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Purpose: Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non–small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown. Patients and Methods: SAFIR02-Lung/IFCT 1301 was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS). Results: Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6–2.9] with TT versus 2.7 months (1.6–4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7–1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3–4.4) with durvalumab versus 3.0 months (2.0–5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62–1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) ≥1%, (n = 29; HR, 0.29; 95% CI, 0.11–0.75) as compared with PD-L1 Conclusions: Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients.

Supplementary Figure 2. Forest plot with subgroup analysis for PFS in substudy 1.

Supplementary Table S1. Representativeness of Study Participants

Purpose:Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non–small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown.Patients and Methods:SAFIR02-Lung/IFCT 1301 was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS).Results:Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6–2.9] with TT versus 2.7 months (1.6–4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7–1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3–4.4) with durvalumab versus 3.0 months (2.0–5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62–1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) ≥1%, (n = 29; HR, 0.29; 95% CI, 0.11–0.75) as compared with PD-L1 n = 31; HR, 0.71; 95% CI, 0.31–1.60; Pinteraction = 0.036).Conclusions:Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients.

Supplementary Figure legends 1-5

Supplementary materials - substudy 1 statistical report

Study protocol

Supplementary Data from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial

Purpose:Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non–small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown.Patients and Methods:SAFIR02-Lung was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS).Results:Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6–2.9] with TT versus 2.7 months (1.6–4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7–1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3–4.4) with durvalumab versus 3.0 months (2.0–5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62–1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) ≥1%, (n = 29; HR, 0.29; 95% CI, 0.11–0.75) as compared with PD-L1 n = 31; HR, 0.71; 95% CI, 0.31–1.60; Pinteraction = 0.036).Conclusions:Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients.

Purpose:The IFCT-GFPC-0701 MAPS phase III trial highlighted significant improvement in overall survival from adding bevacizumab to the standard first-line chemotherapy regimen [cisplatin plus pemetrexed (PC)] in advanced malignant pleural mesothelioma (MPM). We present the results of health-related quality of life (HRQoL), a secondary endpoint of MAPS.Patients and Methods:HRQoL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 and the lung cancer–specific module QLQ-LC13 at randomization and then every 9 weeks until disease progression.HRQoL deterioration–free survival (QFS), used to analyze longitudinal HRQoL data, was defined as the interval between randomization and the occurrence of the first clinically relevant definitive deterioration compared with the HRQoL score at baseline, or death.Results:A total of 448 patients were included in the MAPS trial between 2008 and 2014. At baseline, 425 patients (94.8%) completed the HRQoL questionnaire. We report that adding bevacizumab to cisplatin and pemetrexed (PCB) significantly improved QFS for the peripheral neuropathy dimension, with a median QFS of 12.09 months [95% confidence interval (CI), 9.59–13.67] in the PCB arm versus 7.59 months (95% CI, 6.57–8.61) in the PC arm [HR (PCB vs. PC) = 0.74; 95% CI, 0.61–0.91; P = 0.004]. QFS was also longer in the PCB arm for the pain dimension (HR = 0.84; 95% CI, 0.69–1.02; P = 0.08).Conclusions:This study demonstrated that adding bevacizumab to standard chemotherapy in patients with advanced MPM had no negative impact on HRQoL. A significant improvement in the peripheral neuropathy and pain HRQoL dimensions was even observed.

Table 1

Supplementary Figure from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial

Supplementary Table from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial

Telomere length appears to correlate with survival in early non-small-cell lung cancer (NSCLC), but the prognostic impact of telomere status in advanced NSCLC remains undetermined. Our purpose was to evaluate telomere parameters as prognostic and predictive biomarkers in advanced NSCLC. In 79 biopsies obtained before treatment, we analyzed the telomere length and expression of TERT and shelterin complex genes (TRF1, TRF2, POT1, TPP1, RAP1, and TIN2), using quantitative PCR. Non-responders to first-line chemotherapy were characterized by shorter telomeres and low RAP1 expression (p = 0.0035 and p = 0.0069), and tended to show higher TERT levels (p = 0.058). In multivariate analysis, short telomeres were associated with reduced event-free (EFS, p = 0.0023) and overall survival (OS, p = 0.00041). TERT and TRF2 overexpression correlated with poor EFS (p = 0.0069 and p = 0.00041) and OS (p = 0.0051 and p = 0.007). Low RAP1 and TIN2 expression-levels were linked to reduced EFS (p = 0.00032 and p = 0.0069) and OS (p = 0.000051 and p = 0.02). Short telomeres were also associated with decreased survival after nivolumab therapy (p = 0.097). Evaluation of telomere status in advanced NSCLC emerges as a useful biomarker that allows for the selection of patient groups with different clinical evolutions, to establish personalized treatment.

Introduction/objectifs Le cancer du poumon est la premiere cause de mortalite en France et dans le monde. Le cancer bronchique non a petites cellules (CBNPC) est le sous-type histologique le plus frequent. Malgre les progres therapeutiques recents avec notamment l’introduction d’immunotherapie, le CBNPC est souvent diagnostique a stade avance et son pronostic est pejoratif. La dysfonction des telomeres est une etape cle du processus tumoral et l’etude du statut telomerique dans le CBNPC pourrait apporter les nouveaux biomarqueurs pour mieux evaluer le pronostic et la reponse au traitement. Nous avons recherche une correlation entre le statut telomerique et la survie dans le CBNPC metastatique. Patients et methodes Les acides nucleiques (ADN et ARN) ont ete extraits a partir de 89 biopsies tumorales. Le statut telomerique a ete evalue par la longueur des telomeres, l’expression de TERT (telomerase) et des genes du complexe Shelterin impliques dans la regulation de la maintenance des telomeres (TRF1, TRF2, POT1, TPP1, RAP1 et TIN2) par PCR quantitative. Resultats Des telomeres courts et une surexpression de TERT etaient associes a la survie globale (SG) plus courte (p = 0,0053 et p = 0,05, respectivement). Une forte expression de TRF2 (p = 0,025) et une faible expression de RAP1 et TIN2 (p = 0,0037 et p = 0,017, respectivement) etait egalement correlee a la SG reduite. De facon tres interessante, un raccourcissement des telomeres influencait negativement la SG dans le sous-groupe de patients ayant recu une immunotherapie (p = 0,0037). Conclusion A notre connaissance, il s’agit de la premiere etude analysant le statut telomerique dans le CBNPC metastatique. Nous avons demontre que la dysfonction telomerique etait associee au mauvais pronostic et a la resistance au traitement. Ainsi, la determination de ces parametres pourrait permettre d’ajuster les therapies proposees aux patients et represente une voie d’espoir pour le developpement de nouveaux traitements cibles.

A retrospective monocentric study of consecutive patients with superior sulcus tumor non-small cell lung cancer (SS-NSCLC), treated by induction concurrent chemoradiotherapy (CRT), article management.From 1994 to 2005, 36 patients (15 T3, 21 T4 tumors, including N2-N3 node involvement) received induction CRT with cisplatin/vinorelbine/fluorouracil combined with 44 Gy radiotherapy (5 daily 2 Gy fractions/week). After CRT completion, RECIST evaluation and operability were assessed. In resectable patients, surgery was performed one month after CRT. Patients with unresectable disease followed CRT up to 66 Gy. The median of follow-up period was 38.6 months [2-206].Induction CRT was completed for 94.4% with 71% radiological objective response (OR). Sixteen patients (44%) underwent surgical resection, and pathologic complete resection was performed in 93.8%. There were 7 patients (44%) with pathologic complete response. The median disease-free survival (DFS) time was 12.9 months with DFS rates at 1 and 2 years 53.6% and 39.1% respectively. The median overall survival (OS) was 46.4 months. The OS rates at 2 and 5 years were 68.8% and 37.5% respectively with no difference between T3 and T4 tumors. In unresectable disease, the median DFS time was 8.1 months. The DFS rate at 1 year was 25.2%. The median OS was 9.1 months. The OS rates at 1 and 2 years were 45% and 16.9% respectively. Recurrences were found in 72% of patients. Brain metastasis was the most common site of recurrence. Prognostic factors for OS were the response to induction treatment, the possibility of surgery, and pathologic complete response.This trimodality treatment regimen confers a survival outcome in agreement with previous studies. Patients with pretreatment N3 lymph node should be included in trimodality treatment.

This study was designed to investigate the interaction of mild and localized cold exposure and hypoxia on pulmonary hemodynamics in chronic obstructive pulmonary disease (COPD). Nineteen patients with COPD were studied at sea level and seven at an altitude of 2,640 m. For all patients, pulmonary hemodynamic measurements were performed 10 min after insertion of a catheter in a femoral vein and following 10 min of cold exposure. Cold exposure was restricted to the forehead, and subjects breathed air at ambient temperature. Flow and temperature of air (1.5 L.s(-1), 5 degrees C) to the forehead were chosen to cool down the forehead skin to approximately 20 degrees C without discomfort for the subject. For the seven patients studied at high altitude, the same measurements were also performed after 5 min of oxygen supplementation with and without cold exposure. At sea level, an increase in pulmonary vascular resistance (PVR) during cold exposure was inversely related to the initial PaO2. In six severe hypoxic subjects (PaO2 < 50 mm Hg), PVR increased by 24%. At high altitude, PVR was significantly increased by 15%. After O2 supplementation, cold exposure did not induce an increase in PVR. We concluded that mild and localized cold exposure to the forehead only induced an increase in PVR in COPD patients with severe hypoxia. Moreover, in cold exposure responders, O2 supplementation negated the effect of cold exposure on pulmonary hemodynamics.

Objectifs :L’efficacité d’une chimiothérapie par paclitaxel-doxorubicine a été étudiée dans une étude de phase II, chez les patients atteints d’un cancer à petites cellules en rechute. Dans une analyse de sous-groupe de malades en rechute résistante ou réfractaire, cette chimiothérapie a montré un taux de réponse intéressant de 14%. En l’absence de traitement standard actuellement, en cas de rechute résistante ou réfractaire, nous avons cherché à confirmer ces résultats de manière rétrospective, en étudiant l’efficacité et la tolérance de ce doublet dans cette population par rapport au topotécan, seule molécule à bénéficier de l’AMM en rechute.Méthodes :Nous avons repris les dossiers de 42 patients atteints d’un cancer à petites cellules en rechute réfractaire ou résistante traités par paclitaxel-doxorubicine de janvier 2008 à décembre 2017, après une première ligne par sel de platine- étoposide. Notre critère de jugement principal est le taux de réponse. Les critères de jugement secondaires sont la durée de réponse, le taux de contrôle, la survie sans progression et la survie globale.Résultats :Le taux de réponse est de 26,2%, IC 95% [13,9-42,0] et le taux de contrôle de 45,2%, IC 95% [29,8-61,3]. La médiane de survie sans progression est de 2,4 mois, IC 95% [1,8 ; 4,0] et la médiane de durée de réponse est de 2,5 mois [2,2 ; 4,5]. La médiane de survie globale est de 4,9 mois, IC 95% [3,8 ; 6,8]. 21,4% des patients présentent une toxicité grade 3 ou 4; neutropénie (9,5%) dont une aplasie médullaire fébrile, infection (4,8%), nausées (4,8%) et asthénie (2,3%). Aucun décès toxique n’est survenu.Conclusion :La chimiothérapie par paclitaxel-doxorubicine améliore le taux de réponse des patients atteints d’un cancer à petites cellules en rechute réfractaire ou résistante par rapport au topotécan selon les données d’une méta-analyse de 2015 (taux de réponse de 5%, IC 95% [1-8]), avec une toxicité acceptable. Aucune différence ne semble exister sur la survie sans progression et la survie globale.

Dans le cancer bronchique non à petites cellules (CBNPC) métastatique, l'immunothérapie représente une réelle avancée thérapeutique avec un bénéfice sur la survie et sur la tolérance. Cependant, aucun facteur prédictif n'a encore été clairement identifié. La recherche de l'expression de PD-L1 est insuffisante. L'objectif de l'étude était de déterminer si le taux de lymphocytes, d'éosinophiles et le rapport neutrophiles sur lymphocytes (NLR) étaient des biomarqueurs prédictifs de réponse au nivolumab chez les patients traités pour un CBNPC à un stade avancé. À partir de l'étude des dossiers médicaux, nous avons recueilli les valeurs d'éosinophiles et de lymphocytes sanguins, ainsi que le rapport NLR au diagnostic de la maladie, à l'initiation du nivolumab, et à chaque évaluation thérapeutique (toutes les 4 cures). Les seuils définis pour les valeurs étudiées ont été déterminés avec une analyse de sensibilité, à partir de courbes de ROC. Le critère de jugement principal était la survie globale (SG), définie comme le temps entre la première injection de nivolumab et le décès toute cause. Au total, nous avons inclus 124 patients traités pour un CBNPC avancé, qui avaient reçu leur première injection de nivolumab entre le 22 juin 2015 et le 22 juillet 2016. La date de point du suivi était fixée au 31 octobre 2016. Tous les patients avaient été traités par une première ligne comprenant un sel de platine. Dans 68.5% des cas, le nivolumab avait été prescrit en deuxième ligne. La SG médiane de la population était 11.6 mois [2.5-NA]. En analyse multivariée, à l'initiation du nivolumab : un taux de lymphocytes = 1.5 G/I n'était pas statistiquement associé à la survie; un taux d'éosinophiles = 0.3 G/I améliorait le SG (HR=0.23, IC95% [0.07-0.77), p=0.017) et la survie sans progression (SSP) (HR-0.17, IC95% [0.05-0.60], p=0.005). À l'inverse, un rapport NLR =3.5 réduisait la SG (HR=2.09, IC95% [1.18-3.70], p=0.011) ainsi que la SSP (HR=1.79, IC95% [1.01-3.17], p=0.047). Contrairement à l'éosinophilie, le NLR en cours de traitement et au diagnostic de la maladie, était également associé à une SG réduite (HR=1.93, IC95% [1.16-3.21], p=0.011). Il s'agit de la première étude à démontrer qu'une éosinophilie = 0.3G/I à l'initiation du nivolumab dans le CBNPC avancé, est associée à une meilleure SG et SSP sous immunothérapie. Alors qu'il n'est pas clair si le NLR est prédictif ou pronostique, l'éosinophilie à l'initiation du nivolumab semble être prédictive. Récemment, le rôle des éosinophiles intra-tumoraux au recrutement des lymphocytes T a été démontré, et pourrait expliquer ces résultats. D'autres études prospectives et à large échelle sont justifiées pour valider l'éosinophilie comme biomarqueur, et il serait intéressant de compléter ces données en étudiant un éventuel lien entre l'éosinophilie et l'expression de PD-L1.