How much does the hospital stay for infusion of anti-CD19 CAR-T cells cost to the French National Health Insurance?

Chimeric antigen receptor T-cells (CAR-T cells) have the potential to be a major innovation as a new type of cancer treatment, but are associated with extremely high prices and a high level of uncertainty. This study aims to assess the cost of the hospital stay for the administration of anti-CD19 CAR-T cells in France. Data were collected from the French Medical Information Systems Program (PMSI) and all hospital stays associated with an administrated drug encoded 9439938 (tisagenlecleucel, Kymriah®) or 9440456 (axicabtagene ciloleucel, Yescarta®) between January 2019 and December 2020 were included. 485 hospital stays associated with an injection of anti-CD19 CAR-T cells were identified, of which 44 (9%), 139 (28.7%), and 302 (62.3%) were for tisagenlecleucel in acute lymphoblastic leukaemia (ALL), tisagenlecleucel in diffuse large B-cell lymphoma (DLBCL), and axicabtagene ciloleucel respectively. The lengths of the stays were 37.9, 23.8, and 25.9 days for tisagenlecleucel in ALL, tisagenlecleucel in DLBCL, and axicabtagene ciloleucel, respectively. The mean costs per hospital stay were € 372,400 for a tisagenlecleucel in ALL, € 342,903 for tisagenlecleucel in DLBCL, and € 366,562 for axicabtagene ciloleucel. CAR T-cells represented more than 80% of these costs. n=13 hospitals performed CAR-T cell injections, with two hospitals accounting for more than 50% of the total number of injections. This study provides original data in a context of limited information regarding the costs of hospitalization for patients undergoing CAR-T cell treatments. In addition to the financial burden, distance may also be an important barrier for accessing CAR T-cell treatment.

Uptake of biosimilar trastuzumab in Denmark compared with other European countries: a comparative study and discussion of factors influencing implementation and uptake of biosimilars.

PURPOSE: The aim of this study was to describe the implementation and uptake of biosimilar trastuzumab in Denmark compared with other European countries. METHODS: European data for usage of trastuzumab was supplied by IQVIA™, using the MIDAS® dataset. A comparison was performed based on market share estimated in sales volume. A separate comparison was undertaken between countries with a full two-fold switch between different biosimilars. Data was collected spanning the time from first registered sales of biosimilar trastuzumab until the 1st quarter of 2020. RESULTS: Denmark had the fastest and most thorough uptake of biosimilar trastuzumab compared with other EU countries. After 3 months, the market share of biosimilar trastuzumab had increased to 90% while the second fastest country had a 50% market share after 3 months. Only two other countries had undergone a full second switch between biosimilars, Hungary and Norway. All of the three countries made near complete switches between biosimilars while only Denmark had reduced the use of biooriginator below 10%. CONCLUSION: The implementation of biosimilar trastuzumab in Denmark was rapid and achieved high overall uptake compared with other EU countries. The switch from one biosimilar to another was also achieved quickly and thoroughly. We believe that the rapid dissemination of information and involvement of all stakeholders - administrators, pharmacies, prescribers, nurses, and patients - constitute the backbone of the Danish success. A similar strategy is recommend for biosimilar implementation in other countries.

Cost-effectiveness and drug wastage of immunotherapeutic agents for hematologic malignancies: a systematic review.

Introduction: Novel immunotherapeutic agents (e.g. monoclonal antibodies, antibody-drug conjugates, bispecific T-cell engagers) as treatment options for hematologic malignancies continue to emerge. These agents have been used as the standard of care in specific disease states and are associated with high costs. Value assessment of these therapies is of critical importance for coverage and reimbursement decision-making.Areas covered: We identified 15 immunotherapeutic agents through the U.S. FDA approvals for hematologic malignancies until 2018 and systematically reviewed related cost-effectiveness studies. Additionally, we examined whether drug wastage was accounted for in these studies.Expert opinion: We reviewed 51 studies for 14 identified immunotherapeutic agents that met the inclusion criteria for this systematic review. Three studies were observational-based, one study was model-based and incorporated observational data. The remaining studies were model-based with the majority of the model parameters extracted from randomized control trials (RCTs). Among 43 model-based economic evaluations, 13 studies accounted for drug wastage. Most of the studies showed favorable incremental cost-effectiveness ratios of immunotherapeutic agents-containing regimens when compared with no immunotherapeutic agents-containing regimens. Alemtuzumab, brentuximab vedotin, and daratumumab were not considered cost-effective across all the studies. Further investigations are warranted to establish the value of recent immunotherapeutic agents for hematologic malignancies.

Cost-utility analysis of stereotactic body radiotherapy plus cetuximab in previously irradiated recurrent squamous cell carcinoma of the head and neck.

BACKGROUND: This study aimed to estimate the cost-utility of stereotactic body radiotherapy (SBRT) plus cetuximab for patients with previously irradiated recurrent squamous cell carcinoma of the head and neck. METHODS: We constructed a Markov health-state transition model to simulate costs and clinical outcomes of recurrent squamous cell carcinoma of the head and neck. Model parameters were derived from the published literature and the National Health Insurance Administration reimbursement price list. Incremental cost-effectiveness ratio and the net monetary benefit were calculated from a health payer perspective. The impact of uncertainty was modeled with one-way and probabilistic sensitivity analyses. RESULTS: In the base-case, SBRT plus cetuximab compared to SBRT alone resulted in an ICER of NT$ 840,455 per QALY gained. In the one-way sensitivity analysis, the utility of progression-free state for patients treated with SBRT plus cetuximab or SBRT alone and the cost of progression-free survival for SBRT+Cet were the most sensitive parameters in the model. Probabilistic sensitivity analysis showed that the probability of cost-effectiveness at a willingness-to-pay threshold of NT$ 2,252,340 per QALY was 100% for SBRT plus cetuximab but 0% for SBRT alone. CONCLUSIONS: This study showed that SBRT+Cet was cost-effective and benefited patients with previously irradiated rSCCHN.

Cost-effectiveness analyses of targeted therapy and immunotherapy for advanced non-small cell lung cancer in the United States: a systematic review.

Introduction: Mutation-targeting and immuno-oncology drugs are revolutionizing the treatment of advanced non-small cell lung cancer (NSCLC). Cost-effectiveness analyses (CEA) of these drugs have been conducted using various analytical methods and cost-effectiveness thresholds. This systematic review provides a comprehensive summary of the available evidence.Area covered: PubMed, Embase, and Cochrane Library were used to select for CEA of targeted therapies for NSCLC in the United States published between 2008 and 2020. Among the 28 included studies, a majority were published from 2017 to 2020 (n = 18) and more than half targeted non-squamous NSCLC (n = 15). The most frequently evaluated therapy was pembrolizumab (n = 11), followed by bevacizumab (n = 8) and erlotinib (n = 4). After 2009, all included studies applied $100,000 or more thresholds. Thresholds of studies supported by industry (median = $150,000) were more distributed than those of studies supported by nonprofits (median = $100,000).Expert commentary: Medications of interest have changed and are individualized to particular mutations. The cost-effectiveness thresholds varied among sponsors but generally trended to increase over time. This review provides an overview of the available cost-effectiveness findings for stakeholders and contributes to evidence-based practice.

Flexible care in breast cancer.

Treatment of patients with cancer in hospitals or clinics is resource-intensive and imposes a burden on patients. 'Flexible care' is a term that can be used to describe treatment administered outside the oncology ward, oncological outpatient clinic or office-based oncologist setting. Programmes that reduce travel burden by bringing cancer treatment to the patient's home, workplace or closer to the patient's home, in the form of satellite clinics or mobile cancer units, expand treatment capacity and are well received. Clinical trial data show that, compared with intravenous administration, subcutaneous (s.c.) administration of trastuzumab is preferred by patients with breast cancer (BC), saves healthcare professionals' (HCPs) time, reduces drug preparation and administration time and reduces direct and indirect costs. As such, s.c. trastuzumab is well suited to flexible care. The results of a Belgian study (BELIS) show that home administration of s.c. trastuzumab is feasible and preferred by patients with BC. Numerous programmes and pilot studies in Europe show that s.c. trastuzumab can be administered effectively in the patient's home, in primary care settings or local hospitals. Such programmes require planning, training, careful patient selection and technology to link patients, caregivers and specialists in oncology clinics. Once these elements are in place, flexible care offers patients with BC a choice of how treatment may be delivered and lead to improved quality of life, while reducing pressure on HCPs and hospitals. The concept of flexible care is particularly relevant amid the COVID-19 pandemic where guidelines have been developed encouraging remote care.

Clinical Benefit-Risk Assessment of Nivolumab 240 mg Every 2 Weeks in Chinese Patients With Advanced and Metastatic Solid Tumors.

Nivolumab 240 mg every 2 weeks is approved in China by the National Medical Product Agency for squamous cell carcinoma of the head and neck and gastric cancer, based on population pharmacokinetic (PPK) analyses and benefit-risk assessment of safety/efficacy in solid tumors, including Chinese and global populations. The aim of this assessment was to investigate exposure and risk for adverse events (AEs) with flat dosing compared with weight-based dosing. Nivolumab 240-mg and 3-mg/kg every-2-week exposures in Chinese patients were simulated using PPK modeling, and AEs in Chinese and pooled global populations were compared by dosing regimen, exposure, and weight. The 10-mg/kg every-2-week regimen was included because it is known to be well tolerated. Predicted nivolumab exposure in Chinese patients receiving 240 mg every 2 weeks was ∼25% higher versus 3 mg/kg every 2 weeks, but ∼60% lower versus 10 mg/kg every 2 weeks. Grade 3/4 AE incidence in Chinese patients receiving nivolumab 3 mg/kg every 2 weeks was similar with 240-mg every-2-week dosing and with patients from global populations treated with 3 or 10 mg/kg every 2 weeks. There was no trend toward increased AE incidence with high versus low nivolumab exposure or in global patients of varying body weight receiving 3 or 10 mg/kg every 2 weeks. Objective response rates were similar in Chinese and global patients with squamous and nonsquamous NSCLC. Results showed that benefit-risk profiles with nivolumab 240 mg every 2 weeks were similar to those of the 3-mg/kg every-2-week regimen in Chinese patients and global populations, providing an alternative treatment option to Chinese patients.

Real-World Assessment of Patient Care and Practice Efficiency With the Introduction of Subcutaneous Rituximab.

INTRODUCTION: A subcutaneous (SC) formulation of the anti-CD20 monoclonal antibody, rituximab (Rituxan), is approved in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL). Rituximab-SC (R-SC) has been associated with time and clinic resource savings vs the original intravenous formulation (R-IV). Insight into the resource implications of widening R-SC adoption in a US oncology setting is needed. METHODS: A single-institution, retrospective observational analysis was conducted in adult patients with DLBCL, FL, or CLL. The primary outcome measure was chair occupancy time (difference between patient room-in and room-out times). Prescribing patterns were a secondary outcome. RESULTS: Overall, 1190 patients were analyzed (treatment time frame: pre-R-SC adoption: n = 490 [41%], pre- and post R-SC adoption: n = 189 [16%], post R-SC adoption: n = 511 [43%]). Of the patients in the post-R-SC period, 374 (73%) received R-IV, 52 (10%) received R-IV and R-SC, and 85 (17%) received R-SC. When administered, R-SC reduced combination therapy chair time vs R-IV by a mean 37% (93.2 minutes; P < .001). Monotherapy (any route) reduced chair time vs combination by a mean 35.2 minutes (P < .001), with a further 40.2-minute reduction with R-SC (P < .001), a 62% (133.4-minute) total chair time savings vs R-IV. Doctors were more likely to prescribe R-SC to patients with FL than DLBCL. CONCLUSIONS: R-SC is associated with significantly reduced chair time vs R-IV in a US oncology setting. Widespread adoption would be expected to improve practice efficiency and patient access to care, and to reduce health care resource burden.

A cost analysis study of the implementation of fixed-dosing of monoclonal antibodies in the Netherlands Cancer Institute.

Background There is a strong rationale for fixed-dosing of monoclonal antibodies in oncology. Although fixed-dosing of recently introduced monoclonal antibodies is well accepted, the rationale is also applicable for other monoclonal antibodies that already have been used for years, but are still body-size-based dosed in many hospitals. In the Netherlands Cancer Institute, Antoni van Leeuwenhoek (NKI-AVL), fixed-dosing has been implemented now for all monoclonal antibodies and, therefore, this site offers an ideal opportunity for a cost analysis study. Objective To investigate the financial impact of switching to fixed-dosing in the NKI-AVL. Setting The NKI-AVL. Method Information on the preparations of monoclonal antibodies was collected from August 2017 to February 2020. We compared the number of vials needed during preparation for fixed-dosing and body-size -based dosing strategies. The economic impact was calculated for 2 scenarios: scenario 1 assumed clustering of all preparations per day and scenario 2 assumed no clustering of preparations. Main outcome measure Number of saved vials and the correlating savings in health care costs. Results The implementation of fixed-dosing resulted in a substantial reduction in vials used for almost all monoclonal antibodies. The economic savings were calculated to be €0,8 and €3,1 million per year for scenario 1 and 2, respectively. Conclusion Fixed-dosing resulted in substantial savings in health care costs.

Economic evaluation of adjuvant trastuzumab therapy for HER2-positive early-stage breast cancer: systematic review and quality assessment.

INTRODUCTION: As the availability of new economic evaluations (EE) on adjuvant trastuzumab therapy for early-stage breast cancer (EBC) with HER2-positive since last search and other EEs missed warrant a more extensive review, this study aimed to systematically review EEs of adjuvant trastuzumab compared with chemotherapy alone for HER2-positive EBC. AREA COVERED: The search was performed in February 2019 using MEDLINE and Scopus. Reviewers independently selected studies based on eligibility criteria, extracted data, assessed quality of reporting, and appraised quality of data sources. EXPERT OPINION: 22 studies were included which were from high-income (HICs) and upper-middle income countries (UMICs). Incremental cost-effectiveness ratios (ICERs) from HICs were within their cost-effectiveness thresholds and ranged from 6,018 to 78,929 USD per quality-adjusted life year (QALY) gained. ICERs from UMICs mostly exceeded their thresholds ranging from 3,526 to 174,901 USD per QALY gained. Evidence shows cost-effectiveness of trastuzumab for HER2-positive EBC in HICs. There were no methodological variations. The extent and adequacy of reporting were high. The quality of data sources was moderate to high. The quality of future EEs can be improved by enhancing the reporting quality, by using context-based data and real-world efficacy data, which would impact cost-effectiveness.

The challenge of sustainability in healthcare systems: economic and organizational impact of subcutaneous formulations for rituximab and trastuzumab in onco-hematology.

Background: This study estimated the economic and organisational impact of using subcutaneous injection (SC) formulations of two monoclonal antibodies (rituximab and trastuzumab) in patients with non-Hodgkin's lymphoma (NHL) and HER2 + breast cancer (BC).Methods: The database of the Unit of Oncology and Haematology of the IRST of Meldola was used. The analysis was structured as follows: i) measurement of the volume of Day-Hospital activity; ii) identification of activities and time to complete the administration; iii) estimate the mean cost of an SC or IV (intravenous infusion); iv) estimate the impact of SC formulations on the volumes of activities provided; v) estimate the social impact of SC or IV formulations.Results: The use of an SC formulation was associated a significant reduction in the time that the patient takes to complete the administration (trastuzumab -1 hr 18 min; rituximab -2 hr 24 min) and in consumption of healthcare resources and related costs for trastuzumab (IV: € 1781; SC: € 1701) and rituximab (IV: € 2116; SC: € 1941).Conclusion: The adoption of the SC formulation for rituximab and trastuzumab can generate a greater value for both the national healthcare system and the patient compared to an IV formulation.

A real-world data approach to determine the optimal dosing strategy for pembrolizumab.

INTRODUCTION: Cancer drug therapy costs continue to rise and threaten the sustainability of Canada's public healthcare system. Previous studies have calculated potential savings utilizing different dosing regimens of cancer treatments. Our objectives were to determine the financial impact of drug wastage and to explore cost-effective dosing regimens for pembrolizumab. METHODS: This was a retrospective study reviewing data for non-small cell lung cancer and melanoma patients at all six BC Cancer Regional Centres during fiscal years 2017 and 2018. Pembrolizumab waste amounts recorded in pharmacy wastage logs were totalled. Estimates of the number of vials used were compared between vial sharing and non-vial sharing practices to determine the cost differences. Costs for dosing regimens used during fiscal years 2017 and 2018 were compared to 2 mg/kg weight-based dosing (to a maximum of 200 mg), 2 mg/kg dosing rounding down within 5% and 10%, and flat dosing of 200 mg. RESULTS: There were a total of 202 non-small cell lung cancer and 182 melanoma patients with 2948 doses dispensed. Documented wastage was valued at $1,829,047.44 (8.65%) and across all six centres, vial sharing could reduce costs by $3,207,600.00 using the 100 mg vials. Compared to fiscal years 2017 and 2018, 2 mg/kg dosing (to a maximum of 200 mg) was the most cost-effective, decreasing costs by $222,719.20; flat dosing of 200 mg was the most expensive, increasing costs by $6,625,260.40. CONCLUSIONS: Having smaller vial sizes, practicing vial sharing, and using weight-based dosing all improve cost savings. Further investigations on the allocation of resources to optimize drug use and minimize wastage are needed.

Budget impact analysis of subcutaneous trastuzumab compared to intravenous trastuzumab in Saudi HER2-positive breast cancer patients.

Background: This study was aimed to assess the budget impact of SC trastuzumab compared to IV trastuzumab in patients with HER2-positive breast cancer (BC) from the perspective of the governmental health sector in Saudi Arabia, over a 3-year time horizon.Methods: A model was developed to calculate the direct medical and indirect costs for 394 incidents HER2-positive BC patients per year who would receive SC trastuzumab compared to IV formulation. We calculated drug acquisition costs for fixed, loading, and subsequent doses of trastuzumab. One-way sensitivity analysis was conducted.Results: Two scenarios were modeled: the first scenario evaluated the impact of gradual replacement of IV formulation by SC, the second scenario, evaluated impact of totally replacing IV formulation. The total annual costs in the first scenario were estimated to be SAR 177 million (USD 98 million) for IV trastuzumab compared to SAR 143 million (USD 79 million) for SC formulation, leading to a total budget saving of SAR 34,527,346 (USD 19,181,858). In the second scenario, the total annual costs were estimated to be SAR 108 million (USD 60 million) for SC trastuzumab compared to SAR 177 million (USD 98 million) for IV formulation, leading to budget savings of SAR 69,054,692 (USD 36,363,717).Conclusion: Benefits of the SC formulation over IV infusions are being converted to realistic monetary benefits for all providers and payers.

Impact of COVID-19 outbreak on cancer immunotherapy in Italy: a survey of young oncologists.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has overwhelmed the health systems worldwide. Data regarding the impact of COVID-19 on cancer patients (CPs) undergoing or candidate for immune checkpoint inhibitors (ICIs) are lacking. We depicted the practice and adaptations in the management of patients with solid tumors eligible or receiving ICIs during the COVID-19 pandemic, with a special focus on Campania region. METHODS: This survey (25 questions), promoted by the young section of SCITO (Società Campana di ImmunoTerapia Oncologica) Group, was circulated among Italian young oncologists practicing in regions variously affected by the pandemic: high (group 1), medium (group 2) and low (group 3) prevalence of SARS-CoV-2-positive patients. For Campania region, the physician responders were split into those working in cancer centers (CC), university hospitals (UH) and general hospitals (GH). Percentages of agreement, among High (H) versus Medium (M) and versus Low (L) group for Italy and among CC, UH and GH for Campania region, were compared by using Fisher's exact tests for dichotomous answers and χ2 test for trends relative to the questions with 3 or more options. RESULTS: This is the first Italian study to investigate the COVID-19 impact on cancer immunotherapy, unique in its type and very clear in the results. The COVID-19 pandemic seemed not to affect the standard practice in the prescription and delivery of ICIs in Italy. Telemedicine was widely used. There was high consensus to interrupt immunotherapy in SARS-CoV-2-positive patients and to adopt ICIs with longer schedule interval. The majority of the responders tended not to delay the start of ICIs; there were no changes in supportive treatments, but some of the physicians opted for delaying surgeries (if part of patients' planned treatment approach). The results from responders in Campania did not differ significantly from the national ones. CONCLUSION: Our study highlights the efforts of Italian oncologists to maintain high standards of care for CPs treated with ICIs, regardless the regional prevalence of COVID-19, suggesting the adoption of similar solutions. Research on patients treated with ICIs and experiencing COVID-19 will clarify the safety profile to continue the treatments, thus informing on the most appropriate clinical conducts.

Six versus 12 months' adjuvant trastuzumab in patients with HER2-positive early breast cancer: the PERSEPHONE non-inferiority RCT.

BACKGROUND: The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes for people with human epidermal growth factor receptor 2 (HER2)-positive, early, potentially curable breast cancer. Twelve months' trastuzumab, tested in registration trials, was adopted as standard adjuvant treatment in 2006. Subsequently, similar outcomes were demonstrated using 9 weeks of trastuzumab. Shorter durations were therefore tested for non-inferiority. OBJECTIVES: To establish whether or not 6 months' adjuvant trastuzumab is non-inferior to 12 months' in the treatment of HER2-positive early breast cancer using a primary end point of 4-year disease-free survival. DESIGN: This was a Phase III randomised controlled non-inferiority trial. SETTING: The setting was 152 NHS hospitals. PARTICIPANTS: A total of 4088 patients with HER2-positive early breast cancer who it was planned would receive both chemotherapy and trastuzumab took part. INTERVENTION: Randomisation (1 : 1) to 6 months' or 12 months' trastuzumab treatment. MAIN OUTCOMES: The primary end point was disease-free survival. The secondary end points were overall survival, cost-effectiveness and cardiac function during treatment with trastuzumab. Assuming a 4-year disease-free survival rate of 80% with 12 months' trastuzumab, 4000 patients were required to demonstrate non-inferiority of 6 months' trastuzumab (5% one-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life-years were estimated using a within-trial analysis and a lifetime decision-analytic model. RESULTS: Between 4 October 2007 and 31 July 2015, 2045 patients were randomised to 12 months' trastuzumab and 2043 were randomised to 6 months' trastuzumab. Sixty-nine per cent of patients had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% received trastuzumab sequentially after chemotherapy; and 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years' median follow-up, with 389 (10%) deaths and 566 (14%) disease-free survival events, the 4-year disease-free survival rates for the 4088 patients were 89.5% (95% confidence interval 88.1% to 90.8%) in the 6-month group and 90.3% (95% confidence interval 88.9% to 91.5%) in the 12-month group (hazard ratio 1.10, 90% confidence interval 0.96 to 1.26; non-inferiority p = 0.01), demonstrating non-inferiority of 6 months' trastuzumab. Congruent results were found for overall survival (non-inferiority p = 0.0003) and landmark analyses 6 months from starting trastuzumab [non-inferiority p = 0.03 (disease-free-survival) and p = 0.006 (overall survival)]. Six months' trastuzumab resulted in fewer patients reporting adverse events of severe grade [365/1929 (19%) vs. 460/1935 (24%) for 12-month patients; p = 0.0003] or stopping early because of cardiotoxicity [61/1977 (3%) vs. 146/1941 (8%) for 12-month patients; p < 0.0001]. Health economic analysis showed that 6 months' trastuzumab resulted in significantly lower lifetime costs than and similar lifetime quality-adjusted life-years to 12 months' trastuzumab, and thus there is a high probability that 6 months' trastuzumab is cost-effective compared with 12 months' trastuzumab. Patient-reported experiences in the trial highlighted fatigue and aches and pains most frequently. LIMITATIONS: The type of chemotherapy and timing of trastuzumab changed during the recruitment phase of the study as standard practice altered. CONCLUSIONS: PERSEPHONE demonstrated that, in the treatment of HER2-positive early breast cancer, 6 months' adjuvant trastuzumab is non-inferior to 12 months'. Six months' treatment resulted in significantly less cardiac toxicity and fewer severe adverse events. FUTURE WORK: Ongoing translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned. TRIAL REGISTRATION: Current Controlled Trials ISRCTN52968807, EudraCT 2006-007018-39 and ClinicalTrials.gov NCT00712140. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 40. See the NIHR Journals Library website for further project information.

THE BACKGROUND: There are several different types of breast cancer and some are called 'HER2 positive'. These cancers can often be cured by treatment with chemotherapy and a drug called trastuzumab (also known as Herceptin®; Roche, Basel, Switzerland). Although the first trials of trastuzumab used 12 months treatment, we did not know if less treatment could work as well. A small trial in Finland showed that giving trastuzumab for just 9 weeks was also effective. We know that trastuzumab can have some side effects, including heart problems, so it was important to see if we could reduce the length of treatment time, which is usually 12 months. WHAT DID WE DO?: We wanted to find out if we could treat patients safely with 6 months rather than 12 months of trastuzumab. We carried out a clinical trial called PERSEPHONE, in which over 4000 patients with this type of early breast cancer took part. Half of the patients were given 12 months of trastuzumab and half were given 6 months of trastuzumab. WHAT DID WE FIND?: We found that the two groups of patients had very similar benefit from treatment. At 4 years after diagnosis 90.3% of those who had received 12 months of trastuzumab were alive and free of any breast cancer recurrence, compared with 89.5% of those who had received 6 months. In other words, 125 patients would need to be treated with 12 months' trastuzumab rather than 6 months' trastuzumab for one more person to be alive and cancer-free 4 years from diagnosis. THE SIDE EFFECTS?: Severe side effects of trastuzumab were seen on at least one occasion in 24% of 12-month patients compared with 19% of 6-month patients. More patients receiving 12 months of trastuzumab had to stop trastuzumab early because of heart problems (8% of 12-month patients compared with 3% of 6-month patients). WHAT DOES THIS ALL MEAN?: We have shown that 6 months of trastuzumab has similar outcomes to 12 months in treating patients with HER2-positive early breast cancer but with fewer severe side effects, including heart problems, fewer visits to hospital for patients and significant cost savings for the NHS.

Concepts in immuno-oncology: tackling B cell malignancies with CD19-directed bispecific T cell engager therapies.

The B cell surface antigen CD19 is a target for treating B cell malignancies, such as B cell precursor acute lymphoblastic leukemia and B cell non-Hodgkin lymphoma. The BiTE® immuno-oncology platform includes blinatumomab, which is approved for relapsed/refractory B cell precursor acute lymphoblastic leukemia and B cell precursor acute lymphoblastic leukemia with minimal residual disease. Blinatumomab is also being evaluated in combination with other agents (tyrosine kinase inhibitors, checkpoint inhibitors, and chemotherapy) in various treatment settings, including frontline protocols. An extended half-life BiTE molecule is also under investigation. Patients receiving blinatumomab may experience cytokine release syndrome and neurotoxicity; however, these events may be less frequent and severe than in patients receiving other CD19-targeted immunotherapies, such as chimeric antigen receptor T cell therapy. We review BiTE technology for treating malignancies that express CD19, analyzing the benefits and limitations of this bispecific T cell engager platform from clinical experience with blinatumomab.

Movement of Poly-ADP Ribose (PARP) Inhibition into Frontline Treatment of Ovarian Cancer.

The use of poly (ADP-ribose) polymerase (PARP) inhibitors in the front-line management of advanced ovarian cancer has recently emerged as an exciting strategy with the potential to improve outcomes for patients with advanced ovarian cancer. In this article, we review the results of four recently published Phase III randomised controlled trials evaluating the use of PARP inhibitors in the primary treatment of ovarian cancer (SOLO1, PRIMA, PAOLA-1, and VELIA). Collectively, the studies suggest that PARP maintenance in the upfront setting is most beneficial among patients with BRCA-associated ovarian cancers (hazard ratios range from 0.31 to 0.44), followed by patients with tumours that harbour homologous recombination deficiencies (hazard ratios range from 0.33 to 0.57). All three studies that included an all-comer population were able to demonstrate benefit of PARP inhibitors, regardless of biomarker status. The FDA has approved olaparib for front-line maintenance therapy among patients with BRCA-associated ovarian cancers, and niraparib for all patients, regardless of biomarker status. In determining which patients should be offered front-line maintenance PARP inhibitors, and which agent to use, there are multiple factors to consider, including FDA indication, dosing preference, toxicity, risks versus benefits for each patient population, and cost. There are ongoing studies further exploring the front-line use of PARP inhibitors, including the potential downstream effects of PARP-inhibitor resistance in the recurrent setting, combining PARP-inhibitors with other anti-angiogenic drugs, immunotherapeutic agents, and inhibitors of pathways implicated in PARP inhibitor resistance.

Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer.

Importance: Direct intratumoral delivery of immunotherapies is a compelling approach to overcoming barriers to systemic immunotherapy efficacy. While the use of intratumoral delivery of immunotherapy drugs is increasing rapidly in both the investigational and standard of care domains, the feasibility and safety of these interventions, particularly for deeper lesions that require image-guidance, remain unknown. Objective: To address current knowledge gaps in image-guided techniques for intratumoral immunotherapy delivery and the safety of these interventions. Design, Setting, and Participants: This case series study was performed at a single tertiary cancer center over a 2-year period from January 2016 to January 2018. Patients were followed until January 2019. All patients who underwent image-guided intratumoral delivery of immunotherapy agents in the standard of care, off-label, or investigational setting during the study period were included. Data were analyzed from February 1 to June 1, 2019. Exposures: Image-guided biopsies and intratumoral injections of immunotherapies across several clinical trials as well as standard of care talimogene laherparepvec therapy. Main Outcomes and Measures: Technical success, defined as the delivery of the prescribed injectate volume in its entirety, for image-guided biopsy and injections and procedure-related adverse events. Results: A total of 85 patients (median [interquartile range] age, 61 [47-71] years; 42 [52%] men) underwent 498 encounters during the study period. These encounters comprised 327 image-guided intratumoral investigational agent injections in 67 patients in clinical trials, including 33 patients with melanoma (50%), 14 patients with sarcoma (21%), 3 patients with ovarian cancer (4.5%), 2 patients with breast cancer (3%), and 2 patients with colon cancer (3%). An additional 18 patients with melanoma underwent 113 image-guided talimogene laherparepvec injections. There were no adverse events reported related to the technical component of the procedure, specifically needle insertion or biopsy. Serious adverse events (Common Terminology Criteria for Adverse Events score ≥3), including dyspnea and severe flu-like symptoms developing within 24 hours of the injection and requiring hospitalization, occurred after 3 of 327 investigational agent injections (2%) and 4 of 113 talimogene laherparepvec injections (4%). Conclusions and Relevance: The findings of this case series study suggest that intratumoral injections of immunotherapies were feasible across a range of histological conditions and target organs. Immediate postdelivery anticipated adverse events occurred in a small number of instances. Performing physicians should have the necessary safeguards in place to respond as needed. Optimal methods for intratumoral drug delivery remain unresolved, and efforts to standardize drug delivery techniques are required.

Application of comprehensive geriatric assessment in predicting early mortality among elder patients with B-cell lymphoma receiving immunochemotherapy.

OBJECTIVES: Early mortality, defined as death within 120 days after initiated antitumor therapy, is an important issue especially for elder patients with B-cell lymphoma. This study aimed to evaluate the clinical value of comprehensive geriatric assessment (CGA) in early mortality prediction in elderly patients with B-cell lymphoma receiving immunochemotherapy. METHODS: Seventy-six consecutive patients with newly diagnosed B-cell lymphoma receiving immunochemotherapy from a medical center in Taiwan were prospectively enrolled. Patients were divided into fit (n = 49) and frail (n = 27) groups per pretreatment CGA for early mortality comparison. RESULTS: The early mortality rate in our patient cohort was 16% (n = 12): from 6% in patients with no CGA domain impairment to 43% in patients with ≥4 CGA domain impairment. The early mortality rate was 6% and 33% in fit and frail patients (odds ratio, 7.67; 95% CI, 1.86-31.6; P = .005), respectively. Frailty was the significant predictor for early mortality in univariate and multivariate analysis. CONCLUSION: In this study, the number of geriatric domain impairment is positively associated with the early mortality risk in elderly patients with B-cell lymphoma. Therefore, CGA can help clinicians to identify the risk of early mortality in elderly patients and provide alternative treatment.

Cost-effectiveness analysis of nivolumab in the second-line treatment for advanced esophageal squamous cell carcinoma.

Background: To investigate the cost-effectiveness of nivolumab versus chemotherapy in the second-line treatment for advanced esophageal squamous cell carcinoma. Materials & methods: A Markov model reflecting the patients in the ATTRACTION-3 trial was established. Weibull survival model was employed to fit the Kaplan-Meier progression-free survival and overall survival probabilities of the nivolumab and chemotherapy strategy, respectively. Meanwhile, one-way and PSA were performed to test the uncertainty in the model. Results: Overall, the incremental effectiveness and cost of nivolumab versus chemotherapy were 0.107 quality-adjusted life-years and $14,627.90, resulting in an incremental cost-effectiveness ratio of $136,709.35/quality-adjusted life-year. Conclusion: Nivolumab is not a cost-effective treatment option compared with chemotherapy from the perspective of Chinese society.