Real-life clinical management patterns in extensive-stage small cell lung cancer across France: a multi-method study.

BACKGROUND: We designed this study based on both a physician practice survey and real-world patient data to: (1) evaluate clinical management practices in extensive-stage small cell lung cancer (ES-SCLC) among medical centers located across France; and (2) describe first-line treatment patterns among patients with ES-SCLC following the introduction of immunotherapy into clinical practice. METHODS: A 50-item questionnaire was completed by physicians from 45 medical centers specialized in SCLC management. Responses were collected from June 2022 to January 2023. The survey questions addressed diagnostic workup of ES-SCLC, chemoimmunotherapy in first-line and second-line settings, and use of prophylactic cranial irradiation (PCI) and radiotherapy. In parallel, using a chart review approach, we retrospectively analyzed aggregated information from 548 adults with confirmed ES-SCLC receiving first-line treatment in the same centers. RESULTS: In ES-SCLC, treatment planning is based on chest computed tomography (CT) (as declared by 100% of surveyed centers). Mean time between diagnosis and treatment initiation was 2-7 days, as declared by 82% of centers. For detection of brain metastases, the most common imaging test was brain CT (84%). The main exclusion criteria for first-line immunotherapy in the centers were autoimmune disease (87%), corticosteroid therapy (69%), interstitial lung disease (69%), and performance status ≥ 2 (69%). Overall, 53% and 36% of centers considered that patients are chemotherapy-sensitive if they relapse within ≥ 3 months or ≥ 6 months after first-line chemoimmunotherapy, respectively. Among the 548 analyzed patients, 409 (75%) received chemoimmunotherapy as a first-line treatment, 374 (91%) of whom received carboplatin plus etoposide and 35 (9%) cisplatin plus etoposide. Overall, 340/548 patients (62%) received maintenance immunotherapy. Most patients (68%) did not receive radiotherapy or PCI. CONCLUSIONS: There is an overall alignment of practices reflecting recent clinical guidelines among medical centers managing ES-SCLC across France, and a high prescription rate of immunotherapy in the first-line setting.

Impact of EGFR mutations and KRAS amino acid substitution on the response to radiotherapy for brain metastasis of non-small-cell lung cancer.

BACKGROUND: Our study aimed to evaluate response rate (RR) to brain metastasis radiotherapy (RT), depending on the genomic status of non-small-cell lung cancer. MATERIAL & METHODS: We retrospectively reviewed 1971 non-small-cell lung cancer files of patients with EGFR and KRAS testing and focused on 157 patients who had undergone RT for brain metastasis. RESULTS: A total of 16 patients (10.2%) harbored EGFR mutations (mEGFR) and 45 patients (28.7%) KRAS (mKRAS). In univariate analysis, RR was significantly higher for mEGFR compared with wild-type EGFR/KRAS (odds ratio [OR]: 4.96; p = 0.05) or mKRAS (OR: 1.81; p = 0.03). In multivariate analysis, KRAS G12V or G12C status was associated with both poor RR (OR: 0.1; p < 0.0001) and overall survival (OR: 3.41; p < 0.0001). CONCLUSION: mEGFR are associated with higher RR to brain RT than wild-type EGFR/RAS or mKRAS.

Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial.

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.

Second-line therapy in elderly patients with advanced nonsmall cell lung cancer.

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 451 elderly 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.

Impact of 3D conformal radiotherapy on lung function of patients with lung cancer: a prospective study.

BACKGROUND: The development of three-dimensional conformal radiotherapy (3D-RT) has enabled the restriction of the dose to normal lung, limiting radiation-induced lung injury. OBJECTIVES: This study was designed to describe the time course of lung function until 7.5 months after 3D-RT in patients with lung cancer, and assess the relationship between lung function changes and dose-volume histogram (DVH) analysis or computed tomography scan changes. Radiation doses were optimized according to recent guidelines. METHODS: Sixty-five lung cancer patients treated with 3D-RT agreed to participate in this prospective, hospital-based study. Lung volumes, forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO) were measured before radiotherapy (RT), 10 weeks, 4 and 7.5 months after the beginning of 3D-RT. RESULTS: Eleven lung cancer patients (17%) developed grade 2-3 respiratory symptoms after RT. At 7.5 months, vital capacity (VC) was 96 ± 2%, total lung capacity (TLC) 95 ± 2%, FEV1 93 ± 2% and DLCO 90 ± 2% of the initial value. Only 15% of patients showed pulmonary function reduction > 20%. Patients with FEV1 or DLCO < 60% before RT did not show significant changes after RT. There were weak correlations between reduction of VC, TLC, FEV1 or DLCO and radiation dosimetric parameters and between reduction of VC or FEV1 and radiation-induced pneumonitis images. CONCLUSIONS: In lung cancer, the reduction of lung function within 7.5 months after 3D-RT was small and correlated, albeit weakly, with DVH parameters. Patients with initially impaired lung function showed tiny changes in spirometry and DLCO values.

18FDG PET/CT Tumoral and Neurologic Therapeutic Response in a Case of Anti-GABABR Paraneoplastic Limbic Encephalitis.

ABSTRACT: A 70-year-old man with a history of small cell lung carcinoma 2 years earlier was addressed for the suspicion of a paraneoplastic limbic encephalitis. Brain 18FDG PET/CT revealed a bilateral amygdalian and hippocampal hypermetabolism, confirming a limbic encephalitis, and concurrent whole-body 18FDG PET/CT showed a small cell lung carcinoma plurifocal metastatic recurrence, consistent with a paraneoplastic limbic encephalitis. 18FDG PET/CT follow-up under chemotherapy revealed an almost complete normalization of brain metabolism and a partial metabolic response of the metastatic recurrence, consistent with the good clinical neurological evolution of the patient. This case highlights the clinical-metabolic imaging correlation in paraneoplastic limbic encephalitis.

Association between proton pump inhibitors and severe hematological toxicity in patients receiving pemetrexed-based anticancer treatment: The prospective IPPEM study.

OBJECTIVE: 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). MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Brigatinib for Pretreated, ALK-Positive, Advanced Non-Small-Cell Lung Cancers: Long-Term Follow-Up and Focus on Post-Brigatinib Lorlatinib Efficacy in the Multicenter, Real-World BrigALK2 Study.

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.

Treatment strategies for thymic carcinoma in a real-life setting. Insights from the RYTHMIC network.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Lorlatinib for advanced anaplastic lymphoma kinase-positive non-small cell lung cancer: Results of the IFCT-1803 LORLATU cohort.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: Real-world evidence indicates that lorlatinib offers a significant clinical benefit and high intracerebral antitumour activity in heavily pretreated patients with ALK+ NSCLC. GOV IDENTIFIER: NCT03727477.

Randomized Phase II Trial Evaluating Treatment with EGFR-TKI Associated with Antiestrogen in Women with Nonsquamous Advanced-Stage NSCLC: IFCT-1003 LADIE Trial.

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.

Phase II Study Evaluating the Mechanisms of Resistance on Tumor Tissue and Liquid Biopsy in Patients With EGFR-mutated Non-pretreated Advanced Lung Cancer Receiving Osimertinib Until and Beyond Radiologic Progression: The MELROSE Trial.

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.govNCT03865511) 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.

Efficacy of Immune Checkpoint Inhibitors in Lung Sarcomatoid Carcinoma.

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.

Ceritinib-related interstitial lung disease improving after treatment cessation without recurrence under either crizotinib or brigatinib: a case report.

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.

Brigatinib in patients with ALK-positive advanced non-small-cell lung cancer pretreated with sequential ALK inhibitors: A multicentric real-world study (BRIGALK study).

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.

Epoetin Beta once-weekly therapy in anemic patients with solid tumors and non-myeloid hematological malignancies receiving chemotherapy.

OBJECTIVES: This study aimed to provide further clinical evidence for the efficacy and safety of epoetin beta once weekly across a wide range of cancer types. METHODS: This was a multicenter, open-label, prospective, single-arm study in patients with either a solid tumor or non-myeloid hematological malignancy, receiving or scheduled to receive further chemotherapy. Patients received epoetin beta 30,000 IU subcutaneously once weekly for 16 weeks. The primary efficacy endpoint was the change in hemoglobin (Hb) level according to the patient's baseline Hb level. RESULTS: A total of 691 patients were included in the intent-to-treat population. Epoetin beta effectively increased Hb levels (a mean increase from baseline of 1.1 g/dl by week 4 and 2.2 g/dl by week 12). Hb response was achieved in 60.4% of all patients and 61.2% of those with baseline Hb <11 g/dl. Hb response was similar in patients with solid tumors (60.5%) and non-myeloid hematological malignancies (60.2%). Type of chemotherapy and baseline platelet count were independent predictive factors for response. Epoetin beta treatment was well tolerated. CONCLUSIONS: Epoetin beta 30,000 IU once weekly effectively increases Hb levels, is well tolerated and has similar efficacy in anemic patients with solid tumors or non-myeloid hematological malignancies.

KRAS-specific Amino Acid Substitutions are Associated With Different Responses to Chemotherapy in Advanced Non-small-cell Lung Cancer.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: KRAS-specific AAS appears to induce different responses to chemotherapy regimens after first-line platinum-based chemotherapy in advanced NSCLC.

Real-life experience of ceritinib in crizotinib-pretreated ALK+ advanced non-small cell lung cancer patients.

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.

Systemic Therapy in Advanced Thymic Epithelial Tumors: Insights from the RYTHMIC Prospective Cohort.

INTRODUCTION: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

SNAI2 and TWIST1 in lymph node progression in early stages of NSCLC patients.

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 TGFß pathway. EMT-TFs are differentially expressed depending on EMT inducers. CAIX might be a relevant prognostic marker in early stage NSCLC.