bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of residual metabolic primary tumor volume after completion of thoracic irradiation in patients with inoperable stage III NSCLC.
Authors: Roengvoraphoj Olarn , Gjika Arteda , Mille Erik , Taugner Julian , Käsmann Lukas , Eze Chukwuka , Belka Claus , Manapov Farkhad 
Published: May 2020

9049 Background: The metabolic tumor volume (MTV) is a functional and volumetric PET/CT parameter that has been investigated in recent years with respect to its predictive and prognostic value in different tumor entities. In this study, we investigated the role of residual MTV after completion of thoracic irradiation in inoperable stage III non-small cell lung cancer (NSCLC). Methods: We analyzed retrospective and prospective data of 56 patients with inoperable stage III NSCLC treated with chemoradiotherapy (CRT) and chemoradioimmunotherapy (CRT-IO). All patients received an 18F-FDG-PET/CT 3 to max. 6 months after completion of thoracic irradiation. The measurement of the residual MTV of the primary tumor was performed by calculating the SUVmean of the liver + 2SD as threshold. The patients were divided into the following groups: residual-MTV < 1ml; residual-MTV 1-25ml and residual-MTV > 26ml. Survival, local recurrence, and distant metastasis rates were calculated using the Kaplan-Meier method from the last day of thoracic irradiation. Results: The median follow-up was 45 months (range 16-74) in the CRT group and 16 months in the CRT-IO group (range13-19). Twenty-two (39%) patients had a residual MTV < 1ml (1st group), 19 (34%) a residual MTV between 1-25ml (2nd group) and 15 (27%) a residual MTV > 25ml (3rd group) after completion of thoracic irradiation. Median overall survival was 61, 20 and 12 months (p = 0.006) in the 1st, 2nd and 3rd groups, respectively. 12-month survival was 86%, 50% and 33% after CRT vs. 88%, 71% and 50% after CRT-IO in the 1st, 2nd and 3rd groups, respectively. The median time to in-field recurrence in the 1st, 2nd and 3rd groups was 51, 20 and 15 months (p = 0.011). The prognostic value of the residual MTV on OS was confirmed exclusively in the CRT patient cohort (p = 0.04), but not in the CRT-IO patient cohort (p = 0.174). Residual MTV demonstrated no influence on the local recurrence rate in the CRT-IO patient cohort, but only in patients treated with CRT (p = 0.007). Conclusions: Patients with inoperable stage III NSCLC in whom the residual MTV was < 1ml after completion of thoracic irradiation showed significantly better survival than patients with a residual MTV of 1-25ml and MTV > 25ml. The subgroup analysis confirmed the prognostic value of residual MTV only in patients who received chemoradiotherapy without consolidation immunotherapy.
Neoadjuvant endobronchial delivery of gene mediated cytotoxic immunotherapy (GMCI) for non-small cell lung cancer (NSCLC): Safety and immunologic activity.
Authors: Aguilar Laura K. , Predina Jarrod D. , Haas Andrew , O'Brien Shaun , Moon Edmund K. , Martinez Marina , Corbett Christopher , Sulyok Lydia Frenzel , Bryski Mitchell G. , Eruslanov Evgeniy , Deshpande Charuhas , Guzik Brian W. , Manzanera Andrea G. , Aguilar-Cordova Estuardo , Singhal Sunil , Albelda Steven M. 
Published: May 2020

9050 Background: GMCI is a tumor-specific immuno-oncology approach implemented through local delivery of aglatimagene besadenovec(AdV-tk) followed by anti-herpetic prodrug. This leads to immunogenic tumor cell death, antigen presenting cell activation, and T cell stimulation resulting in CD8+ T cell dependent protection, as demonstrated in preclinical models and clinical trials in other tumor types. This is the first study to assess endobronchial delivery of AdV-tk for NSCLC. Methods: This Phase I dose escalation trial enrolled patients with suspected NSCLC who were candidates for surgery. A single AdV-tk injection was performed by endobronchial ultrasound (n = 11) or mediastinoscopy (n = 1) during the diagnostic staging procedure 3 weeks prior to surgery. Three dose levels were evaluated: 2.5x 1011, 5x1011, and 1x1012 vector particles (vp) in a 3+3 design. Valacyclovir was administered for 14 days, starting the day after AdV-tk injection. To assess the local and systemic effects of GMCI, immune biomarkers were evaluated in blood and tumor samples before and after GMCI. Results: From 2017-2019, 12 patients (9 men, 3 women, median age 65 [range 55-80]) received GMCI followed by surgery. Average tumor size was 5.1 cm (largest diameter) and final pathologic stage was I (n = 4), II (n = 3), and III (n = 5). Treatment-related adverse events were CTC grade 1 fever (n = 1), flu-like symptoms (n = 1) and nausea/vomiting/diarrhea (n = 1). The only > grade 2 lab abnormality was transient grade 3 lymphopenia (n = 2). A measurable reduction in tumor size was observed in one patient. The average amount of tumor necrosis was 29.4%. Significant infiltration of CD8+T cells (5.2-fold compared to baseline, p = 0.001) was found in tumor 19-22 days after AdV-tk injection. Within the CD8+tumor infiltrating lymphocytes, there was increased expression of CD38 (2.5-fold, p = 0.002), Ki67 (4.8-fold, p = 0.02), PD1 (1.9-fold, p = 0.002), CD39 (2.9-fold, p = 0.04) and CTLA-4 (4.8-fold, p < 0.001), without significant detected differences in Tim3 or TIGIT. Simultaneously, peripheral blood CD8+ cells displayed significant increases in CD38 (3.4-fold, p = 0.006), HLA-DR (4.2-fold, p = 0.002), and Ki67 (5.8-fold, p = 0.017). Conclusions: Intratumoral injection of AdV-tk into lung tumors was safe and feasible. Further, AdV-tk effectively induced peripheral blood and intra-tumoral CD8 T cell activation. Consequent upregulation of inhibitory receptors suggests a potential benefit for combination therapies. Clinical trial information: NCT03131037.
Phase I study of TRC102 in combination with cisplatin and pemetrexed in patients with advanced solid tumors/Phase II study of TRC102 with pemetrexed in patients with mesothelioma refractory to pemetrexed and cisplatin or carboplatin.
Authors: Koczywas Marianna , Frankel Paul Henry , Riess Jonathan W. , El-Khoueiry Anthony B. , Villaruz Liza C , Leong Stephen , Ruel Christopher , Synold Timothy W. , O'Connor Timothy , Newman Edward M. 
Published: May 2020

9055 Background: Treatment options remain limited in malignant pleural mesothelioma refractory to pemetrexed +/- platinum. TRC102 (methoxyamine hydrochloride) is a novel biochemical inhibitor of the BER pathway. Available data support the hypothesis that TRC102 bound DNA is a substrate for topoisomerase II, which cleaves TRC102-bound DNA sites to produce strand breaks in cancer cells that cause cellular apoptosis and enhance the cytotoxic effects of chemotherapy. Methods: This was a parallel cohort trial of a Phase I of TRC102 in combination with cisplatin (CDDP) and pemetrexed in patients with advanced solid tumors (Arm A) and a Phase II of TRC102 with pemetrexed in patients with mesothelioma refractory to platinum and pemetrexed (Arm B). Results: In Arm A dose escalation, 16 pts (11M/5F) were treated; 9 evaluable through 3 TRC102 dose levels (50, 75, and 100 mg/day, PO), with CDDP 60 mg/m2 and pemetrexed 500 mg/m2 (levels 1- 3); and 5 evaluable at TRC102 100 mg/day PO, CDDP 75 mg/m2, pemetrexed 500 mg/m2 (level 4). Cycles were every 21 days. There were no DLT’s, establishing level 4 as the RP2D. The only grade 4 treatment-related AE was thrombocytopenia on cycle 22 (level 2). Cycle 1 grade 3 AEs were 1 hypophosphatemia (level 1) and 1 leukopenia (level 2). There were 3 PRs (all parotid salivary gland tumors). Median PFS (95%CI) = 7.1% (1.4 – 15.5) mos. Arm B was designed as the first stage of a two stage Gehan design trial of patients with mesothelioma who had progressed on or recurred within 6 months of pemetrexed + platinum frontline treatment. 14 pts were treated with TRC102 50 mg/day D1-4 and pemetrexed 500 mg/m2 every 21 days. There were 2 PRs (both in epithelioid cancer of which 1 was confirmed), meeting the pre-specified criteria for continued interest ( > 0/14). mPFS (95% CI) was 4.3 (1.4 - 6.8) mos. 8 pts had stable disease for at least 1 cycle (4 stable at cycles 6, 9, 10 and 12). There were 1 grade 4 neutropenia and 5 grade 3 AE’s (1 each – anemia, neutropenia, leukopenia, fatigue, hyponatremia). Conclusions: TRC102 in combination with CDDP and pemetrexed exhibited antitumor activity, particularly in salivary gland tumors, and a tolerable safety profile at the doses tested. The combination of TRC102 and pemetrexed demonstrated activity in malignant mesothelioma that progressed on prior pemetrexed. Additional studies are warranted to confirm preliminary signals of activity. Clinical trial information: NCT02535312.
Effect of anlotinib in advanced small cell lung cancer (SCLC) patients relapsed within three months after second-line treatment: A subgroup analysis from a randomized, double-blind phase II trial (ALTER 1202).
Authors: Shi Jianhua , Cheng Ying , Wang Qiming , Li Kai , Wu Lin , Han Baohui , Chen Gongyan , He Jianxing , Wang Jie , Qin Haifeng , Li Xiao-Ling 
Published: May 2020

9063 Background: Anlotinib had significantly improved progress-free survival (PFS) and overall survival (OS) of advanced small cell lung cancer (SCLC) patients received at least two lines chemotherapy in the ALTER 1202 trial. Here, we reported the effect of anlotinib in advance SCLC patients relapsed within 3 months after second-line treatment. Methods: The ALTER 1202 was a randomized, double-blind phase 2 trial including patients with advanced SCLC that received at least two previous lines of chemotherapy. Eligible patients were randomized in a 2:1 ratio to receive either anlotinib or placebo until tumor progression or unacceptable toxicity. The subgroup analysis assessed the effect of anlotinib in patients relapsed within 3 months after second-line treatment. The primary outcome was PFS. The secondary outcomes were OS, objective response rate (ORR), disease control rate (DCR) and safety. This trial was registered with ClinicalTrials.gov, number NCT03059797. Results: In the ALTER1202 trial, 67 patients in anlotinib group and 34 patients in placebo group relapsed within 3 months after second-line treatment. Among them, the median PFS was 3.98 months (95% confidence interval [CI], 2.79 to 4.24) with anlotinib versus 0.72 months (95% CI, 0.69 to 0.82) with placebo (hazard ratio [HR], 0.14; 95% CI, 0.08 to 0.26; P < 0.0001). Meanwhile, anlotinib significantly prolonged OS compared with placebo (7.29 months [95% CI, 6.51 to 10.51] versus 4.37 months [95% CI, 2.33 to 6.47]; HR, 0.42 [95% CI, 0.23 to 0.74]; P = 0.0059) in patients relapsed within 3 months after second-line treatment. ORR was 4.48% (3 PR) for anlotinib and 2.94% (1 PR) for placebo (P = 0.708). DCR was 73.13% for anlotinib and 11.76% for placebo (P < 0.0001). The most common adverse events were hypertension (38.81%), anorexia (28.36%), fatigue (22.39%) and Elevation of alanine aminotransferase (17.91%). Conclusions: Anlotinib improved PFS and OS in advanced SCLC patients relapsed within 3 months after second-line treatment and was well tolerated.
Prevalence of autoimmune diseases in thymic epithelial tumors (TET) insights from RYTHMIC.
Authors: Benitez Jose Carlos , Boucher Marie Eve , Dansin Eric , Kerjouan Mallorie , Mazieres Julien , Pichon Eric , Thillays Francois , Falcoz Pierre-Emmanuel , Roch Benoit , Oulkhouir Youssef , Fabien Calcagno , Thiberville Luc , Clément Duchene Christelle , Morin Franck , Missy Pascale , Thomas Pascal Alexandre , Maury Jean-Michel , Molina Thierry , Girard Nicolas , Besse Benjamin 
Published: May 2020

9073 Background: TET are associated with autoimmune disorders (AID) in up to 30% of patients (pts). However, there have been wide variations in the reported prevalence of AID in TET pts in small single-center series. RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a French network mandated to systematically discuss every case of TET. We aimed to describe the prevalence of AID in a large French population. Methods: RYTHMIC database, hosted by IFCT (Intergroupe Francophone de Cancérologie Thoracique), prospectively includes all consecutive pts with a diagnosis of TET discussed in French national or regional tumor boards. We analyzed epidemiologic, clinical and pathological characteristics of pts with TET’s related AID. Results: From January 2012 to December 2019, 2909 pts were included in the database. The mean age at diagnosis of TET was 54 and 52% were male. In the overall population, Masaoka Koga stages were well balanced with 12.6% (n = 187) stage I, 8.8% (n = 131) stage IIa, 8.4% (n = 124) stage IIb, 11.1% (n = 164) stage III and 8.5% (n = 125) stage IV. There were 364 (12.5%) events of AID in 302 pts. 62 pts (17%) had more than 1 AID. Among the events, 236 were myasthenia gravis (MG) (64.8%), 19 Hypo-gammaglobulinemia syndrome (5.2%), 15 pure red cell aplasia (4.1%), 18 thyroiditis (4.9%) and 16 systemic erythematous lupus (4.4%). Diagnosis of AID was mostly done at tumor diagnosis (n = 239, 65.7%) but some patient had AID diagnosed before diagnosis (n = 67, 18.4%) or during follow up (n = 32, 8.8%). Among pts presenting AID, B2 was the most common subtype (n = 133, 36.5%). The incidence of AID per subtype was as follow: A (n = 10/81, 12.3%), AB (n = 48/225, 21.3%), B1 (n = 35/130, 26.9%), B2 (n = 133/295, 45.0%), B3 (n = 46/113, 40.7%), thymic carcinoma (n = 16/275, 5.8%). Conclusions: The prevalence of AID in pts with TET was 12.5%, > 40% in B2 and B3 subtypes. Diagnosis of AID can be delayed compared to the diagnosis of TET. Immunotherapy indication should be carefully assessed in pts with TET other than thymic carcinoma.
Low-dose oral etoposide is an active option for patients with heavily pre-treated thymic epithelial tumors.
Authors: Ottaviano Margaret , Tortora Marianna , Giuliano Mario , Terracciano Daniela , Di Lauro Vincenzo , Picozzi Fernanda , Parola Sara , Riccio Vittorio , De Placido Pietro , Pietroluongo Erica , Liotti Antonietta , La Civita Evelina , Guggino Gianluca , Cicalese Marcellino , Curcio Carlo , Longo Michele , Botti Gerardo , Daniele Bruno , De Placido Sabino , Palmieri Giovannella 
Published: May 2020

9074 Background: Platinum based regimens are used in the first line setting for advanced Thymic Epithelial Tumors (TETs). Angiogenesis plays an important role in TETs: VEGF is overexpressed in TETs, and associated with aggressiveness and advanced stage. Etoposide inhibits angiogenesis in vitro and in vivo by decreasing VEGF production and microvessel density. The aim of this study is to assess the activity of metronomic oral etoposide, with identification of circulating predictive and pharmacodynamics biomarkers. Methods: Patients with advanced platinum pretreated TET referred from 2014 to 2019 at Rare Tumors Reference Center of Naples, were prospectively enrolled in this study. Oral etoposide 50 mg daily for 3 weeks on and 1 week off every 28 days, has been delivered until progression of disease, complete response or unacceptable toxicity. Response rate (RR), progression free survival (PFS), toxicity and ratio between time to etoposide progression (TTPe) and time to previous best treatment progression (TTPp) were evaluated. Serum samples were prospectively obtained from ten patients with simultaneously radiological assessment. cfDNA quantification was assessed using Qubit Fluorometric Quantitation. Results: 21 patients were enrolled: median age 59 years range (41 - 88); 70% male, 60% T (4 B1, 3 B2, 4 B3, 1 B1-B2); 40% had TC. A median of 5 (range 1-9) prior therapy regimens had been administered. Median follow-up since etoposide was 5 years (range 0.5-5). Obtaining an overall response rate of 85%, 3 patients achieved complete response and 15 partial response. Median PFS was 16 months [95%CI 3-60] with respectively a median PFS of 12 for T (95%CI 3-38) and 19 for TC (95%CI 6-60). No grade 3-4 related events occurred, G1-2 myelotoxicity has been registered in 20% of patients. Therapy is still ongoing for 15 patients and all are still alive. Median TTPe was 16 months, TTPp was 9 months and TTPe / TTPp ratio equal to 1.7. The median cfDNA of 8 responder patients, before starting therapy, was 2.2 ng/μl (0.178-5.24), dropping dramatically at radiological response to 0.5 ng/μl (0.323-2.56). 2 out of 3 non-responder patients had a median baseline value of 2.49 ng/μl, increasing to 4.6 ng/μl at progression. Variation of circulating VEGF correlates with radiological response. Conclusions: Taking into account that other antiangiogenic drugs, showing some activity in second and further lines treatment, are very expensive and associated with several side effects, we suggest that low dose oral etoposide might become the preferred treatment option in heavily pretreated TETs.
Nivolumab + ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: Three-year update from CheckMate 227 Part 1.
Authors: Ramalingam Suresh S. , Ciuleanu Tudor Eliade , Pluzanski Adam , Lee Jong-Seok , Schenker Michael , Bernabe Caro Reyes , Lee Ki Hyeong , Zurawski Bogdan , Audigier-Valette Clarisse , Provencio Mariano , Linardou Helena , Kim Sang-We , Borghaei Hossein , Hellmann Matthew David , O'Byrne Kenneth John , Paz-Ares Luis G. , Reck Martin , Nathan Faith Ellen , Brahmer Julie R. 
Published: May 2020

9500 Background: In the phase 3 CheckMate 227 Part 1 (NCT02477826; minimum follow-up, 29.3 mo), 1L NIVO + IPI significantly improved overall survival (OS) vs chemo in treatment-naive patients (pts) with aNSCLC and tumor PD-L1 expression ≥ 1% (primary analysis) or < 1% (pre-specified descriptive analysis). Here we report data with 3-y minimum follow-up. Methods: Pts with stage IV / recurrent NSCLC and PD-L1 ≥ 1% (n = 1189) were randomized 1:1:1 to NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), NIVO (240 mg Q2W) alone, or chemo. Pts with PD-L1 < 1% (n = 550) were randomized to NIVO + IPI, NIVO (360 mg Q3W) + chemo, or chemo. Primary endpoint was OS with NIVO + IPI vs chemo in pts with PD-L1 ≥ 1%. An exploratory analysis of OS in pts by response status (CR/PR, SD, progressive disease [PD]) at 6 mo was conducted. Results: After a median follow-up of 43.1 mo (database lock, 28 Feb 2020), pts with PD-L1 ≥ 1% continued to derive OS benefit from NIVO + IPI vs chemo (HR: 0.79; 95% CI, 0.67–0.93); 3-y OS rates were 33% (NIVO + IPI), 29% (NIVO), and 22% (chemo). At 3 y, 18% of pts with PD-L1 ≥ 1% treated with NIVO + IPI remained progression-free vs 12% with NIVO and 4% with chemo; 38% of confirmed responders remained in response in the NIVO + IPI arm at 3 y vs 32% in the NIVO arm and 4% in the chemo arm. In pts with PD-L1 < 1%, OS HR for NIVO + IPI vs chemo was 0.64 (95% CI, 0.51–0.81); 3-y OS rates were 34% (NIVO + IPI), 20% (NIVO + chemo), and 15% (chemo); 13%, 8%, and 2% of pts remained progression-free; and 34%, 15%, and 0% of confirmed responders remained in response, respectively. Pts with PD-L1 ≥ 1% with either CR/PR at 6 mo had longer subsequent OS with NIVO + IPI vs chemo; pts with SD or PD at 6 mo had generally similar subsequent OS between treatments (Table); results in PD-L1 < 1% pts will be presented. Any-grade / grade 3–4 treatment-related AEs were observed in 77% / 33% of all pts treated with NIVO + IPI, and 82% / 36% with chemo. Conclusions: With 3 y minimum follow-up, NIVO + IPI continued to provide durable and long-term OS benefits vs chemo for pts in 1L aNSCLC. Pts with PD-L1 ≥ 1% who achieved CR/PR at 6 mo had marked OS benefit with NIVO + IPI vs chemo. No new safety signals were identified for NIVO + IPI. Clinical trial information: NCT02477826. [Table: see text]
NEJ026: Final overall survival analysis of bevacizumab plus erlotinib treatment for NSCLC patients harboring activating EGFR-mutations.
Authors: Maemondo Makoto , Fukuhara Tatsuro , Saito Haruhiro , Furuya Naoki , Watanabe Kana , Sugawara Shunichi , Iwasawa Shunichiro , Tsunezuka Yoshio , Yamaguchi Ou , Okada Morihito , Yoshimori Kouzou , Nakachi Ichiro , Gemma Akihiko , Azuma Koichi , Hagiwara Koichi , Nukiwa Toshihiro , Morita Satoshi , Kobayashi Kunihiko ,   North East Japan Study Group
Published: May 2020

9506 Background: In NEJ026, a phase III trial comparing bevacizumab plus erlotinib (BE) to erlotinib monotherapy (E) for EGFR-mutated non-small-cell lung cancer (NSCLC), we demonstrated the progression-free survival (PFS) of BE was significantly superior to E (Saito et al. Lancet Oncol. 2019 May;20(5):625-635.). However overall survival analysis were immature at the cutoff date. Methods: Chemotherapy-naïve pts with advanced non-squamous NSCLC harboring EGFR-mutation were randomly assigned to receive either combination with erlotinib (150 mg daily) plus bevacizumab (15 mg/kg iv q3w) or erlotinib (150 mg daily). The primary endpoint was PFS. Secondary endpoints were OS, RR, safety, and QoL. Results: The 226 pts were assigned to BE (n=112) and E (n=114). For the follow-up OS analysis, the data cut-off date was 30 November 2019. Median follow up time was 39.2 months. Median OS was 50.7 months (95% CI, 37.3 months to not reached) with BE and 46.2 months (95% CI, 38.2 months to not reached) with E (hazard ratio, 1.00; 95% CI, 0.68 to 1.48). Twenty-nine patients (25.9%) in BE and twenty-six patients (23.2%) in E were treated by osimertinib as second line treatment. The median survival time between enrollment and progressive disease of second-line treatment (median PFS2) was 28.6 months (95% CI, 22.1 months to 35.9) with BE and 24.3 months (95% CI, 20.4 months to 29.1 months) with E (hazard ratio, 0.80; 95% CI, 0.59 to 1.10). In both arms, the median OS of patients with osimertinib second-line treatment were longer than other second-line chemotherapy groups [50.7 months (95% CI, 38.0 months to 50.7 months) vs 40.1 months (95% CI, 29.5 months to not reached), (hazard ratio, 0.645; 95% CI, 0.40 to 1.03), respectively. Conclusion: The additional effect of bevacizumab on erlotinib monotherapy for NSCLC with EGFR mutations gradually decreased in the order of PFS2 and survival, with no significant differences. Clinical trial information: UMIN000017069 .