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Pemetrexed is associated with hematological toxicity. Drug-drug interactions (DDIs) between methotrexate and proton pump inhibitors (PPIs) induce a higher risk of hematological toxicity due to the inhibition of methotrexate excretion by PPIs. As pemetrexed and methotrexate are both excreted by human organic anion transporter 3 (hOAT3), this study investigates the hypothetical DDI between pemetrexed and PPIs in lung cancer patients. The primary objective was the occurrence of severe (grade ≥ 3) hematological toxicity. The secondary objectives were to describe the type of hematological toxicity and associated clinical consequences (NCT03537833).PPI consumption was collected for each patient receiving pemetrexed-based anticancer chemotherapy from May 2018 to October 2020 in a prospective multicentric observational and nonrandomized study. Multivariate Cox regression and propensity score (PS) adjustment, PS matching and inverse weighting on PS (IPTW) methods were used.PPI consumption (55 among 156 included patients) was associated with a significantly higher risk of severe hematological toxicity in the multivariable Cox regression model (hazard ratio HR = 2.51, 95% confidence interval [1.47-4.26]; p = 0.005). Similar results were found with PS adjustment (HR = 1.91 CI95% [1.14-3.20]; p = 0.002), PS-matching (HR = 1.93 CI95% [1.08-3.45]; p = 0.02) and IPTW method (HR = 2.06 CI95% [1.27-3.35]; p = 0.004). Severe neutropenia and anemia occurred in 32.7% and 14.1% of patients, respectively. This resulted in 48 anticancer chemotherapy postponements and 24 dose adjustments, 26 growth factor prescriptions, 24 red blood cell transfusions, and 20 hospitalizations.The results strongly suggest an association between PPI consumption and pemetrexed-related severe hematological toxicity. Deprescription of PPIs when feasible should be considered to prevent this DDI.

Thymic carcinomas are aggressive and difficult to treat a subset of thymic epithelial tumours that represent a heterogeneous group of rare intrathoracic malignancies. The treatment strategy of thymic carcinomas is based on whether surgical resection may be achieved, which represents the most significant favourable prognostic factor on survival. For this study, we took advantage of the unique prospective Réseau tumeurs THYMiques et Cancer (RYTHMIC) database to describe baseline characteristics, analyse treatment strategies in light of existing guidelines and provide landmark patient outcomes data with regards to response and survival of patients in a real-life clinical practice setting.Inclusion criteria for this analysis were the following: (1) histologically-confirmed thymic carcinomas - excluding neuroendocrine tumours-after pathological review by the RYTHMIC pathology panel, (2) discussion of the case at the RYTHMIC multidisciplinary tumour board, (3) at least one active treatment modality.A total of 213 patients were analysed. Overall, 60 (28%) patients were considered as surgical candidates upfront, 91 (43%) patients received primary chemotherapy, and 62 (29%) patients received exclusive chemotherapy. Median overall survival (OS) was 49.2 months (IC95%: 34.8-63.6); OS was significantly longer in patients with a lower stage at diagnosis (p 0.001), who were operated on upfront, as opposed to patients who received primary or exclusive chemotherapy (p 0.001). Surgery, conducted upfront or after primary chemotherapy, was significantly associated with more prolonged OS (p 0.001); complete resection and postoperative radiotherapy were also predictors of better outcome (p = 0.018 and p = 0.051, respectively).Our cohort is the first to analyse in-depth outcomes and treatment strategies in a prospective cohort of consecutive patients with thymic carcinoma. While we confirm the major prognostic impact of surgery, our data highlight the need for optimised multidisciplinary management and innovative therapies as the survival of patients remains limited.

Brigatinib is a next-generation ALK inhibitor (ALKi) that shows efficacy in ALK inhibitor naïve and post-crizotinib ALK+ advanced NSCLCs (aNSCLCs). The efficacy of brigatinib was retrospectively assessed in patients with aNSCLCs included in the brigatinib French Early-Access Program (1 August 2016–21 January 2019). The primary endpoint was investigator-assessed progression-free survival (invPFS) and the primary analysis was updated in 2021 with a longer follow-up, focused on post-brigatinib lorlatinib efficacy. Sixty-six centers included 183 patients: median age 60 ± 12.7 years; 78.3% never/former smokers; median of 3 ± 1 previous lines and 2 ± 0.5 ALKis; 37.1% ECOG PS 2 and 55.6% >3 metastatic sites. The median follow-up from brigatinib initiation was 40.4 months (95% CI 38.4–42.4). InvPFS was 7.4 months (95% CI 5.9–9.6), median duration of treatment (mDOT) was 7.3 months (95% CI 5.8–9.4) and median overall survival (mOS) was 20.3 months (95% CI 15.6–27.6). The median DOT and OS from brigatinib initiation tend to decrease with the number of ALK inhibitors used in previous lines of therapy. Based on the data collected, 92 (50.3%) patients received ≥1 agent(s) post-brigatinib and 68 (73.9%) of them received lorlatinib, with 51 (75%) immediately receiving it post-brigatinib, 12 (17.6%) receiving it after one and 5 (7.4%) after ≥2 subsequent treatments. The median follow-up was 29.9 (95% CI 25.7–33.1) months. Lorlatinib mDOT was 5.3 (95% CI 3.6–7.6) months with a median OS from lorlatinib initiation of 14.1 (95% CI 10.3–19.2) months. The results of the brigALK2 study confirm the efficacy of brigatinib in a population of heavily pretreated ALK+ aNSCLC patients and provide new data on the activity of lorlatinib after brigatinib.

Anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC) represents a rare subset of lung cancer, with specific presentation, and multiple treatment options, including selective tyrosine kinase inhibitors (TKIs). Real-world evidence is insufficient regarding the actual real-life treatment sequences in the late line setting, and available clinical trials may not reflect real-world situation. Here, we took advantage of the French Expanded Access Program (EAP) of lorlatinib, a third-generation TKI targeting ALK and ROS1, to assess treatment sequencing, and lorlatinib efficacy and safety, in patients with ALK+ NSCLC.All consecutive patients with advanced ALK+ NSCLC treated between October 2015 and June 2019 with lorlatinib as part of EAP were included. Data were collected and reviewed from medical records by independent research staff of the French Thoracic Cancer Intergroup. The primary endpoint was progression-free survival (PFS).Of the 208 patients included, 117 (56%) were female, 142 (69%) were never smokers, and 180 (87%) had stage IV NSCLC at diagnosis. The most frequent histology was adenocarcinoma (94%), and the median age was 60.9 years. At the time of lorlatinib initiation, 160 (77%) patients had brain metastases, and 125 (72%) were performance status 0/1. Lorlatinib was delivered as 2nd/3rd/4th/5th+ line in 4%/17%/30%/49% of patients. A total of 162 (78%) patients had previously been treated with chemotherapy, 194 (93%) with a first-generation ALK-TKI, 195 (94%) with a second-generation ALK-TKI. The median follow-up from lorlatinib initiation was 23.3 months. The median PFS, median overall survival (OS) from lorlatinib initiation and median OS from advanced NSCLC diagnosis were 9.9 months (95% confidence interval [CI] 6-12.3 months), 32.9 months (95% CI 18.7 months to not reached) and 97.3 months (95% CI 75.7-152.8 months), respectively. The median duration of treatment with lorlatinib was 11.8 months (95% CI 8.5-18.8 months). Overall response and disease control rate were 49% and 86%, respectively. Central nervous system objective response rate was 56%. Treatment was stopped due to toxicity in 28 patients (14%). The safety profile of lorlatinib was consistent with previously published data.Real-world evidence indicates that lorlatinib offers a significant clinical benefit and high intracerebral antitumour activity in heavily pretreated patients with ALK+ NSCLC.NCT03727477.

9615 Background: Lorlatinib, a third-generation tyrosine kinase inhibitor targeting ALK and ROS1, has been made available in France starting October 2015 through an EAP for advanced, refractory, ALK+ NSCLC after the failure of chemotherapy and TKIs. Besides the landmark, multi-cohort phase II trial that assessed lorlatinib in ALK+ NSCLC, real-life evidence regarding the efficacy and safety, as well as treatment sequences including lorlatinib, is lacking. Methods: We report the cohort of consecutive patients with advanced, refractory, ALK or ROS1+ NSCLC enrolled in the French EAP of lorlatinib from October 2015 to October 2019. Data were collected from medical records by French Cooperative Thoracic Intergroup (IFCT) research study assistants on site. Primary endpoint was progression-free survival. Results: 200 patients were included: 143 (71.5%) ALK+, 57 (28.5%) ROS1+, 87 (44%) men, 127 (66%) never-smokers, and 167 (85%) stage IV disease. Mean age was 59 years. At the time of initiation of lorlatinib, 146 (74%) patients had Central Nervous System (CNS) disease (78 % for ALK+, 63% for ROS1+), 131 (76%) were PS 0/1. Lorlatinib was delivered as 2nd/3rd/4th/5th+ line in 3%/17%/27%/53%of ALK+ patients and in 30%/30%/16%/24%of ROS1+ patients, respectively. 150 (75%), 185 (93%), 138 (69%), and 80 (40%) patients had received prior chemotherapy, crizotinib, 2nd generation TKIs, and brain radiotherapy, respectively. Median PFS and OS from the initiation of lorlatinib were 11.8 (95% CI 7.3-14.6) months and NR (95% CI 18.6-NR) months, respectively for ALK+ patients and 7.6 (95% CI 6.2-10.2) months and 20.9 (95% CI 10.0-NR) months, respectively for ROS1+ patients. ORR and DCR were 46.2% (95% CI 37.6-54.7) and 86.2% (95% CI 80.2-92.1), respectively for ALK+ patients and 47.1% (95% CI 33.4-60.8) and 88.2% (95% CI 79.4-97.1), respectively for ROS1+ patients. CNS ORR was 41.7% (95% CI 33.3-50.1) and 37.7% (95% CI 24.7-50.8), respectively. With a median follow-up of 15.6 (95% CI 14.0-17.6) months, progression under lorlatinib treatment was observed in 71 (50%) ALK+ patients and 35 (61%) ROS1+ patients, and CNS progression in 24 (34%) and 8 (23%) patients, respectively. The safety profile of lorlatinib was consistent with published data. Conclusions: These real-life results confirmed lorlatinib as a major treatment option for patients with advanced refractory ALK or ROS1+ NSCLC.

Background Osimertinib, a third-generation tyrosine kinase inhibitor, is a new therapeutic option in epidermal growth factor receptor (EGFR)-mutated non-pretreated advanced non–small-cell lung cancer (NSCLC). The tumor escape mechanisms after first-line treatment with osimertinib are partially known; most of the data being obtained by analysis of circulating tumor DNA (ctDNA) from the FLAURA phase III trial. Study Design The MELROSE study, a French multicentric, open label, phase II trial ( ClinicalTrials.gov NCT03865511 ) plans to enroll 150 patients with treatment-naive advanced EGFR-mutated (L858R or exon 19 deletion) NSCLC, age ≥ 18 years, with an Eastern Cooperative Oncology Group performance status 0 or 1. All patients will receive osimertinib at the dose of 80 mg/d. Tumor assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria will be performed every 3 months, with brain and thoracoabdominal computed tomographic scan. The continuation of osimertinib is at the discretion of the referring physician, particularly if clinical benefit is observed. The primary objective is the genetic tumor profile, both on tissue biopsy and ctDNA analyses, at the time of disease progression. Other endpoints include kinetic studies of ctDNA, biological progression-free survival (bPFS) (time from first study dose to first biological event on ctDNA), median PFS according to RECIST criteria 1.1 (called radiological [r] PFS), and median clinical (c) PFS (time from the first study dose to off-osimertinib). This study started in April 2019, and 18 centers in France are participants.

Resume Etat des connaissances Programmed cell death-ligand 1 (PD-L1) est une proteine membranaire facilitant l’echappement tumoral vis-a-vis de l’immunite. Le durvalumab est un anticorps monoclonal bloquant l’interaction PD-L1/PD-1 entre lymphocytes T et cellules tumorales, ayant montre des reponses durables et une toxicite acceptable en phase I/II dans les cancers bronchiques non a petites cellules (CBNPC) metastatiques. Methodes Dans cette etude de phase II, 3 perfusions de durvalumab (10 mg/kg a j1, j15, j29) sont administrees en neo-adjuvant a des patients ≥ 18 ans, indice de performance (PS) 0–1, ayant un CBNPC de stade clinique IB (> 4 cm) ou II. La chimiotherapie et la radiotherapie preoperatoire ne sont pas permises. L’objectif principal est la faisabilite d’une resection chirurgicale complete. Un taux de resection complete Resultats attendus L’immunotherapie neo-adjuvante est faisable et pourrait ameliorer la survie des CBNPC de stade precoce.

Lymph node metastasis is an important prognosis factor in non-small cell lung cancer (NSCLC) patients. The aim of this study was to investigate the role of epithelial to mesenchymal transition (EMT) in lymph node progression in the early stages of NSCLC. We studied a retrospective cohort of 160 consecutive surgically treated NSCLC patients with available frozen tumor samples for expression of EMT markers (CDH1, CTNNB1, CDH2, and VIMENTIN), inducers (TGFB1, c-MET, and CAIX), and transcription factors (EMT-TF: SNAI1, SNAI2, ZEB1, TWIST1, and TWIST2). Partial EMT was more frequent in N1-2 (N+) vs N0 patients (P < .01). TGFB1 (P = .02) as well as SNAI2 (P < .01) and TWIST1 (P = .04) were the most differentially expressed genes in N+ tumors. In this group, ZEB1 was correlated with all EMT inducers and other EMT-TFs were overexpressed depending on the inducers. CAIX was an independent prognostic factor for overall survival (IC 95% HR: 1.10-5.14, P = .03). Partial EMT is involved in lymph node progression of NSCLC patients and depends on the TGFβ pathway. EMT-TFs are differentially expressed depending on EMT inducers. CAIX might be a relevant prognostic marker in early stage NSCLC.

Introduction Le lorlatinib est un inhibiteur de tyrosine kinase (ITK) de troisieme generation ciblant ALK et ROS1 disponible en France depuis octobre 2015 via une ATU pour les CBNPC avances ALK+ apres echec d’au moins un ITK ALK. Les donnees concernant l’efficacite et la tolerance du lorlatinib utilise dans cette indication sont encore parcellaires et reposent sur les Resultats d’un seul essai de phase II. Methodes Tous les patients consecutifs atteints d’un CBNPC de stade avance ALK+ traites par lorlatinib dans le cadre de l’ATU ont ete inclus entre octobre 2015 et juin 2019. Les donnees ont ete collectees a partir des dossiers medicaux. Le critere d’evaluation principal etait la survie sans progression (SSP). Resultats Parmi les 197 patients inclus, 112 (56,9 %) etaient des femmes, 134 (69,1 %) des non-fumeurs et 170 (86,3 %) presentaient un CBNPC de stade IV au diagnostic. Il s’agissait dans 93.4 % des cas d’adenocarcinome et l’âge median etait de 60,6 ans. Au moment de l’initiation du lorlatinib, 152 (77,2 %) patients presentaient des metastases cerebrales et 121 (72,9 %) etaient PS0/1. Cent cinquante-deux (77,2 %) patients avaient deja ete traites par chimiotherapie, 182 (92,4 %) par crizotinib, et 183 (92,9 %) par un ITK ALK de 2e generation. Le lorlatinib a ete administre en 2e/3e/4e/5e ligne ou plus chez 4,1 %/18,3 %/29,4 %/48,2 % des patients. La duree mediane de suivi a l’initiation au lorlatinib etait de 17,1 mois IC95 % (15,9–19,3). Les medianes de SSP et de survie globale apres l’initiation du lorlatinib etaient de 9,7 mois IC95 % (5,9-12,0) et 32,9 mois IC95 % (18,7-NR) respectivement. La duree mediane de traitement par lorlatinib etait de 7,5 mois. Le taux de reponse global (TRG) et le taux de controle de la maladie etaient de 50,6 % IC95 % (43,3 %-57,9 %) et 86,7 % IC95 % (81,7 %-91,6 %) respectivement. Le TRG cerebral etait de 42,9 % IC95 % (35,8 %-50,1 %). Cent (50,8 %) patients ont presente une progression tumorale sous lorlatinib. Le traitement a ete arrete pour toxicite chez 28 patients. Le profil de tolerance du lorlatinib etait conforme aux donnees publiees anterieurement. Conclusion Ces resultats de vie reelle montrent que le lorlatinib offre un benefice clinique important ainsi qu’une activite antitumorale intra-cerebrale significative chez les patients atteints d’un CBNPC de stade avance ALK+, lourdement pretraites.

Background In 2013, the French National Cancer Institute initiated the AcSe program to provide patients with secure access to targeted therapies outside of their marketed approvals. Efficacy and safety was then assessed using a two-stage Simon phase II trial design. When the study design was designed, crizotinib was approved only as monotherapy for adults with anaplastic lymphoma kinase plus non-small-cell lung cancers (NSCLC). Patients and methods Advanced NSCLC patients with c-MET ≥6 copies, c-MET-mutated, or ROS-1-translocated tumours were enrolled in one of the three cohorts. Patients were treated with crizotinib 250 mg twice daily. Efficacy was assessed using the objective response rate (ORR) after two cycles of crizotinib as primary outcome. Secondary outcomes included disease control rate at four cycles, best ORR, progression-free survival, overall survival, and drug tolerance. Results From August 2013 to March 2018, 5606 patients had their tumour tested for crizotinib targeted molecular alterations: 252 patients had c-MET ≥6 copies, 74 c-MET-mutation, and 78 ROS-1-translocated tumour. Finally, 25 patients in the c-MET ≥6 copies cohort, 28 in the c-MET-mutation cohort, and 37 in the ROS-1-translocation cohort were treated in the phase II trial. The ORR was 16% in the c-MET ≥6 copies cohort, 10.7% in the mutated, and 47.2% in the ROS-1 cohort. The best ORR during treatment was 32% in the c-MET-≥6 copies cohort, 36% in the c-MET-mutated, and 69.4% in the ROS-1-translocation cohort. Safety data were consistent with that previously reported. Conclusions Crizotinib activity in patients with ROS1-translocated tumours was confirmed. In the c-MET-mutation and c-MET ≥6 copies cohorts, despite insufficient ORR after two cycles of crizotinib, there are signs of late response not sufficient to justify the development of crizotinib in this indication. The continued targeting of c-MET with innovative therapies appears justified. Clinical trial number NCT02034981.

Purpose: The incidence of lung cancer has dramatically increased in women. Preclinical data have suggested that combining EGFR–tyrosine kinase inhibitor (TKI) with an antiestrogen may overcome resistance to EGFR-TKI. Patients and Methods: The IFCT-1003 LADIE trial was a 2 × 2 arms parallel open-label randomized phase II trial. EGFR-TKI–naïve postmenopausal women with advanced lung cancer were treated with gefitinib (G) versus gefitinib + fulvestrant (G+F) in the EGFR-mutated group (EGFR+) or with erlotinib (E) versus erlotinib + fulvestrant (E+F) in the EGFR wild-type group (EGFR-WT). The primary objective was progression-free survival (PFS) at 3 and 9 months for EGFR-WT and EGFR+ patients. Results: Overall, 204 patients (gefitinib 104 and G+F 100) and 175 patients (erlotinib 87 and E+F 88) were enrolled in the EGFR+ and EGFR-WT cohorts. In the EGFR+ cohort, the primary endpoint was reached, with 58% of the G+F group patients being nonprogressive at 9 months. Adding fulvestrant to gefitinib was not associated with improved PFS (9.9 vs 9.4 months) or overall survival (OS; 22.1 vs 28.6 months). In the EGFR-WT cohort, the primary endpoint was also achieved (33.7% of the patients were nonprogressive at 3 months). Adding fulvestrant to erlotinib was not associated with improved outcome (PFS 1.8 vs 2.0 and OS 10.3 vs 7.3 months). No PFS difference was observed regarding estrogen receptor alpha expression. The tolerance was as expected with no treatment-related death. Conclusions: Adding fulvestrant to EGFR-TKI is feasible, but not associated with prolonged PFS regardless of EGFR status. The lack of benefits while combining fulvestrant to EGFR-TKI does not support its future development in an unselected population.

Introduction Immune checkpoint inhibitors (ICIs) have improved cancer prognosis but have not been evaluated specifically in sarcomatoid carcinoma (SC), a rare lung cancer subtype with poor prognosis. As such, our study sought to retrospectively assess the efficacy of ICI in SC. Methods All consecutive patients with centrally confirmed SC treated using ICI as a second-line treatment or beyond between 2011 and 2017 were enrolled. Programmed death-ligand 1 (PD-L1) tumor expression was assessed using immunohistochemistry (SP263 clone) and the tumor mutational burden (TMB) with the Foundation One panel. TMB was considered high if it was greater than or equal to 10 mutations per megabase. Results Overall, 37 patients with SC were evaluated, predominantly men (73%) with a median age of 63.2 years (36.8–79.7) and who were current or former smokers (94.6%). Immunotherapy (nivolumab, 86.5% of cases) was given as a second-line treatment in 54% of the patients and as third-line treatment or beyond in 46% of the patients. The objective response rate was 40.5% and disease control rate was 64.8%, regardless of PD-L1 status. Median overall survival was 12.7 months (range: 0.3–45.7). One-third of patients exhibited early progression. The median PD-L1 expression was 70% (0–100). There was a trend toward higher PD-L1 expression in responsive diseases, with an objective response rate of 58.8% in patients with PD-L1+ and 0% in the one patient with PD-L1- (p = 0.44). The median TMB was 18 (4–39) mutations per megabase, with 87.5% of the cases displaying a high TMB. There was a trend toward higher TMB in responders versus stable or progressive diseases (p = 0.2). Conclusions Patients with SC exhibited high response rates and prolonged overall survival under ICI treatment. These data support the prospective investigation of ICI in patients with SC who are under first-line treatment.

Objectives Brigatinib is a next-generation ALK inhibitor initially developed in ALK-positive NSCLC pretreated with crizotinib. Materials and Methods This retrospective multicentric study analyzed ALK-positive advanced NSCLC patients pretreated with at least one tyrosine-kinase inhibitor, including crizotinib, and enrolled in the brigatinib French early access program. The primary endpoint was investigator-assessed progression-free survival (PFS). Results 104 patients were included (mean age, 56.6 years; never smokers, 61.5%; adenocarcinoma, 98.1%). Patients had received a median of 3 previous treatment lines, including at least 2 ALK inhibitors (mainly crizotinib then ceritinib). At brigatinib initiation, 59.1% had performance status 0–1, 51.9% had ≥ 3 metastatic sites, 74.5% had central nervous system metastases (CNS) and 8.8% had carcinomatous meningitis. Median duration of brigatinib treatment was 6.7 (95% CI, 0.06–20.7) months. Median PFS was 6.6 (4.8–9.9) months for the entire population. For patients who received 2, 3–4 and >4 lines of treatment before brigatinib, PFS was 4.3 (2.5–8.9), 10.4 (5.9–13.9) and 3.8 (0.8–7.4) months, respectively. In the 91 evaluable patients, disease control rate was 78.2%. From brigatinib start, median overall survival was 17.2 (11.0–not reached) months. Among the 68 patients with progressive disease after brigatinib, CNS was involved in 29.4% of cases. Median OS from the diagnosis of NSCLC was 75.3 (38.2–174.6) months. Conclusion These real-world results confirm the efficacy of brigatinib in a cohort of patients heavily pretreated for ALK-positive advanced NSCLC.

Anaplastic lymphoma kinase inhibitors (ALKi) like ceritinib are considered standard for front-line treatment of non-small cell lung cancers (NSCLC) harboring a translocation of the anaplastic lymphoma kinase (ALK) gene. We report herein a case of interstitial lung disease (ILD) that developed following a 7-month ceritinib treatment without recurrence under either crizotinib or brigatinib, two others ALKi.

Resume L’âge median de diagnostic d’un cancer bronchique se situe, selon les pays, entre 65 et 70 ans. Pourtant, peu de recommandations sur la prise en charge des personnes âgees existent. Il faut tenir compte de l’etat general, mais aussi des comorbidites, des variations physiologiques liees a l’âge, des principales fonctions de l’organisme ainsi que des traitements pris au long cours. Pour les stades precoces de cancer bronchique non a petites cellules, l’indication chirurgicale doit etre discutee. La chimiotherapie adjuvante n’est pas indiquee apres 75 ans. Dans les formes localement avancees on privilegiera l’administration sequentielle de la chimiotherapie et de la radiotherapie. Dans les formes metastatiques, lorsqu’il existe des mutations ciblables, une therapie ciblee doit etre mise en œuvre quel que soit le PS. Pour les formes non mutees et les epidermoides, le traitement sera un doublet carboplatine-paclitaxel hebdomadaire pour les patients de PS 0-2. Les inhibiteurs de points de controle de l’immunite ont ete investigues en premiere et en deuxieme ligne et des personnes âgees font partie des essais mais il n’y a pas d’essai dedie. En ce qui concerne le cancer bronchique a petites cellules, le traitement reste l’association carboplatine + etoposide.

9072 Background: Thymic carcinomas are an aggressive and difficult to treat subset of thymic epithelial tumors (TETs) that represent a heterogeneous group of rare intrathoracic malignancies. Most of the current knowledge and guidelines tumors rely on surgically-oriented databases focusing on early-stage disease, and small prospective, single-arm trials conducted in metastatic thymic carcinomas, mostly in a refractory, late-line setting. “Réseau tumeurs THYMiques et Cancer” (RYTHMIC) is the nationwide network for TETs in France. The management of any patient has to be systematically discussed on a real-time basis at a national multidisciplinary tumor board; a database is hosted by the French Thoracic Cancer Intergroup (IFCT). Methods: We took advantage of the RYTHMIC prospective database to describe baseline characteristics, analyze treatment strategies, and provide landmark outcomes in a cohort of consecutive patients with thymic carcinoma. The inclusion period was January 2012 to April 2017. Results: A total of 213 patients were analyzed. Overall, 60 (28%) patients were considered as surgical candidates upfront, 91 (43%) received primary chemotherapy, and 62 (29%) received exclusive chemotherapy. Median OS was 49.2 months (IC95%: 34.8-63.6); OS was significantly longer in patients with a lower stage at diagnosis (p < 0.001), who were operated on upfront, as opposed to patients who received primary or exclusive chemotherapy (p < 0.001). Surgery, conducted upfront or after primary chemotherapy, was significantly associated with more prolonged OS (p < 0.001); complete resection and postoperative radiotherapy were also predictors of better outcome (p = 0.018 and p = 0.081, respectively). Exclusive chemotherapy was delivered to 62 patients with advanced disease, who all received platinum-based regimen as first-line treatment; PAC regimen was delivered to 66% of patients. Best objective response to first-line chemotherapy was partial response in 33 (53%) patients. Median PFS was 8.0 months (IC95%: 5.0-11.1). Median OS was 32.9 months (IC95%: 20.6-45.1). Response to first-line chemotherapy and squamous histology were the only significant predictors of OS (p = 0.002 and p = 0.040, respectively). Conclusions: Our cohort is the first to analyze in depth outcomes and treatment strategies in a prospective cohort of consecutive patients with thymic carcinoma. While we confirm the major prognostic impact of surgery, our data highlight the need for optimized multidisciplinary management and innovative therapies as the survival of patients remains limited.

Thymic epithelial tumors (TETs) are rare malignancies that may be aggressive and difficult to treat. In the advanced setting, systemic treatments may be delivered as primary therapy before surgery or definitive radiotherapy, as exclusive treatment when no focal treatment is feasible, or in the setting of recurrences. Réseau tumeurs THYMIques et Cancer (RYTHMIC) is the nationwide network for TETs in France. The objective of the study was to describe the modalities and analyze the efficacy of systemic treatments for patients with advanced TETs included in the RYTHMIC prospective database hosted by the French Thoracic Cancer Intergroup.All consecutive patients for whom systemic treatment was discussed at the RYTHMIC multidisciplinary tumor board from 2012 to 2015 and who received at least one cycle of treatment were included. The main end points were objective response and progression-free survival (PFS).A total of 236 patients were included in this analysis. Of those 236 patients, 91 received primary chemotherapy, leading to response rates of 83% for thymomas and 75% for thymic carcinomas and a median PFS of 23.2 months. A strong predictor of longer PFS was histologic type of thymoma (p 0.001). Exclusive chemotherapy was delivered to 54 patients. The response rates were 31% for thymomas and 37% for thymic carcinomas. The median PFS was 6.2 months, and it was correlated to response rate (p = 0.001). Systemic therapy for a first, second, third, and fourth recurrence was delivered to 114, 81, 51, and 27 patients, respectively. The response rates ranged between 15% and 39% for thymomas and 4% to 21% for thymic carcinomas. The median PFS times were 7.7, 6.2, 5.9, and 6.5 months, respectively.Patients with advanced thymic malignancies may receive multiple lines of systemic therapy, with an opportunity for clinically relevant PFS rates for which objective response may be a surrogate. Our real-life study provides landmark efficacy data that are needed when designing clinical trials to assess innovative agents.

Here we report our experience of ceritinib in crizotinib-pretreated patients with anaplastic lymphoma kinase (ALK) positive (ALK+) non-small cell lung cancer (NSCLC) in a French temporary authorisation for use (TAU) study. The French TAU study included crizotinib-pretreated patients with advanced ALK+ or ROS proto-oncogene 1 positive (ROS1+) tumours. Patients received oral ceritinib (750 mg·day−1 as a starting dose) and best tumour response (as evaluated by the investigator) and safety were reported every 3 months. A total of 242 TAUs were granted from March 12, 2013 to August 05, 2015. Of the 242 patients, 228 had ALK+ NSCLC and 13 had ROS1+ NSCLC. The median age of ALK+ patients (n=214) was 58.5 years, 51.9% were female, 70.8% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1 and 50.0% had brain metastases. Of the 149 efficacy evaluable ALK+ NSCLC patients, 5.4% had a complete response (CR), 47.0% had a partial response (PR) and 22.8% had stable disease (SD). At September 05, 2015, the median duration of ceritinib treatment (n=182) was 3.9 months but 5.5 months for patients (n=71) with a follow-up of ≥12 months. Higher objective response rate (ORR) was observed for patients with ECOG PS 0 to 1 (55.0% versus 42.4%) and those receiving prior crizotinib for >5 months (51.6% versus 36.1%). Treatment-related adverse events (AEs) were reported in 118 of 208 patients (56.7%), the most common being diarrhoea (22.1%) and hepatic toxicity (19.7%). Ceritinib (750 mg·day−1) demonstrated efficacy similar efficacy to ASCEND-1, ASCEND-2 and phase 3 ASCEND-5 trials with manageable safety in crizotinib-pretreated patients with ALK+ NSCLC., Ceritinib (750 mg per day) showed similar efficacy as in clinical trials in crizotinib-pretreated ALK+ NSCLC patients http://ow.ly/8oXe30h27D0

Emerging data highlight different clinical behaviors according to KRAS amino acid substitutions (AASs) in patients with non-small-cell lung cancer (NSCLC). We aimed to evaluate whether different KRAS AASs were associated with different responses to chemotherapy.We retrospectively reviewed data from 1190 patients with KRAS mutations who underwent first-line platinum-based chemotherapy for stage IV NSCLC. The response to different chemotherapy regimens was evaluated using the Response Evaluation Criteria In Solid Tumors criteria (v 1.1). Overall survival and time to progression (TTP) were secondary endpoints.Taxane was associated with the best response in the entire cohort (odds ratio, 2.52; 95% confidence interval [CI], 1.82-3.48; P .001), especially in G12V patients (odds ratio, 2.15; 95% CI, 1.05-4.41; P = .036). Taxane was associated with improved TTP in the entire cohort (hazard ratio [HR], 0.31; 95% CI, 0.26-0.38; P .001), especially in G13D patients (HR, 0.47; 95% CI, 0.22-1.01; P = .054). Pemetrexed was associated with the worst TTP in the entire cohort, particularly in G12V patients, who had the worst response rates (HR, 0.55; 95% CI, 0.30-0.99; P = .049). No impact on overall survival was observed according to different chemotherapy regimens and AASs.KRAS-specific AAS appears to induce different responses to chemotherapy regimens after first-line platinum-based chemotherapy in advanced NSCLC.

Introduction Les inhibiteurs de checkpoint immunitaire (ICI) ont permis une nette amelioration du pronostic dans le cancer bronchique non a petites cellules (CBNPC). Des donnees prealables ont montre que l’expression de PD-L1 et l’infiltrat immunitaire etaient eleves dans les carcinomes sarcomatoides (CS), un type histologique rare associe a un mauvais pronostic. Cette etude vise donc a evaluer de maniere retrospective l’efficacite des ICI dans le CS. Methodes Tous les patients consecutifs avec un diagnostic confirme (relecture centralisee) de CS de stades III/IV et ayant recu au moins une dose d’ICI entre 2011 et 2017 ont ete inclus. L’expression de PD-L1 etait positive lorsqu’elle etait superieure a 1 %. Resultats Quarante-deux centres ont participe, et 27 ont inclus 39 patients. Au diagnostic, les patients etaient principalement des hommes (81 %), fumeurs actifs (41 %) ou sevres (53,8 %), d’âge median 63,2 ans [36,8–84,6]. Le PS etait de 0–1 pour 71,8 % des patients. Une analyse moleculaire a ete realisee sur 16 tumeurs (48,8 %) : 38,7 % mutees KRAS, 7,7 % mutees MET exon 14 et 2,6 % mutees EGFR. La quasi-totalite des patients (94,9 %) ont recu une chimiotherapie a base de platine avant l’ICI, qui etait administre en 1e / 2e / ≥ 3e lignes dans respectivement 5,1 %/51,3 %/43,6 %. Les patients ont recu du nivolumab (87,2 %), pembrolizumab (7,7 %) ou atezolizumab (5,1 %) (duree mediane : 4,5 mois [0,5–24]). Le taux de reponse objective (TRO) etait de 38,5 %, le taux de controle de la maladie (TCM) de 61,6 % et le taux de progression de 30,8 %. La principale raison d’arret du traitement etait la progression (69,2 %), avec une mediane de survie sans progression (SSP) de 4,6 mois [0,3–24,1] et un taux de SSP a 1 an de 10,3 % (4 / 39). Cinq patients (12,8 %) sont decedes avant la 1e evaluation (mediane : 0,6 mois [0,26–1,51]). La survie mediane etait de 20 mois [1,7–61,7]. Dix-huit patients (46,1 %) ont recu un traitement apres l’ICI (chimiotherapie (n = 15) ou ITK (n = 3)) avec 55,5 % de progressions, 27,8 % de stabilisations et pas de reponse partielle. Le statut PD-L1 a ete evalue dans 18 tumeurs (46,1 %). Les TRO et TCM etaient respectivement de 53,3 % (8 / 15) et 66,7 % (10 / 15) chez les PD-L1 + , et 33,3 % (1 / 3) pour les 2 criteres chez les PD-L1− . Il n’y avait pas de differences en termes de reponse et de survie en fonction du statut KRAS. Conclusion Les patients atteints de CS pourraient donc beneficier d’un ICI. Nous collectons actuellement les echantillons tumoraux pour evaluer la correlation entre la reponse et le statut PD-L1.

Introduction Le brigatinib est une nouvelle option therapeutique pour les patients presentant un cancer bronchique non a petites cellules (CBNPC) metastatique avec translocation ALK. Peu de donnees existent sur son efficacite en dehors d’essais cliniques [1] . Methodes BRIGALK est une etude de cohorte analysant les caracteristiques des patients traites par brigatinib dans le cadre d’un programme d’acces precoce et evaluant l’efficacite et la tolerance du brigatinib dans cette population. Resultats L’etude a inclus 103 patients dans 43 centres. L’analyse intermediaire sur les 40 premiers patients inclus dans la cohorte retrouve : âge median :54,2 ± 9,4 ans, non ou ex-fumeurs : 92 %, PS 0–1 : 55 %, adenocarcinomes : 92 %, nombre median de sites metastatiques a l’initiation du brigatinib : 2,5, 75 % d’atteintes cerebrales, symptomatiques dans 60 % des cas (dont 5 cas de meningite carcinomateuse). Au moment de la progression sous brigatinib, 18 patients (45 %) ont eu une rebiopsie soit tissulaire soit liquidienne (LCR, plevre pour 1/3 mais aucune biopsie liquide). Les nouvelles analyses en genetique moleculaire ont permis de mettre en evidence un cas de mutation de resistance ALK et trois nouvelles mutations (EGFR, METexon14 et TP53). Le nombre median de lignes de traitements avant brigatinib etait de 3 ± 1,3. Parmi les 33 patients evaluables, le taux de reponse est de 63 % (toutes des reponses partielles), le taux de controle de la maladie de 84 %. On note 10 % d’arrets definitifs du traitement pour intolerance. La mediane de PFS sous brigatinib est de 7,8 mois (95 %CI : 4,3–15,7). Le site principal de progression est cerebral dans 34 % des cas. La mediane de survie sous Brigatinib n’est pas atteinte. L’analyse complete sur l’ensemble des patients inclus sera presentee au CPLF. Conclusion Cette etude confirme les donnees d’efficacite et de tolerance du brigatinib dans une cohorte de patients lourdement pretraites pour un CBNPC metastatique, transloque ALK : les resultats sont concordants avec les donnees des essais cliniques.

Summary Background Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. Methods We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. Findings Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7–22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2–4·8), and median duration of response was not reached (95% CI 8·31–not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7–10·9). 20 (17%) of 117 patients reported grade 3–4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. Interpretation Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. Funding Bristol-Myers Squibb.

Crizotinib (XALKORI™, Pfizer) is a tyrosine kinase inhibitor targeting ALK, MET and ROS1, currently approved for the treatment of adults with ALK-rearranged non-small-cell lung cancer. Optimizing the management of frequent crizotinib-related adverse events is crucial to ensure its continuous administration and reproduce the response and survival rates reported in clinical trials. Here, we propose some practical measures, which are mostly derived from the recommendations given to the investigators of the PROFILE 1001, 1005, 1007 and 1014 trials and are based on experience and scientific findings regarding the management of these disorders. While visual disturbances or bradycardia are frequent but benign, the severity of the cardiac and hepatic adverse events requires special attention potential to QT interval prolongations and to the monitoring of electrolyte levels and liver function, taking into account potential drug-drug interactions.

The pretreatment detection of an activating mutation of EGFR is now routinely performed in metastatic nonsquamous non-small cell lung cancer (NSCLC). The therapeutic impact of such a detection is major, as patients with advanced NSCLC exhibiting a mutation of exon 19 or 21 will benefit from EGFR-tyrosine kinase inhibitors (TKI). The presence of an EGFR resistance mutation, such as T790M in EGFR-TKI-naïve patients, is seldom looked for and is related either to a germinal mutation or to somatically mutated subclones. It has a negative predictive impact. We present the case of a patient with a lung papillary adenocarcinoma and miliary intrapulmonary metastases whose tumor displays a somatic complex heterozygous EGFR mutation, combining L858R (exon 21) and a primary resistance mutation T790M (exon 20), both detected by direct sequencing.

Crizotinib (XALKORI(™), Pfizer) is a tyrosine kinase inhibitor of ALK, MET, and ROS1, which is currently approved for the second line treatment for ALK-rearranged lung cancer. This work from an expert group, based on the review of the data from the Profile studies, aims to provide practical elements in order to optimize the tolerability of crizotinib. Specific major or frequent side effects of crizotinib are discussed: visual disturbances, cardiac effects, elevated transaminases, and hypogonadism. In the routine practice, patients should be advised about visual disturbances, especially with regard to driving in low brightness. Digestive disorders related to crizotinib are exceptionally persistent or severe. Dietary measures and symptomatic treatments usually control these disorders. It is recommended to perform an electrocardiogram before introduction of crizotinib, to identify prolonged QT interval. Torsades de pointes may produce dizziness or syncope. Hypogonadism should be considered in case of fatigue, decreased libido, and even depression, taking into account that these symptoms may be related to cancer; testosterone serum level should be measured to identify patients that may be eligible to receive a supplementation. Monitoring of liver function tests, including transaminases and bilirubin, is necessary. To conclude, these practical elements are helpful to optimize treatment with crizotinib in patients with ALK-rearranged lung cancer; in the future, academic initiatives should be taken to study these aspects, based on the monitoring of large cohorts of patients treated with crizotinib.

N. Girarda,∗, V. Gounantb, B. Mennecierc, L. Greillierd, A.B. Cortote, S. Couraudf, B. Besseg, L. Broucheth, O. Castelnau i, G.R. Ferretti j, P. Frappek, A. Khalil l, P. Lefeburem, F. Laurentn,o, S. Liebartk, J. Margeryp, O. Molinierq, E. Quoixc, M.-P. Revel r, B. Stachs, P.-J. Souquet f, P. Thomast, J. Tredanielu, E. Lemariev, G. Zalcmanw,x, F. Barlesid, B. Milleronb,x, pour le groupe de travail multidisciplinaire de l’Intergroupe francophone de cancerologie thoracique, de la Societe d’imagerie thoracique et du Groupe d’oncologie de langue francaise

In the present article, Dr Bott and associates (1) seek to address the absorbing question of the safety and utility of pulmonary resection in the setting of patients with residual disease following immune checkpoint inhibitors.

9045 Background: Brigatinib is a next-generation ALK inhibitor initially developed in pre-treated ALK+ NSCLC. Data on the efficacy of brigatinib in real world remain rare. Methods: This retrospective multicentric study analyzed ALK-+ advanced NSCLC patients pretreated with at least two tyrosine-kinase inhibitors, including crizotinib, and enrolled in the brigatinib French early access program. The primary endpoint was investigator-assessed progression-free survival (PFS). Results: 104 patients were included (mean age, 56.6 years; never smokers, 61.5%; adenocarcinoma, 98.1%). Patients had received a median of 3 previous treatment lines, including at least 2 ALK inhibitors, mainly crizotinib then ceritinib in 93% patients. At brigatinib initiation, 59.1% had performance status 0-1, 51.9% had ≥ 3 metastatic sites, 74.5% had central nervous system metastases (CNS) and 8.8% had carcinomatous meningitis. Median duration of brigatinib treatment was 6.7 (0.06–20.7) months. Median PFS was 6.6 (95% CI, 4.8–9.9) months for the entire population. In the 91 evaluable patients, disease control rate was 78.2% (stable, 28.2%; partial response, 45.7%; complete response, 4.3%). From brigatinib start, median overall survival was 17.2 (95% CI:11.0–not reached) months. Among the 68 patients with progressive disease after brigatinib, CNS was involved in 29.4% of cases. Ten (9.6%) patients had treatment discontinuation due to intolerance or patient request. Median OS from the diagnostic of NSCLC was 75,3 (95% CI, 38,2-174,6) months. Conclusions: This study confirms the efficacy of brigatinib in a cohort of patients heavily pretreated for ALK-+advanced NSCLC. These real-world results are consistent with clinical data reported in clinical trials.

There is no dedicated study on second-line treatment for elderly patients with advanced nonsmall cell lung cancer (NSCLC). We report the results on second-line erlotinib therapy from our previously published phase III study comparing single-agent therapy with platinum-based doublet (carboplatin plus paclitaxel) therapy in 451elderly patients. Erlotinib was given to patients exhibiting disease progression or experiencing excessive toxicity during first-line therapy, until further progression or unacceptable toxicity. In total, 292 (64.7%) patients received erlotinib as second-line therapy. Initial performance status 0–1, stage IV NSCLC and an Activities of Daily Living score of 6 were independent factors for receiving erlotinib. Median (95% CI) overall survival was 4 (3.2–6.7) versus 6.8 (5.0–8.3) months in the single-agent and doublet arms, respectively (p=0.089). Performance status 0–1, never having smoked, adenocarcinoma and weight loss ≤5% were favourable independent prognostic factors of survival, whereas the randomisation arm had no significant impact. Among the 292 patients who received erlotinib, 60 (20.5%) experienced grade 3–4 toxic effects, the most frequent being rash. Erlotinib as second-line therapy is feasible, leading to efficacy results similar to those obtained in a previous randomised study that was not dedicated to elderly patients, with acceptable toxicity. Erlotinib is a feasible second-line therapy in elderly patients with advanced nonsmall cell carcinoma

Resume Les patients âges, les patients de PS 2 et a fortiori > 2, les patients infectes par le VIH constituent une population fragilisee avec des risques de toxicite lies au traitement systemique des cancers bronchiques non a petites cellules (CBNPC) accrus. Les personnes âgees de 70 ans et plus representent pas loin de la moitie des cas diagnostiques de CBNPC et, les recherches recentes ont montre qu’un doublet carboplatine et paclitaxel hebdomadaire etait faisable avec une survie comparable a celle obtenue chez des patients plus jeunes. Les patients de PS 2 constituent une population relativement heterogene mais egalement susceptible de beneficier d’un doublet a base de carboplatine, plutot que d’une monotherapie, l’usage du cisplatine etant par ailleurs deconseille. Enfin, les patients infectes par le VIH sont une population a risque de developper un cancer bronchique pour des raisons a la fois d’intoxication tabagique tres importante en general mais aussi en raison de l’immunosuppression. Leur traitement doit prendre en compte les interactions possibles avec les antiretroviraux, parfois responsables d’une toxicite tres majoree.

// Michael Duruisseaux 1 , Benjamin Besse 2 , Jacques Cadranel 3 , Maurice Perol 4 , Bertrand Mennecier 5 , Laurence Bigay-Game 6 , Renaud Descourt 7 , Eric Dansin 8 , Clarisse Audigier-Valette 9 , Lionel Moreau 10 , Jose Hureaux 11 , Remi Veillon 12 , Josiane Otto 13 , Anne Madroszyk-Flandin 14 , Alexis Cortot 15 , Francois Guichard 16 , Pascaline Boudou-Rouquette 17 , Alexandra Langlais 18 , Pascale Missy 19 , Franck Morin 19 , Denis Moro-Sibilot 1 1 Centre Hospitalier Universitaire Grenoble Alpes, Thoracic Oncology Unit, Chest Department, Grenoble, France 2 Medical Oncology Department, Gustave Roussy, Villejuif, France 3 Assistance Publique Hopitaux de Paris, Tenon Hospital, Chest Department, Paris, France 4 Leon-Berard Cancer Center, Lyon, France 5 Centre Hospitalier Universitaire de Strasbourg, Chest Department, Strasbourg, France 6 Larrey Hospital, Chest Department, Toulouse, France 7 Centre Hospitalier Universitaire de Brest, Brest, France 8 Oscar Lambret Cancer Center, Medical Oncology Department, Lille, France 9 Centre Hospitalier Sainte Musse, Chest Department, Toulon, France 10 Centre Hospitalier General de Colmar, Louis Pasteur Hospital, Chest Department, Colmar, France 11 Centre Hospitalier Universitaire d’Angers, Chest Department, Angers, France 12 Centre Hospitalier Universitaire de Bordeaux, Respiratory Disease Department, Pessac, France 13 Antoine Lacassagne Cancer Center, Nice, France 14 Paoli Calmettes Institute, Marseille, France 15 Centre Hospitalier Universitaire de Lille, Thoracic Oncology Unit, Lille, France 16 Medical Oncology Department, Polyclinique Bordeaux Nord Aquitaine, Bordeaux, France 17 Assistance Publique Hopitaux de Paris, Cochin-Port Royal Hospital, Medical Oncology Department, Paris, France 18 French Cooperative Thoracic Intergroup, Department of Biostatistics, Paris, France 19 French Cooperative Thoracic Intergroup, Clinical Research Unit, Paris, France Correspondence to: Denis Moro-Sibilot, email: DMoro-Sibilot@chu-grenoble.fr Keywords: lung cancer, ALK, crizotinib, ceritinib, alectinib Received: September 28, 2016 Accepted: January 10, 2017 Published: February 26, 2017 ABSTRACT Overall survival (OS) with the anaplastic lymphoma kinase (ALK) inhibitor (ALKi) crizotinib in a large population of unselected patients with ALK -positive non-small-cell lung cancer (NSCLC) is not documented. We sought to assess OS with crizotinib in unselected ALK -positive NSCLC patients and whether post-progression systemic treatments affect survival outcomes. ALK -positive NSCLC patients receiving crizotinib in French expanded access programs or as approved drug were enrolled. We collected clinical and survival data, RECIST-defined progressive disease (PD) and post-PD systemic treatment efficacy. We performed multivariable analysis of OS from crizotinib initiation and PD under crizotinib. At time of analysis, 209 (65.7%) of the 318 included patients had died. Median OS with crizotinib was 16.6 months. The line of crizotinib therapy did not impact survival outcomes. Of the 263 patients with PD, 105 received best supportive care, 74 subsequent drugs other than next-generation ALKi and 84 next-generation ALKi. Next-generation ALKi treatment correlated with better survival outcomes in multivariate analysis. These patients had a median post-PD survival of 25.0 months and median OS from metastatic disease diagnosis of 89.6 months. Unselected ALK -positive NSCLC patients achieve good survival outcomes with crizotinib therapy. Next-generation ALKi may provide survival improvement after PD under crizotinib.

Erlotinib has been approved as second-line treatment in patients with non-small cell lung cancer (NSCLC) experiencing relapse after first-line platinum-based chemotherapy. Herein, we report two occurrences of erlotinib-associated gastrointestinal perforation (GIP) in NSCLC patients. Two patients aged 60 and 79 years received erlotinib as third- and second-line NSCLC treatment, respectively. GIP occurred following 3 weeks and 6 months of erlotinib treatment, leading to death a few days later in both patients, neither of whom had any intestinal metastasis. Risk factors related to erlotinib-induced GIP were concomitant oral corticosteroid therapy and ciprofloxacin administration, which may result in erlotinib overexposure. GIP is a severe adverse drug reaction of erlotinib, infrequently described in the literature, compared to other targeted therapies. The lethal risk of erlotinib-associated GIP should be taken into account when evaluating the benefit-risk balance of erlotinib in patients without epidermal growth factor receptor activating mutations.

Introduction L’ajout du bevacizumab a un doublet de chimiotherapie avec sels de platine (pCT-BEVA) en premiere ligne de traitement des cancers du poumon non a petites cellules (CBNPC) non-epidermoides avances permet un benefice en survie globale. Aucune donnee d’efficacite de la pCT-BEVA n’est disponible dans les CBNPC ALK+. Methodes L’etude IFCT-1302 CLINALK est une etude observationnelle, retrospective et multicentrique ayant inclus 318 patients avec un CBNPC ALK+ prouve, de stade III avance/IV, traites par crizotinib dans le cadre du programme ATU ou de l’AMM de 2e ligne. L’efficacite des traitements avant crizotinib etait collectee. Les donnees des patients traites en 1re ligne par un doublet de chimiotherapie avec cisplatine ou carboplatine (pCT) associe au pemetrexed ou au paclitaxel ou a la gemcitabine ont ete analysees. Les caracteristiques cliniques, le taux de reponse objective selon RECIST (TRO) et la survie sans progression (SSP) etaient comparees selon que du BEVA etait administre (pCT-BEVA) ou non (pCT). Un modele de Cox etait utilise pour determiner les variables cliniques (âge, sexe, tabac) et les traitements (BEVA, pemetrexed, gemcitabine, paclitaxel) associees a la SSP. Resultats Au total, 244 patients (pts) recevaient une 1re ligne par pCT dont 60 un traitement par pCT-BEVA (24,6 %). La chimiotherapie comportait du pemetrexed pour 180 pts (73,8 %), du paclitaxel pour 40 pts (16,4 %) et de la gemcitabine pour 24 pts (9,8 %). Le type de molecule de troisieme generation utilisee etait equilibree entre les groupes pCT-BEVA et pCT. Le groupe pCT-BEVA etait significativement plus jeune (mediane 53,6 vs. 58,6 ans, p = 0,01), avait plus frequemment une maladie metastatique au diagnostic (97 vs. 84,8 %, p = 0,01) et recevaient plus frequemment une maintenance (62 vs. 28 %, p Conclusion Un traitement par pCT-BEVA etait associe a un TRO superieur compare a un traitement par pCT. De plus, un traitement par pCT-BEVA etait associe a une meilleure SSP en analyse multivariee. Ces donnees suggerent que l’association pCT-BEVA serait une option therapeutique efficace apres echec des inhibiteurs d’ALK.

Key points Patients aged 70 and over represent the third of the population of patients with lung cancer. There has been for a long time a certain nihilism regarding the treatment of elderly patients with advanced lung cancer as well from medical doctors but also from families and patients themselves with the false belief of an indolent course of the disease in elderly patients. As a result, clinical trials devoted to elderly patients were quite scarce until the end of the last decade. Nevertheless, an important trial was published in 1999 with the comparison of vinorelbine as a single agent versus best supportive care only in patients aged 70 and over with an advanced non-small cell lung cancer. The survival benefit with vinorelbine was important. Then two trials were published comparing monotherapy with either vinorelbine or gemcitabine to the doublet vinorelbine and gemcitabine without convincing results. As a consequence, the ASCO 2004 recommendations were to treat elderly patients with a monotherapy (gemcitabine or vinorelbine). Recently an IFCT trial was presented at the plenary session of the ASCO 2010. A carboplatin (every 4 weeks) + weekly paclitaxel doublet was compared to a vinorelbine or gemcitabine (choice of the center). The survival benefit was of such magnitude that the paradigm of treatment of elderly patients PS 0-2 with advanced NSCLC should be modified in favor of the tested doublet. There should be a reappraisal of the geriatric indexes recommended by the oncogeriatricians regarding their exact prognostic or predictive role.

To the Editor: Somatic epidermal growth factor receptor ( EGFR ) mutations are now routinely integrated in the molecular diagnosis of nonsmall cell lung cancers (NSCLC) [1, 2]. Thus, germ-line EGFR mutations are rarely mentioned or looked for in the context of patients with a family history of cancer, as their association with NSCLC familial cancer risk is not well established. Moreover, the predictive value of these mutations for response to EGFR tyrosine kinase inhibitors (TKIs) is not well known [3]. We report here two different heterozygous germ-line EGFR variants identified in two Caucasian NSCLC patients, who demonstrated different responses to EGFR-TKI. A 63-year-old Caucasian, male former smoker with no family history of cancer (fig. 1a), was admitted for dyspnoea in August 2011, leading to discovery of a lower left lobe lung tumour and pleural effusion. Trans-thoracic biopsy diagnosed an invasive, acinar-predominant adenocarcinoma, classified cT2a N3 M1a (stage IV). Molecular analyses of the tumour by direct sequencing identified two concomitant heterozygous EGFR exon 21 mutations, L858R and V843I, confirmed in two independent experiments (fig. 1b). The V843I variant, but not L858R, was also detected in DNA obtained from a blood sample, with written informed consent, confirming a germ-line mutation (fig. 1c). Following treatment with cisplatin and pemetrexed, the patient relapsed in December 2012 with vertebral metastasis. An EGFR-TKI (erlotinib) was initiated, resulting in a stable disease for 9 months. Figure 1. a–c) Case 1, with epidermal growth factor receptor ( EGFR ) exon 21 mutations (V843I and L858R). a) Pedigree chart. The black case corresponds to the index patient. b) DNA sequencing electrophoretograms for DNA obtained from lung tumour tissue identifying EGFR exon 21 mutations; both mutations are present. c) DNA sequencing electrophoretograms for DNA obtained from blood, identifying one EGFR exon 21 mutation, the V834I variant, is present and confirming …