Publications by authors named "Pilar Garrido"

116 Publications

[Multidisciplinary consensus on optimizing the detection of NTRK gene alterations in tumours].

Rev Esp Patol 2021 Oct-Dec;54(4):250-262. Epub 2021 Jul 10.

Sociedad Española de Oncología Médica (SEOM), Hospital Universitario Ramón y Cajal, Universidad de Alcalá, IRYCIS, CIBERONC, Madrid, España.

The recent identification of rearrangements of neurotrophic tyrosine receptor kinase (NTRK) genes and the development of specific fusion protein inhibitors, such as larotrectinib and entrectinib, have revolutionized the diagnostic and clinical management of patients presenting with tumours with these alterations. Tumours that harbour NTRK fusions are found in both adults and children and are either rare tumours with common NTRK fusions that may be diagnostic, or more common tumours with rare NTRK fusions. To assess the currently available evidence, 3key Spanish medical societies (the Spanish Society of Medical Oncology (SEOM), the Spanish Society of Pathology (SEAP) and the Spanish Society of Paediatric Haematology and Oncology (SEHOP) have brought together a group of experts to develop a consensus document that includes guidelines on the diagnostic, clinical and therapeutic aspects of NTRK-fusion tumours. It also discusses the challenges related to the routine detection of these genetic alterations in a mostly public health care system.
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http://dx.doi.org/10.1016/j.patol.2021.05.003DOI Listing
July 2021

Acute anti-Ma2 paraneoplastic encephalitis associated to pembrolizumab: a case report and review of literature.

Transl Lung Cancer Res 2021 Jul;10(7):3303-3311

Medical Oncology Department, Ramón y Cajal University Hospital, Madrid, Spain.

Anti-Ma2 encephalitis is a rare neurological disorder with a predominant involvement of brainstem, limbic and diencephalic structures. Although an unspecific encephalopathy is the usual form of presentation, acute-onset neurologic symptoms and other atypical manifestations have been described and account for the challenging diagnosis of this entity. Despite being usually detected as a paraneoplastic syndrome in patients with early-stage tumors or without a previous history of malignancy, a growing concern has arisen from several cases reported in metastatic patients under treatment with immune checkpoint inhibitors. We report what to our knowledge is the first known case of anti-Ma2 encephalitis associated to pembrolizumab and presenting as an acute-onset focal neurological syndrome, consisting on acute global aphasia, right upper limb paresia, hypoacusia, sleep disorder, decreased conscious level and a motor focal status that was refractory to anticonvulsant therapy. A brain MRI scan showed a focal alteration of the cortical-subcortical signal on the left parietal lobe. CSF study found a significant hyperproteinorrhachia and electroencephalography showed lateralized periodic discharges (LPDs), suggestive of a diffuse encephalopathy. A positive result for anti-Ma2 antibodies was obtained both in blood and CSF samples through indirect immune-fluorescence (IFI) and later confirmed by western-blot technique. Our patient obtained a mild response to steroid therapy and a significant improvement after the administration of intravenous immunoglobulins. The hypothesis that checkpoint inhibitors may trigger the expression of previously subclinical paraneoplastic events, through the strengthening of cytotoxic T cells-mediated immune response, is supported by our finding of preexisting anti-Ma2 antibodies in preserved blood samples obtained before the initiation of pembrolizumab in our patient. Further research is needed to reveal if the detection of onconeural antibodies prior to a treatment with checkpoint inhibitors may be used as a predictive biomarker of neurologic immune-related high-grade toxicity.
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http://dx.doi.org/10.21037/tlcr-21-222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350103PMC
July 2021

Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study.

J Clin Oncol 2021 Aug 2:JCO2100662. Epub 2021 Aug 2.

Janssen R&D, Spring House, PA.

Purpose: Non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor () exon 20 insertion (Exon20ins) mutations exhibits inherent resistance to approved tyrosine kinase inhibitors. Amivantamab, an EGFR-MET bispecific antibody with immune cell-directing activity, binds to each receptor's extracellular domain, bypassing resistance at the tyrosine kinase inhibitor binding site.

Methods: CHRYSALIS is a phase I, open-label, dose-escalation, and dose-expansion study, which included a population with Exon20ins NSCLC. The primary end points were dose-limiting toxicity and overall response rate. We report findings from the postplatinum Exon20ins NSCLC population treated at the recommended phase II dose of 1,050 mg amivantamab (1,400 mg, ≥ 80 kg) given once weekly for the first 4 weeks and then once every 2 weeks starting at week 5.

Results: In the efficacy population (n = 81), the median age was 62 years (range, 42-84 years); 40 patients (49%) were Asian, and the median number of previous lines of therapy was two (range, 1-7). The overall response rate was 40% (95% CI, 29 to 51), including three complete responses, with a median duration of response of 11.1 months (95% CI, 6.9 to not reached). The median progression-free survival was 8.3 months (95% CI, 6.5 to 10.9). In the safety population (n = 114), the most common adverse events were rash in 98 patients (86%), infusion-related reactions in 75 (66%), and paronychia in 51 (45%). The most common grade 3-4 adverse events were hypokalemia in six patients (5%) and rash, pulmonary embolism, diarrhea, and neutropenia in four (4%) each. Treatment-related dose reductions and discontinuations were reported in 13% and 4% of patients, respectively.

Conclusion: Amivantamab, via its novel mechanism of action, yielded robust and durable responses with tolerable safety in patients with Exon20ins mutations after progression on platinum-based chemotherapy.
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http://dx.doi.org/10.1200/JCO.21.00662DOI Listing
August 2021

Management of Intracranial Metastases in EGFR-Mutated NSCLC: A Review of Literature following an Unusual Case Report.

Case Rep Oncol Med 2021 2;2021:5526809. Epub 2021 Jul 2.

Thoracic Tumors Unit from Medical Oncology Department, Ramón Y Cajal University Hospital, Madrid, Spain.

The arrival of subsequent generations of tyrosine-kinase inhibitors (TKIs) has significantly broaden the EGFR-mutated lung cancer therapeutic landscape. Results from the FLAURA clinical trial have pushed osimertinib to the first-line treatment for patients with advanced-stage disease, showing outstanding control rates of intracranial metastases, considerably higher than those of the first and second-generation EGFR TKIs. A progressively better knowledge of short and long-term neurocognitive side effects of radiotherapy, as well as the lack of evidence about the benefit of its combination with TKIs, has opened a debate about its indication at diagnosis of intracranial disease, at least before the response to targeted therapy has been evaluated. However, there is a small percentage of primarily resistant cases to osimertinib, mainly due to histologic transformation, acquired EGFR mutations and off-target genetic resistances that lead to a scenery of poor clinical prognosis in which radiotherapy may have a higher relevance for the management of brain metastases. We offer a review of the current recommendations for the management of intracranial metastases in EGFR-mutated NSCLC and the resistance mechanisms to third-generation TKIs, following the report of an unusual clinical case with a rapid progression to osimertinib.
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http://dx.doi.org/10.1155/2021/5526809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272655PMC
July 2021

LungBEAM: A prospective multicenter study to monitor stage IV NSCLC patients with EGFR mutations using BEAMing technology.

Cancer Med 2021 Sep 23;10(17):5878-5888. Epub 2021 Jul 23.

Medical Oncology Department, Hospital Universitario Vall d'Hebron, Barcelona, Spain.

Objectives: The aim of LungBEAM was to determine the value of a novel epidermal growth factor receptor (EGFR) mutation test in blood based on BEAMing technology to predict disease progression in advanced non-small cell lung cancer (NSCLC) patients treated with first- or second-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Another goal was to monitor the dynamics of EGFR mutations, as well as to track EGFR exon 20 p.T790M (p.T790M) resistance during treatment, as critical indicators of therapeutic efficacy and patient survival.

Methods: Stage IV NSCLC patients with locally confirmed EGFR-TKI sensitizing mutations (ex19del and/or L858R) in biopsy tissue who were candidates to receive first- or second-generation EGFR-TKI as first-line therapy were included. Plasma samples were obtained at baseline and every 4 weeks during treatment until a progression-free survival (PFS) event or until study completion (72-week follow-up). The mutant allele fraction (MAF) was determined for each identified mutation using BEAMing.

Results: A total of 68 of the 110 (61.8%) patients experienced a PFS event. Twenty-six patients (23.6%) presented with an emergent p.T790M mutation in plasma at some point during follow-up, preceding radiologic progression with a median of 76 (interquartile ratio: 54-111) days. Disease progression correlated with the appearance of p.T790M in plasma with a hazard ratio (HR) of 1.94 (95% confidence interval [CI], 1.48-2.54; p < 0.001). The HR for progression in patients showing increasing plasma sensitizing mutation levels (positive MAF slope) versus patients showing either decreasing or unchanged plasma mutation levels (negative or null MAF slopes) was 3.85 (95% CI, 2.01-7.36; p < 0.001).

Conclusion: Detection and quantification of EGFR mutations in circulating tumor DNA using the highly sensitive BEAMing method should greatly assist in optimizing treatment decisions for advanced NSCLC patients.
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http://dx.doi.org/10.1002/cam4.4135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419773PMC
September 2021

Tumor mutational burden assessment in non-small-cell lung cancer samples: results from the TMB harmonization project comparing three NGS panels.

J Immunother Cancer 2021 05;9(5)

H12O-CNIO Lung Cancer Clinical Research Unit, Health Research Institute Hospital 12 de Octubre (imas12) / Spanish National Cancer Research Center (CNIO), Madrid, Spain.

Background: Tumor mutational burden (TMB) is a recently proposed predictive biomarker for immunotherapy in solid tumors, including non-small cell lung cancer (NSCLC). Available assays for TMB determination differ in horizontal coverage, gene content and algorithms, leading to discrepancies in results, impacting patient selection. A harmonization study of TMB assessment with available assays in a cohort of patients with NSCLC is urgently needed.

Methods: We evaluated the TMB assessment obtained with two marketed next generation sequencing panels: TruSight Oncology 500 (TSO500) and Oncomine Tumor Mutation Load (OTML) versus a reference assay (Foundation One, FO) in 96 NSCLC samples. Additionally, we studied the level of agreement among the three methods with respect to PD-L1 expression in tumors, checked the level of different immune infiltrates versus TMB, and performed an inter-laboratory reproducibility study. Finally, adjusted cut-off values were determined.

Results: Both panels showed strong agreement with FO, with concordance correlation coefficients (CCC) of 0.933 (95% CI 0.908 to 0.959) for TSO500 and 0.881 (95% CI 0.840 to 0.922) for OTML. The corresponding CCCs were 0.951 (TSO500-FO) and 0.919 (OTML-FO) in tumors with <1% of cells expressing PD-L1 (PD-L1<1%; N55), and 0.861 (TSO500-FO) and 0.722 (OTML-FO) in tumors with PD-L1≥1% (N=41). Inter-laboratory reproducibility analyses showed higher reproducibility with TSO500. No significant differences were found in terms of immune infiltration versus TMB. Adjusted cut-off values corresponding to 10 muts/Mb with FO needed to be lowered to 7.847 muts/Mb (TSO500) and 8.380 muts/Mb (OTML) to ensure a sensitivity >88%. With these cut-offs, the positive predictive value was 78.57% (95% CI 67.82 to 89.32) and the negative predictive value was 87.50% (95% CI 77.25 to 97.75) for TSO500, while for OTML they were 73.33% (95% CI 62.14 to 84.52) and 86.11% (95% CI 74.81 to 97.41), respectively.

Conclusions: Both panels exhibited robust analytical performances for TMB assessment, with stronger concordances in patients with negative PD-L1 expression. TSO500 showed a higher inter-laboratory reproducibility. The cut-offs for each assay were lowered to optimal overlap with FO.
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http://dx.doi.org/10.1136/jitc-2020-001904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108670PMC
May 2021

Mitral regurgitation caused by perforation of a pseudoaneurysm of the mitral-aortic intervalvular fibrosa.

Eur Heart J Case Rep 2021 Apr 30;5(4):ytab163. Epub 2021 Apr 30.

Department of Cardiology, Hospital Universitario de Canarias, Ofra s/n, La Cuesta, La Laguna, Tenerife 38320, Spain.

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http://dx.doi.org/10.1093/ehjcr/ytab163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086415PMC
April 2021

Phase I Trial of Cemiplimab, Radiotherapy, Cyclophosphamide, and Granulocyte Macrophage Colony-Stimulating Factor in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.

Oncologist 2021 Sep 22;26(9):e1508-e1513. Epub 2021 May 22.

Regeneron Pharmaceuticals, Inc., Basking Ridge, New Jersey, USA.

Lessons Learned: Cemiplimab in combination with radiation therapy, cyclophosphamide, and granulocyte macrophage colony-stimulating factor did not demonstrate efficacy above what can be achieved with other PD-1 inhibitor monotherapies in patients with refractory and metastatic head and neck squamous cell carcinoma. The safety profile of cemiplimab combination therapy was consistent with previously reported safety profiles of cemiplimab monotherapy. No new safety signal was observed.

Background: Refractory and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) generally does not respond to PD-1 inhibitor monotherapy. Cemiplimab is a human anti-PD-1 monoclonal antibody. An expansion cohort enrolled patients with R/M HNSCC in a phase I study combining cemiplimab plus radiation therapy (RT), cyclophosphamide, and granulocyte macrophage colony-stimulating factor (GM-CSF).

Methods: Patients with R/M HNSCC refractory to at least first-line therapy and for whom palliative RT is clinically indicated received cemiplimab plus RT, cyclophosphamide, and GM-CSF. The co-primary objectives were the safety, tolerability, and efficacy of cemiplimab plus RT, cyclophosphamide, and GM-CSF in 15 patients with R/M HNSCC.

Results: Fifteen patients were enrolled. Patients discontinued treatment due to progression of disease. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (40.0%), constipation (26.7%), and asthenia, dyspnea, maculo-papular rash, and pneumonia (each 20%). The only grade ≥3 TEAE that occurred in two patients was pneumonia (13.3%). By investigator assessment, there was one partial response (6.7%); disease control rate was 40.0% (95% confidence interval [CI], 16.3-67.7; five patients with stable disease); seven patients had progressive disease, and two were not evaluable. Median progression-free survival by investigator assessment was 1.8 months (95% CI, 1.7-4.7).

Conclusion: The regimen demonstrated tolerability but not efficacy above that which can be achieved with anti-PD-1 inhibitor monotherapy for R/M HNSCC.
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http://dx.doi.org/10.1002/onco.13810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417861PMC
September 2021

Screening for fusions in patients with advanced non-small cell lung carcinomas using the VENTANA ROS1 (SP384) Rabbit Monoclonal Primary Antibody.

Expert Rev Mol Diagn 2021 May 6;21(5):437-444. Epub 2021 May 6.

Pathology and Laboratory of Therapeutic Targets, Hospital Universitario HM Sanchinarro, HM Hospitales, CIBERONC, Madrid, Spain.

: The development of several ROS1 inhibitors means that the importance of accurately identifying -positive lung cancer patients has never been greater. Therefore, it is crucial that testing assays become more standardized.: Based on primary literature, combined with personal diagnostic and research experience, this review provide a pragmatic update on the use of the recently released VENTANA ROS1 (SP384) Rabbit Monoclonal Primary Antibody.: This assay provides high sensitivity, so it is an excellent analytical option when screening for fusions in patients with advanced non-small cell lung carcinomas.
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http://dx.doi.org/10.1080/14737159.2021.1919512DOI Listing
May 2021

Tolerability and antitumor activity of cemiplimab, a human monoclonal anti-PD-1, as monotherapy in patients with pretreated non-small cell lung cancer (NSCLC): Data from the Phase 1 NSCLC expansion cohort.

Lung Cancer 2021 05 4;155:151-155. Epub 2021 Mar 4.

Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.

Objectives: Blockade of programmed cell death-1 (PD-1) and its ligand (PD-L1) has transformed the treatment of NSCLC. In a first-in-human, Phase 1, dose escalation and cohort expansion study, cemiplimab, a monoclonal antibody directed against PD-1, was evaluated for the treatment of patients with advanced solid tumors (NCT02383212). Here, we report results in patients with advanced NSCLC from the dose expansion cohort.

Materials And Methods: Immune-checkpoint inhibitor naive patients with advanced NSCLC (stage III/IV), irrespective of PD-L1 status, who had progressed after, or were refractory to first- or later-line therapy were enrolled and received cemiplimab 200 mg every 2 weeks intravenously for up to 48 weeks. Primary study objectives were to assess safety and tolerability, and to evaluate clinical activity of cemiplimab.

Results: Twenty patients with NSCLC were enrolled. Median age was 64.0 years (range: 50-82); 65.0 % were male; 80.0 % had an ECOG performance status of 1; 60.0 % had a histology of adenocarcinoma. Median number of prior lines of systemic therapy was 2 (range: 1-4). Median duration of follow-up was 7.0 months (range: 1.0-18.2). All patients experienced ≥1 treatment-emergent adverse event (TEAE) of any grade. Most common TEAEs were arthralgia, asthenia, cough, and dyspnea (each 4/20; 20.0 %). Grade ≥3 TEAEs occurred in 60.0 % (12/20) of patients. Of patients with measurable disease per independent central review (ICR), five had partial response (PR), four had stable disease (SD) and 10 had progressive disease. Objective response rate (ORR; complete response + PR) was 25.0 % (95 % CI: 8.7-49.1 %). Duration of response exceeded 8 months in four of the five responding patients at the time of data cut-off (April 30, 2019). The disease control rate per ICR (ORR + SD) was 50.0 % (95 % CI: 27.2-72.8 %).

Conclusion: Cemiplimab showed an acceptable safety profile and demonstrated antitumor activity in pretreated patients with NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2021.02.034DOI Listing
May 2021

Osimertinib in advanced EGFR-T790M mutation-positive non-small cell lung cancer patients treated within the Special Use Medication Program in Spain: OSIREX-Spanish Lung Cancer Group.

BMC Cancer 2021 Mar 6;21(1):230. Epub 2021 Mar 6.

Medical Oncology Department, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.

Background: AURA study reported 61% objective response rate and progression-free survival of 9.6 months with osimertinib in patients with EGFR/T790M+ non-small cell lung cancer. Due to lack of real-world data, we proposed this study to describe the experience with osimertinib in Spain.

Methods: Post-authorization, non-interventional Special Use Medication Program, multicenter, retrospective study in advanced EGFR/T790M+ non-small cell lung cancer. One hundred-fifty five patients were enrolled (August 2016-December 2018) from 30 sites.

Primary Objective: progression-free survival. Secondary objectives: toxicity profile, objective response rate, and use of health service resources.

Results: 70% women, median age 66. 63.9% were non-smokers and 99% had adenocarcinoma. Most patients had received at least one prior treatment (97%), 91.7% had received previous EGFR-tyrosine kinase inhibitors and 2.8% osimertinib as first-line treatment. At data cutoff, median follow-up was 11.8 months. One hundred-fifty five patients were evaluable for response, 1.3% complete response, 40.6% partial response, 31% stable disease and 11.6% disease progression. Objective response rate was 42%. Median progression-free survival was 9.4 months. Of the 155 patients who received treatment, 76 (49%) did not reported any adverse event, 51% presented some adverse event, most of which were grade 1 or 2. The resource cost study indicates early use is warranted.

Conclusion: This study to assess the real-world clinical impact of osimertinib showed high drug activity in pretreated advanced EGFR/T790M+ non-small cell lung cancer, with manageable adverse events.

Trial Registration: Clinical trial registration number: NCT03790397 .
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http://dx.doi.org/10.1186/s12885-021-07922-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937205PMC
March 2021

Canakinumab with and without pembrolizumab in patients with resectable non-small-cell lung cancer: CANOPY-N study design.

Future Oncol 2021 Apr 2;17(12):1459-1472. Epub 2021 Mar 2.

The Chinese University of Hong Kong, Hong Kong, 999077, China.

Canakinumab is a human IgGκ monoclonal antibody, with high affinity and specificity for IL-1β. The Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS) trial, evaluating canakinumab for cardiovascular disease, provided the first signal of the potential of IL-1β inhibition on lung cancer incidence reduction. Here, we describe the rationale and design for CANOPY-N, a randomized Phase II trial evaluating IL-1β inhibition with or without immune checkpoint inhibition as neoadjuvant treatment in patients with non-small-cell lung cancer. Patients with stage IB to IIIA non-small-cell lung cancer eligible for complete resection will receive canakinumab or pembrolizumab as monotherapy, or in combination. The primary end point is major pathological response by central review; secondary end points include overall response rate, major pathological response (local review), surgical feasibility rate and pharmacokinetics. NCT03968419 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-1098DOI Listing
April 2021

Assessment of the psychosocial and economic impact according to sex in non-small cell lung cancer patients: an exploratory longitudinal study.

BMC Psychol 2020 Nov 23;8(1):123. Epub 2020 Nov 23.

Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.

Background: Little is known about the impact of sex on lung cancer patients from the psychological, economic and social perspectives. This study was designed to explore the psychosocial and economic impact according to sex of metastatic non-small cell lung cancer (mNSCLC) in patients and caregivers.

Methods: Exploratory study of two cohorts of patients starting first-line treatment for mNSCLC. The following questionnaires were administered at baseline, 4 months later and following the first and second disease progression: APGAR, relationship impact scale, DUKE-UNC scale, economic impact in patients and caregiver, and Zarit scale. It was planned to include 1250 patients to get an 80% possibility of detecting as significant (p < 0.05) effect sizes less than 0.19 between men and women. Univariate comparisons were made between the tests applied to men and women. Overall survival was estimated with Kaplan-Meier method. Cox analyses were done to estimate hazard ratios (HRs) with 95% CI.

Results: 333 patients were included. Most families reported to continue being functional despite the lung cancer diagnosis. Regardless of sex, they did not perceive changes in their partner relationship. Most patients felt their social support was normal. Roughly 25% of people reported a worsening in their economic situation, without remarkable differences by sex. Statistically significant differences were found between both groups regarding the caregiver's relationship to the patient (more parents were the caregiver in females than in males, p < 0.0001) and the caregiver's employment situation (more employed caregivers in females) (p < 0.0001). Most caregivers of both sexes considered that taking care of their relative did not pose a significant burden.

Conclusions: This study provides a preliminary insight into sex-related characteristics in the management of advanced NSCLC and its impact on the emotional, social and economic burden of patients and their caregivers, and recall the high priority of researching in cancer from a sex perspective. Nevertheless, due to the low recruitment rate and the relevant loss of patients during the follow-up, it was difficult to find differences by sex.

Trial Registration: ClinicalTrials.gov identifier: NCT02336061.

Ethics Committee: Comité Ético de Investigación Clínica del Hospital Clínic de Barcelona, Spain. Reference number: HCB/2014/0705.
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http://dx.doi.org/10.1186/s40359-020-00489-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685640PMC
November 2020

Phase I Study of the Efficacy and Safety of Ramucirumab in Combination with Osimertinib in Advanced T790M-positive -mutant Non-small Cell Lung Cancer.

Clin Cancer Res 2021 02 12;27(4):992-1002. Epub 2020 Oct 12.

Department of Medical Oncology, Thoracic Unit, Gustave Roussy, Villejuif, France.

Purpose: We report the final analysis of JVDL (NCT02789345), which examined the combination of the EGFR tyrosine kinase inhibitor (TKI) osimertinib plus the VEGFR2-directed antibody ramucirumab in patients with T790M-positive -mutant non-small cell lung cancer (NSCLC).

Patients And Methods: This open-label, single-arm phase I study enrolled patients with T790M-positive NSCLC, who had progressed following EGFR TKI but were third-generation EGFR TKI-naïve. A dose-limiting toxicity (DLT) period with as-needed dose deescalation was followed by an expansion cohort. Patients received daily oral osimertinib and intravenous ramucirumab every 2 weeks until progression or discontinuation.

Results: Twenty-five patients were enrolled. No DLTs were observed. Median follow-up time was 25.0 months. Common grade 3 or higher treatment-related adverse events (TRAE) were hypertension (8%) and platelet count decreased (16%); grade 5 TRAE (subdural hemorrhage) occurred in 1 patient. Patients with ( = 10) and without central nervous system (CNS) metastasis ( = 15) had similar safety outcomes. Five patients remain on treatment. Objective response rate (ORR) was 76%. Median duration of response was 13.4 months [90% confidence interval (CI): 9.6-21.2]. Median progression-free survival (PFS) was 11.0 months (90% CI: 5.5-19.3). Efficacy was observed in patients with and without CNS metastasis (ORR 60% and 87%; median PFS 10.9 and 14.7 months, respectively). Exploratory biomarker analyses in circulating tumor DNA suggested that on-treatment loss of EGFR Exon 19 deletion or L858R mutations, detectable at baseline, correlated with longer PFS, but on-treatment loss of T790M did not. Emergent genetic alterations postprogression included C797S, MET amplification, and EGFR amplification.

Conclusions: Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive -mutant NSCLC..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1690DOI Listing
February 2021

[Liquid biopsy in oncology: A consensus statement of the Spanish Society of Pathology and the Spanish Society of Medical Oncology].

Rev Esp Patol 2020 Oct - Dec;53(4):234-245. Epub 2020 Mar 2.

Departamento de Oncología Médica, Centro Integral Oncológico Clara Campal Barcelona (CIOCCB), HM Delfos, Barcelona, España.

The proportion of cancer patients with tumours that harbour a potentially targetable genomic alteration is increasing considerably. The diagnosis of these genomic alterations can lead to tailoring of treatment, at the onset of disease or during progression, as well as providing additional, predictive information on the efficacy of immunotherapy. However, in up to 25% of cases, the initial tissue biopsy is inadequate for precision oncology and, in many cases, tumour genomic profiling at progression is not possible due to technical limitations of obtaining new tumour tissue specimens. Efficient diagnostic alternatives are therefore required for molecular stratification, such as liquid biopsy. This technique enables the evaluation of the tumour genomic profile dynamically and as well as capturing intra-patient genomic heterogeneity. To date, there are several diagnostic techniques available for use in liquid biopsy, each with different precision and performance levels. The objective of this consensus statement of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM) is to evaluate the viability and effectiveness of the different methodological approaches of liquid biopsy in cancer patients, and the potential application of this method to current clinical practice. The experts contributing to this consensus statement agree that, according to current evidence, liquid biopsy is an acceptable alternative to tumour tissue biopsy for the study of biomarkers in various clinical settings. It is therefore important to standardise pre-analytical and analytical procedures to ensure reproducibility and to generate structured and accessible clinical reports. It is essential to appoint multidisciplinary tumour molecular committees to oversee these processes and to enable the most suitable therapeutic decisions for each patient according to the genomic profile.
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http://dx.doi.org/10.1016/j.patol.2019.12.001DOI Listing
March 2020

[Updated guidelines for predictive biomarker testing in advanced non-small-cell lung cancer: A National Consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology].

Rev Esp Patol 2020 Jul - Sep;53(3):167-181. Epub 2020 Jun 16.

Departamento de Oncología Médica, Hospital Universitario Ramón y Cajal, Universidad Alcalá, IRYCIS, CIBERONC, Madrid, España.

In 2011, the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP) initiated a joint project to establish guidelines for biomarker testing in patients with advanced non-small-cell lung cancer based on the information available at the time. As this field is constantly evolving, these guidelines were updated in 2012 and 2015 and now in 2019. Current evidence suggests it should be mandatory to test all patients with this kind of advanced lung cancer for EGFR and BRAF mutations, ALK and ROS1 rearrangements and PD-L1 expression. The growing need to study other emerging biomarkers has promoted the routine use of massive sequencing (next-generation sequencing, NGS). However, the coordination of every professional involved and the prioritisation of the most suitable tests and technologies for each case remain a challenge.
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http://dx.doi.org/10.1016/j.patol.2019.11.004DOI Listing
June 2020

Gender gap: surveying the world for tomorrow.

ESMO Open 2020 07;5(4)

Oncology Department, CHUV, Lausanne, VD, Switzerland.

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http://dx.doi.org/10.1136/esmoopen-2020-000805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7342817PMC
July 2020

COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study.

Lancet Oncol 2020 07 12;21(7):914-922. Epub 2020 Jun 12.

Oncology Department, Lausanne University Hospital, Lausanne University, Lausanne, Switzerland.

Background: Early reports on patients with cancer and COVID-19 have suggested a high mortality rate compared with the general population. Patients with thoracic malignancies are thought to be particularly susceptible to COVID-19 given their older age, smoking habits, and pre-existing cardiopulmonary comorbidities, in addition to cancer treatments. We aimed to study the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with thoracic malignancies.

Methods: The Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry is a multicentre observational study composed of a cross-sectional component and a longitudinal cohort component. Eligibility criteria were the presence of any thoracic cancer (non-small-cell lung cancer [NSCLC], small-cell lung cancer, mesothelioma, thymic epithelial tumours, and other pulmonary neuroendocrine neoplasms) and a COVID-19 diagnosis, either laboratory confirmed with RT-PCR, suspected with symptoms and contacts, or radiologically suspected cases with lung imaging features consistent with COVID-19 pneumonia and symptoms. Patients of any age, sex, histology, or stage were considered eligible, including those in active treatment and clinical follow-up. Clinical data were extracted from medical records of consecutive patients from Jan 1, 2020, and will be collected until the end of pandemic declared by WHO. Data on demographics, oncological history and comorbidities, COVID-19 diagnosis, and course of illness and clinical outcomes were collected. Associations between demographic or clinical characteristics and outcomes were measured with odds ratios (ORs) with 95% CIs using univariable and multivariable logistic regression, with sex, age, smoking status, hypertension, and chronic obstructive pulmonary disease included in multivariable analysis. This is a preliminary analysis of the first 200 patients. The registry continues to accept new sites and patient data.

Findings: Between March 26 and April 12, 2020, 200 patients with COVID-19 and thoracic cancers from eight countries were identified and included in the TERAVOLT registry; median age was 68·0 years (61·8-75·0) and the majority had an Eastern Cooperative Oncology Group performance status of 0-1 (142 [72%] of 196 patients), were current or former smokers (159 [81%] of 196), had non-small-cell lung cancer (151 [76%] of 200), and were on therapy at the time of COVID-19 diagnosis (147 [74%] of 199), with 112 (57%) of 197 on first-line treatment. 152 (76%) patients were hospitalised and 66 (33%) died. 13 (10%) of 134 patients who met criteria for ICU admission were admitted to ICU; the remaining 121 were hospitalised, but were not admitted to ICU. Univariable analyses revealed that being older than 65 years (OR 1·88, 95% 1·00-3·62), being a current or former smoker (4·24, 1·70-12·95), receiving treatment with chemotherapy alone (2·54, 1·09-6·11), and the presence of any comorbidities (2·65, 1·09-7·46) were associated with increased risk of death. However, in multivariable analysis, only smoking history (OR 3·18, 95% CI 1·11-9·06) was associated with increased risk of death.

Interpretation: With an ongoing global pandemic of COVID-19, our data suggest high mortality and low admission to intensive care in patients with thoracic cancer. Whether mortality could be reduced with treatment in intensive care remains to be determined. With improved cancer therapeutic options, access to intensive care should be discussed in a multidisciplinary setting based on cancer specific mortality and patients' preference.

Funding: None.
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http://dx.doi.org/10.1016/S1470-2045(20)30314-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292610PMC
July 2020

European Society for Medical Oncology (ESMO) 2018 Congress Twitter analysis: from ethics to results through the understanding of communication and interaction flows.

ESMO Open 2020 02 5;5(1). Epub 2020 Feb 5.

Division of Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy.

Background: Twitter is a microblogging service providing a platform for social networking. For medical information, Twitter is an interesting channel for sharing and spreading information and as an engagement platform for different stakeholders. Benefits and caveats of uncontrolled medical information must be carefully pondered, considering the possible intended and unintended adverse outcomes of uncontrolled influencing. The aim of this study was to describe the non-commercial content shared on Twitter and to analyse the level of influence of commercial tweeters during the European Society of Medical Oncology (ESMO) 2018 annual meeting held in Munich.

Design/methodology: A retrospective analysis of the tweets shared in the period 19-23 October 2018 indexed with the hashtag #ESMO18 or #ESMO2018 was performed; methodology of systematic reviews was mirrored. Commercial tweeters (pharmaceutical and biotechnology companies, device manufacturers and spam tweeters) were excluded from the primary analysis, and only non-commercial tweets from and about the congress were included. Tweets were analysed using a network analytical tool (NodeXL).

Results: A total of 7100 tweets posted by 1334 tweeters were identified for the period of interest. Less than 10% of tweeters were identified as commercial, posting 15.7% of tweets and receiving almost one-quarter of retweets. However, pharmaceutical and biotech tweeters were substantially less likely to be mentioned by other tweeters. All of the top 10 retweeters of non-commercial content were clinicians and/or professional organisations, in stark contrast with the commercial content.

Conclusions: The use of social networks in medical meetings, including oncology, is increasing for real-time communication and informed opinion-making. The uncontrolled spread of information on Twitter can both stimulate discussions on non-official and non-canonical channels of communication and provide uncontrolled influencing of diverse stakeholders. The disclosure of financial declarations of interest on Twitter could enhance the transparency of the information, as is already happening in medical journals.
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http://dx.doi.org/10.1136/esmoopen-2019-000598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046424PMC
February 2020

Efficacy and safety of necitumumab and pembrolizumab combination therapy in patients with Stage IV non-small cell lung cancer.

Lung Cancer 2020 04 19;142:63-69. Epub 2020 Feb 19.

Thoracic Oncology Unit, University Hospital of Nantes, Nantes, France.

Objectives: Efficacy and safety of necitumumab when combined with pembrolizumab was assessed in patients with Stage IV non-small cell lung cancer (NSCLC) of squamous and nonsquamous histology, who had progressed after treatment with a platinum-based doublet.

Materials And Methods: This single-arm, multicenter, phase Ib study had a dose-finding phase, in which escalating doses of necitumumab (600 mg and 800 mg IV) were administered on Day 1 and 8 every 3 weeks (Q3W) in combination with pembrolizumab (200 mg IV) on Day 1 Q3W, and expansion cohorts. Patients were treated until progressive disease (PD), toxicity requiring cessation, protocol noncompliance, or withdrawal of consent. Efficacy was evaluated by overall response rate (ORR).

Results: In 64 treated patients (32 patients [50 %] were programmed death-ligand 1 [PD-L1] negative), confirmed ORR was 23.4 % (95 % confidence interval [CI] 13.8 %-35.7 %). Two patients (3.1 %) had complete response (CR), 13 patients (20.3 %) had partial response (PR), 26 patients (40.6 %) had stable disease, 17 patients (26.6 %) had PD, and 6 patients (9.4 %) were not evaluable. Regardless of histology or PD-L1 status, median PFS (mPFS) was 4.1 months (95 % CI 2.4-6.9 months) and OS at 6 months was 74.7 % (61.5%-83.9%). Confirmed disease control rate was 64.1 % (95 % CI 51.5-75.7). Patients with programmed death-ligand 1 (PD-L1) ≥1% had numerically improved ORR and median progression-free survival when compared with patients with PD-L1 negative cancer. No dose-limiting toxicities were recorded and the combination of necitumumab 800 mg with pembrolizumab 200 mg was considered tolerable.

Conclusion: Results suggest modest benefits of second-line necitumumab and pembrolizumab combination therapy in patients with Stage IV NSCLC. Safety profiles were consistent with class effects typical of epidermal growth factor receptor inhibitors and immunotherapies with no additive toxicities.
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http://dx.doi.org/10.1016/j.lungcan.2020.02.003DOI Listing
April 2020

Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials.

Lancet Oncol 2020 02 11;21(2):271-282. Epub 2019 Dec 11.

Department of Developmental Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Background: Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood-brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials.

Methods: An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0-2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001).

Findings: Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77-18·76). 31 (57%; 95% CI 43·2-70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred.

Interpretation: Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours.

Funding: Ignyta/F Hoffmann-La Roche.
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http://dx.doi.org/10.1016/S1470-2045(19)30691-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461630PMC
February 2020

Tumor genetic alterations and features of the immune microenvironment drive myelodysplastic syndrome escape and progression.

Cancer Immunol Immunother 2019 Dec 8;68(12):2015-2027. Epub 2019 Nov 8.

Servicio de Hematología, Hospital Universitario Virgen de las Nieves, Granada, Spain.

The transformation and progression of myelodysplastic syndromes (MDS) to secondary acute myeloid leukemia (sAML) involve genetic, epigenetic, and microenvironmental factors. Driver mutations have emerged as valuable markers for defining risk groups and as candidates for targeted treatment approaches in MDS. It is also evident that the risk of transformation to sAML is increased by evasion of adaptive immune surveillance. This study was designed to explore the immune microenvironment, immunogenic tumor-intrinsic mechanisms (HLA and PD-L1 expression), and tumor genetic features (somatic mutations and altered karyotypes) in MDS patients and to determine their influence on the progression of the disease. We detected major alterations of the immune microenvironment in MDS patients, with a reduced count of CD4 T cells, a more frequent presence of markers related to T cell exhaustion, a more frequent presence of myeloid-derived suppressor cells (MDSCs), and changes in the functional phenotype of NK cells. HLA Class I (HLA-I) expression was normally expressed in CD34 blasts and during myeloid differentiation. Only two out of thirty-six patients with homozygosity for HLA-C groups acquired complete copy-neutral loss of heterozygosity in the HLA region. PD-L1 expression on the leukemic clone was also increased in MDS patients. Finally, no interplay was observed between the anti-tumor immune microenvironment and mutational genomic features. In summary, extrinsic and intrinsic immunological factors might severely impair immune surveillance and contribute to clonal immune escape. Genomic alterations appear to make an independent contribution to the clonal evolution and progression of MDS.
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http://dx.doi.org/10.1007/s00262-019-02420-xDOI Listing
December 2019

An open-label phase IB study to evaluate GSK3052230 in combination with paclitaxel and carboplatin, or docetaxel, in FGFR1-amplified non-small cell lung cancer.

Lung Cancer 2019 10 14;136:74-79. Epub 2019 Aug 14.

Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain. Electronic address:

Objectives: GSK3052230 (FP-1039) is a soluble fusion protein that acts as ligand trap sequestering fibroblast growth factors (FGFs) involved in tumor growth and angiogenesis, while sparing the hormonal FGFs. Because of this selectivity, the molecule is predicted to avoid toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Herein we report the results of a phase 1b study where GSK3052330 was administered with standard of care chemotherapy in FGFR1-amplified squamous non-small cell lung cancer (sqNSCLC) patients.

Methods And Methods: Eligible patients with stage IV or recurrent metastatic sqNSCLC harboring FGFR1 gene amplification received escalating doses of GSK3052230 in combination with paclitaxel and carboplatin at the starting doses 200 mg/m and AUC of 6, respectively, in the first line setting (Arm A) or docetaxel 75 mg/m in second line (Arm B). The primary endpoints of the study were safety and tolerability, to identify a maximum tolerated dose (MTD), and to assess overall response rate (ORR) based on investigator assessment.

Results: Twenty-nine patients were enrolled into the study, including 20 patients on Arm A and 9 patients on Arm B. There were no dose limiting toxicities in either Arm and the MTD was not reached. The most common adverse events (AEs) were compatible with the chemotherapy backbone used in each Arm, including neutropenia, alopecia, nausea, arthralgia, asthenia, diarrhea and peripheral neuropathy. The overall response rate and median progression-free survival were 47% and 5.5 months, respectively, for Arm A and 0% and 4.6 months, respectively, for Arm B.

Conclusion: GSK3052230 is a novel FGFR pathway inhibitor, which is well tolerated in combination with chemotherapy. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug.
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http://dx.doi.org/10.1016/j.lungcan.2019.08.011DOI Listing
October 2019

Assessment of a New ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in Patients with Non-Small Cell Lung Carcinoma: the ROSING Study.

J Thorac Oncol 2019 12 23;14(12):2120-2132. Epub 2019 Jul 23.

Alvaro Cunqueiro Hospital, Vigo, Spain.

Introduction: The ROS1 gene rearrangement has become an important biomarker in NSCLC. The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology testing guidelines support the use of ROS1 immunohistochemistry (IHC) as a screening test, followed by confirmation with fluorescence in situ hybridization (FISH) or a molecular test in all positive results. We have evaluated a novel anti-ROS1 IHC antibody (SP384) in a large multicenter series to obtain real-world data.

Methods: A total of 43 ROS1 FISH-positive and 193 ROS1 FISH-negative NSCLC samples were studied. All specimens were screened by using two antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 from Ventana Medical Systems), and the different interpretation criteria were compared with break-apart FISH (Vysis). FISH-positive samples were also analyzed with next-generation sequencing (Oncomine Dx Target Test Panel, Thermo Fisher Scientific).

Results: An H-score of 150 or higher or the presence of at least 70% of tumor cells with an intensity of staining of 2+ or higher by the SP384 clone was the optimal cutoff value (both with 93% sensitivity and 100% specificity). The D4D6 clone showed similar results, with an H-score of at least 100 (91% sensitivity and 100% specificity). ROS1 expression in normal lung was more frequent with use of the SP384 clone (p < 0.0001). The ezrin gene (EZR)-ROS1 variant was associated with membranous staining and an isolated green signal FISH pattern (p = 0.001 and p = 0.017, respectively).

Conclusions: The new SP384 ROS1 IHC clone showed excellent sensitivity without compromising specificity, so it is another excellent analytical option for the proposed testing algorithm.
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http://dx.doi.org/10.1016/j.jtho.2019.07.005DOI Listing
December 2019

Clinical utility of plasma-based digital next-generation sequencing in oncogene-driven non-small-cell lung cancer patients with tyrosine kinase inhibitor resistance.

Lung Cancer 2019 08 30;134:72-78. Epub 2019 May 30.

CIBERONC, Spain; Medical Oncology Department, IRYCIS Hospital Universitario Ramón y Cajal, Universidad Alcalá, Madrid, Spain. Electronic address:

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.
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http://dx.doi.org/10.1016/j.lungcan.2019.05.032DOI Listing
August 2019

Phase I, Open-Label, Dose-Escalation Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of GSK2879552 in Relapsed/Refractory SCLC.

J Thorac Oncol 2019 10 28;14(10):1828-1838. Epub 2019 Jun 28.

Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri. Electronic address:

Introduction: This first-time-in-humans study assessed the safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of GSK2879552 in patients with relapsed or refractory SCLC.

Methods: This phase I, multicenter, open-label study (NCT02034123) enrolled patients (≥18 years old) with relapsed or refractory SCLC (after ≥1 platinum-containing chemotherapy or refusal of standard therapy). Part 1 was a dose-escalation study; Part 2 was a dose-expansion study. Dose escalations were based on safety, PK, and PD. The primary end point (Part 1) was to determine the safety, tolerability, and recommended dose and regimen of GSK2879552. Secondary end points were to characterize PK and PD parameters and measure disease control rate at week 16. Part 2 was not conducted.

Results: Between February 4, 2014, and April 18, 2017, a total of 29 patients were allocated to one of nine dose cohorts (0.25 mg-3 mg once daily and 3-mg or 4-mg intermittent dosing). In all, 22 patients completed the study; 7 withdrew, primarily owing to adverse events (AEs). Most patients (24 of 29 [83%]) had at least one treatment-related AE, most commonly thrombocytopenia (12 of 29 [41%]). Twelve serious AEs (SAEs) were reported by nine patients; six were considered treatment related, the most common of which was encephalopathy (four SAEs). Three patients died; one death was related to SAEs. PK was characterized by rapid absorption, slow elimination, and a dose-proportional increase in exposure.

Conclusions: GSK2879552 is a potent, selective inhibitor of lysine demethylase 1A and has demonstrated favorable PK properties but provided poor disease control and a high AE rate in patients with SCLC. The study was terminated, as the risk-benefit profile did not favor continuation.
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http://dx.doi.org/10.1016/j.jtho.2019.06.021DOI Listing
October 2019

Indoor Radon in EGFR- and BRAF-Mutated and ALK-Rearranged Non-Small-Cell Lung Cancer Patients.

Clin Lung Cancer 2019 07 3;20(4):305-312.e3. Epub 2019 May 3.

Medical Oncology Department, Ramón y Cajal University Hospital, Madrid, Spain; Medicine Department, Universidad de Alcalá, Research Institute Ramón y Cajal (IRYCIS), CIBER Oncology (CIBERONC), Madrid, Spain. Electronic address:

Background: Radon gas is the leading cause of lung cancer in the nonsmoking population. The World Health Organization (WHO) recommends indoor concentrations of < 100 Bq/m³. Several molecular alterations have been described in non-small-cell lung cancer (NSCLC), mainly in nonsmokers, with no risk factors identified. We studied the role of indoor radon in NSCLC patients harboring specific driver alterations.

Patients And Methods: We assessed the radon concentration from EGFR-, BRAF-mutated (m), and ALK-rearranged (r) NSCLC patients measured by an alpha-track detector placed in their homes between September 2014 and August 2015. Clinical characteristics were collected prospectively, and pathologic samples were reviewed retrospectively.

Results: Forty-eight patients were included (36 EGFRm, 10 ALKr, 2 BRAFm). Median radon concentration was 104 Bq/m³ (IQR 69-160) overall, and was 96 Bq/m³ (42-915) for EGFRm, 116 (64-852) for ALKr, and 125 for BRAFm, with no significant differences. Twenty-seven patients (56%) had indoor radon above WHO recommendations, 8 (80%) of 10 ALKr, 2 (100%) of 2 BRAFm, and 17 (47%) of 36 EGFRm.

Conclusion: The median indoor radon concentration was above the WHO recommendations, with no differences between EGFR, ALK, and BRAF patients. Concentrations above the WHO recommendations were most common with ALKr and BRAFm. These findings should be validated in larger studies.
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http://dx.doi.org/10.1016/j.cllc.2019.04.009DOI Listing
July 2019

New oncologic emergencies: What is there to know about inmunotherapy and its potential side effects?

Eur J Intern Med 2019 Aug 23;66:1-8. Epub 2019 May 23.

Medical Oncology Department, Ramon y Cajal University Hospital, Ctra. Colmenar Km 9100 s/n, Madrid 28034, Spain.

Over the last decade anticancer treatment has experienced encouraging changes. One of the latest developments is immunotherapy, which is increasingly becoming a mainstay for the treatment of these malignancies. Unlike conventional chemotherapy, immunotherapy enhances anti-tumor immune response by blocking inhibitory immune checkpoints, and allowing our own immune system to fight against the tumor cells, arising as a new and innovative mechanism of action. Therefore, although well tolerated, these drugs have a unique side effect profile and are known to cause immune-related adverse events (irAEs). Adverse effects of immunotherapy are most commonly observed in the skin, gastrointestinal tract, liver, lung and endocrine systems. Less common toxicities may include neurological, haematological, cardiac, ocular or rheumatologic involvement. As far as we know, cancer patients are frequently seen in the Emergency Department due to treatment related toxicities, thus there is an increasing necessity to learn about this particular side effect profile given that they entail a different and unique management than that of classic chemotherapy drugs.
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http://dx.doi.org/10.1016/j.ejim.2019.05.020DOI Listing
August 2019

Consolidative thoracic radiotherapy in stage IV small cell lung cancer: Selection of patients amongst European IASLC and ESTRO experts.

Radiother Oncol 2019 06 15;135:74-77. Epub 2019 Mar 15.

Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands.

Background: The role of consolidative thoracic radiotherapy (TRT) in stage IV small cell lung cancer (SCLC) is not uniformly accepted.

Methods: We obtained a list of 13 European medical oncologists from the International Association for the Study of Lung Cancer (IASLC) and 13 European radiation oncologists from the European Society for Therapeutic Radiation Oncology (ESTRO). The strategies in decision making for TRT in stage IV SCLC were collected. Decision trees were created representing these strategies. Frequencies of recommending TRT were analysed for various parameter combinations based on the objective consensus methodology.

Results: The factors associated with the recommendation for TRT included fitness of the patient, limited extrathoracic tumour burden, initial bulky thoracic disease and response to chemotherapy. The highest consensus for TRT was in fit patients with limited extrathoracic tumour burden and initial bulky disease with either a complete extrathoracic response or partial thoracic response (92% recommend TRT). For these patients the recommendations were the same for medical and radiation oncologists. In the setting of partial response (intra- and extra-thoracically) without initial bulky thoracic disease radiation oncologists were more likely to recommend TRT than medical oncologists. For unfit patients or for patients with poor overall response to chemotherapy, the majority did not recommend TRT.

Conclusion: European radiation and medical oncologists specializing in lung cancer recommend TRT in selected patients with stage IV SCLC and restrict its use primarily to fit patients who responded to chemotherapy with limited extrathoracic tumour burden.
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http://dx.doi.org/10.1016/j.radonc.2019.02.010DOI Listing
June 2019
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