Expert consensus to optimize the management of older adult patients with advanced EGFR-mutated non-small cell lung cancer

Lung cancer (LC) is associated with ageing, with the average age of affected individuals being approximately 70 years. However, despite a higher incidence and prevalence among older people, the older adult population is underrepresented in clinical trials. For LC with Epidermal Growth Factor Receptor (EGFR) mutations, there is no clear association of this mutation with age. Geriatric assessments (GAs) and a multidisciplinary approach are essential for defining the optimal treatment. In this consensus, a group of experts selected from the Oncogeriatrics Section of the Spanish Society of Medical Oncology (Sección de Oncogeriatría de la Sociedad Española de Oncología Médica—SEOM), the Spanish Lung Cancer Group (Grupo Español de Cáncer de Pulmón—GECP) and the Association for Research on Lung Cancer in Women (Asociación para la Investigación del Cáncer de Pulmón en Mujeres—ICAPEM) evaluate the scientific evidence currently available and propose a series of recommendations to optimize the management of older adult patients with advanced LC with EGFR mutations (AU)

Expert consensus to optimize the management of older adult patients with advanced EGFR-mutated non-small cell lung cancer.

Lung cancer (LC) is associated with ageing, with the average age of affected individuals being approximately 70 years. However, despite a higher incidence and prevalence among older people, the older adult population is underrepresented in clinical trials. For LC with Epidermal Growth Factor Receptor (EGFR) mutations, there is no clear association of this mutation with age. Geriatric assessments (GAs) and a multidisciplinary approach are essential for defining the optimal treatment. In this consensus, a group of experts selected from the Oncogeriatrics Section of the Spanish Society of Medical Oncology (Sección de Oncogeriatría de la Sociedad Española de Oncología Médica-SEOM), the Spanish Lung Cancer Group (Grupo Español de Cáncer de Pulmón-GECP) and the Association for Research on Lung Cancer in Women (Asociación para la Investigación del Cáncer de Pulmón en Mujeres-ICAPEM) evaluate the scientific evidence currently available and propose a series of recommendations to optimize the management of older adult patients with advanced LC with EGFR mutations.

miR-124 as a Liquid Biopsy Prognostic Biomarker in Small Extracellular Vesicles from NSCLC Patients.

Despite advances in non-small cell lung cancer (NSCLC) research, this is still the most common cancer type that has been diagnosed up to date. microRNAs have emerged as useful clinical biomarkers in both tissue and liquid biopsy. However, there are no reliable predictive biomarkers for clinical use. We evaluated the preclinical use of seven candidate miRNAs previously identified by our group. We collected a total of 120 prospective samples from 88 NSCLC patients. miRNA levels were analyzed via qRT-PCR from tissue and blood samples. miR-124 gene target prediction was performed using RNA sequencing data from our group and interrogating data from 2952 NSCLC patients from two public databases. We found higher levels of all seven miRNAs in tissue compared to plasma samples, except for miR-124. Our findings indicate that levels of miR-124, both free-circulating and within exosomes, are increased throughout the progression of the disease, suggesting its potential as a marker of disease progression in both advanced and early stages. Our bioinformatics approach identified KPNA4 and SPOCK1 as potential miR-124 targets in NSCLC. miR-124 levels can be used to identify early-stage NSCLC patients at higher risk of relapse.

Prognostic Impact of Dihydropyrimidine Dehydrogenase Germline Variants in Unresectable Non-Small Cell Lung Cancer Patients Treated with Platin-Based Chemotherapy.

Platin-based chemotherapy is the standard treatment for patients with non-small cell lung cancer (NSCLC). However, resistance to this therapy is a major obstacle in successful treatment. In this study, we aimed to investigate the impact of several pharmacogenetic variants in patients with unresectable NSCLC treated with platin-based chemotherapy. Our results showed that DPYD variant carriers had significantly shorter progression-free survival and overall survival compared to DPYD wild-type patients, whereas DPD deficiency was not associated with a higher incidence of high-grade toxicity. For the first time, our study provides evidence that DPYD gene variants are associated with resistance to platin-based chemotherapy in NSCLC patients. Although further studies are needed to confirm these findings and explore the underlying mechanisms of this association, our results suggest that genetic testing of DPYD variants may be useful for identifying patients at a higher risk of platin-based chemotherapy resistance and might be helpful in guiding future personalized treatment strategies in NSCLC patients.

Cardiovascular toxicity of checkpoint inhibitors: review of associated toxicity and design of the Spanish Immunotherapy Registry of Cardiovascular Toxicity.

Immune checkpoint inhibitors (ICI) have changed the prognosis of many tumors. However, concerning associated cardiotoxicity has been reported. Little is known about the real-life incidence-specific surveillance protocols or the translational correlation between the underlying mechanisms and the clinical presentation of ICI-induced cardiotoxicity. The lack of data from prospective studies led us to review the current knowledge and to present the creation of the Spanish Immunotherapy Registry of Cardiovascular Toxicity (SIR-CVT), a prospective registry of patients receiving ICI that aims to examine the role of hsa-miR-Chr8:96, (a specific serum biomarker of myocarditis) in the early diagnosis of ICI-induced myocarditis. An exhaustive prospective cardiac imaging study will be performed before and during the first 12 months of treatment. The correlation between clinical, imaging, and immunologic parameters may improve our understanding of ICI-induced cardiotoxicity and enable simpler surveillance protocols. We assess ICI-induced cardiovascular toxicity and describe the rationale of the SIR-CVT.

Unravelling oligometastatic disease from the perspective of radiation and medical oncology. Part II: prostate cancer and colorectal cancer

Oligometastatic disease (OMD) defines a status of cancer that is intermediate between localized and widely spread metastatic disease, and can be treated with curative intent. While imaging diagnostic tools have considerably improved in recent years, unidentified micrometastases can still escape from current detection techniques allowing disease to progress. The variety of OMD scenarios are mainly defined by the number of metastases, the biological and molecular tumour profiles, and the timing of the development of metastases. Increasing knowledge has contributed to the earlier and improved detection of OMD, underlining the importance of an early disease control. Based on increasing detection rates of OMD in the current real clinical practice and the lack of standardized evidence-based guidelines to treat this cancer status, a board of experts from the Spanish Societies of Radiation Oncology (SEOR) and Medical Oncology (SEOM) organized a series of sessions to update the current state-of-the-art on OMD from a multidisciplinary perspective, and to discuss how results from clinical studies may translate into promising treatment options. This experts’ review series summarizes what is known and what it is pending clarification in the context of OMD in the scenarios of Non-Small Cell Lung Cancer and Breast Cancer (Part I), and Prostate Cancer and Colorectal Cancer (Part II), aiming to offer specialists a pragmatic framework that might contribute to the improved management of patients (AU)

Unravelling oligometastatic disease from the perspective of radiation and medical oncology. Part II: prostate cancer and colorectal cancer.

Oligometastatic disease (OMD) defines a status of cancer that is intermediate between localized and widely spread metastatic disease, and can be treated with curative intent. While imaging diagnostic tools have considerably improved in recent years, unidentified micrometastases can still escape from current detection techniques allowing disease to progress. The variety of OMD scenarios are mainly defined by the number of metastases, the biological and molecular tumour profiles, and the timing of the development of metastases. Increasing knowledge has contributed to the earlier and improved detection of OMD, underlining the importance of an early disease control. Based on increasing detection rates of OMD in the current real clinical practice and the lack of standardized evidence-based guidelines to treat this cancer status, a board of experts from the Spanish Societies of Radiation Oncology (SEOR) and Medical Oncology (SEOM) organized a series of sessions to update the current state-of-the-art on OMD from a multidisciplinary perspective, and to discuss how results from clinical studies may translate into promising treatment options. This experts' review series summarizes what is known and what it is pending clarification in the context of OMD in the scenarios of Non-Small Cell Lung Cancer and Breast Cancer (Part I), and Prostate Cancer and Colorectal Cancer (Part II), aiming to offer specialists a pragmatic framework that might contribute to the improved management of patients.

Unravelling oligometastatic disease from the perspective of radiation and medical oncology. Part I: non-small cell lung cancer and breast cancer.

Oligometastatic disease (OMD) defines a cancer status that is intermediate between localized and widely spread metastatic disease, and can be treated with curative intent. While diagnostic imaging tools have considerably improved in recent years, unidentified micrometastases can still evade current detection techniques, allowing the disease to progress. The various OMD scenarios are mainly defined by the number of metastases, the biological and molecular tumour profiles, and the timing of the development of metastases. Increasing knowledge has contributed to the earlier and improved detection of OMD, underlining the importance of early disease control. In view of increasing OMD detection rates in current real-world clinical practice and the lack of standardized evidence-based guidelines to treat this cancer status, a board of experts from the Spanish Societies of Radiation Oncology (SEOR) and Medical Oncology (SEOM) organized a series of sessions to update the current state-of-the-art on OMD from a multidisciplinary perspective, and to discuss how results from clinical studies might translate into promising treatment options. This expert review series summarizes what is known and what it is pending clarification in the context of OMD in the scenarios of non-small cell lung cancer and breast cancer (Part I), and prostate cancer and colorectal cancer (Part II), aiming to offer specialists a pragmatic framework to help improve patient management.

Tumor microenvironment gene expression profiles associated to complete pathological response and disease progression in resectable NSCLC patients treated with neoadjuvant chemoimmunotherapy.

BACKGROUND: Neoadjuvant chemoimmunotherapy for non-small cell lung cancer (NSCLC) has improved pathological responses and survival rates compared with chemotherapy alone, leading to Food and Drug Administration (FDA) approval of nivolumab plus chemotherapy for resectable stage IB-IIIA NSCLC (AJCC 7th edition) without ALK or EGFR alterations. Unfortunately, a considerable percentage of tumors do not completely respond to therapy, which has been associated with early disease progression. So far, it is impossible to predict these events due to lack of knowledge. In this study, we characterized the gene expression profile of tumor samples to identify new biomarkers and mechanisms behind tumor responses to neoadjuvant chemoimmunotherapy and disease recurrence after surgery. METHODS: Tumor bulk RNA sequencing was performed in 16 pretreatment and 36 post-treatment tissue samples from 41 patients with resectable stage IIIA NSCLC treated with neoadjuvant chemoimmunotherapy from NADIM trial. A panel targeting 395 genes related to immunological processes was used. Tumors were classified as complete pathological response (CPR) and non-CPR, based on the total absence of viable tumor cells in tumor bed and lymph nodes tested at surgery. Differential-expressed genes between groups and pathway enrichment analysis were assessed using DESeq2 and gene set enrichment analysis. CIBERSORTx was used to estimate the proportions of immune cell subtypes. RESULTS: CPR tumors had a stronger pre-established immune infiltrate at baseline than non-CPR, characterized by higher levels of IFNG, GZMB, NKG7, and M1 macrophages, all with a significant area under the receiver operating characteristic curve (ROC) >0.9 for CPR prediction. A greater effect of neoadjuvant therapy was also seen in CPR tumors with a reduction of tumor markers and IFNγ signaling after treatment. Additionally, the higher expression of several genes, including AKT1, BST2, OAS3, or CD8B; or higher dendritic cells and neutrophils proportions in post-treatment non-CPR samples, were associated with relapse after surgery. Also, high pretreatment PD-L1 and tumor mutational burden levels influenced the post-treatment immune landscape with the downregulation of proliferation markers and type I interferon signaling molecules in surgery samples. CONCLUSIONS: Our results reinforce the differences between CPR and non-CPR responses, describing possible response and relapse immune mechanisms, opening the possibility of therapy personalization of immunotherapy-based regimens in the neoadjuvant setting of NSCLC.

Identification of sSIGLEC5 and sLAG3 as New Relapse Predictors in Lung Cancer.

Lung cancer (LC) continues to be the leading cause of cancer-related deaths in both men and women worldwide. After complete tumour resection, around half of the patients suffer from disease relapse, emphasising the critical need for robust relapse predictors in this disease. In search of such biomarkers, 83 patients with non-microcytic lung cancer and 67 healthy volunteers were studied. Pre-operative levels of sSIGLEC5 along with other soluble immune-checkpoints were measured and correlated with their clinical outcome. Soluble SIGLEC5 (sSIGLEC5) levels were higher in plasma from patients with LC compared with healthy volunteers. Looking into those patients who suffered relapse, sSIGLEC5 and sLAG3 were found to be strong relapse predictors. Following a binary logistic regression model, a sSIGLEC5 + sLAG3 score was established for disease relapse prediction (area under the curve 0.8803, 95% confidence intervals 0.7955−0.9652, cut-off > 2.782) in these patients. Based on score cut-off, a Kaplan−Meier analysis showed that patients with high sSIGLEC5 + sLAG3 score had significantly shorter relapse-free survival (p ≤ 0.0001) than those with low sSIGLEC5 + sLAG3 score.Our study suggests that pre-operative sSIGLEC5 + sLAG3 score is a robust relapse predictor in LC patients.

Overall Survival and Biomarker Analysis of Neoadjuvant Nivolumab Plus Chemotherapy in Operable Stage IIIA Non-Small-Cell Lung Cancer (NADIM phase II trial).

PURPOSE: Neoadjuvant chemotherapy plus nivolumab has been shown to be effective in resectable non-small-cell lung cancer (NSCLC) in the NADIM trial (ClinicalTrials.gov identifier: NCT03081689). The 3-year overall survival (OS) and circulating tumor DNA (ctDNA) analysis have not been reported. METHODS: This was an open-label, multicenter, single-arm, phase II trial in which patients with stage IIIA NSCLC, who were deemed to be surgically resectable, were treated with neoadjuvant paclitaxel (200 mg/m2 once a day) and carboplatin (area under curve 6) plus nivolumab (360 mg) once on day 1 of each 21-day cycle, for three cycles, followed by adjuvant nivolumab monotherapy for 1 year (240 mg once every 2 weeks for 4 months, followed by 480 mg once every 4 weeks for 8 months). The 3-year OS and ctDNA analysis were secondary objectives of the trial. RESULTS: OS at 36 months was 81.9% (95% CI, 66.8 to 90.6) in the intention-to-treat population, rising to 91.0% (95% CI, 74.2 to 97.0) in the per-protocol population. Neither tumor mutation burden nor programmed cell death ligand-1 staining was predictive of survival. Conversely, low pretreatment levels of ctDNA were significantly associated with improved progression-free survival and OS (hazard ratio [HR], 0.20; 95% CI, 0.06 to 0.63, and HR, 0.07; 95% CI, 0.01 to 0.39, respectively). Clinical responses according to RECIST v1.1 criteria did not predict survival outcomes. However, undetectable ctDNA levels after neoadjuvant treatment were significantly associated with progression-free survival and OS (HR, 0.26; 95% CI, 0.07 to 0.93, and HR, 0.04; 95% CI, 0.00 to 0.55, respectively). The C-index to predict OS for ctDNA levels after neoadjuvant treatment (0.82) was superior to that of RECIST criteria (0.72). CONCLUSION: The efficacy of neoadjuvant chemotherapy plus nivolumab in resectable NSCLC is supported by 3-year OS. ctDNA levels were significantly associated with OS and outperformed radiologic assessments in the prediction of survival.

PD-L1 Inhibitors as Monotherapy for the First-Line Treatment of Non-Small-Cell Lung Cancer in PD-L1 Positive Patients: A Safety Data Network Meta-Analysis.

This network meta-analysis (NMA) evaluates the safety of first-line programmed death-ligand 1 (PD-L1) inhibitor monotherapy in advanced NSCLC patients compared to platinum-based chemotherapy. We also compared the risk of adverse events (AEs) according to programmed cell death-1 receptor (PD-1) or PD-L1 inhibitors therapy. To that end, we conducted a series of metanalyses (MAs) using data from six phase III clinical trials, including 4053 patients. Our results show a reduced risk of any grade treatment-related AEs (risk ratio (RR) = 0.722 95% CI: 0.667-0.783, p = 0.002), and grade 3-5 AEs (RR = 0.406 95% CI: 0.340-0.485, p = 0.023) in immunotherapy as compared to chemotherapy. In contrast, a higher risk of immune-related AEs (irAEs) was estimated for immunotherapy versus chemotherapy. The subgroup MAs comparing PD-L1 to PD-1 inhibitors, determined a lower risk of AEs leading to treatment discontinuation in the anti-PD-L1 subgroup (RR = 0.47 95% CI: 0.29-0.75, p = 0.001); however, this statistically significant difference between anti-PD-L1 and anti-PD-1 subgroups was not reached for other safety outcomes analyzed. In conclusion, our findings show that PD-L1 inhibitor monotherapy improves safety outcomes in the 1L treatment of advanced NSCLC patients as compared to chemotherapy except for irAEs.

Neoadjuvant Chemoimmunotherapy in Patients with Resectable Non-small Cell Lung Cancer.

OPINION STATEMENT: Worldwide, lung cancer is the most common cause of cancer morbidity and mortality. Despite a trend towards an escalating diagnosis of resectable non-small cell lung cancer (NSCLC), overall survival (OS) in patients with resectable NSCLC remains poor. The incorporation of chemotherapy into the neoadjuvant setting has improved disease-free survival (DFS), time to distant recurrence, and OS. Furthermore, the incorporation of immunotherapy and the combination of chemotherapy and immunotherapy have improved pathological responses, which seems to be associated with increased survival. Therefore, immunotherapy represents a paradigm shift in treating resectable NSCLC. However, validation in large randomized trials is mandatory and a longer postoperative follow-up period is required. Additionally, neoadjuvant therapy trials offer an exceptional environment for testing predictive biomarkers. PD-L1 expression and tumor mutational burden (TMB) are the most helpful tools for predicting the likelihood of response with immunotherapy in metastatic NSCLC. However, in the neoadjuvant setting, PD-L1 expression and TMB have had opposite results until now. Recently, the immune profiling and some immune-related genes also appear to be involved in the prognosis and response to immunotherapy in NSCLC. Further prospective studies are needed to derive definitive conclusions.

Pretreatment Tissue TCR Repertoire Evenness Is Associated with Complete Pathologic Response in Patients with NSCLC Receiving Neoadjuvant Chemoimmunotherapy.

PURPOSE: Characterization of the T-cell receptor (TCR) repertoire may be a promising source for predictive biomarkers of pathologic response to immunotherapy in locally advanced non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: In this study, next-generation TCR sequencing was performed in peripheral blood and tissue samples of 40 patients with NSCLC, before and after neoadjuvant chemoimmunotherapy (NADIM clinical trial, NCT03081689), considering their complete pathologic response (CPR) or non-CPR. Beyond TCR metrics, tissue clones were ranked by their frequency and spatiotemporal evolution of top 1% clones was determined. RESULTS: We have found a positive association between an uneven TCR repertoire in tissue samples at diagnosis and CPR at surgery. Moreover, TCR most frequently ranked clones (top 1%) present in diagnostic biopsies occupied greater frequency in the total clonal space of CPR patients, achieving an AUC ROC to identify CPR patients of 0.967 (95% confidence interval, 0.897-1.000; P = 0.001), and improving the results of PD-L1 tumor proportion score (TPS; AUC = 0.767; P = 0.026) or tumor mutational burden (TMB; AUC = 0.550; P = 0.687). Furthermore, tumors with high pretreatment top 1% clonal space showed similar immune cell populations but a higher immune reactive gene expression profile. Finally, the selective expansion of pretreatment tissue top 1% clones in peripheral blood of CPR patients suggests also a peripheral immunosurveillance, which could explain the high survival rate of these patients. CONCLUSIONS: We have identified two parameters derived from TCR repertoire analysis that could outperform PD-L1 TPS and TMB as predictive biomarkers of CPR after neoadjuvant chemoimmunotherapy, and unraveled possible mechanisms of CPR involving enhanced tumor immunogenicity and peripheral immunosurveillance.

Clinical and molecular parameters associated to pneumonitis development in non-small-cell lung cancer patients receiving chemoimmunotherapy from NADIM trial.

BACKGROUND: Pneumonitis (Pn) is one of the main immune-related adverse effects, having a special importance in lung cancer, since they share affected tissue. Despite its clinical relevance, Pn development remains an unpredictable treatment adverse effect, whose mechanisms are mainly unknown, being even more obscure when it is associated to chemoimmunotherapy. METHODS: In order to identify parameters associated to treatment related Pn, we analyzed clinical variables and molecular parameters from 46 patients with potentially resectable stage IIIA non-small-cell lung cancer treated with neoadjuvant chemoimmunotherapy included in the NADIM clinical trial (NCT03081689). Pn was defined as clinical or radiographic evidence of lung inflammation without alternative diagnoses, from treatment initiation to 180 days. RESULTS: Among 46 patients, 12 developed Pn (26.1%). Sex, age, smoking status, packs-year, histological subtype, clinical or pathological response, progression-free survival, overall survival and number of nivolumab cycles, were not associated to Pn development. Regarding molecular parameters at diagnosis, Pn development was not associated to programmed death ligand 1, TPS, T cell receptor repertoire parameters, or tumor mutational burden. However, patients who developed Pn had statistically significant lower blood median levels of platelet to monocyte ratio (p=0.012) and teratocarcinoma-derived growth factor 1 (p=0.013; area under the curve (AUC) 0.801), but higher median percentages of natural killers (NKs) (p=0.019; AUC 0.786), monocytes (p=0.017; AUC 0.791), MSP (p=0.006; AUC 0.838), PARN (p=0.017; AUC 0.790), and E-Cadherin (p=0.022; AUC 0.788). In addition, the immune scenario of Pn after neoadjuvant treatment involves: high levels of neutrophils and NK cells, but low levels of B and T cells in peripheral blood; increased clonality of intratumoral T cells; and elevated plasma levels of several growth factors (EGF, HGF, VEGF, ANG-1, PDGF, NGF, and NT4) and inflammatory cytokines (MIF, CCL16, neutrophil gelatinase-associated lipocalin, BMP-4, and u-PAR). CONCLUSIONS: Although statistically underpowered, our results shed light on the possible mechanisms behind Pn development, involving innate and adaptative immunity, and open the possibility to predict patients at high risk. If confirmed, this may allow the personalization of both, the surveillance strategy and the therapeutic approaches to manage Pn in patients receiving chemoimmunotherapy.

Blood biomarkers associated to complete pathological response on NSCLC patients treated with neoadjuvant chemoimmunotherapy included in NADIM clinical trial.

BACKGROUND: Immunotherapy is being tested in early-stage non-small cell lung cancer (NSCLC), and achieving higher rates of complete pathological responses (CPR) as compared to standard of care. Early identification of CPR patients has vital clinical implications. In this study, we focused on basal peripheral immune cells and their treatment-related changes to find biomarkers associated to CPR. METHODS: Blood from 29 stage IIIA NSCLC patients participating in the NADIM trial (NCT03081689) was collected at diagnosis and post neoadjuvant treatment. More than 400 parameters of peripheral blood mononuclear cells (PBMCs) phenotype and plasma soluble factors were analyzed. RESULTS: Neoadjuvant chemoimmunotherapy altered more than 150 immune parameters. At diagnosis, 11 biomarkers associated to CPR were described, with an area under the ROC curve >0.70 and p-value <.05. CPR patients had significantly higher levels of CD4+ PD-1+ cells, NKG2D, and CD56 expression on T CD56 cells, intensity of CD25 expression on CD4+ CD25hi+ cells and CD69 expression on intermediate monocytes; but lower levels of CD3+ CD56- CTLA-4+ cells, CD14++ CD16+ CTLA-4+ cells, CTLA-4 expression on T CD56 cells and lower levels of b-NGF, NT-3, and VEGF-D in plasma compared to non-CPR. Post treatment, CPR patients had significantly higher levels of CD19 expression on B cells, BCMA, 4-1BB, MCSF, and PARC and lower levels of MPIF-1 and Flt-3L in plasma compared to non-CPR. CONCLUSIONS: Patients achieving CPR seem to have a distinctive peripheral blood immune status at diagnosis, even showing different immune response to treatment. These results reinforce the different biology behind CPR and non-CPR responses.

Metodología de la comparación indirecta ajustada con emparejamiento en la evaluación de fármacos hematooncológicos / Matching-Adjusted Indirect Comparisons in the assessment of hemato-oncological drugs

Objetivo: La comparación indirecta ajustada con emparejamiento es unametodología desarrollada para la evaluación de nuevos tratamientos frente asus alternativas cuando no se dispone de comparación directa mediante unensayo clínico aleatorizado y controlado. Estas comparaciones son de especial interés en el área de la hematooncología, en la que la incertidumbre en latoma de decisiones sobre la inclusión de nuevos fármacos se ve frecuentementeacentuada tanto por la gravedad de la enfermedad como por el elevadocoste del tratamiento. El objetivo de este artículo es describir cómo la metodología de comparación indirecta ajustada con emparejamiento ha sido empleadahasta la fecha en la evaluación de fármacos hematooncológicos por parte deagencias internacionales.Método: Para la obtención de los datos del análisis se ha realizado una búsqueda exhaustiva en las páginas web de las agencias nacionales europeasentre enero de 2015 y octubre de 2019 que mostraran información públicadel proceso evaluativo. Se revisaron las evaluaciones de estas agencias paraobtener un listado de fármacos oncohematológicos para los que constara lapresentación de documentación de una comparación indirecta ajustada con emparejamiento. Para este listado de fármacos se analizó para cada agenciaseleccionada el papel que dicha comparación tuvo en la evaluación.Resultados: Se han encontrado 13 tratamientos para patologías hematooncológicas en las que el laboratorio había presentado comparaciones conmetodología de comparación indirecta ajustada con emparejamiento en sudocumentación, principalmente a partir del primer semestre de 2018. (AU)

Objective: Matching-Adjusted Indirect Comparison is a methodologythat has been developed to assess new treatments vs alternatives whena direct comparison is not available through a randomized controlledtrial. These comparisons are of particular interest in the areas of oncology and hematology where uncertainty in decision-making on the inclusion of new drugs is frequently accentuated by both the severity of thedisease and the high cost of treatment. The objective of this study wasto describe how Matching-Adjusted Indirect Comparison methodologyhas been used to date in the assessment of hematological cancer drugsby international agencies.Method: Between January 2015 and October 2019, an exhaustivesearch was conducted of the websites of European National Agencies that provided public information on the assessment process. Theassessments provided by these agencies were reviewed to obtain a listof hematological cancer drugs for which the presentation of a MatchedAdjusted Indirect Comparison was recorded. For this list of drugs, the role of the comparison in the assessment process was analyzed for eachselected agency.Results: Thirteen hematological and oncological treatments were foundin which the pharmaceutical marketing authorization holder had presentedMatching-Adjusted Indirect Comparisons: most of this information referredto the first half of 2018. Acceptance of this methodology diverges amongagencies, ranging from 50% in the case of the British National Institutefor Health and Clinical Excellence, to 40% in the case of French NationalAuthority for Health, to not having been taken into account in any of the3 cases assessed by the German Institute for Quality and Efficiency inHealth Care. The main cause of non-acceptance was matching-relatedproblems.Conclusions: Matching- Adjusted Indirect Comparison methodology isa tool that is being utilized in the decision-making process for assessingnew hematological cancer treatments. (AU)

Matching-Adjusted Indirect Comparisons in the assessment of hemato-oncological drugs.

OBJECTIVE: Matching-Adjusted Indirect Comparison is a methodology that has been developed to assess new treatments vs alternatives when a direct comparison is not available through a randomized controlled trial. These comparisons are of particular interest in the areas of oncology and hematology where uncertainty in decision-making on the inclusion of new drugs is frequently accentuated by both the severity of the disease and the high cost of treatment. The objective of this study was to describe how Matching-Adjusted Indirect Comparison methodology has been used to date in the assessment of hematological cancer drugs by international agencies. METHOD: Between January 2015 and October 2019, an exhaustive search was conducted of the websites of European National Agencies that provided public information on the assessment process. The assessments provided by these agencies were reviewed to obtain a list of hematological cancer drugs for which the presentation of a Matched-Adjusted Indirect Comparison was recorded. For this list of drugs, the role of the comparison in the assessment process was analyzed for each selected agency. RESULTS: Thirteen hematological and oncological treatments were found in which the pharmaceutical marketing authorization holder had presented Matching-Adjusted Indirect Comparisons: most of this information referred to the first half of 2018. Acceptance of this methodology diverges among agencies, ranging from 50% in the case of the British National Institute for Health and Clinical Excellence, to 40% in the case of French National Authority for Health, to not having been taken into account in any of the 3 cases assessed by the German Institute for Quality and Efficiency in Health Care. The main cause of non-acceptance was matching-related problems. CONCLUSIONS: Matching- Adjusted Indirect Comparison methodology is a tool that is being utilized in the decision-making process for assessing new hematological cancer treatments.

Objetivo: La comparación indirecta ajustada con emparejamiento es una metodología desarrollada para la evaluación de nuevos tratamientos frente a sus alternativas cuando no se dispone de comparación directa mediante un ensayo clínico aleatorizado y controlado. Estas comparaciones son de especial interés en el área de la hematooncología, en la que la incertidumbre en la toma de decisiones sobre la inclusión de nuevos fármacos se ve frecuentemente acentuada tanto por la gravedad de la enfermedad como por el elevado coste del tratamiento. El objetivo de este artículo es describir cómo la metodología de comparación indirecta ajustada con emparejamiento ha sido empleada hasta la fecha en la evaluación de fármacos hematooncológicos por parte de agencias internacionales.Método: Para la obtención de los datos del análisis se ha realizado una búsqueda exhaustiva en las páginas web de las agencias nacionales europeas entre enero de 2015 y octubre de 2019 que mostraran información pública del proceso evaluativo. Se revisaron las evaluaciones de estas agencias para obtener un listado de fármacos oncohematológicos para los que constara la presentación de documentación de una comparación indirecta ajustada con  emparejamiento. Para este listado de fármacos se analizó para cada agencia seleccionada el papel que dicha comparación tuvo en la evaluación.Resultados: Se han encontrado 13 tratamientos para patologías hematooncológicas en las que el laboratorio había presentado comparaciones con metodología de comparación indirecta ajustada con emparejamiento en su documentación, principalmente a partir del primer semestre de 2018. La aceptación de la metodología diverge entre agencias, pasando de un 50% en el caso del Instituto Nacional para la Salud y la Excelencia Clínica británico, a un 40% en el Alto Comisionado de Salud francés, a no haberse tenido en cuenta en ninguno de los tres casos evaluados por el Instituto para la Calidad y Eficiencia en los cuidados de salud alemán. La principal causa de no aceptación fue la existencia de problemas relacionados con el emparejamiento.Conclusiones: La metodología de comparación indirecta ajustada con emparejamiento es una herramienta de comparación indirecta que está siendo considerada por las agencias analizadas en el proceso de toma de decisiones de evaluación de nuevos medicamentos.

Five-Year Outcomes From the Randomized, Phase III Trials CheckMate 017 and 057: Nivolumab Versus Docetaxel in Previously Treated Non-Small-Cell Lung Cancer.

PURPOSE: Immunotherapy has revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and CheckMate 057), nivolumab showed an improvement in overall survival (OS) and favorable safety versus docetaxel in patients with previously treated, advanced squamous and nonsquamous NSCLC, respectively. We report 5-year pooled efficacy and safety from these trials. METHODS: Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG PS ≤ 1, and progression during or after first-line platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg once every 2 weeks) or docetaxel (75 mg/m2 once every 3 weeks) until progression or unacceptable toxicity. The primary end point for both trials was OS; secondary end points included progression-free survival (PFS) and safety. Exploratory landmark analyses were investigated. RESULTS: After the minimum follow-up of 64.2 and 64.5 months for CheckMate 017 and 057, respectively, 50 nivolumab-treated patients and nine docetaxel-treated patients were alive. Five-year pooled OS rates were 13.4% versus 2.6%, respectively; 5-year PFS rates were 8.0% versus 0%, respectively. Nivolumab-treated patients without disease progression at 2 and 3 years had an 82.0% and 93.0% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression-free at 5 years, respectively. Treatment-related adverse events (TRAEs) were reported in 8 of 31 (25.8%) nivolumab-treated patients between 3-5 years of follow-up, seven of whom experienced new events; one (3.2%) TRAE was grade 3, and there were no grade 4 TRAEs. CONCLUSION: At 5 years, nivolumab continued to demonstrate a survival benefit versus docetaxel, exhibiting a five-fold increase in OS rate, with no new safety signals. These data represent the first report of 5-year outcomes from randomized phase III trials of a programmed death-1 inhibitor in previously treated, advanced NSCLC.