The use of 'added benefit' to determine the price of new anti-cancer drugs in France, 2004-2017.

BACKGROUND: Increasing drug prices strains budgets. Assessing the relation between added benefit and prices can help clinical decision-making and resource allocation. METHODS: We assessed, over a period of 13 years, the relation between added therapeutic benefit and prices for drugs to treat solid tumours in France using the French High Authority of Health Scale (ASMR) and the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (MCBS). RESULTS: In total, 36 medications were approved for 68 indications. There was a weak correlation between ASMR and MCBS scales (Spearman's |ρ| = 0.28). Drugs had low added benefit on both ASMR (71%) and MCBS (49%). Mean monthly price for new drugs was €4616 (S.D., €3096), ranging from €1795 to €19,675 and increased by 47% comparing 2004-2012 with 2013-2017. The mean monthly price difference of new drugs over their comparator was €3700 (S.D., €3934) ranging between a €13,853 decrease and a €19,675 increase. There was a weak but statistically significant correlation between ASMR and price (|ρ| = 0.35, p = 0.004) and between MCBS and price (|ρ| = 0.33, p = 0.005). Correlations between added benefit and prices were similar or higher for first indications (ASMR, |ρ| = 0.37, p = 0.030; MCBS, |ρ| = 0.48, p = 0.004). In first indications, mean monthly prices increased €3954 for drugs without ASMR added benefit. The mean annual price and price increase for first indications offering no ASMR benefit was €57,312 and €47,448, respectively. CONCLUSION: Prices and benefit are weakly correlated. However, prices increased substantially even for drugs with no added benefit.

Nivolumab in routine practice for older patients with advanced or metastatic non-small cell lung cancer.

BACKGROUND: Nivolumab is approved worldwide as second-line treatment for metastatic non-small cell lung cancer (NSCLC). Despite the fact that most of these cancers are being diagnosed in the older patients, few of the patients were included in pivotal trials. We aimed to describe efficacy and safety in a "real-world" older population. PATIENTS AND METHODS: We retrospectively collected data from older patients (≥70 years old) with advanced or metastatic NSCLC treated with Nivolumab in our institution. We analyzed safety (CTCAE v4.0 criteria), efficacy (clinical benefit rate, progression-free survival, and overall survival), and correlated these features to geriatric parameters and PD-L1 expression. Along with this cohort, we assessed safety at a national level by retrieving all cases of Nivolumab (prescribed for NSCLC) induced adverse events analyzed by the French pharmacovigilance network during the inclusion period. RESULTS: From July 2015 to September 2016, 30 patients were enrolled with a median age of 75.2. Clinical benefit rate was 30.6%. Median progression-free survival and overall survival were 3.3 and 7.1 months, respectively. Fifteen patients (50%) presented an immune-related adverse event (IrAE) of any grade, including four high grade IrAEs. Two hundred and eighty IrAEs had been notified to the French pharmacovigilance network including 91 (35.2%) concerning older patients. Frequency and pattern of IrAEs were similar for older patients and younger subjects. CONCLUSIONS: Even though frequency and patterns of IrAEs are different from pivotal studies, these results don't seem specific to older patients. Further prospective investigations are needed to better characterize and predict the impact of Nivolumab on older patients with NSCLC.

De-escalation of antimicrobial treatment in neutropenic patients with severe sepsis: results from an observational study.

BACKGROUND: In severe sepsis, guidelines recommend de-escalating the empirical antimicrobial treatment as soon as the microbiological results are available. We aimed to determine the rate of de-escalation of the empirical antimicrobial treatment in neutropenic patients with severe sepsis. The characteristics of antimicrobial treatment associated with de-escalation and its impact on short- and long-term survival were also determined. METHODS: In the intensive care unit (ICU) of a cancer referral center, we prospectively collected observational data related to the antimicrobial management in neutropenic patients who developed severe sepsis and were admitted to ICU for at least 48 h. De-escalation of antimicrobial therapy consisted either of deleting one of the empirical antibiotics of a combined treatment, or, whenever possible, to use a betalactam antibiotic with a narrower spectrum of activity. Multivariate logistic regression was conducted to determine the factors associated with de-escalation, while a Cox proportional hazards model with a time-dependent covariate was fitted to assess the effect of de-escalation on 30-day survival. Finally 1-year survival after ICU discharge was compared across de-escalation groups. RESULTS: Cumulative incidence of de-escalation of the empirical antimicrobial treatment among the 101 patients of the cohort was 44%, [95% confidence interval (CI) 38-53%], including 30 (68%) patients with ongoing neutropenia. A microbiological documentation was available in 63 (63%) patients. Factors associated with de-escalation were the adequation of the empirical antimicrobial treatment in ICU [OR = 10.8 (95% CI 1.20-96)] for adequate documented treatment versus appropriate empirical treatment, the compliance with guidelines regarding the empirical choice of the anti-pseudomonal betalactam [OR = 10.8 (95% CI 1.3-89.5)]. De-escalation did not significantly modify the hazard of death within the first 30 days [HR = 0.51 (95% CI 0.20-1.33)], nor within 1 year after ICU discharge [HR = 1.06 (95% CI 0.54-2.08)]. CONCLUSION: Our data suggest that, in ICU, de-escalation of the empirical antimicrobial treatment is frequently applied in neutropenic cancer patients with severe sepsis. No evidence of any prognostic impact of this de-escalation was found.

Brentuximab vedotin followed by allogeneic transplantation as salvage regimen in patients with relapsed and/or refractory Hodgkin's lymphoma.

Patients with relapsed or refractory Hodgkin lymphoma (RR-HL) have poor outcomes. Brentuximab vedotin (BV), an antibody-drug conjugate comprising an anti-CD30 antibody conjugated to the potent anti-microtubule agent, monomethyl auristatin E, induces high tumour responses with moderate adverse effects. In a retrospective study, we describe objective response rates and subsequent allogeneic stem cell transplantation (allo-SCT) in patients with RR-HL treated by BV in a named patient program in two French institutions. Twenty-four adult patients with histologically proven CD30(+) RR-HL treated with BV were included from July 2009 to November 2012. Response to BV treatment was evaluated after four cycles. Eleven patients were in complete response (45.8%), while five patients were in partial response (20.8%), with an overall response rate of 66.6%. Eight patients failed to respond to BV (33.3%). All of the responding patients could receive consolidation treatment after BV: three patients underwent autologous stem cell transplantation (auto-SCT), three patients received a tandem auto-SCT/allo-SCT, nine patients received allo-SCT and one patient was treated with donor lymphocyte infusion. We found no treatment-related mortality at day 100 among the 12 patients who underwent BV following by allogeneic transplantation. With a median follow-up of 20 months (range 10.5-43.2), none of them relapsed or died. BV followed by allo-SCT represents an effective salvage regimen in patients with RR-HL.

Lenalidomide plus donor-lymphocytes infusion after allogeneic stem-cell transplantation with reduced-intensity conditioning in patients with high-risk multiple myeloma.

Myeloma relapse is the main cause of death after allogeneic stem cell transplantation. The aim of our observational study was to evaluate the anti-myeloma effect of lenalidomide followed by donor-lymphocyte infusion (DLI) as post-transplantation adoptive immunotherapy. Twelve patients with refractory myeloma were analyzed. The median age at transplantation was 56 years (range, 46-64 years). All patients received reduced-intensity conditioning. Patients were included if progressive or residual disease was observed at day +100 and if no signs of graft-vs-host disease were evident. DLIs were administered after two cycles of lenalidomide. Median dose of lenalidomide was 15 mg (range, 10-25 mg). Patients received a median of six cycles (range, 1-10 cycles). Nine patients (60%) received an escalating dose of DLI. The 1 and 2-year probability of progression-free survival was 75% and 50%, and overall survival was 83% and 69%, respectively. Median overall survival was not reached and median progression-free survival was 23 months. Lenalidomide is well tolerated after allogeneic stem cell transplantation; the combination with DLI did not cause a higher risk of graft-vs-host disease; an immunological synergistic effect was probably present with this strategy. This combination should be evaluated further in a larger cohort of patients.

Once-weekly liposomal amphotericin B for prophylaxis of invasive fungal infection after graft-versus-host disease in allogeneic hematopoietic stem cell transplantation: a comparative retrospective single-center study.

BACKGROUND AND OBJECTIVES: The liposomal formulation of amphotericin B (LAmB) has been shown to cause few and mild infusion-related reactions, while achieving high plasma and tissue concentrations compared with conventional amphotericin B. We investigated the efficacy and safety of high-dose LAmB (7.5 mg/kg once weekly) prophylaxis of fungal infections in allogeneic stem-cell transplanted (allo-SCT) patients with graft-versus-host disease (GvHD). DESIGN AND SETTING: Retrospective, comparative, single-center. METHODS: Forty-two patients receiving high-dose prednisone for GvHD after allo-SCT had LAmB prophylaxis; 83 patients in the control group received other antifungal prophylaxis. RESULTS: In the LAmB prophylaxis group, the median duration of treatment was 7 weeks. The cumulative incidence of invasive fungal infection was 8% at 1 year after transplantation, 8% at 2 years and 16% at 3 years in the LAmB group vs. 36% at 1 year, 44% at 2 years and 49% at 3 years in the other prophylaxis group (P=.008). Fungal infection-related mortality after transplantation was observed in none of the patients in the LAmB prophylaxis group vs. 12 patients (14%) at 1 year, 14 patients (17%) at 2 years and 16 patients (19%) at 3 years in the control group (P=.005). The tolerance of the treatment was good with only 5 patients (12%) having a reversible nephrotoxicity leading to temporary treatment discontinuation. CONCLUSIONS: High-dose LAmB prophylaxis seems effective and well tolerated in this short series of allo-SCT patients with GvHD. Prospective clinical studies are required to confirm these results.

The detection of non-adherence by self-administered questionnaires can be optimized by protease inhibitor plasma concentration determination.

Self-reported adherence and plasma protease inhibitor concentration (PPIC) were assessed in 642 HIV-infected patients at month 4 of a single protease inhibitor-containing regimen. PPIC was below the limit of quantification (LOQ) in 32% of non-adherent patients and in 8% of adherent patients. The relationship between non-adherence and a detectable HIV viral load was enhanced when adherent patients with PPIC below LOQ were considered to be non-adherent. PPIC combined with self-report may more reliably detect non-adherence.

Health-related quality of life after 1 year of highly active antiretroviral therapy.

OBJECTIVE: We investigated the impact of the first year of highly active antiretroviral therapy (HAART) on health-related quality of life (HRQL). METHODS: Medical data for patients in the French APROCO cohort were collected at enrollment (M0) and month 12 (M12). A self-administered questionnaire gathered information about HRQL (Medical Outcome Study 36-Item Short Form Health Survey) and toxicity-related symptoms. Using the twenty-fifth percentile of HRQL scales in the French population as a threshold, patients with normal values in at least three mental and three physical scales were considered to have a "normal HRQL." RESULTS. Of the 1053 patients followed through M12, HRQL data at M0 and M12 were available for 654. Among the 233 patients with a normal baseline HRQL, 63 (27.0%) experienced a deterioration of HRQL at M12. Among the 421 patients with a low baseline HRQL, 121 achieved a normal HRQL at M12. Logistic regression showed that factors independently associated with a normal HRQL at M12 were normal baseline HRQL, baseline CD4 count <500 cells/mm, time since HIV diagnosis <8 years, undetectable HIV-RNA at M12, and lower number of self-reported symptoms at M12. CONCLUSION: An assessment of HRQL should be integrated to efficacy outcomes to evaluate and compare long-term strategies properly and to optimize the durability of response to antiretroviral therapy.

Mechanisms of early virologic failure in antiretroviral-naive patients starting protease inhibitor-containing regimens: the APROVIR Study.

The virologic and pharmacologic mechanisms of virologic failure (VF) were studied in 243 antiretroviral-naive patients starting first-line protease inhibitor (PI)-containing therapy (nelfinavir in 66% and indinavir in 19%). Among the 220 patients with follow-up data, VF occurred in 35 (16%) during the first year of follow-up. A higher baseline virus load and poorer adherence to therapy were associated with VF. At the time of VF, key PI-resistance mutations were detected in 11 (48%) of 23 patients who started on nelfinavir but were absent in 6 patients with indinavir treatment failure. PI plasma levels were more often below the range of active concentrations in VF with wild-type viruses (74%) than in VF with PI-resistant viruses (25%; P=.02). The mechanisms of early VF and of selection of PI-resistant viruses differed by type of PI and were dependent on PI plasma levels.

Adherence to highly active antiretroviral therapies (HAART) in HIV-infected patients: from a predictive to a dynamic approach.

To-date, most socio-behavioural research about HTV-infected patients' adherence to highly active antiretroviral therapies (HAART) has been based on cross-sectional studies. The French APROCO cohort gave us the opportunity to conjointly analyse the relationships between short-term adherence to HAART and HIV-infected patients' characteristics before initiation of treatment on the one hand, factors related to patients' subjective experience with HAART on the other hand. At the fourth-month follow-up visit (M4) after first prescription of HAART (M0), 26.7% of our sample of 445 patients self-reported non-adherence behaviour. Some patients' characteristics at M0 (younger age, poor housing conditions, lack of social support, and problems of adherence with previous antiretroviral regimens) were related to non-adherence at M4 in multivariate analysis. Non-adherence at M4 was, however, also related to the evolutions that affected a number of factors between M0 and M4: levels of depression, symptoms associated with treatment side effects, perception of individual state of health, beliefs towards effectiveness and toxicity of HAART. increases in alcohol and tobacco consumption, as well as contacts with other physicians than hospital HAART prescribers. Our prospective study brings additional evidence that even short-term non-adherence cannot be reliably predicted on the sole basis of a few a priori patient characteristics that clinicians could easily identify before initiation of HAART. It suggests that a dynamic approach to adherence, continuously monitoring the impact of experience with HAART on patients' daily lives, is needed for improving management of HIV/AIDS care.

Impact of discontinuation of initial protease inhibitor therapy on further virological response in a cohort of human immunodeficiency virus-infected patients.

Although discontinuation of antiretroviral drug therapy is common, the impact on outcome in routine clinical practice is unknown. The Antiprotéases Cohorte (APROCO) Cohort Study enrolled 1281 patients at the time they started a protease inhibitor (PI)-containing regimen from 1997 through 1999. After a median duration of follow-up of 20 months, 51% of patients had discontinued their initial PI. Prospectively recorded reasons for discontinuation were intolerance (52% of patients), poor adherence (22%), and failure of therapy (15%). In a multivariate logistic regression analysis, only discontinuation due to poor adherence was associated with a lower frequency of human immunodeficiency virus RNA level in plasma of <500 copies/mL 12 months after initiation of therapy (odds ratio, 0.27 vs. no change; P<.0001); discontinuation due to intolerance was not associated with virological response (odds ratio, 0.89; P=.58). Patients experiencing intolerance should be reassured that changing therapy will probably not be harmful. Multidisciplinary efforts should concentrate on ways to avoid discontinuation of treatment for adherence reasons.