male/female. 250 patients (60.1%) were erythropoiesis-stimulating agent (ESA)-naive, and 166 (39.9%) were receiving ESA maintenance therapy at study start; mean (SD) on-study treatment duration with HX575 was 43.4 (15.8) weeks and 45.3 (13.7) weeks, respectively. Binding antierythropoietin (EPO) antibodies were detected by radioimmunoprecipitation (RIP) assay in 7 patients (1.7%; incidence 0.019); 5 of these were ESA-naive at study entry. No patient developed neutralizing antibodies as determined in a cell-based epoetin neutralizing assay. Of the 7 patients with a positive binding anti-EPO RIP assay, 4 tested negative at later time points while continuing HX575 treatment. Three patients had low titers of anti-EPO antibodies at the last study assessment. There were no clinical signs of immunogenicity or hypersensitivity. Conclusions SC HX575 was effective for correcting and maintaining correction of anemia, and the mean weekly dose remained stable over time. .

Background: Biosimilars are highly similar to a biological reference product with no clinically meaningful differences in terms of efficacy and safety. Here we present the pooled analysis of two randomized trials (PROTECT1 and 2) comparing the efficacy, safety and immunogenicity of proposed biosimilar pegfilgrastim (LA-EP2006) with reference pegfilgrastim (Neulasta®*). Methods: Two multinational, independent, prospective, double-blind, phase III studies (EudraCT: 2011-004532-58; 2012-002039-28) enrolled adult chemotherapy-naïve women with breast cancer scheduled to receive ≤6 cycles of (neo)-adjuvant chemotherapy with docetaxel 75 mg/m2, doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (TAC). Patients were randomized to receive a single 6 mg injection of LA-EP2006 or reference on Day 2 of each cycle. Primary endpoint was duration of severe neutropenia (DSN) (number of consecutive days with ANC Results: A total of 624 patients were randomized (LA-EP2006: n=314; reference: n=310). Baseline demographics were well balanced (mean age: LA-EP2006: 49.3 years, reference: 49.8; median duration (months) since initial diagnosis: LA-EP2006: 1.33 [0.1−76.0], reference: 1.35 [0.2−11.2]; ECOG status 0: LA-EP2006: 78%, reference: 75%). Mean DSN difference in Cycle 1 was -0.04 days (95% CI: -0.19, 0.11), showing statistical equivalence. FN was reported in 5.7% of patients with LA-EP2006 vs. 8.4% with reference in Cycle 1 (all cycles: 8.0% vs. 10.3%). Across all cycles, frequency of fever (LA-EP2006: 18.5%; reference: 19.7%) and infections (LA-EP2006: 15.6%; reference: 18.1%) were similar in both groups. Mean ANC time courses were almost superimposable in the two groups, with similar time and depth of ANC nadir and median time to ANC recovery was 2 days in both groups in Cycle 1. Treatment-emergent adverse events (TEAEs) were similar across groups (LA-EP2006: 92%; reference: 89%), and TEAEs with a suspected relationship to pegfilgrastim were reported in 22.6% of patients with LA-EP2006 and 21.3% with reference across all cycles, with the most frequent being musculoskeletal and connective tissue disorders (LA-EP2006: 10.2%; reference: 9.7%). Serious TEAEs were reported in 14.3% (LA-EP2006) vs. 17.1% (reference) across all cycles. No neutralizing or clinically relevant anti-pegfilgrastim antibodies were identified. Conclusions: LA-EP2006 demonstrated similar clinical efficacy and safety to reference pegfilgrastim in patients with breast cancer receiving myelotoxic chemotherapy. *Neulasta® is a registered trademark of Amgen Inc. Citation Format: Blackwell K, Gascon P, Jones CM, Nixon A, Nakov R, Mo M, Krendyukov A, Nadia H. Safety, immunogenicity and efficacy of proposed biosimilar pegfilgrastim (LA-EP2006) compared with reference pegfilgrastim in breast cancer: Pooled analysis of two randomized, double-blind, phase III trials [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-11-05.

Purpose In the MONITOR-GCSF study of chemotherapy-induced (febrile) neutropenia with biosimilar filgrastim, 56.6% of patients were prophylacted according to amended EORTC guidelines, but 17.4% were prophylacted below and 26.0% above guideline recommendations. Methods MONITOR-GCSF is a prospective, observational study of 1447 evaluable patients from 140 cancers centers in 12 European countries treated with myelosuppressive chemotherapy for up to 6 cycles receiving biosimilar GCSF prophylaxis. Patients were classified as under-, correctly-, or over-prophylacted with GCSF relative to guideline recommendations based on their chemotherapy risk, individual risk factors, and type of GCSF prophylaxis (primary versus secondary). Results Differences between under- (17.4%), correctly- (56.6%), or over-prophylacted (26.0%) groups were found in terms of patient risk factors (age, performance status, history of FN, comorbid conditions) as well as prophylaxis patterns (type of prophylaxis, day of GCSF initiation, and GCSF duration). Rates of chemotherapy-induced neutropenia (CIN) (all grades), FN, and CIN-related hospitalizations were consistently lower in over-prophylacted patients relative to under- and correctly-prophylacted patients. No differences were observed between under- and correctly-prophylacted patients except for CIN/FN-related chemotherapy disturbances. No GCSF safety differences were found between groups (except for headaches). Conclusions The real-world evidence provided by the MONITOR-GCSF study indicates that providing GCSF support may yield better CIN, FN, and CIN/FN-related hospitalization outcomes if patients are prophylacted at levels above guideline recommendations. Patients who are under-prophylacted are at higher risk for disturbances to their chemotherapy regimens. Our findings support the guideline recommendation that CIN/FN risk be assessed at the beginning of each chemotherapy cycle.

Introduction Si la neutropenie est une consequence notoire de la chimiotherapie myelosuppressive chez les patients cancereux, les donnees probantes sur son incidence sont plus limitees dans le cas des traitements cibles. Les inhibiteurs de la kinase du lymphome anaplasique (anaplastic lymphoma kinase [ALK]) ont transforme le traitement du cancer du poumon non a petites cellules (CPNPC) presentant un rearrangement du gene ALK. Sur le plan de la securite, il semblerait que les inhibiteurs de l’ALK puissent provoquer une neutropenie de grade 3/4. Cette meta-analyse avait pour but de comparer l’incidence de la neutropenie de grade 3/4 chez des patients atteints d’un CPNPC recevant soit des inhibiteurs de l’ALK, soit une chimiotherapie. Methodes Une recherche documentaire dans Medline (articles publies jusqu’en mars 2018) a permis d’identifier des essais cliniques randomises (ECR) comparant un inhibiteur de l’ALK a une chimiotherapie ou a un autre inhibiteur de l’ALK. Le critere d’evaluation principal etait l’incidence de la neutropenie de grade 3/4. Resultats Cinq ECR admissibles ont ete inclus (n = 1504) ; quatre comparaient un inhibiteur de l’ALK a une chimiotherapie et un comparait deux inhibiteurs de l’ALK. Au total, 648 patients avaient recu une chimiotherapie (groupe CT) et 856 un inhibiteur de l’ALK (groupe ALK). Les caracteristiques a l’inclusion etaient globalement similaires entre les deux groupes : âge Tableau 1 ). Le stade tumoral a l’inclusion n’influait pas sur cette probabilite. Conclusion Chez les patients atteints d’un CPNPC, il n’y a pas de difference significative de l’incidence de la neutropenie de grade 3/4 entre l’inhibition ciblee de l’ALK et la chimiotherapie.

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.

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.

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.

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.

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.

Background DOPPS reported that thousands of life-years could be gained in the US and Europe over 5 years by correcting six modifiable haemodialysis practices. We estimated potential life-years gained across 10 European countries using MONITOR-CKD5 study data. Methods The DOPPS-based target ranges were used, except for haemoglobin due to label changes, as well as DOPPS-derived relative mortality risks. Percentages of MONITOR-CKD5 patients outside targets were calculated. Consistent with the DOPPS-based analyses, we extrapolated life-years gained for the MONITOR-CKD5 population over 5 years if all patients were within targets. Results Bringing the 10 MONITOR-CKD5 countries’ dialysis populations into compliance on the six practices results in a 5-year gain of 97,428 patient-years. In descending order, survival impact was the highest for albumin levels, followed by phosphate levels, vascular access, haemoglobin, dialysis adequacy, and interdialytic weight gain. Conclusions Optimal management of the six modifiable haemodialysis practices may achieve 6.2% increase in 5-year survival. Trial Registration NCT01121237. Clinicaltrials.gov registration May 12, 2010 (retrospectively registered). Electronic supplementary material The online version of this article (10.1186/s12882-019-1251-z) contains supplementary material, which is available to authorized users.

e19070 Background: Cancer is a major public health problem worldwide and is the second leading cause of death in the USA. While continuous efforts are being made by the US Food and Drug Administration to bring more new oncology products (NOP) to patients, there is a high unmet medical need for oncology patients to get access to care, and in particular access to NOP outside of clinical trials before the NOP is approved or commercialized. To improve access to NOP, several pathways are endorsed by competent authorities including: early dialogue with regulatory agencies; accelerated assessments; conditional marketing authorization; and early access provision, known as expanded access (EA) in the USA and compassionate use (CU) in the EU. Methods: A literature search and explorative analysis of available EA data from Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) relating to submission and approval of existing or investigational new drugs (IND) was performed for individual (single) patient emergency and non-emergency IND (IPIND), intermediate size IND (ISIND), and treatment IND (TIND). The findings were compared to centralized CU programs. The analysis was primarily focused on understanding the current landscape of EA for patient groups compared with individual patient categories. Results: Based on available CDER and CBER data submissions for ISIND and TIND categories were dramatically low compared with IPIND and total applications for EA: 1.25% (ISIND) and 0.13% (TIND) out of 1,598 EA applications received in 2018; and respectively 2.7% and 0.11% out of 1,741 EA applications in 2017; 2.6% and 0.24% out of 1,634 EA applications in 2016; 3.6% and 0.15% out of 1,328 EA applications in 2015; and 2.8% and 0.05% out of 1,886 EA applications in 2014. A high approval rate was reported for all three EA categories, and in particular approval of 95% (174 out 183) for ISIND and 100% (1 application) for TIND by CDER, and approval of 89% (24 out of 27) for ISIND and 80% (8 out of 10) for TIND by CBER. No applications for CU were reported by the European Medicines Agency for the same period of time, however several oncological products have been approved for CU in some European countries. Conclusions: Despite high approval rates, applications for ISIND and TIND remain low, especially in comparison to IPIND. In the absence of, or limited, alternative treatments, access provision to patient groups such as ISIND and TIND in the USA, and CU in the European Union, might represent an underutilized opportunity for oncological patients to obtain early access to care.

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.

Background: Febrile neutropenia (FN) is a common occurrence during chemotherapy. Granulocyte colony-stimulating factors (G-CSFs) can significantly reduce the risk of FN. International guidelines recommend G-CSF for patients receiving chemotherapy with FN risk of ≥20% or 10% to 20% with defined risk factors. Prophylaxis is not typically recommended for FN risk of < 10%; however, few studies have investigated FN incidence in lower-risk patients in real-world settings and tried to identify higher-risk subgroups. Methods: This real-world prospective, observational, multinational study aims to estimate the rate of development of FN with a chemotherapy line expected to be associated with a 10% to 20% risk of FN. Eligible patients (> 18 years of age) will have a solid tumour or Hodgkin/non-Hodgkin lymphoma and a planned chemotherapy regimen with expected risk of FN of 10% to 20% (according to published guidelines). Patients will be observed for the duration of the chemotherapy line (first cycle administered without FN prophylaxis). Primary endpoint is incidence of FN after the first chemotherapy cycle. Secondary outcomes include: FN-associated morbidity and mortality; time to first FN occurrence; other FN risk factors and impact of FN on quality of life. A risk model using occurrence of FN as a binary outcome will be developed. Data will be stratified by age, comorbidities and other risk factors. Discussion: This study will provide insight into the real FN risk for common chemotherapy regimens and predictive factors for FN, including patients generally excluded from randomised clinical trials, from which reported FN rates have been variable. This study builds on knowledge of predictive factors from other research and will provide information on patients with 10% to 20% FN risk., SCOPUS: ar.j, info:eu-repo/semantics/published

Biosimilars are biological medicines that are approved via stringently defined regulatory pathways on the basis that comparable safety, efficacy, and quality have been demonstrated to their reference medicine. The advantage of biosimilar drugs is that they may be less expensive than the reference medicine, allowing for greater patient access and cost savings in already stretched healthcare budgets. Biosimilar epoetins have been available in Europe for a decade. Complementing in vitro and preclinical characterization, and pharmacokinetic/pharmacodynamic studies, clinical trials provided the additional data needed to reassure European authorities that biosimilar epoetins were sufficiently similar to the reference epoetin to warrant approval. Post-approval, real-world studies have provided further evidence that biosimilar epoetins are an effective and well-tolerated option for the treatment of renal anemia, with ongoing pharmacovigilance and observational studies monitoring for any unexpected long-term signals that have not been identified in clinical development studies. As the evidence and experience with these products increase, many of the initial concerns are being alleviated. Nephrologists can be increasingly confident that European Medicines Agency-approved biosimilars offer high-quality, affordable, effective alternatives to existing reference medicines used to treat renal anemia, and may help yield cost savings and improve patient access.

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.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.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.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.

Early in 2017, The European Society for Medical Oncology (ESMO) published a position paper on biosimilars for oncology prescribers.1 Since then, both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved biosimilar versions of monoclonal antibodies (mAbs) used for the treatment of several cancer types (eg, rituximab in Europe, bevacizumab and trastuzumab in the USA).2 3 The ESMO position paper was rightly welcomed as a timely addition to the discussion around this important topic.4 The position paper correctly highlighted the importance of accurate information about biosimilars if misconceptions and misunderstanding are to be avoided among oncologists and other stakeholders.1 It is encouraging that ESMO has continued on this mission to provide information and education; special sessions on biosimilars were incorporated into the main programmes for both the ESMO and ESMO Asia congresses in 2017, and the organisation has been represented at several other important meetings (including the 15th Biosimilar Medicines Conference). They also launched a survey on awareness of biosimilars among oncologists in 2017, the results of which are eagerly awaited. Extrapolation is arguably the part of the biosimilar concept that is most commonly misunderstood. It is defined as the authorisation of a biosimilar medicine for clinical indications of the reference …

Background Evaluation of adverse events (AEs) in pivotal registration trials and ongoing postmarketing surveillance is important for all biologics, including biosimilars. A combined analysis of two pivotal registration studies was performed to strengthen evidence on safety for biosimilar filgrastim EP2006 in patients with breast cancer receiving myelosuppressive chemotherapy, a sensitive clinical setting to confirm biosimilarity of filgrastim. Materials and Methods Data were combined from two phase III studies of biosimilar filgrastim EP2006. The U.S. registration study was a randomized, double-blind comparison of biosimilar and reference filgrastim in women aged ≥18 years with breast cancer, receiving (neo)adjuvant treatment with TAC (docetaxel + doxorubicin + cyclophosphamide). The European Union registration study was a single-arm, open-label study of biosimilar filgrastim in women aged ≥18 years with breast cancer receiving doxorubicin + docetaxel. Patients received filgrastim as a subcutaneous injection on day 2 of each cycle for Results A total of 277 patients received biosimilar filgrastim EP2006. Patients had a mean (± standard deviation) age of 51.1 (± 10.8) years, and 78.7% of patients had stage II or III breast cancer. A total of 46 (20.6%) patients receiving biosimilar filgrastim had AEs considered filgrastim-related. The most frequently reported filgrastim-related AEs were musculoskeletal or connective tissue disorders (15.2%), including bone pain (7.2%). One death (due to pulmonary embolism) occurred of a patient receiving biosimilar filgrastim (not considered filgrastim-related). No patient developed antidrug antibodies during the study. Conclusion Biosimilar filgrastim has a safety profile consistent with previous filgrastim studies and is effective in preventing febrile neutropenia in patients with breast cancer. Implications for Practice The biosimilar filgrastim EP2006 (Zarzio, Zarxio, biosimilar filgrastim-sndz) has been approved in Europe since 2009 and in the U.S. since 2015. This combined analysis of two phase III studies provides additional clinical evidence that the biosimilar filgrastim EP2006 has a safety profile consistent with previous studies of reference filgrastim and supports large postmarketing studies of EP2006 in Europe. Strengthening the evidence for biosimilar filgrastim can help improve acceptance of biosimilars and increase patient access to biologics.

Objective Prospective data on the use of granulocyte-colony-stimulating factor (G-CSF) in non-Hodgkin's lymphoma and its aggressive subtypes, including diffuse large B-cell lymphoma (DLBCL), are limited. MONITOR-GCSF is a pan-European, multicenter, prospective, observational study aiming to describe treatment patterns and clinical outcomes in patients receiving biosimilar filgrastim in the prophylaxis of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN). Methods This analysis describes patient characteristics, treatment patterns, and outcomes for 245 patients with stage 3 or 4 DLBCL receiving ≤6 chemotherapy cycles as part of MONITOR-GCSF study, including patients aged ≥65 years and ≥70 years. Outcomes of interest included the incidence of CIN and FN, antibiotic prophylaxis, biosimilar filgrastim prophylaxis, and adverse events (AEs). Results MONITOR-GCSF included 245 patients with DLBCL. Of these patients, 87 (35.5%) experienced one or more CIN (any grade) episode and 24 (9.8%) experienced FN (any grade). The most frequent AE reported was bone pain (n = 7, 2.9%), followed by arthralgia (n = 2, 0.8%) and back pain (n = 2, 0.8%). Conclusion In real-life practice, biosimilar filgrastim demonstrated clinical effectiveness and safety in patients with DLBCL. The large percentage of patients aged ≥65 years adds to the evidence on how to best treat older patients with DLBCL receiving myelosuppressive chemotherapy.

Background In 2015, the biosimilar filgrastim EP2006 became the first biosimilar approved by the US Food and Drug Administration for commercial use in the United States, marketed as Zarxio® (Sandoz). This phase III randomised, double-blind registration study in patients with breast cancer receiving (neo)adjuvant myelosuppressive chemotherapy (TAC; docetaxel + doxorubicin + cyclophosphamide) compares reference filgrastim, Neupogen® (Amgen), with two groups receiving alternating treatment with reference and biosimilar every other cycle. Patients and methods A total of 218 patients receiving 5 µg/kg/day filgrastim over six chemotherapy cycles were randomised 1: 1: 1: 1 into four arms. Two arms received only one product, biosimilar or reference (unswitched), and two arms (switched) received alternating treatments every other cycle (biosimilar then reference or vice versa over six cycles). Since the switch occurred from cycle 2 onwards, this analysis compared pooled switched groups to the unswitched reference group for efficacy during cycles 2–6. Safety was also assessed. Non-inferiority in febrile neutropenia (FN) rates between groups for cycles 2–6 was shown if 95% were within a pre-defined margin of -15%. Results A total of 109 patients switched treatment, and 52 patients received reference in all cycles. Baseline characteristics were similar between groups. The incidence of FN was 0% (reference) versus 3.4% (n = 3, switched) across cycles 2–6, with a difference of −3.4% (95% confidence interval: −9.65% to 4.96%), showing non-inferiority. Infections occurred in 9.3% (switched) versus 9.9% (reference). Hospitalisation due to FN was low (one patient in cycle 6; switched). Adverse events related to filgrastim were reported in 42.1% (switched) versus 39.2% (reference) (all cycles). Musculoskeletal/connective tissue disorders related to filgrastim occurred in 35.5% (switched) versus 39.2% (reference) (all cycles), including bone pain (30.8% versus 33.3%). No neutralising antibodies were detected. Conclusions There were no clinically meaningful results regarding efficacy, safety or immunogenicity when switching from reference to biosimilar filgrastim/EP2006, or vice versa.

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.

High-quality, safe, and effective biosimilars have the potential to increase access to biological therapies worldwide and to reduce cancer care costs. The European Medicines Agency (EMA) was the first regulatory authority to establish legislative procedures for the approval of biosimilars when they published their guidelines on similar biological medicinal products in 2005. Biosimilar epoetins were first approved in 2007, and a wealth of data has been collected over the last decade. Two biosimilar epoetins (under five commercial names) have been approved by the EMA so far. The availability of epoetin biosimilars generated discussion among the oncology community regarding prescribing these products, their efficacy, and their safety. These agents are approved only if they are shown in extensive analytical and clinical testing to have comparable quality, safety, and efficacy to the reference medicine, and real-world studies provide further data that biosimilar epoetins are an effective and well-tolerated option for the treatment of chemotherapy-induced anemia in patients with cancer. Other countries have adopted similar regulatory pathways to those in Europe and have approved epoetin biosimilars. The now extensive European experience with biosimilar epoetins should reassure regulators from other territories.