The relevance of therapeutic positioning in the post-approval evaluation of new medicines. / La importancia del posicionamiento terapéutico en la evaluación posautorización de nuevos medicamentos.

The objective of regulatory authorities is to ensure a favorable risk-benefit balance for medicines in their licensed indication, without seeking to establish their place in the therapeutic armamentarium beyond that. The licensed indication covers heterogeneous subpopulations and often does not sufficiently specify the characteristics of the patients who may benefit. The regulatory information does not always show the benefit over the standard treatments; moreover, it only reacts to the conditions specified in the developer's application, and lacks an assessment of the clinical relevance of the benefit and its uncertainties. Many cases highlight the need to establish a more specific therapeutic benefit scenario than the licensed indication. For example, abemaciclib was approved in the adjuvant setting for high-risk patients with early breast cancer, but the appropriate level of risk and how to assess it needs to be specified. Also, pembrolizumab is approved for neoadjuvant plus adjuvant treatment in lung cancer; but it remains to be analyzed whether it is superior to nivolumab in neoadjuvant treatment alone, which involves less treatment and economic burden. As therapeutic positioning is always a necessary decision, whether made at a national, regional, local or individual level, it must be made in the most appropriate way. The absence of a multidisciplinary discussion and consensus, relying only on individual decisions to determine positioning from the outset, underestimates information gaps, inter-individual variability and the influence of drug promotion. It can be harmful and costly. To properly manage the introduction of new medicines, it is essential to establish their benefit scenario in a multidisciplinary way. This, together with consideration of the clinical benefit provided versus the appropriate alternatives and the uncertainties of the benefit, constitutes the objective of the clinical assessment and the basis for designing a well-focused economic analysis. This allows policy makers to make the most appropriate decisions on pricing and funding new treatments. In an ideal situation, the benefit scenario considered for the new medicine would coincide with the one established for funding, but costs that are difficult to bear may lead to restrictions and affect the final positioning after the economic and budgetary impact assessment.

Abemaciclib as adjuvant treatment for high-risk early breast cancer / Abemaciclib en adyuvancia para el tratamiento del cáncer de mama precoz de alto riesgo

Objective: To adapt the GHEMA report of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6. European Medicines Agency authorization (April 2022) includes, in combination with endocrine therapy, the adjuvant treatment of adult patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive, early breast cancer at high risk of recurrence. Method: The efficacy and safety of abemaciclib were evaluated in a randomized, open-label, and multicenter phase III study. A total of 5637 patients diagnosed with early breast cancer with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive, and high risk of recurrence were included. High risk was defined as patients with 4 or more positive axillary lymph nodes, or 1–3 positive axillary lymph nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3, or Ki-67≥20%. Patients were randomized (1:1) to receive adjuvant abemaciclib+endocrine therapy (n = 2808) or endocrine therapy alone (n = 2829) for 2 years, with endocrine therapy prescribed for at least 5 years. Results: With a median follow-up of 15.5 months, abemaciclib+endocrine therapy demonstrated a statistically significant improvement in invasive disease-free survival versus endocrine therapy alone [HR = 0.747 (95% CI 0.598–0.932), P = 0.0096]; achieving an absolute improvement of 3.5% invasive disease-free survival rate at 2-years. These results were maintained, with a median follow-up of 27.7 months: absolute improvement of 2.7% and 5.4% in invasive disease-free survival rate at 2 and 3 years, respectively. All-causality grade 3 or 4 adverse events were 45.9% for abemaciclib and 12.9% for endocrine therapy, and included neutropenia (19.6% vs. 0.8%), leukopenia (11.4% vs. 0.4%), and diarrhea (7.8% vs. 0.2%). Conclusions: The results of the pivotal trial are sufficient to consider abemaciclib as adjuvant treatment for...(AU)

Objetivo: Adaptar el informe GHEMA de abemaciclib, un inhibidor de quinasas dependientes de ciclinas 4 y 6, con autorización de la Agencia Europea del Medicamento en abril de 2022 para el tratamiento adyuvante de pacientes adultos con cáncer de mama precoz, receptor hormonal positivo, receptor del factor de crecimiento epidérmico negativo, con afectación ganglionar y riesgo elevado de recaída; en combinación con hormonoterapia. Método: La eficacia y seguridad de abemaciclib se evaluó en un estudio fase III multicéntrico, aleatorizado y abierto. Se incluyeron 5.637 pacientes diagnosticados de cáncer de mama precoz con ganglios positivos, receptor hormonal positivo, receptor del factor de crecimiento epidérmico negativo y alto riesgo de recaída. El criterio de alto riesgo se definió como la presencia de ≥ 4 ganglios positivos, o de 1–3 ganglios y al menos una de las siguientes características: tamaño del tumor ≥5 cm, grado histológico 3 o Ki-67 ≥ 20%. Los pacientes fueron aleatorizados (1:1) a recibir durante 2 años abemaciclib + hormonoterapia (n = 2.808) u hormonoterapia sola (n = 2.829). En ambos brazos el tratamiento con hormonoterapia se mantuvo mínimo 5 años. Resultados: Con una mediana de seguimiento de 15,5 meses, abemaciclib + hormonoterapia mostró beneficio significativo frente a la hormonoterapia sola [HR = 0,747 (IC95% 0,598-0,932), p = 0,0096], con una mejora absoluta del 3,5% en la tasa de supervivencia libre de enfermedad invasiva a 2 los años. Este beneficio se mantuvo con una mediana de seguimiento de 27,7 meses, logrando una mejora en la tasa de supervivencia libre de enfermedad invasiva del 2,7% y del 5,4% a los 2 y 3 años, respectivamente. La incidencia de efectos adversos grado 3–4 fue superior en el brazo de abemaciclib (45,9% vs. 12,9%); e incluía neutropenia (19,6% vs. 0,8%), leucopenia (11,4% vs. 0,4%) y diarrea (7,8% vs. 0,2%). Conclusiones: Los resultados del ensayo pivotal son suficientes para considerar abemaciclib como...(AU)

Abemaciclib en adyuvancia para el tratamiento del cáncer de mama precoz de alto riesgo / Abemaciclib as adjuvant treatment for high-risk early breast cancer

Objective: To adapt the GHEMA report of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6. European Medicines Agency authorization (April 2022) includes, in combination with endocrine therapy, the adjuvant treatment of adult patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive, early breast cancer at high risk of recurrence. Method: The efficacy and safety of abemaciclib were evaluated in a randomized, open-label, and multicenter phase III study. A total of 5637 patients diagnosed with early breast cancer with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive, and high risk of recurrence were included. High risk was defined as patients with 4 or more positive axillary lymph nodes, or 1–3 positive axillary lymph nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3, or Ki-67≥20%. Patients were randomized (1:1) to receive adjuvant abemaciclib+endocrine therapy (n = 2808) or endocrine therapy alone (n = 2829) for 2 years, with endocrine therapy prescribed for at least 5 years. Results: With a median follow-up of 15.5 months, abemaciclib+endocrine therapy demonstrated a statistically significant improvement in invasive disease-free survival versus endocrine therapy alone [HR = 0.747 (95% CI 0.598–0.932), P = 0.0096]; achieving an absolute improvement of 3.5% invasive disease-free survival rate at 2-years. These results were maintained, with a median follow-up of 27.7 months: absolute improvement of 2.7% and 5.4% in invasive disease-free survival rate at 2 and 3 years, respectively. All-causality grade 3 or 4 adverse events were 45.9% for abemaciclib and 12.9% for endocrine therapy, and included neutropenia (19.6% vs. 0.8%), leukopenia (11.4% vs. 0.4%), and diarrhea (7.8% vs. 0.2%). Conclusions: The results of the pivotal trial are sufficient to consider abemaciclib as adjuvant treatment for...(AU)

Objetivo: Adaptar el informe GHEMA de abemaciclib, un inhibidor de quinasas dependientes de ciclinas 4 y 6, con autorización de la Agencia Europea del Medicamento en abril de 2022 para el tratamiento adyuvante de pacientes adultos con cáncer de mama precoz, receptor hormonal positivo, receptor del factor de crecimiento epidérmico negativo, con afectación ganglionar y riesgo elevado de recaída; en combinación con hormonoterapia. Método: La eficacia y seguridad de abemaciclib se evaluó en un estudio fase III multicéntrico, aleatorizado y abierto. Se incluyeron 5.637 pacientes diagnosticados de cáncer de mama precoz con ganglios positivos, receptor hormonal positivo, receptor del factor de crecimiento epidérmico negativo y alto riesgo de recaída. El criterio de alto riesgo se definió como la presencia de ≥ 4 ganglios positivos, o de 1–3 ganglios y al menos una de las siguientes características: tamaño del tumor ≥5 cm, grado histológico 3 o Ki-67 ≥ 20%. Los pacientes fueron aleatorizados (1:1) a recibir durante 2 años abemaciclib + hormonoterapia (n = 2.808) u hormonoterapia sola (n = 2.829). En ambos brazos el tratamiento con hormonoterapia se mantuvo mínimo 5 años. Resultados: Con una mediana de seguimiento de 15,5 meses, abemaciclib + hormonoterapia mostró beneficio significativo frente a la hormonoterapia sola [HR = 0,747 (IC95% 0,598-0,932), p = 0,0096], con una mejora absoluta del 3,5% en la tasa de supervivencia libre de enfermedad invasiva a 2 los años. Este beneficio se mantuvo con una mediana de seguimiento de 27,7 meses, logrando una mejora en la tasa de supervivencia libre de enfermedad invasiva del 2,7% y del 5,4% a los 2 y 3 años, respectivamente. La incidencia de efectos adversos grado 3–4 fue superior en el brazo de abemaciclib (45,9% vs. 12,9%); e incluía neutropenia (19,6% vs. 0,8%), leucopenia (11,4% vs. 0,4%) y diarrea (7,8% vs. 0,2%). Conclusiones: Los resultados del ensayo pivotal son suficientes para considerar abemaciclib como...(AU)

Economic assessment of abemaciclib for the adjuvant treatment of luminal HER2- breast cancer from the perspective of the Spanish health system.

INTRODUCTION: Abemaciclib is an oral inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). Data from the clinical trial monarchE (2023) showed improved survival from invasive disease. The aim of the present article was to conduct an economic assessment of adjuvant treatment with abemaciclib in women with luminal, HER2- and node-positive breast cancer. METHODS: A Markov model was constructed with four mutually exclusive health states (disease-free, local recurrence, distal recurrence and death). Analyses were based on the clinical trial monarchE which compared an intervention group (abemaciclib + hormone therapy [HT]) with HT alone. The effectiveness measure used was quality-adjusted life years (QALY), with unit costs and utilities being obtained from existing literature. The incremental cost-utility ratio (ICUR) was used to compare the two treatment strategies. RESULTS: Total costs were €98,765 and €17,935 for the abemaciclib plus HT group and the HT alone group, respectively. The health outcome was 10.076QALY for the intervention group and 9.495QALY for the control group, with the ICUR being€139,173/QALY. CONCLUSION: Despite the significant gains of abemaciclib as adjuvant treatment in terms of progression-free survival, this treatment is not cost-effective for the Spanish National Health System at published prices. It may be cost-effective with an appropriate discount on the official price.

Comparación indirecta ajustada de zanubrutinib e ibrutinib en el tratamiento de primera línea de la leucemia linfocítica crónica / Adjusted indirect comparison of zanubrutinib and ibrutinib in first-line treatment of chronic lymphocytic leukemia

Objetivo el objetivo del presente trabajo fue realizar una comparación indirecta ajustada, según el perfil citogenético, en términos de eficacia, entre los distintos inhibidores de la tirosin cinasa de bruton empleados como monoterapia en primera línea para la leucemia linfocítica crónica. Asimismo, se evaluaron los resultados de seguridad considerados de interés para establecer si dichas opciones pueden ser consideras alternativas terapéuticas equivalentes. Método con fecha 10 de noviembre del 2022, se llevó a cabo una búsqueda bibliográfica en las bases de datos de Pubmed y Embase de ensayos clínicos fase III que estudiaran los inhibidores de la tirosin cinasa de Bruton en monoterapia en contexto de primera línea para la leucemia linfocítica crónica. Se incluyeron ensayos en los que se empleara la combinación de bendamustina y rituximab como comparador y que presentaran poblaciones y tiempos de seguimiento semejantes. Se combinaron mediante metaanálisis los resultados de los subgrupos según las características mutacionales clasificando a los pacientes en alto y bajo riesgo citogenético. Se desarrolló una comparación indirecta ajustada utilizando el método de Bucher. Se determinó la posible equivalencia terapéutica aplicando para ello la guía de alternativas terapéuticas equivalentes. Resultado de los 39 estudios obtenidos en la revisión, se seleccionaron 2 ensayos clínicos: uno para zanubrutinib y otro para ibrutinib. El resto de estudios no se incluyeron por incumplimiento de los criterios de inclusión. Los resultados obtenidos en la comparación indirecta ajustada para ambos subgrupos de riesgo citogenético no mostraron diferencias estadísticamente significativas. En cuanto a la seguridad, las diferencias más relevantes se encontraron en la incidencia de fibrilación auricular, hipertensión arterial y eventos cardiovasculares en los pacientes tratados con ibrutinib, y mayor incidencia de cánceres secundarios en los pacientes tratados con zanubrutinib (AU)

Objective The aim of this study was to perform an adjusted indirect treatment comparison, according to the cytogenetic profile, in terms of efficacy between different Bruton tyrosine kinase inhibitors used as first-line monotherapy for chronic lymphocytic leukemia. Safety outcomes considered of interest were also evaluated to establish whether these options can be considered equivalent therapeutic alternatives. Method A literature search was conducted in Pubmed and Embase on 10 November 2022 for phase III clinical trials studying Bruton's tyrosine kinase inhibitors in monotherapy in the first-line setting for CLL. Results were filtered according to whether the combination of bendamustine and rituximab was used as comparator and whether they had similar populations and follow-up times. Subgroup results were meta-analyzed according to mutational characteristics by classifying patients into high and low cytogenetic risk. An adjusted indirect comparison was developed using Bucher's method. Possible therapeutic equivalence was determined by applying the guide to equivalent therapeutic alternatives. Result Of the 39 studies obtained in the review, two clinical trials were selected: one for zanubrutinib and one for ibrutinib. The remaining studies were not included because they did not meet the inclusion criteria. The results obtained in the adjusted indirect treatment comparison for both cytogenetic risk subgroups showed no statistically significant differences. The most relevant safety differences were auricular fibrillation, hypertension and cardiovascular events in patients treated with ibrutinib and higher incidence of secondary cancers in patients treated with zanubrutinib. Applying the ATE guideline criteria, both treatments cannot be considered equivalent therapeutic alternatives (AU)

Adjusted indirect comparison of zanubrutinib and ibrutinib in first-line treatment of chronic lymphocytic leukemia. / Comparación indirecta ajustada de zanubrutinib e ibrutinib en el tratamiento de primera línea de la leucemia linfocítica crónica.

OBJECTIVE: The aim of this study was to perform an adjusted indirect treatment comparison, according to the cytogenetic profile, in terms of efficacy between different Bruton tyrosine kinase inhibitors used as first-line monotherapy for chronic lymphocytic leukemia. Safety outcomes considered of interest were also evaluated to establish whether these options can be considered equivalent therapeutic alternatives. METHOD: A literature search was conducted in Pubmed and Embase on 10 November 2022 for phase III clinical trials studying Bruton's tyrosine kinase inhibitors in monotherapy in the first-line setting for CLL. Results were filtered according to whether the combination of bendamustine and rituximab was used as comparator and whether they had similar populations and follow-up times. Subgroup results were meta-analyzed according to mutational characteristics by classifying patients into high and low cytogenetic risk. An adjusted indirect comparison was developed using Bucher's method. Possible therapeutic equivalence was determined by applying the guide to equivalent therapeutic alternatives. RESULT: Of the 39 studies obtained in the review, two clinical trials were selected: one for zanubrutinib and one for ibrutinib. The remaining studies were not included because they did not meet the inclusion criteria. The results obtained in the adjusted indirect treatment comparison for both cytogenetic risk subgroups showed no statistically significant differences. The most relevant safety differences were auricular fibrillation, hypertension and cardiovascular events in patients treated with ibrutinib and higher incidence of secondary cancers in patients treated with zanubrutinib. Applying the ATE guideline criteria, both treatments cannot be considered equivalent therapeutic alternatives. CONCLUSIONS: Assuming the uncertainty associated with the adjusted indirect comparison, zanubrutinib could be considered equivalent in efficacy to ibrutinib, however, the presence of differentiating safety features precludes assigning the two alternatives as equivalent therapeutic alternatives.

Abemaciclib as adjuvant treatment for high-risk early breast cancer.

OBJECTIVE: To adapt the GHEMA report of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6. European Medicines Agency authorization (April 2022) includes, in combination with endocrine therapy, the adjuvant treatment of adult patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive, early breast cancer at high risk of recurrence. METHOD: The efficacy and safety of abemaciclib were evaluated in a randomized, open-label, and multicenter phase III study. A total of 5637 patients diagnosed with early breast cancer with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive, and high risk of recurrence were included. High risk was defined as patients with 4 or more positive axillary lymph nodes, or 1-3 positive axillary lymph nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3, or Ki-67≥20%. Patients were randomized (1:1) to receive adjuvant abemaciclib+endocrine therapy (n = 2808) or endocrine therapy alone (n = 2829) for 2 years, with endocrine therapy prescribed for at least 5 years. RESULTS: With a median follow-up of 15.5 months, abemaciclib+endocrine therapy demonstrated a statistically significant improvement in invasive disease-free survival versus endocrine therapy alone [HR = 0.747 (95% CI 0.598-0.932), P = 0.0096]; achieving an absolute improvement of 3.5% invasive disease-free survival rate at 2-years. These results were maintained, with a median follow-up of 27.7 months: absolute improvement of 2.7% and 5.4% in invasive disease-free survival rate at 2 and 3 years, respectively. All-causality grade 3 or 4 adverse events were 45.9% for abemaciclib and 12.9% for endocrine therapy, and included neutropenia (19.6% vs. 0.8%), leukopenia (11.4% vs. 0.4%), and diarrhea (7.8% vs. 0.2%). CONCLUSIONS: The results of the pivotal trial are sufficient to consider abemaciclib as adjuvant treatment for high-risk early breast cancer in highly selected patients. However, in order to the efficacy results present less uncertainty, we must wait for a evaluation later, in which we can have a mature determination at 3 years (with more patients at risk).

[Translated article] Adjusted indirect comparison of zanubrutinib and ibrutinib in first-line treatment of chronic lymphocytic leukemia.

OBJECTIVE: The aim of this study was to perform an adjusted indirect treatment comparison, according to the cytogenetic profile, in terms of efficacy between different Bruton tyrosine kinase inhibitors used as first-line monotherapy for chronic lymphocytic leukemia. Safety outcomes considered of interest were also evaluated to establish whether these options can be considered equivalent therapeutic alternatives. METHOD: A literature search was conducted in Pubmed and Embase on November 10, 2022 for phase III clinical trials studying Bruton tyrosine kinase inhibitors in monotherapy in the first-line setting for chronic lymphocytic leukemia. Results were filtered according to whether the combination of bendamustine and rituximab was used as comparator and whether they had similar populations and follow-up times. Subgroup results were meta-analyzed according to mutational characteristics by classifying patients into high and low cytogenetic risk. An adjusted indirect comparison was developed using Bucher's method. Possible therapeutic equivalence was determined by applying the guide to equivalent therapeutic alternatives. RESULT: Of the 39 studies obtained in the review, 2 clinical trials were selected: 1 for zanubrutinib and 1 for ibrutinib. The remaining studies were not included because they did not meet the inclusion criteria. The results obtained in the adjusted indirect treatment comparison for both cytogenetic risk subgroups showed no statistically significant differences. The most relevant safety differences were atrial fibrillation, hypertension, and cardiovascular events in patients treated with ibrutinib and higher incidence of secondary cancers in patients treated with zanubrutinib. Applying the equivalent therapeutic alternatives guideline criteria, both treatments cannot be considered equivalent therapeutic alternatives. CONCLUSIONS: Assuming the uncertainty associated with the adjusted indirect comparison, zanubrutinib could be considered equivalent in efficacy to ibrutinib, however, the presence of differentiating safety features precludes assigning the 2 alternatives as equivalent therapeutic alternatives.

Abemaciclib as adjuvant treatment for high-risk early breast cancer. / [Artículo traducido] Abemaciclib en adyuvancia para el tratamiento del cáncer de mama precoz de alto riesgo.

OBJECTIVE: To adapt the GHEMA report of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6. European Medicines Agency authorisation (April 2022) includes, in combination with endocrine therapy, the adjuvant treatment of adult patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive, early breast cancer at high risk of recurrence. METHOD: The efficacy and safety of abemaciclib were evaluated in a randomized, open-label and multicenter phase III study. A total of 5,637 patients diagnosed with early breast cancer with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive and high risk of recurrence were included. High risk was defined as patients with 4 or more positive axillary lymph nodes, or 1-3positive axillary lymph nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3 or Ki-67 ≥ 20%. Patients were randomized (1:1) to receive adjuvant abemaciclib + endocrine therapy (n = 2,808) or endocrine therapy alone (n = 2,829) for 2 years, with endocrine therapy prescribed for at least 5 years. RESULTS: With a median follow-up of 15.5 months, abemaciclib + endocrine therapy demonstrated a statistically significant improvement in invasive disease-free survival versus endocrine therapy alone (HR = 0.747 [95% CI 0.598-0.932], p = 0.0096); achieving an absolute improvement of 3.5% invasive disease-free survival rate at 2-years. These results were maintained, with a median follow-up of 27.7 months: absolute improvement of 2.7% and 5.4% in invasive disease-free survival rate at 2 and 3-years, respectively. All-causality grade 3 or 4 adverse events were 45.9% for abemaciclib and 12.9% for endocrine therapy, and included neutropenia (19.6% vs. 0.8%), leukopenia (11.4% vs. 0.4%) and diarrhea (7.8% vs. 0.2%). CONCLUSIONS: The results of the pivotal trial are sufficient to consider abemaciclib as adjuvant treatment for high-risk early breast cancer in highly selected patients. However, in order to the efficacy results present less uncertainty, we must wait for a evaluation later, in which we can have a mature determination at 3 years (with more patients at risk).

Economic evaluation of adjuvant therapy with osimertinib in patients with early-stage non-small cell lung cancer and mutated EGFR.

PURPOSE: The ADAURA trial demonstrated the superiority of osimertinib over a placebo with regard to disease-free survival, showing it to be indicated as an adjuvant therapy for treatment of non-small cell lung cancer with mutated epidermal growth factor receptor (EGFR). The aim of the present study was to conduct a cost-utility analysis and an analysis of the budgetary impact of adjuvant therapy with osimertinib in patients with non-small cell lung cancer with mutated EGFR who had undergone resection surgery with curative intent. METHODS: Analyses were based on the outcomes of the ADAURA clinical trial and were conducted through a Spanish National Health Service perspective. The outcome measures used were quality-adjusted life years (QALY). RESULTS: The average overall cost of adjuvant treatment with osimertinib over a period of 100 months in the overall sample of trial patients (stages IB-IIIA) was 220,961 €, compared with 197,849 € in the placebo group. Effectiveness, estimated according to QALY, was 6.26 years in the osimertinib group and 5.96 years in the placebo group, with the incremental cost-utility ratio being 77,040 €/QALY. With regard to the budgetary impact, it was estimated that, in 2021, approximately 1130 patients would be subsidiaries to receive osimertinib. This pertains to a difference of 17,375,330 € over 100 months to fund this treatment relative to no treatment. CONCLUSION: Taking into account a Spanish threshold of 24,000 €/QALY, the reduction in the acquisition cost of osimertinib will have to be greater than 10%, to obtain a cost-effective alternative.

Daratumumab-based therapies in transplant-ineligible patients with untreated multiple myeloma and hepatic dysfunction: A systematic review of subgroup analyses.

INTRODUCTION: There is subgroup analysis suggesting a lack of benefit of daratumumab use in multiple myeloma (MM) and hepatic disease (HD). The objectives of this study were to conduct a systematic review and interpretation of daratumumab-based regimen efficacy in transplant-ineligible patients with untreated MM and HD. METHODS: A systematic search in Pubmed® database about randomized clinical trials (RCTs) with subgroup analysis regarding hepatic function for overall survival (OS) or progression-free survival (PFS) were developed. Two methodologies were applied. One of them considered statistical interaction, prespecification, biological support and consistency of subgroup results. Second methodology was two-part validated tool: preliminary questions to reject subset analysis without minimal relevance, and a checklist relating a recommendation for applicability in clinical practice. RESULTS: It was included three records. About first methodology, statistical interaction among subgroups was found for PFS in one RCT. Subsets were prespecified in all RCTs. Biological support of efficacy differences could be reasonable. Inconsistent results were found. Second methology directly rejected applicability of subset analysis in two records. Checklist recommended "null" application of results in the remaining RCT. CONCLUSIONS: No consistent heterogeneity for daratumumab-based regimen efficacy was observed among subgroups regarding hepatic function in transplant-ineligible patients with untreated MM. Patients with normal hepatic function and HD could benefit from these treatments.

Systematic review and meta-analysis of interleulin-6 inhibitors in reducing mortality for hospitalized patients with COVID-19.

OBJECTIVE: One year after the declaration of the SARS-CoV-2 pandemic, only  dexamethasone has clearly shown a reduction in mortality for COVID-19  hospitalized patients. For interleukin-6 inhibitors, results are variable and  nclear. The objective was to review and analyze the effect of tocilizumab and  sarilumab on survival in this setting. METHOD: The PRISMA statements were fulfilled for the systematic review. A  systematic search in Medline, Embase and medRxiv was conducted to identify  randomized controlled trials with tocilizumab or sarilumab in hospitalized  patients with COVID-19. Mortality data from non-critical and critical patients  were extracted. A random-effects (DerSimonian-Laird) meta-analysis was  performed for both subgroups and the whole population using MAVIS software  v. 1.1.3. Similarity and homogeneity among trials were assessed. RESULTS: Twenty-five and 23 articles were identified in Medline and Embase,  respectively, five were trials with tocilizumab and/or sarilumab; two more were  identified at medRxiv. Seven randomized clinical trials fulfilled the  inclusion criteria. Another trial was pre-published and included post-hoc. The  meta-analysis, with eight randomized clinical trials and 6,340 patients, showed  a benefit on mortality for interleukin-6  heterogeneity (I2 = 7%), but  a low similarity among studies. The results showed no differences among  critical and non-critical patients. A sensitivity analysis excluding non-similar or  heterogeneous studies showed different results, without benefit and with low  precision of the result in non-critical patients. CONCLUSIONS: A benefit in mortality for interleukine-6 inhibitors was found, but  with important differences among the scenarios analyzed in the clinical  trials. Positive results are mainly caused by two randomized clinical trials which  are similar in concomitant use of steroids and veryhigh mortality in  critical patents. Sarilumab was poorly represented in the meta-analysis.  Nevertheless, an association between the benefit and the critical/non-critical  condition was not found. More randomized clinical trials, mainly focused in  atients at high mortality risk, are needed to confirm the benefit of interleukine- 6 inhibitors for COVID-19. Sarilumab was underrepresented in the meta- analysis.

OBJETIVO: Un año después de la declaración de la pandemia por SARS­CoV-2,  solo dexametasona había mostrado claramente una reducción de la mortalidad  en pacientes hospitalizados por COVID-19. Los resultados de los inhibidores de  interleucina 6 son diversos y poco claros. El objetivo de este trabajo es  revisar y analizar el efecto de tocilizumab y sarilumab sobre la supervivencia  de los pacientes en este escenario.Método: La revisión sistemática siguió las recomendaciones de PRISMA. Se  realizó una búsqueda sistemática en Medline, Embase y medRxiv para identificar ensayos controlados aleatorizados con tocilizumab o sarilumab  en pacientes hospitalizados con COVID-19. Se recopilaron los datos de mortalidad de pacientes críticos y no críticos y se llevó a cabo un metaanálisis de efectos aleatorios (Der Simonian-Laird) para ambos  subgrupos y para toda la población, usando el software MAVIS v. 1.1.3. La similitud y homogeneidad entre los ensayos fue evaluada. RESULTADOS: Se identificaron 25 y 23 artículos en Medline y Embase, respectivamente; cinco eran ensayos con tocilizumab y/o sarilumab;  se identificaron dos más en medRxiv. En total, siete ensayos clínicos  aleatorizados cumplieron los criterios de inclusión. Posteriormente, se  prepublicó otro ensayo que cumplía los criterios de inclusión y se incorporó al  análisis. El metaanálisis, con ocho ensayos clínicos aleatorizados y 6.340  pacientes, mostró un beneficio sobre la mortalidad para los inhibidores de  interleucina-6 (hazard ratio 0,85; intervalo de confianza al 95% 0,74-0,99),  con baja heterogeneidad (I2 = 7%), pero reducida similitud entre los estudios.  Los resultados no mostraron diferencias entre pacientes críticos y no  críticos. Un análisis de sensibilidad excluyendo estudios heterogéneos o no  similares mostró resultados diferentes, sin beneficio y con baja precisión del  resultado en pacientes no críticos. CONCLUSIONES: Se encontró un beneficio en la mortalidad de los inhibidores de  la interleucina 6, pero con importantes diferencias entre los escenarios analizados en los ensayos clínicos. Los resultados positivos se  eben principalmente a dos ensayos que son similares en el uso concomitante  de esteroides y una mortalidad muy alta en pacientes críticos. Sarilumab estuvo escasamente representado en el metaanálisis. Sin embargo, el metaanálisis por subescenarios no encontró una relación entre  el beneficio y la condición de pacientes críticos/no críticos. Se necesitan más ensayos clínicos aleatorizados, principalmente enfocados en  pacientes con alto riesgo de mortalidad, para confirmar el beneficio de los  inhibidores de interleucina-6 en COVID-19.

Revisión sistemática y metaanálisis de inhibidores de interleucina-6 para reducir la mortalidad en pacientes hospitalizados con COVID-19 / Systematic review and meta-analysis of interleulin-6 inhibitors in reducing mortality for hospitalized patients with COVID-19

Objetivo: Un año después de la declaración de la pandemia porSARS‑CoV-2, solo dexametasona había mostrado claramente una reducciónde la mortalidad en pacientes hospitalizados por COVID-19. Losresultados de los inhibidores de interleucina 6 son diversos y poco claros.El objetivo de este trabajo es revisar y analizar el efecto de tocilizumaby sarilumab sobre la supervivencia de los pacientes en este escenario.Método: La revisión sistemática siguió las recomendaciones de PRISMA.Se realizó una búsqueda sistemática en Medline, Embase y medRxiv paraidentificar ensayos controlados aleatorizados con tocilizumab o sarilumaben pacientes hospitalizados con COVID-19. Se recopilaron los datosde mortalidad de pacientes críticos y no críticos y se llevó a cabo unmetaanálisis de efectos aleatorios (Der Simonian-Laird) para ambos subgruposy para toda la población, usando el software MAVIS v. 1.1.3. Lasimilitud y homogeneidad entre los ensayos fue evaluada.Resultados: Se identificaron 25 y 23 artículos en Medline y Embase,respectivamente; cinco eran ensayos con tocilizumab y/o sarilumab; seidentificaron dos más en medRxiv. En total, siete ensayos clínicos aleatorizadoscumplieron los criterios de inclusión. Posteriormente, se prepublicóotro ensayo que cumplía los criterios de inclusión y se incorporó absoalanálisis. El metaanálisis, con ocho ensayos clínicos aleatorizados y6.340 pacientes, mostró un beneficio sobre la mortalidad para los inhibidoresde interleucina-6 (hazard ratio 0,85; intervalo de confianza al 95%0,74-0,99), con baja heterogeneidad (I2 = 7%), pero reducida similitudentre los estudios. Los resultados no mostraron diferencias entre pacientescríticos y no críticos. Un análisis de sensibilidad excluyendo estudios heterogéneoso no similares mostró resultados diferentes, sin beneficio y conbaja precisión del resultado en pacientes no críticos.

Objective: One year after the declaration of the SARS-CoV-2 pandemic,only dexamethasone has clearly shown a reduction in mortality forCOVID-19 hospitalized patients. For interleukin-6 inhibitors, results arevariable and unclear. The objective was to review and analyze the effectof tocilizumab and sarilumab on survival in this setting.Method: The PRISMA statements were fulfilled for the systematic review.A systematic search in Medline, Embase and medRxiv was conductedto identify randomized controlled trials with tocilizumab or sarilumab inhospitalized patients with COVID-19. Mortality data from non-critical andcritical patients were extracted. A random-effects (DerSimonian-Laird)meta-analysis was performed for both subgroups and the whole populationusing MAVIS software v. 1.1.3. Similarity and homogeneity amongtrials were assessed.Results: Twenty-five and 23 articles were identified in Medline andEmbase, respectively, five were trials with tocilizumab and/or sarilumab;two more were identified at medRxiv. Seven randomized clinical trialsfulfilled the inclusion criteria. Another trial was pre-published and includedpost-hoc. The meta-analysis, with eight randomized clinical trialsand 6,340 patients, showed a benefit on mortality for interleukin-6 inhibitor (hazard ratio 0.85; confidence interval 95% 0.74-0.99), lowheterogeneity (I2 = 7%), but a low similarity among studies. The resultsshowed no differences among critical and non-critical patients. A sensitivityanalysis excluding non-similar or heterogeneous studies showeddifferent results, without benefit and with low precision of the result innon-critical patients.

Cost-utility of talazoparib monotherapy treatment for locally advanced or metastatic breast cancer in Spain.

Breast cancer is one of the most frequent malignancies. The aim of the article is to analyse the cost-utility ratio and budgetary impact of talazoparib treatment for patients with locally advanced or metastatic gBRCA + breast cancer from the perspective of the Spanish National Health System. Analyses were based on the EMBRACA clinical trial and the model was constructed according to "partitioned survival analysis". Two scenarios were considered in order to compare talazoparib with the alternatives of capecitabine, vinorelbine and eribulin: 1. Chemotherapy in patients pre-treated with anthracyclines/taxanes and, 2. A second- and subsequent-line treatment option. Treatment types following relapse were recorded in the mentioned clinical trial. The effectiveness measure used was quality-adjusted life years (QALY). The average health cost of patients treated at 43 months with talazoparib was 84,360.86€, whilst current treatment costs were 26,683.90€. The effectiveness of talazoparib was 1.93 years of survival (1.09 QALY) relative to 1.58 years (0.83 QALY) in the treatment group. The incremental cost-utility ratio was 252,420.04€/QALY. This represents the additional cost required to earn an additional QALY when changing from regular treatment to talazoparib. Regarding budgetary impact, the number of patients susceptible to receiving treatment with between 94 and 202 talazoparib was estimated, according to scenario and likelihood. The 3-year cost difference was between 6.9 and 9 million euros. The economic evaluation conducted shows an elevated incremental cost-utility ratio and budgetary impact. Taking these results into account, the price of talazoparib would have to be lower than that taken as a reference to reach the cost-utility thresholds.

Comparación indirecta ajustada de anticuerpos monoclonales contra el péptido relacionado con el gen de la calcitonina en migraña crónica / Monoclonal antibodies against calcitonin gene-related peptide in chronic migraine: an adjusted indirect treatment comparison

OBJETIVO: Recientemente se han desarrollado anticuerpos monoclonales contra la vía del péptido relacionado con el gen de la calcitonina para la prevención de la migraña. El objetivo de este estudio es comparar la eficacia de los fármacos anticuerpos monoclonales contra la vía del péptido relacionado con el gen de la calcitonina en migraña crónica a través de una comparación indirecta ajustada, y establecer si pueden considerarse alternativas terapéuticas equivalentes en esta patología. MÉTODO: Se realizó una búsqueda bibliográfica de ensayos clínicos aleatorizados en la base de datos PubMed el 26 de diciembre de 2019. Los criterios de inclusión fueron: ensayos clínicos aleatorizados fase II/III de anticuerpos monoclonales contra la vía del péptido relacionado con el gen de la calcitonina con similar población, duración de seguimiento y comparador. Se seleccionó la reducción de al menos un 50% de días de migraña/mes como variable de eficacia. Se definió migraña crónica como ≥ 15 días de dolor de cabeza/mes, de los cuales ≥ 8 fueron días de migraña (duración del evento ≥ 4 horas). Se excluyeron los ensayos clínicos aleatorizados con diferentes contextos clínicos de migraña crónica y definición de enfermedad. Se desarrolló una compa-ración indirecta ajustada utilizando el método de Bucher. Para la evaluación de la posible equivalencia terapéutica se siguieron las directrices de la guía de alternativas terapéuticas equivalentes de posicionamiento. El valor delta (Δ, máxima diferencia como criterio clínico de equivalencia) se calculó como la mitad de la reducción absoluta del riesgo obtenida en un metaanálisis de los ensayos clínicos aleatorizados incluidos en la comparación indirecta ajustada. RESULTADOS: Se encontraron 30 ensayos clínicos aleatorizados: erenumab (n = 12), fremanezumab (n = 7), galcanezumab (n = 10) y eptinezumab (n = 1). Se seleccionaron tres estudios: uno de erenumab, uno de fremanezumab y otro de eptinezumab. El resto no se incluyó en la comparación indi-recta ajustada por incumplimiento de los criterios de inclusión. Los resultados de la comparación indirecta ajustada entre las diferentes posologías de los fármacos estudiados no mostraron diferencias estadísticamente signifi-cativas, y la mayor parte del intervalo de confianza del 95% se encontró dentro de los márgenes delta calculados (Δ = 9,5%). No se encontraron diferencias de seguridad relevantes entre los tres medicamentos. CONCLUSIONES: La comparación indirecta ajustada no mostró diferencias estadísticamente significativas en la reducción de ≥ 50% de días de migraña/mes entre erenumab, fremanezumab y eptinezumab. Se encontró una probable equivalencia clínica entre estos fármacos en términos de eficacia y seguridad, por lo que podrían considerarse alternativas terapéuticas equivalentes en migraña crónica

OBJECTIVE: New monoclonal antibodies against the calcitonin gene-related peptide pathway have recently been developed for the prevention of migraine. The aim of this study is to compare the efficacy of monoclonal antibodies against the calcitonin generelated peptide pathway drugs in chronic migraine through an adjusted indirect treatment comparison, and to establish whether they can be considered equivalent therapeutic alter-natives in this pathology. METHOD: A bibliographic search of randomized clinical trials was performed in PubMed database on December 26, 2019. The inclusion criteria were phase II/III randomized clinical trials of monoclonal anti-bodies against the calcitonin generelated peptide pathway with similar population, length of follow-up and treatment comparator. The reduction of at least 50% migraine-days/month was selected as efficacy endpoint. Chronic migraine was defined as ≥ 15 headache days/month, of which ≥ 8 were migraine-days (event duration ≥ 4 hours). Randomized clinical trials with different clinical chronic migraine context and definition of disease were excluded. An indirect treatment comparison was developed using Bucher's method. The equivalent therapeutic alternatives positioning guide was used for the evaluation of potentially equivalent alternatives. Delta value (Δ, maximum difference as clinical criterion of equivalence) was calculated as half of absolute risk reduction obtained in a meta-analysis of randomized clinical trials included in indirect treatment comparison. RESULTS: Thirty randomized clinical trials were found: erenumab (n = 12), fremanezumab (n = 7), galcanezumab (n = 10) and eptinezumab (n = 1). Three studies were selected: one of erenumab, one of fremanezumab and another of eptinezumab. The rest were not included in indirect treatment comparison for non-compliance of inclusion criteria. Results of indirect treatment comparison among different regimens of studied drugs showed no statistically significant differences, and the most part of 95% confidence interval was within calculated delta margins (Δ = 9.5%). No relevant safety differences among the three drugs were found. CONCLUSIONS: Indirect treatment comparison showed no statistically sig-nificant differences in reduction of ≥ 50% migraine days/month between erenumab, fremanezumab and eptinezumab. Probable clinical equiva-lence was found between these drugs in terms of efficacy and safety, therefore they could be considered equivalent therapeutic alternatives in chronic migraine

Monoclonal antibodies against calcitonin gene-related peptide in chronic migraine: an adjusted indirect treatment comparison.

OBJECTIVE: New monoclonal antibodies against the calcitonin generelated peptide pathway have recently been developed for the  prevention of migraine. The aim of this study is to compare the efficacy  of monoclonal antibodies against the calcitonin generelated peptide  pathway drugs in chronic migraine through an adjusted indirect  treatment comparison, and to establish whether they can be considered  equivalent therapeutic alternatives in this pathology. METHOD: A bibliographic search of randomized clinical trials was performed in PubMed database on December 26, 2019. The inclusion criteria were phase II/III randomized clinical trials of  monoclonal antibodies against the calcitonin generelated peptide  pathway with similar population, length of follow-up and treatment  comparator. The reduction of at least 50% migraine-days/month was  selected as efficacy endpoint. Chronic migraine was defined as ≥ 15  headache days/month, of which ≥ 8 were migraine-days (event duration  ≥ 4 hours). Randomized clinical trials with different clinical chronic  migraine context and definition of disease were excluded. An indirect  treatment comparison was developed using Bucher's method. The  equivalent therapeutic alternatives positioning guide was used for the  evaluation of potentially equivalent alternatives. Delta value (Δ,  maximum difference as clinical criterion of equivalence) was calculated  as half of absolute risk reduction obtained in a meta-analysis of  randomized clinical trials included in indirect treatment comparison. RESULTS: Thirty randomized clinical trials were found: erenumab (n =  12), fremanezumab (n = 7), galcanezumab (n = 10) and eptinezumab (n = 1). Three studies were selected: one of erenumab, one of  fremanezumab and another of eptinezumab. The rest were not included  in indirect treatment comparison for non-compliance of inclusion criteria.  Results of indirect treatment comparison among different regimens of  studied drugs showed no statistically significant differences, and the  most part of 95% confidence interval was within calculated delta margins (Δ = 9.5%). No relevant safety differences among the three drugs were  found. CONCLUSIONS: Indirect treatment comparison showed no statistically  significant differences in reduction of ≥ 50% migraine days/month  between erenumab, fremanezumab and eptinezumab. Probable clinical  equivalence was found between these drugs in terms of efficacy and  safety, therefore they could be considered equivalent therapeutic  alternatives in chronic migraine.

Objetivo: Recientemente se han desarrollado anticuerpos monoclonales contra la vía del péptido relacionado con el gen de la  calcitonina para la prevención de la migraña. El objetivo de este estudio  es comparar la eficacia de los fármacos anticuerpos monoclonales contra  la vía del péptido relacionado con el gen de la calcitonina en migraña  crónica a través de una comparación indirecta ajustada, y establecer si  pueden considerarse alternativas terapéuticas equivalentes en esta  patología.Método: Se realizó una búsqueda bibliográfica de ensayos clínicos  aleatorizados en la base de datos PubMed el 26 de diciembre de 2019.  Los criterios de inclusión fueron: ensayos clínicos aleatorizados fase II/III de anticuerpos monoclonales contra la vía del péptido relacionado con el  gen de la calcitonina con similar población, duración de seguimiento y  comparador. Se seleccionó la reducción de al menos un 50% de días de  migraña/mes como variable de eficacia. Se definió migraña crónica como ≥ 15 días de dolor de cabeza/mes, de los cuales ≥ 8 fueron días de  migraña (duración del evento ≥ 4 horas). Se excluyeron los ensayos  clínicos aleatorizados con diferentes contextos clínicos de migraña  crónica y definición de enfermedad. Se desarrolló una comparación indirecta ajustada utilizando el método de Bucher. Para la  evaluación de la posible equivalencia terapéutica se siguieron las  directrices de la guía de alternativas terapéuticas equivalentes de  posicionamiento. El valor delta (Δ, máxima diferencia como criterio  clínico de equivalencia) se calculó como la mitad de la reducción absoluta del riesgo obtenida en un metaanálisis de los ensayos clínicos  aleatorizados incluidos en la comparación indirecta ajustada.Resultados: Se encontraron 30 ensayos clínicos aleatorizados:  erenumab (n = 12), fremanezumab (n = 7), galcanezumab (n = 10) y  eptinezumab (n = 1). Se seleccionaron tres estudios: uno de erenumab,  uno de fremanezumab y otro de eptinezumab. El resto no se incluyó en  la comparación indirecta ajustada por incumplimiento de los criterios de  inclusión. Los resultados de la comparación indirecta ajustada entre las  diferentes posologías de los fármacos estudiados no mostraron  diferencias estadísticamente significativas, y la mayor parte del intervalo  de confianza del 95% se encontró dentro de los márgenes delta  calculados (Δ = 9,5%). No se encontraron diferencias de seguridad  relevantes entre los tres medicamentos.Conclusiones: La comparación indirecta ajustada no mostró diferencias estadísticamente significativas en la reducción de ≥ 50% de  días de migraña/mes entre erenumab, fremanezumab y eptinezumab. Se encontró una probable equivalencia clínica entre estos fármacos en  términos de eficacia y seguridad, por lo que podrían considerarse  alternativas terapéuticas equivalentes en migraña crónica.

Network meta-analysis of first-line treatments in transplant-ineligible multiple myeloma patients.

OBJECTIVES: Multiple myeloma (MM) is a complex disease. Lack of direct comparisons among treatments and incorporation of new alternatives make it necessary to perform studies that allow for clinical decision-making. A network meta-analysis (NMA) was developed to evaluate the comparative efficacy among different therapeutic alternatives in newly diagnosed transplant-ineligible MM patients. METHODS: MEDLINE® and EMBASE® were systematically searched up for these drugs: lenalidomide, thalidomide, bortezomib, and daratumumab. Comparative phase II-III randomized clinical trials (RCTs) were included. Progression-free survival (PFS) was selected as efficacy outcome. The NMA was developed using Bayesian methods. Fixed- and random-effects models were assessed using deviance information criteria. RESULTS: The systematic search yielded 593 results. Ten RCTs were included. No differences were observed between fixed- and random-effects models. The combination of daratumumab, bortezomib, melphalan, and prednisone showed the best HR in PFS (reference treatment). Along with this scheme, the best PFS results were obtained by combination of daratumumab, lenalidomide, and dexamethasone (HR 1.2, 95% CrI 0.64-2.4) and bortezomib with lenalidomide and dexamethasone (HR 1.6, 95% CrI 0.81-3.0). CONCLUSIONS: Schemes with the best PFS results were daratumumab treatments and combination of bortezomib, lenalidomide, and dexamethasone, although the latter scheme has been analyzed in heterogeneous populations.