Efectes adversos immuno-relacionats i associació amb l'eficàcia de la immunoteràpia en pacients amb càncer de pulmó de cèl·lula no petita

Els inhibidors dels immune-checkpoint han revolucionat l'estratègia terapèutica del càncer de pulmó de cèl·lula no petita (CPCNP). Tot i així poden produir efectes adversos immuno-relacionats o irAEs, que són relativament freqüents i sovint cursen amb símptomes inespecífics, dificultant i endarrerint el seu diagnòstic i fent que avancin a formes més greus, obligant així a la suspensió permanent del tractament. Diferents estudis han demostrat una associació entre el desenvolupament dels irAEs i uns millors resultats del tractament amb inhibidors dels immune-checkpoint en diferents tipus de tumors sòlids, convertint-se així en un factor predictiu de resposta a aquests. També, s'ha observat una correlació negativa entre l'eficàcia dels inhibidors dels immune-checkpoint i l'ús de corticosteroides pel maneig de símptomes derivats de la malaltia oncològica, però quan aquests són utilitzats pel tractament dels irAEs no s'ha analitzat específicament. L'objectiu principal d'aquesta tesi era analitzar l'associació entre els irAEs i l'eficàcia del tractament amb inhibidors dels immune-checkpoint en pacients afectes de CPCNP avançat, utilitzant l'anàlisi landmark per evitar el biaix degut a la naturalesa temps-depenent dels efectes adversos. Com a objectius secundaris, definir l'impacte de l'ús concomitant de corticosteroides, distingint entre l'ús pel maneig dels irAEs i pel control de símptomes derivats de la malaltia oncològica; així com avaluar el paper dels complexes leucòcits-plaquetes (PLT) com a biomarcador predictiu del desenvolupament de la toxicitat immuno-relacionada. Aplicant l'anàlisi landmark, el grup de pacients que va desenvolupar irAEs va presentar una millora significativa en supervivència global (SG), supervivència lliure de progressió (SLP) i resposta al tractament amb inhibidors dels immune-checkpoint. En l'anàlisi multivariat, la presència dels irAEs va ser la variable independent associada tant a una major supervivència global com a una major taxa de resposta objectiva. Els pacients que van rebre corticosteroides a dosis equivalents ≥10 mg de prednisona diaris pel control de símptomes relacionats amb el càncer presentaven una pitjor supervivència global respecte la resta de pacients. No es van observar diferències entre els pacients que rebien corticosteroides a dosis equivalents ≥10 mg de prednisona diaris pel maneig dels irAEs, els que rebien dosis equivalents <10 mg de prednisona diaris per qualsevol indicació o els que no prenien corticosteroides de forma concomitant al tractament amb inhibidors dels immune-checkpoint. Respecte a donants sans, els pacients amb CPCNP avançat presentaven percentatges més alts de complexes leucòcits-PLT circulants. Els anàlisis es van focalitzar en els monòcits (complexes CD14+PLT+) i limfòcits CD4+ units a plaquetes (complexes CD4+PLT+), donada la seva correlació amb els neutròfils i altres subpoblacions de limfòcits units a plaquetes, considerant-se representatius de les línies mieloide i limfoide, respectivament. El grup amb el percentatge més elevat de CD4+ PLT+ presentava una major incidència d'irAEs dermatològics, la majoria de grau 1; mentre que el grup amb un percentatge més baix de complexes CD4+PLT+ presentava més irAEs no dermatològics i de grau ≥2. No es van observar diferències entre els percentatges alts o baixos dels complexes CD14+PLT+ i el tipus i severitat dels irAEs. Els pacients amb percentatges alts de complexes CD4+PLT+ i baixos de CD14+PLT+ van presentar menys irAEs, tots ells de tipus dermatològic i de grau 1. En canvi, aquells amb percentatges baixos de CD4+PLT+ i alts CD14+PLT+ presentaven una major incidència d'irAEs i de tipus no-dermatològic, predominant la colitis i l'hepatitis, amb la major proporció d'irAEs grau ≥3. Així, aquests resultats suggereixen que els complexes leucòcits-PLT circulants i la combinació dels percentatges de CD4+PLT+ i CD14+PLT+ podrien utilitzar-se com a biomarcadors predictius del tipus i la gravetat dels irAEs en pacients amb CPCNP avançat tractats amb inhibidors dels immune-checkpoint, l'eficàcia dels quals es correlaciona amb la presència d'aquest tipus de toxicitat.Los inhibidores de los inmune-checkpoint han revolucionado la estrategia terapéutica del cáncer de pulmón de célula no pequeña (CPCNP). Aún así pueden producir efectos adversos inmuno-relacionados o irAEs, que son frecuentes y a menudo cursan con síntomas inespecíficos, dificultando y retrasando su diagnóstico haciendo que avancen a formas más graves, obligando así a la suspensión permanente del tratamiento. Diferentes estudios han demostrado una asociación entre el desarrollo de los irAEs y unos mejores resultados del tratamiento con inhibidores de los inmune-checkpoint en diferentes tipos de tumores sólidos, convirtiéndose así en un factor predictivo de respuesta a estos. También, se ha observado una correlación negativa entre la eficacia de los inhibidores de los inmune-checkpoint y el uso de corticosteroides para el manejo de síntomas derivados de la enfermedad oncológica, pero cuando estos son utilizados para el tratamiento de los Irae no se ha analizado específicamente. El objetivo principal de esta tesis era analizar la asociación entre los irAEs y la eficacia del tratamiento con inhibidores de los inmune-checkpoint en pacientes afectos de CPCNP avanzado, utilizando el análisis landmark para evitar el sesgo debido a la naturaleza tiempo-dependiente de los irAEs. Como objetivos secundarios, definir el impacto del uso concomitante de corticosteroides, distinguiendo entre el uso por el manejo de los irAEs y por el control de síntomas derivados de la enfermedad oncológica; así como evaluar el papel de los complejos leucocitos-plaquetas (PLT) como biomarcador predictivo del desarrollo de la toxicidad inmuno-relacionada. Aplicando el análisis landmark, el grupo de pacientes que desarrolló irAEs presentó una mejora significativa en supervivencia global (SG), supervivencia libre de progresión (SLP) y respuesta al tratamiento con inhibidores de los inmune-checkpoint. En el análisis multivariado, la presencia de los irAEs fue la variable independiente asociada tanto a una mayor supervivencia global como una mayor tasa de respuesta objetiva. Los pacientes que recibieron corticosteroides a dosis equivalentes ≥10 mg de prednisona diarios por el control de síntomas relacionados con el cáncer presentaban una peor supervivencia global respecto al resto de pacientes. No se observaron diferencias entre los pacientes que recibían corticosteroides a dosis equivalentes ≥10 mg de prednisona diarios para el manejo de los irAEs, los que recibían dosis equivalentes <10 mg de prednisona diarios para cualquier indicación o los que no tomaban corticosteroides de forma concomitante al tratamiento con inhibidores de los inmune-checkpoint. Respecto a donantes sanos, los pacientes con CPCNP avanzado presentaban porcentajes más altos de complejos leucocitos-PLT circulantes. Los análisis se focalizaron en los monocitos (complejas CD14 + PLT +) y linfocitos CD4 + unidos a plaquetas (complejas CD4 + PLT +), dada su correlación con los neutrófilos y otras subpoblaciones de linfocitos unidos a plaquetas, considerándose representativos de las líneas mieloide y linfoide, respectivamente. El grupo con el porcentaje más elevado de CD4 + PLT + presentaba una mayor incidencia de irAEs dermatológicos, la mayoría de grado 1; mientras que el grupo con un porcentaje más bajo de complejas CD4 + PLT + presentaba más irAEs no dermatológicos y de grado ≥2. No se observaron diferencias entre los porcentajes altos o bajos de los complejos CD14 + PLT + y el tipo y severidad de los irAEs. Los pacientes con porcentajes altos de complejos CD4 + PLT + y bajos de CD14 + PLT + presentaron menos irAEs, todos ellos de tipo dermatológico y de grado 1. En cambio, aquellos con porcentajes bajos de CD4 + PLT + y altos CD14 + PLT + presentaban una mayor incidencia de irAEs y de tipo no-dermatológico, predominando la colitis y la hepatitis, con la mayor proporción de irAEs grado ≥3. Así, estos resultados sugieren que los complejos leucocitos-PLT circulantes y la combinación de los porcentajes de CD4 + PLT + y CD14 + PLT + podrían utilizarse como biomarcadores predictivos del tipo y la gravedad de los irae en pacientes con CPCNP avanzado tratados con inhibidores de los inmune -checkpoint, cuya eficacia se correlaciona con la presencia de este tipo de toxicidad.Immune-checkpoint inhibitors have revolutionized the therapeutic strategy in non-small cell lung cancer (NSCLC). However, given their mechanism of action, they can produce inflammatory-type adverse effects, called immune-related adverse events or irAEs, which are relatively common (60-85%). IrAEs often present with nonspecific symptoms, making it difficult and delaying their diagnosis, what leads their progression to more severe forms in an important percentage of cases, forcing the permanent suspension of treatment. In turn, different studies have shown an association between the development of irAEs and better treatment outcomes with immune-checkpoint inhibitors in different solid tumors, thus becoming a predictive factor for their response. Also, a negative correlation has been observed between the efficacy of immune-checkpoint inhibitors and the use of corticosteroids for the management of symptoms derived from the oncological disease, but when they are used for the treatment of irAEs has not been specifically analyzed. The main objective of this thesis was to analyze the association between irAEs and the efficacy of immune-checkpoint inhibitors in patients with advanced NSCLC, using the landmark analysis to avoid the immortal-time bias derived from the time-depending nature of this type of toxicity. As secondary objectives, to define the impact of concomitant corticosteroids use, distinguishing between their use for the management of irAEs and for the control of symptoms derived from the oncological condition; as well as evaluating the role of leukocyte-platelet (PLT) complexes as a form of predictive biomarker of immune-related toxicity development. Applying the landmark analysis, the group of patients who developed irAEs presented statistically significantly better survival outcomes, both overall and progression-free survival, as well as response to treatment with immune-checkpoint inhibitors. In the multivariate analysis, the presence of irAEs was the only independent variable associated with both a greater overall survival and a higher objective response rate. Patients who received corticosteroids at equivalent doses of ≥10 mg of prednisone daily for the management of cancer-related symptoms had worse overall survival than the rest of patients. No differences were observed between patients receiving corticosteroids at equivalent doses of ≥10 mg of prednisone daily for the treatment of irAEs, patients receiving equivalent doses of <10 mg for any indication, or those not taking corticosteroids concomitantly with immune-checkpoint inhibitors. In contrast to healthy donors, patients with advanced NSCLC presented higher percentages of circulating leukocyte-PLT complexes. Analyzes focused on platelet-bound monocytes (CD14+PLT+ complexes) and platelet-bound CD4+ lymphocytes (CD4+PLT+ complexes), given their correlation with neutrophils and other platelet-bound lymphocyte subpopulations, considering them representative of the myeloid and lymphoid lines, respectively. The group with the highest percentage of CD4+PLT+ had a higher incidence of dermatological irAEs, most of them grade 1; while the group with a lower percentage of CD4+PLT+ showed more non-dermatological and grade ≥2 irAEs. No differences were observed between the high or low percentages of the CD14+PLT+ complexes and the type and severity of irAEs. Patients with high percentages of CD4+PLT+ and low percentages of CD14+PLT+ presented the lowest rate of irAEs, all of them dermatological and grade 1. In contrast, those with low percentages of CD4+PLT+ and high CD14+PLT+ had a higher incidence of irAEs overall, of non-dermatological irAEs, predominating colitis and hepatitis, with the highest proportion of irAEs grade ≥3. Therefore, these results suggest that circulating leukocyte-PLT complexes and the combination of percentages of CD4+PLT+ and CD14+PLT+ may be used as circulating predictive biomarkers of irAEs type and severity in patients with advanced NSCLC treated with immune-checkpoint inhibitors, the effectiveness of which correlates with the presence of this type of toxicity

Radon and Lung Cancer: Current Trends and Future Perspectives

Lung cancer is a public health problem and the first cause of cancer death worldwide. Radon is a radioactive gas that tends to accumulate inside homes, and it is the second lung cancer risk factor after smoking, and the first one in non-smokers. In Europe, there are several radon-prone areas, and although the 2013/59 EURATOM directive is aimed to regulate indoor radon exposition, regulating measures can vary between countries. Radon emits alpha-ionizing radiation that has been linked to a wide variety of cytotoxic and genotoxic effects; however, the link between lung cancer and radon from the genomic point of view remains poorly described. Driver molecular alterations have been recently identified in non-small lung cancer (NSCLC), such as somatic mutations (EGFR, BRAF, HER2, MET) or chromosomal rearrangements (ALK, ROS1, RET, NTRK), mainly in the non-smoking population, where no risk factor has been identified yet. An association between radon exposure and oncogenic NSCLC in non-smokers has been hypothesised. This paper provides a practical, concise and updated review on the implications of indoor radon in lung cancer carcinogenesis, and especially of its potential relation with NSCLC with driver genomic alterations

Complete Remission After Immunotherapy-Induced Abdominal Tuberculosis in a Patient With Advanced NSCLC Treated With Pembrolizumab: A Case Report

International audienc

Association between Changes in the Patterns of Antinuclear Autoantibodies during Immune Checkpoint Inhibition Therapy and the Development of Severe Immune Related Adverse Events

Immune-related adverse events (irAEs) are unpredictable autoimmune-like toxicities induced by immune checkpoint inhibitors (ICI). irAEs are a consequence of a breakdown in self-tolerance. ICIs can induce autoantibody formation, and the presence of antinuclear autoantibodies (ANAs) has been reported in patients who developed irAEs. Our goal was to compare ANA patterns by indirect immunofluorescence at different timepoints before (baseline) and after the initiation of ICI treatment and to analyze the role of ANA pattern changes as predictors of irAEs. This is a 2-year-follow-up prospective study of 152 consecutive patients with solid tumors treated with anti-PD-(L)1 blockade agents. They were included from September 2018 until March 2020 in the Hospital de la Santa Creu I Sant Pau (Barcelona, Spain). We grouped patients into three groups: ANA de novo (patients who showed new ANA patterns at any time after ICI initiation), ANA (ANA positive at baseline without changes in the ANA patterns after initiation of treatment) and non-ANA (ANA negative at baseline and after ICI initiation). We did not find any association between the appearance of ANAs and irAE rates or the number and types of irAEs. However, patients in the ANA de novo group showed higher severe irAE rates (grade &ge; 3) than the other groups. Additionally, in most of the patients with severe irAEs (83.3%), changes in ANA patterns preceded irAE onset. In conclusion, we found ANA induction during ICI therapies in 22 patients and our results suggest that the appearance of ANAs may predict the severity of the irAE

Immune-Related Adverse Events and Corticosteroid Use for Cancer-Related Symptoms Are Associated With Efficacy in Patients With Non-small Cell Lung Cancer Receiving Anti-PD-(L)1 Blockade Agents

Background: Immune-related adverse events (irAEs) have been associated with improved efficacy in advanced non-small cell lung cancer (NSCLC) patients receiving anti-PD-(L)1 blockade agents, while the concurrent use of corticosteroids seems to worsen it. We evaluated outcomes in advanced NSCLC patients treated with anti-PD-(L)1 blockade agents in relation to the presence of irAEs and the reasons for using corticosteroids: whether for palliative cancer-related reasons or for the management of irAEs. Methods: Clinical outcomes in advanced NSCLC patients treated with anti-PD-(L)1 blockade agents were calculated with regard to the presence of irAEs and the use of corticosteroids. A landmark analysis was performed to avoid immortal time bias due to the time-dependent nature of irAEs. Results: Out of a total of 267 patients, the 56.9% of patients who experienced irAEs had significantly improved outcomes. In the landmark analysis, median progression-free survival (PFS) was 12.4 months for patients with irAEs vs. 4.1 months for patients without irAEs (p < 0.001), while median overall survival (OS) was 28.2 vs. 12.5 months, respectively (p < 0.001). Likewise, objective response and disease control rates were significantly higher in patients experiencing irAEs: 48.6 vs. 22.8% and 77.1 vs. 39.6% (p < 0.001), respectively. Median OS was significantly shorter for patients receiving ≥10 mg of prednisone equivalent daily for cancer-related symptoms than for the rest of patients (<10 mg prednisone equivalent daily or for management of irAEs): 6 vs. 15.9 months (p < 0.001). Conclusions: IrAEs were associated with improved efficacy in advanced NSCLC patients when a landmark analysis was applied. Patients receiving corticosteroids had significantly poorer outcomes when they were used for cancer-related symptoms

Impact of Intercurrent Introduction of Steroids on Clinical Outcomes in Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients under Immune-Checkpoint Inhibitors (ICI)

Simple Summary Recently, the introduction of immunotherapy radically changed the therapeutic algorithm of non-small-cell lung cancer as an upfront or secondary strategy. Unfortunately, the small amount of patient benefits from immune-checkpoint inhibitors (ICI) and the prognostic role of concomitant treatments are a burning open issue. The use of steroids was associated with poor outcomes during ICI. We investigated the impact of intercurrent steroids, according to clinical indication, which is actually unclear. Interestingly, the use of intercurrent steroids given for cancer-unrelated symptoms has no survival impact on our study cohort. Background: Baseline steroids before ICI have been associated with poor outcomes, particularly when introduced due to cancer symptoms. Methods: Retrospective analysis of advanced NSCLC patients treated with ICI. We collected the use of intercurrent steroids (>= 10 mg of prednisone-equivalent) within the first eight weeks of ICI. We correlated steroid use with patient outcomes according to the indications. Results: 413 patients received ICI, 299 were steroids-naive at baseline. A total of 49 patients received intercurrent steroids (16%), of whom 38 for cancer-related symptoms and 11 for other indications, such as immune-related events. Overall, median (m) progression-free survival (PFS) was 1.9 months (mo.) [95% CI, 1.8-2.4] and overall survival (OS) 10 mo. [95% CI, 8.1-12.9]. Intercurrent steroids under ICI correlated with a shorter PFS/OS (1.3 and 2.3 mo. respectively, both p <0.0001). Intercurrent steroids for cancer-related symptoms correlated with poorest mPFS [1.1 mo.; 95% CI, 0.9-1.5] and mOS [1.9 mo.; 95%CI, 1.5-2.4; p <0.0001)]. No mOS and mPFS differences were found between cancer-unrelated-steroid group and no-steroid group. Steroid use for cancer-related symptoms was an independent prognostic factor for poor PFS [HR 2.64; 95% CI, 1.2-5.6] and OS [HR 4.53; 95% CI, 1.8-11.1], both p <0.0001. Conclusion: Intercurrent steroids during ICI had no detrimental prognostic impact if the indication was unrelated to cancer symptoms

Clinical utility of ddPCR for detection of sensitizing and resistance EGFRm in pts with advanced NSCLC [22P]

BACKGROUND: EGFR mutations (EGFRm) represent 10–15% of advanced non-small cell lung cancer (NSCLC) in European patients (pts). Tissue molecular profiling is the gold-standard, but liquid biopsy (LB) offers a non-invasive alternative. Digital droplet PCR (ddPCR) is a fast, highsensitive and low-cost LB to detect specific molecular alterations. We aimed to describe ddPCR clinical utility for EGFRm detection in advanced NSCLC. METHODS: Prospective blood sample collection in advanced NSCLC pts harboring EGFRm either at baseline and/or at progression (PD) between Jan/16 and Sep/20 at Gustave Roussy. LB was performed by ddPCR (Stilla®): sensitizing (exon19 deletion; exon21 [L858R]) and T790M resistance EGFRm. We defined high tumor burden as >2 metastatic sites. We analyzed EGFRm detection by ddPCR at these timepoints. [...

Durvalumab consolidation in patients with unresectable stage III non-small cell lung cancer with driver genomic alterations.

INTRODUCTION: Durvalumab is the standard-of-care as consolidation therapy after chemo-radiotherapy in stage III unresectable non-small cell lung cancer (NSCLC); however, its activity across patients with NSCLC harbouring driver genomic alterations (dGA) is poorly characterised. MATERIAL AND METHODS: Multicentre retrospective study including patients with stage III unresectable NSCLC treated with durvalumab after chemo-radiotherapy between April 2015 and October 2020 at 26 centres in Europe and America. Clinical and biological data were collected; dGA included: EGFR/BRAF/KRAS mutations (m) and ALK/ROS1 rearrangements (r). We evaluated progression-free survival (PFS) and overall survival (OS) based on dGA. RESULTS: Out of 323 patients included, 43 patients had one dGA: KRASm (n = 26; 8 G12C), EGFRm (n = 8; 6 del19/ex21), BRAFm (n = 5; 4 V600E) and ALKr (n = 4). The median age was 66 years [39-84], gender ratio 1:1, with 98% performance status (PS) 0-1 and 19% non-smokers; 88% had adenocarcinoma. PD-L1 was positive in 85% (n = 4 missing). In the whole cohort, the median PFS was 17.5 months (mo.) (95% CI, 13.2-24.9) and median OS 47 mo (95%CI, 47-not reached [NR]). No statistically significant differences in terms of the median PFS were observed between patients with dGA vs. non-dGA: 14.9 mo (95% CI, 8.1-NR) vs. 18 mo. (95% CI, 13.4-28.3) (P = 1.0); however, when analysed separately: the median PFS was NR (11.3-NR) in the KRASm G12C vs. 8.1 mo (5.8-NR) in the EGFRm del19/ex21 vs. 7.8 mo (7.7-NR) in the BRAFm V600E/ALKr (P = 0.02). CONCLUSIONS: We observed limited activity of durvalumab consolidation in patients with stage III unresectable NSCLC with EGFR/BRAFm and ALKr but not for those harbouring KRASm. Larger prospective studies are needed to confirm these findings

Association Between Lung Immune Prognostic Index and Durvalumab Consolidation Outcomes in Patients With Locally Advanced Non-Small-Cell Lung Cancer

The LIPI, based on pretreatment derived neutrophils/[leukocytes-neutrophils] ratio (dNLR) and LDH, is associated with immune checkpoint inhibitors (ICI) outcomes in advanced non-small-cell lung cancer (NSCLC). We aimed to assess baseline LIPI correlation with durvalumab consolidation outcomes in the locally advanced setting. Multicentre retrospective study (330 patients) with stage III unresectable NSCLC treated with durvalumab after chemo-radiotherapy between April 2015 and December 2020; 65 patients treated with chemo-radiotherapy only. Baseline LIPI characterized 3 groups: good (dNLR≤3+LDH≤ULN), intermediate (dNLR>3/LDH>ULN) and poor (dNLR>3+LDH>ULN). Primary endpoint was overall survival (OS). In the durvalumab cohort, median age was 67 years, 95% smokers, 98% with a performance status of 0-1; 60% had nonsquamous histology and 16% a PD-L1 expression <1%. Radiotherapy was delivered concurrently in 81%. LIPI was evaluable in 216 patients: 66% good, 31% intermediate, 3% poor. LIPI significantly correlated with median OS (median follow-up: 19 months): 18.1 months vs. 47.0 months vs. not reached in poor, intermediate and good LIPI groups, respectively (P = .03). A trend between objective response rate and LIPI groups was observed: 0% vs. 41% vs. 45%, respectively (P = .05). The pooled intermediate/poor LIPI group was associated with shorter OS (HR 1.97; P = .03) and higher risk of progressive disease (OR 2.68; P = .047). Survivals and response were not influenced in the control cohort. Baseline LIPI correlated with outcomes in patients with locally advanced NSCLC treated with durvalumab consolidation, but not in those who only received chemo-radiotherapy, providing further evidence of its prognostic and potential predictive role of ICI benefit in NSCLC