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International audience; Thymic epithelial tumors are rare neoplastic proliferations of thymic epithelial cells. The aggressiveness of these malignancies increases as higher is the histologic subtype, being thymic carcinoma the most aggressive subtype, with a greater tendency to metastatic spread. In metastatic setting, there is no standard treatment after progression on platinum-based chemotherapy. In this scenario, monotherapy treatment either with lenvatinib, a multi-tyrosine kinase inhibitor with antiangiogenic properties, or pembrolizumab, an immune-checkpoint inhibitor, has reported clinical activity. Potential combination of both agents may have synergistic activity as reported in other cancer types. PECATI trial is a single-arm, investigator-initiated phase II study aiming to assess the activity and safety of the combination of lenvatinib and pembrolizumab in 43 patients with advanced B3-thymoma or thymic carcinoma who progressed on or after at least one previous line of platinum-based chemotherapy. The primary endpoint of the trial is 5-month progression-free survival rate and the secondary endpoints include overall response rate, duration of response, and overall survival.

Background: While osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is the standard treatment in patients with advanced non-small-cell lung cancer (NSCLC) with sensitising EGFR and acquired T790M mutations, progression inevitably occurs. The angiogenic pathway is implicated in EGFR TKI resistance. Patients and methods: BOOSTER is an open-label randomised phase II trial investigating the efficacy and safety of combined osimertinib 80 mg daily and bevacizumab 15 mg/kg every 3 weeks, versus osimertinib alone, in patients with EGFR-mutant advanced NSCLC and acquired T790M mutations after failure on previous EGFR TKI therapy. Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR) and adverse events (AEs). Results: Between May 2017 and February 2019, 155 patients were randomised (combination: 78; osimertinib: 77). At data cut-off of 22 February 2021, median follow-up was 33.8 months [interquartile range (IQR): 26.5-37.6 months] and 129 (83.2%) PFS events were reported in the intention-to-treat population. There was no difference in median PFS between the combination [15.4 months; 95% confidence interval (CI) 9.2-18.0 months] and osimertinib arm (12.3 months; 95% CI 6.2-17.2 months; stratified log-rank P = 0.83), [hazard ratio (HR) = 0.96; 95% CI 0.68-1.37]. Median OS was 24.0 months (95% CI 17.8- 32.1 months) in the combination arm and 24.3 months (95% CI 16.9-37.0 months) in the osimertinib arm (stratified log-rank P = 0.91), (HR = 1.03; 95% CI 0.67-1.56). Exploratory analysis revealed a significant interaction of smoking history with treatment for PFS (adjusted P = 0.0052) with a HR of 0.52 (95% CI 0.30-0.90) for smokers, and 1.47 (95% CI 0.92-2.33) for never smokers. ORR was 55% in both arms and the median time to treatment failure was significantly shorter in the combination than in the osimertinib arm, 8.2 months versus 10.8 months, respectively (P = 0.0074). Safety of osimertinib and bevacizumab was consistent with previous reports with grade >= 3 treatment-related AEs (TRAEs) reported in 47% and 18% of patients on combination and osimertinib alone, respectively. Conclusions: No difference in PFS was observed between osimertinib plus bevacizumab and osimertinib alone. Grade >= 3 TRAEs were more common in patients on combination.

Chemotherapy; Lenvatinib; Thymic epithelial tumours Quimioterapia; lenvatinib; Tumores epiteliales tímicos Quimioteràpia; Lenvatinib; Tumors epitelials tímics Thymic epithelial tumours (TET) represent a heterogeneous group of rare malignancies that include thymomas and thymic carcinoma. Treatment of TET is based on the resectability of the tumour. If this is considered achievable upfront, surgical resection is the cornerstone of treatment. Platinum-based chemotherapy is the standard regimen for advanced TET. Due to the rarity of this disease, treatment decisions should be discussed in specific multidisciplinary tumour boards, and there are few prospective clinical studies with new strategies. However, several pathways involved in TET have been explored as potential targets for new therapies in previously treated patients, such as multi-tyrosine kinase inhibitors with antiangiogenic properties and immune checkpoint inhibitors (ICI). One third of patient with thymoma present an autoimmune disorders, increasing the risk of immune-related adverse events and autoimmune flares under ICIs. In these guidelines, we summarize the current evidence for the therapeutic approach in patients with TET and define levels of evidence for these decisions.

BackgroundCurrent front-line treatment for ES-SCLC includes chemotherapy plus a PD-L1 inhibitor. FDA has recently approved LUR for pretreated patients with SCLC. 2SMALL is a two-part phase 1/2 study assessing the safety, tolerability and efficacy of LUR in combination with ATZ as second line treatment for ES-SCLC. Here we report data from phase I part of the 2SMALL trial (data cut off 14-07-2021)Methods2SMALL phase I was an open-label, single arm, dose exploration trial. Elegible patients had confirmed ES-SCLC, who progressed to first line platinum based treatment, ECOG performance status score 0-1 and adequate organ function; prior exposure to immunotherapy was not allowed. During dose finding phase pts received increasing doses of LUR (2.5 mg/m2 - 3.2 mg/m2) on day (D) 1 plus a fixed dose of ATZ (1200 mg) every 3 weeks following a standard 3+3 dose escalation design. Study endpoints included the definition of the safety profile and the recommended dose. Additional objectives included efficacy (ORR and PFS).Results26 patients were treated, including male 14 pts (53,84%), with median age 60.6 years. Five pts received LUR 2.5 mg/m2 + ATZ 1200 mg, and 3 pts were evaluable without DLT. Out of the 21 pts who received LUR 3.2 mg/m2+ ATZ 1200 mg (6 pts with primary G-CSF), 5 pts (20.83%) developed DTLs: 2 pts G3 febrile neutropenia (9.52%) (1 pt with G4 thrombocytopenia), 2 pts G4 neutropenia lasting more than 72h (9.52%), 1 pt G4 thrombocytopenia (4.76%). Most frequent haematological adverse events ≥ grade 2 (21 pts) were neutropenia (42.86%), thrombocytopenia (28.57%), anaemia (19.05%); lymphopenia (4.76%) and febrile neutropenia (4.76%). The most common non-haematological TAEs ≥ grade 2 was asthenia 30,76%. No deaths treatment-related were reported. Objective responses were observed in 15 pts (ORR: 57.69%), including complete responses in 2 pts (7.69%), partial response in 13 pts (50%). 6 pts had stable disease (26.92%) and 3 pts progressive disease (11.54%). Disease control rate was 84.61%. With 8 pts censored for progression, median PFS was 4.93 months (range 3.37 - 7.67 months).ConclusionsThe combination of LUR plus ATZ was well tolerated, without unexpected toxicities. Transient haematological toxicity was dose limiting. The RD for further studies is LUR 3.2 mg/m2 on D1 + ATZ 1200 mg D1 with G-CSF. Preliminary anti-tumor activity is remarkable. 2SMALL trial part II is ongoing, and will provide further data regarding efficacy and safety of the regimen for second line SCLC.Trial RegistrationNCT04253145ReferencesSubbiah V, Paz-Ares L, Besse B, et al. Antitumor activity of lurbinectedin in second-line small cell lung cancer patients who are candidates for re-challenge with the first-line treatment. Lung Cancer 2020;150:90–96.Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol 2020; 21(5):645–654.Ethics ApprovalEthics committe Hospital Universitario 12 de Octubre

Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si le hubiere, y los autores pertenecientes a la UAM, Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations, Background There is a lack of useful diagnostic tools to identify EGFR mutated NSCLC patients with long-term survival. This study develops a prognostic model using real world data to assist clinicians to predict survival beyond 24 months. Methods EGFR mutated stage IIIB and IV NSCLC patients diagnosed between January 2009 and December 2017 included in the Spanish Lung Cancer Group (SLCG) thoracic tumor registry. Long-term survival was defined as being alive 24 months after diagnosis. A multivariable prognostic model was carried out using binary logistic regression and internal validation through bootstrapping. A nomogram was developed to facilitate the interpretation and applicability of the model. Results 505 of the 961 EGFR mutated patients identified in the registry were included, with a median survival of 27.73 months. Factors associated with overall survival longer than 24 months were: being a woman (OR 1.78); absence of the exon 20 insertion mutation (OR 2.77); functional status (ECOG 0–1) (OR 4.92); absence of central nervous system metastases (OR 2.22), absence of liver metastases (OR 1.90) or adrenal involvement (OR 2.35) and low number of metastatic sites (OR 1.22). The model had a good internal validation with a calibration slope equal to 0.781 and discrimination (optimism corrected C-index 0.680). Conclusions Survival greater than 24 months can be predicted from six pre-treatment clinicopathological variables. The model has a good discrimination ability. We hypothesized that this model could help the selection of the best treatment sequence in EGFR mutation NSCLC patients.

PURPOSE Squamous non–small-cell lung cancer (sqNSCLC) is genetically complex with evidence of DNA damage. This phase III study investigated the efficacy and safety of poly (ADP-ribose) polymerase inhibitor veliparib in combination with conventional chemotherapy for advanced sqNSCLC ( NCT02106546 ). PATIENTS AND METHODS Patients age ≥ 18 years with untreated, advanced sqNSCLC were randomly assigned 1:1 to carboplatin and paclitaxel with veliparib 120 mg twice daily (twice a day) or placebo twice a day for up to six cycles. The primary end point was overall survival (OS) in the veliparib arm versus the control arm in current smokers, based on phase II findings. Archival tumor samples were provided for biomarker analysis using a 52-gene expression histology classifier (LP52). RESULTS Overall, 970 patients were randomly assigned to carboplatin and paclitaxel plus either veliparib (n = 486) or placebo (n = 484); 57% were current smokers. There was no significant OS benefit with veliparib in current smokers, with median OS 11.9 versus 11.1 months (hazard ratio [HR], 0.905; 95% CI, 0.744 to 1.101; P = .266). In the overall population, OS favored veliparib; median OS was 12.2 versus 11.2 months (HR, 0.853; 95% CI, 0.747 to 0.974), with no difference in progression-free survival (median 5.6 months per arm). In patients with biomarker-evaluable tumor samples (n = 360), OS favored veliparib in the LP52-positive population (median 14.0 v 9.6 months; HR, 0.66; 95% CI, 0.49 to 0.89), but favored placebo in the LP52-negative population (median 11.0 v 14.4 months; HR, 1.33; 95% CI, 0.95 to 1.86). No new safety signals were observed in the experimental arm. CONCLUSION In current smokers with advanced sqNSCLC, there was no therapeutic benefit of adding veliparib to first-line chemotherapy. The LP52 signature may identify a subgroup of patients likely to derive benefit from veliparib with chemotherapy.

[Background] Approximately 30% of tumor biopsies from patients with advanced-stage lung adenocarcinomas yield insufficient tissue for successful molecular subtyping. We have analyzed the clinical utility of next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) in patients with inadequate tumor samples for tissue genotyping. [Patients and methods] We conducted the study in a multi-institutional prospective cohort of clinically unselected patients with advanced-stage lung adenocarcinomas with insufficient tissue for EGFR, ALK or ROS1 genotyping across 12 Spanish institutions (n = 93). ctDNA NGS was carried out by Guardant Health (Guardant360, Redwood City, CA), using a hybrid-capture-based 73-gene panel. Variants were deemed actionable if they were part of the OncoKB precision oncology knowledge database and classified in four levels of actionability based on their clinical or preclinical evidence for drug response. [Results] Eighty-three out of 93 patients (89%) had detectable levels of ctDNA. Potentially actionable level 1–4 genomic alterations were detected in 53 cases (57%), of which 13 (14%) had level 1–2A alterations (Food and Drug Administration-approved and standard-care biomarkers according to lung cancer guidelines). Frequencies of each genomic alteration in ctDNA were consistent with those observed in unselected pulmonary adenocarcinomas. The majority of the patients (62%), particularly those with actionable alterations (87%), had more than one pathogenic variant in ctDNA. The median turnaround time to genomic results was 13 days. Twelve patients (13%) received genotype-matched therapies based on ctDNA results, deriving the expected clinical benefit. Patients with co-occurring pathogenic alterations had a significantly shorter median overall survival as compared with patients without co-occurring pathogenic alteration (multivariate hazard ratio = 5.35, P = 0.01). [Conclusion] Digital NGS of ctDNA in lung cancers with insufficient tumor samples for tissue sequencing detects actionable variants that frequently co-occur with other potentially clinically relevant genomic alterations, allowing timely initiation of genotype-matched therapies., Research grant support was provided by Guardant Health Inc. (grant number C16/12/00442) for plasma-based comprehensive genomic testing. Instituto de Salud Carlos IIICM15/00196; CIBERONCCB16/12/00350;ISCIIIPI1401964PIE15/00076; RTICCR12/0036/0028; CIBERONCC16/12/00442; Regional Development European Funds Guardant Health IncC16/12/00442.

[Purpose] Chronic inflammation contributes to cancer development via multiple mechanisms. We hypothesized that cardiovascular diseases (CVD) are also an independent risk factor for survival in non-small cell lung cancer (NSCLC)., [Materials and methods] Prospective multicenter data from 345 consecutive NSCLC patients treated from January 2013 to January 2017 were assessed. Median follow-up for all patients was 13 months (range 3–60 months). There were 109 patients with baseline heart disease (HD 32%), 149 with arterial hypertension (43%), 85 with diabetes mellitus (25%), 129 with hyperlipidemia (37%) and 45 with venous thromboembolism events (VTE 13%). A total of 289 patients (84%) were treated with platinum-based chemotherapy (CT), 300 patients (87%) received thoracic radiation therapy (RT; median radiation dose: 60 Gy [range 12–70]); and 50 (15%) patients underwent surgery., [Results] Our cohort consisted of 305 men (88%) and 40 (12%) women, with a median age of 67 years (range 31–88 years). Seventy percent had a Karnofsky performance status (KPS) ≥ 80. Multivariate analyses showed a lower OS and higher risk of distant metastasis in patients with advanced stages (p = 0.05 and p, [Conclusions] HD and VTE are associated with a higher risk of mortality and distant metastasis in NSCLC patients. Chronic inflammation associated with CVDs could be an additional pathophysiologic factor in the development of distant metastasis., This work was supported by grants from ISCIII (Fis: PI13/01155, PI16/02104) and Consejeria de Salud of the Junta de Andalucia (PI-0096-2012).

Introduction: There are currently no predictive biomarkers for long-term survival after neoadjuvant chemoimmunotherapy. However, the identification of non-small lung cancer (NSCLC) patients who obtain long-term benefit from chemoimmunotherapy is essential to optimize therapies. Methods: Using samples from NADIM clinical trial (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant chemo-immunotherapy with nivolumab, we have evaluated the capacity of ctDNA levels before treatment initiation to predict overall survival (OS) and progression-free survival (PFS) by calculating Harrell’s C-statistic and we compare its predictive value with classical survival surrogates as the pathological response and clinical response assessed according to RECIST criteria v.1.1. The ctDNA was analyzed by NGS, using the Oncomine Pan-Cancer Cell-Free Assay™ (Thermo Fisher Scientific®). To explore the prognostic value of the amount of ctDNA at baseline, for each positive plasma sample, we calculated the sum of the mutant allele frequency (MAF) for all detected mutations. Patients who died from COVID19 were excluded from this analysis. Results: In our study, clinical responses based on RECIST criteria were not predictive for OS or PFS. On the contrary, in the multivariate analysis, patients with low ctDNA levels (

Plasma samples from 72 EGFR‐mutant advanced NSCLC patients, collected upon progression to first‐line TKI, were analyzed by seven methodologies (two NGS‐based methods, three high‐sensitivity PCR‐based platforms, and two FDA‐approved methods). Our study demonstrates a good to excellent agreement between methodologies and supports the use of liquid biopsies for therapy decision‐making., Several platforms for noninvasive EGFR testing are currently used in the clinical setting with sensitivities ranging from 30% to 100%. Prospective studies evaluating agreement and sources for discordant results remain lacking. Herein, seven methodologies including two next‐generation sequencing (NGS)‐based methods, three high‐sensitivity PCR‐based platforms, and two FDA‐approved methods were compared using 72 plasma samples, from EGFR‐mutant non‐small‐cell lung cancer (NSCLC) patients progressing on a first‐line tyrosine kinase inhibitor (TKI). NGS platforms as well as high‐sensitivity PCR‐based methodologies showed excellent agreement for EGFR‐sensitizing mutations (K = 0.80–0.89) and substantial agreement for T790M testing (K = 0.77 and 0.68, respectively). Mutant allele frequencies (MAFs) obtained by different quantitative methods showed an excellent reproducibility (intraclass correlation coefficients 0.86–0.98). Among other technical factors, discordant calls mostly occurred at mutant allele frequencies (MAFs) ≤ 0.5%. Agreement significantly improved when discarding samples with MAF ≤ 0.5%. EGFR mutations were detected at significantly lower MAFs in patients with brain metastases, suggesting that these patients risk for a false‐positive result. Our results support the use of liquid biopsies for noninvasive EGFR testing and highlight the need to systematically report MAFs.

Introduction: Neoadjuvant chemoimmunotherapy been shown to be highly effective in resectable stage IIIA NSCLC. Now we provide long term survival data Methods: This was an open-label, multicentre, single-arm phase 2 trial in which patients with histologically or cytologically documented stage IIIA NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1 and who were deemed locally to be surgically resectable by a multidisciplinary clinical team were treated with neoadjuvant intravenous paclitaxel (200 mg/m2) and carboplatin (area under curve 6;6 mg/mL per min) plus nivolumab (360 mg) on day 1 of each 21-day cycle, for three cycles before surgical resection, followed by adjuvant intravenous nivolumab monotherapy for 1 year (240 mg every 2 weeks for 4 months, followed by 480 mg every 4 weeks for 8 months). Here we report progression-free survival (PFS) and Overall survival (OS) at 36 and 42 months, assessed in the modified intention-to-treat population (ITT), which included all patients who received neoadjuvant treatment, and in the per-protocol population (PP), which included all patients who had tumour resection and received at least one cycle of adjuvant treatment. Results: Median follow-up time was 37.9 months (95%CI: 36.7-40.7), with a 94% maturity at 36 months. Among the ITT population (N=46), 37 patients, constituting the PP population, received subsequent adjuvant therapy. Of them, 27 (58.7%) patients completed the adjuvant treatment (16 cycles), 10 (21.7%) patients received between 3 and 15 cycles of adjuvant therapy, and 9 (19.6%) patients did not receive adjuvant therapy. At the time of data cutoff (March 2021), progression disease was diagnosed in 14 patients and 9 deaths were recorded in the ITT population. Of these, three deaths corresponded to patients who did not undergo surgery and had disease progression, four deaths corresponded to patients who underwent surgery and had disease progression, and the two remaining deaths corresponded to patients who were diagnosed as being disease free but died from COVID19 infection. Notably, among patients who could not undergo surgery (N=5), one of them is still alive and with no evidence of disease. PFS at 36 and 42 months in the ITT population were 69.6% (95%CI: 54.1-80.7), in both cases. Similarly, PFS at 36 and 42 in the PP population were 81.1% (95%CI: 64.4-90.5) in both cases. The percentage of patients who were alive at 36 and 42 months in the modified ITT population were 81.86% (95% CI: 66.8-90.6) and 78.94% (95%CI: 63.1-88.6), respectively. Likewise, OS at 36 and 42 months in the PP population was 91.0% (95%CI: 74.2-97.0) and 87.3% (95%CI: 69.3-95.1), respectively. Conclusion: The efficacy of nivolumab in combination with platinum-based chemotherapy in patients with resectable stage IIIA NSCLC is clearly supported by long term survival data. Keywords: NADIM trial, neoadjuvant chemo-therapy, long term survival

There is growing evidence supporting that long-term survival of neoadjuvant chemo-immunotherapy for locally advanced NSCLC patients can be achieved. However, some patients invariably progress within the short-term. Identification of patients at high risk of progression is needed to achieve a better control of the disease. Concentrations of baseline ctDNA have been shown to be of prognostic significance. Patients and methods 42 pre-treatment plasma samples from the NADIM clinical trial (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant chemo-immunotherapy with Nivolumab, were analyzed by NGS, using the Oncomine Pan-Cancer Cell-Free Assay™ (Thermo Fisher Scientific®). Variant calling, annotation and filtering were performed on the Ion Reporter (v5.14) platform using the OncomineTagSeq Pan-Cancer Liquid Biopsy workflow (v2.3). The final variant matrix was obtained from vcf files as generated from Ion Reporter (v5.14) platform and applying an internal pipeline (R-code is available upon request). Progression disease was evaluated by RECIST criteria V1.1. Results A total of 116 variants were detected in 88.10% (N=37) of the plasma samples collected before neoadjuvant treatment. The average number of variants detected per sample was 3.13. The most frequently mutated genes were TP53, which accounts for 59.52% of the detected variants, followed by PIK3CA (30.95%), MAP2K1 (30.95%), APC (23.81%), MTOR (9.52%) and KIT (9.52%). Patients in whom a GNA11 mutation was detected in the plasma sample by NGS showed worsen progression free survival (PFS) (HR: 14. 95%; CI: 2.6-71, P-value with Fold Discovery Rate correction: 0.019). Finally, ctDNA levels at Mutant Allele Frequency (MAF) below 1% at baseline were associated with improved PFS (P=0.025). At 30 months, PFS was 80.30% for these patients compared with 58.33% in patients with ctDNA levels ≥ 1%. Conclusions Molecular profiling of liquid biopsies collected before neoadjuvant chemo-immunotherapy using NGS can identify patients at high risk of progression who might require more aggressive adjuvant treatment in order to achieve a better control of the disease. Citation Format: Mariano Provencio, Roberto Serna-Blasco, Ernest Nadal, Amelia Insa, M. Rosario Garcia-Campelo, Diego Pereiro Corbacho, Manuel Domine, Margarita Majem, Delvys Rodriguez-Abreu, Alex Martinez-Marti, Javier de Castro, Manuel Cobo, Guillermo Lopez-Vivanco, Edel del Barco, Reyes Bernabe, Nuria Viñolas, Isidoro Barneto, Santiago Viteri, Eva Pereira, Ana Royuela, Marta Casarrubios, Clara Salas, Edwin R Parra, Ignacio Wistuba, Virginia Calvo, Raquel Laza-Briviesca, Bartomeu Massuti, Alberto Cruz-Vermudez, Atocha Romero. High levels of baseline ctDNA constitute a poor prognostic factor in progression-free survival in patients receiving neo-adjuvant chemo-immunotherapy: Results from NADIM clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 560.

[Objectives] Resistance to tyrosine-kinase inhibitors (TKIs) is a clinical challenge in patients with oncogene-driven non-small-cell lung cancers (NSCLC). We have analyzed the utility of next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) to impact the clinical care of patients with TKI resistance., [Materials and methods] We conducted a multi-institutional prospective study including consecutive EGFR, ALK, or ROS1-altered NSCLC patients with TKI resistance from 12 Spanish institutions. Post-progression ctDNA NGS was performed by Guardant Health (Guardant360 assay)., [Results] We included 53 patients separated in 3 cohorts: 31 EGFR-mutant NSCLCs with first/second-generation TKI resistance (cohort 1), 15 EGFR T790M + NSCLCs with osimertinib resistance (cohort 2), and 7 ALK/ROS1-rearranged NSCLCs with crizotinib and/or next-generation TKI resistance (cohort 3). Besides Guardant360, 22 patients from cohort 1 (71%) underwent post-progression tumor biopsies and/or alternative plasma-based genotyping. In the entire study population, 34 patients (64%) had reliable evidence of tumor-DNA shed for resistance assessment, and 24 patients (45%) had actionable alterations. Target-independent pathogenic alterations were frequently detected, particularly at osimertinib resistance. Eleven patients (20%) received subsequent molecular-guided therapies indicated by plasma NGS alone (n = 9, 17%), or plasma NGS and tissue sequencing (n = 2, 4%), deriving the expected clinical benefit. Of these, 9 had EGFR T790 M mutation and received osimertinib, 1 had ALK G1202R mutation and received lorlatinib, and 1 had ROS1 G2032R mutation and received cabozantinib. Two additional cases from cohort 1 (6%) had undetectable EGFR T790 M by Guardant360 but were T790M + by tissue and BEAMing digital PCR respectively, and also received osimertinib., [Conclusion] NGS of ctDNA detects actionable alterations in a large proportion of oncogene-driven NSCLC patients with TKI resistance, and can be used to guide subsequent treatments as a complement or alternative to tissue or PCR-based plasma genotyping in the real-world clinical setting., J. Zugazagoitia was funded by Instituto de Salud Carlos III (Rio Hortega, CM15/00196). E. Jantus-Lewintre and C. Camps were funded by CIBERONC (CB16/12/00350). P Garrido was funded by ISCIII: PIE15/00050, and CIBERONC (C16/12/00442). L. Paz-Ares was funded by ISCIII: PI1401964, PIE15/00076, RTICC (R12/0036/0028), CIBERONC (C16/12/00442), and CAM (B2017/BMP-3884), co-funded by FEDER from Regional Development European Funds (European Union). M: Provencio was funded by ISCIII: PIE 1400/64, PI16/01818 and European Union Funds: H2020-sc1-2016-2017.

[Background] Lung cancer remains a leading cause of cancer incidence and mortality worldwide. Although Spain contributes to global statistics related to cancer, it is difficult to discern aspects linked to clinical presentation of the disease or molecular testing. The Thoracic Tumor Registry (TTR) was created with the aim of filling this gap., [Methods] Observational cohort multicenter study performed in Spain, including patients with lung cancer or other types of thoracic tumors undergoing active treatment or palliative care only. Enrollment took place between August 2016 and December 2018. The evaluation included a review of demographic, epidemiological, clinical and molecular data., [Results] A total of 6,600 patients diagnosed with non-small cell lung cancer (NSCLC) were recruited at 56 Spanish hospitals. The mean age at diagnosis was 64 years. The majority of patients (80%) presented with advanced disease, being adenocarcinoma the most frequent histological type. Up to 86% of patients were current- or ex-smokers, with men starting to smoke earlier than women (average age 17.9 vs. 19.2 years). Sixty-seven percent of patients underwent some type of molecular testing. Mutations in EGFR and KRAS genes were found in 18% and 28% of patients, respectively., [Conclusions] Our findings suggest that the TTR study accurately describes the clinical reality of lung cancer in Spain, including useful information on smoking status as well as molecular profiling and tumor histology, and can therefore be used to drive improvements in health care. Social and political pressure to reduce tobacco consumption among the population should be reinforced, particularly among youth., This work was supported by Grupo Español de Cáncer de Pulmón (GECP), Novartis, Lilly and Merck Sharp & Dohme (MSD).

[Background] To assess the efficacy and safety of a metronomic schedule of oral vinorelbine (mVNR) in advanced non-small-cell lung cancer (NSCLC) in patients unfit for platinum-based combination chemotherapy., [Patients and methods] This was a multicenter, prospective, randomized, open-label phase II study in treatment-naive patients with TNM stage IIIB/IV NSCLC. Patients received mVNR at a fixed dose of 50 mg × 3 or standard schedule 60-80 mg/m2 weekly until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) without grade 4 toxicity (G4PFS; NCI-CTC v4). Main secondary objectives were safety, disease control rate (DCR) without grade 4 toxicity (G4DCR), DCR, PFS, overall survival (OS) and quality of life (QoL)., [Results] A total of 167 patients were included, 83 and 84 patients in the mVNR and standard arms, respectively. The median G4PFS was 4.0 months [95% confidence interval (CI): 2.6-4.3] and 2.2 months (95% CI: 1.5-2.9), hazard ration (HR) = 0.63 (95% CI: 0.45-0.88), P = 0.0068 in favor of metronomic arm; G4DCR was 45.8% and 26.8% in the mVNR and standard arms, respectively. Grade 3-4 treatment-related adverse events were less frequent in the mVNR arm (25.3% versus 54.4%) mainly owing to a reduction in all grades (15.7% versus 51.9%) and grade 3-4 neutropenia (10.8% versus 42%). PFS was 4.3 (95% CI: 3.3-5.1) and 3.9 months (95% CI: 2.8-5.2) in mVNR and standard arms, respectively. No difference in median OS was observed. QoL was comparable between arms., [Conclusions] Metronomic oral vinorelbine significantly prolonged median G4PFS in advanced NSCLC patients unfit for platinum combinations as first-line treatment. It was associated with a clear reduction in toxicity and may be considered as an important option in this challenging population., Pierre Fabre Médicament was the Sponsor of the study. The study was funded by Pierre Fabre Médicament. Conduct of the study: Pierre Fabre Médicament with the support of Clinipace clinical research organization (CRO) for the monitoring, of C-Med (CRO) for the data management and statistical analyses.

Introduction: Treatment with anti PD-1/PD-L1 antibodies has demonstrated clinical activity in different types of solid tumors, but only 20 to 30% of patients (pts) respond to these immune checkpoint inhibitors (ICIs). Therefore, predictive biomarkers of response that can assist in pt selection are urgently needed. Single biomarker expression, like PD-L1, may not provide enough information about cancer cells and the tumor microenviroment. Novel technologies, analyzing hundreds of genes at the same time, are needed to yield better predictive gene signatures of ICI response. The DURVAST trial analyzed the feasibility of durvalumab treatment in HIV-infected cancer pts, which are usually excluded from ICI clinical trials. The trial included 20 patients with different tumor types and yielded a disease control rate of 56%. Methods: Pre-ICI-treatment FFPE tumor tissue samples from 14 HIV-infected cancer pts (including 11 lung, 1 melanoma, 1 anal and 1 bladder cancer) were analyzed using the nCounter NanoString platform with the IO360 panel, including 770 genes involved in tumor biology, microenvironment and immune response. Gene expression results were correlated with clinical benefit (CB) (objective response and stable disease of more than 24 weeks by RECIST1.1 criteria), and compared to other predictive markers. Results: Exploratory analysis of pre-treatment gene expression profiles (GEPs) revealed differentially expressed genes (DEGs) between the pts with- and without CB. Panel-incorporated biological signatures related to tumor and immune activities were evaluated and some of the most DEGs (based on higher log2FC values and nominal p-values ≤0.05) were shown to be involved in cytokine and chemokine signaling. Although not significant, pts without CB tend to have lower expression of genes involved in cytokine and chemokine signaling (p = 0.097). In contrast, pts without CB tended to have a higher TGF beta signature scores (p = 0.318). When combining both signatures, we obtained an aggregated signature score that was significantly different between pts with- and without CB (p = 0.017). While the positive predictive values were the same for all tests, our signature score outperformed PD-L1 expression positivity by immunohistochemistry and PD-L1 RNA expression as predictors for clinical benefit with a two-fold higher sensitivity and negative predictive value. Conclusion: Gene expression analysis of pre-treatment tumor samples revealed distinct GEPs between HIV-infected cancer pts with- and without CB, where combined high baseline recruitment and activation of immune cells by cytokine and chemokine signaling pathways and low immunosuppressive TGF beta signaling pathways predict CB from durvalumab treatment. This predictive score outperformed other predictive markers of CB. These findings need further validation in an external and non-HIV infected pt cohort, in addition to a pt cohort treated with other ICIs. Citation Format: Jillian Wilhelmina Bracht, Maria Gonzalez-Cao, Teresa Moran, Judith Dalmau, Javier Garcia-Corbacho, Reyes Bernabe, Oscar Juan, Javier de Castro, Ana Gimenez-Capitan, Remedios Blanco, Erika Aldeguer, Sonia Rodriguez, Ana Drozdowskyj, Jordi Argilaguet, Julian Blanco, Julia Prado, Christian Brander, Jorge Carrillo, Bonaventura Clotet, Bartomeu Massuti, Mariano Provencio, Chung-Ying Huang, Clara Mayo de las Casas, Monica Garzon, Andres Felipe Cardona, Oscar Arrieta, Andreas Meyerhans, Miguel Angel Molina-Vila, Javier Martinez-Picado, Rafael Rosell. Transcriptomic analysis of pre-treatment tissue samples to predict clinical benefit to durvalumab in HIV-infected cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 929.