Potential Role of Circulating PD-L1+ Leukocytes as a Predictor of Response to Anti-PD-(L)1 Therapy in NSCLC Patients.

PD-(L)1 inhibitors are part of the treatment strategy for non-small cell lung cancer (NSCLC) although its efficacy is limited to certain patients. Our study aimed to identify patients who might benefit from anti-PD-(L)1 inhibitors by analyzing the PD-L1 expression on circulating leukocytes and its evolution during treatment. One hundred thirteen NSCLC patients, according to their radiological response after 10-12 weeks of treatment, were classified into responders, stable, and progressive disease. Percentages of circulating PD-L1+ leukocytes, PD-L1+ platelets (PLTs), and leukocyte-PLT complexes were assessed using flow cytometry, and plasma concentrations of soluble immunomodulatory factors were quantified by ELISA. Responders exhibited significantly higher pre-treatment percentages of PD-L1+ neutrophils, PD-L1+ CD14+ cells, and PD-L1+ PLTs than progressors. The percentages of these populations decreased in responders post-treatment, contrasting with stables and progressors. PLTs notably contributed to PD-L1 expression in CD14+ cells and neutrophils. Plasma cytokine analysis revealed baseline differences only in IL-17 concentration among groups, whereas network analyses highlighted distinct association patterns between plasma molecules and PD-L1+ leukocytes after 10-12 weeks of treatment. Our findings suggest that pre-treatment assessment of circulating PD-L1+ neutrophils, PD-L1+ CD14+ cells, and PD-L1+ PLTs may be helpful in identifying NSCLC patients who are potential candidates for anti-PD-(L)1 therapy.

Kinetics of IFNγ-Induced Cytokines and Development of Immune-Related Adverse Events in Patients Receiving PD-(L)1 Inhibitors.

Immune checkpoint inhibitors (ICI) have the potential to trigger unpredictable immune-related adverse events (irAEs), which can be severe. The underlying mechanisms of these events are not fully understood. As PD-L1 is upregulated by IFN, the heightened immune activation resulting from PD-1/PD-L1 inhibition may enhance the IFN response, triggering the expression of IFN-inducible genes and contributing to irAE development and its severity. In this study, we investigated the interplay between irAEs and the expression of IFN-inducible chemokines and cytokines in 134 consecutive patients with solid tumours treated with PD-(L)1 inhibitors as monotherapy or in combination with chemotherapy or other immunotherapy agents. We compared the plasma levels of IFN-associated cytokines (CXCL9/10/11, IL-18, IL-10, IL-6 and TGFß) at various time points (at baseline, at the onset of irAE and previous to irAE onset) in three patient groups categorized by irAE development and severity: patients with serious irAEs, mild irAEs and without irAEs after PD-(L)1 inhibitors. No differences were observed between groups at baseline. However, patients with serious irAEs exhibited significant increases in CXCL9/10/11, IL-18 and IL-10 levels at the onset of the irAE compared to baseline. A network analysis and correlation patterns highlighted a robust relationship among these chemokines and cytokines at serious-irAE onset. Combining all of the analysed proteins in a cluster analysis, we identified a subgroup of patients with a higher incidence of serious irAEs affecting different organs or systems. Finally, an ROC analysis and a decision tree model proposed IL-18 levels ≥ 807 pg/mL and TGFß levels ≤ 114 pg/mL as predictors for serious irAEs in 90% of cases. In conclusion, our study elucidates the dynamic changes in cytokine profiles associated with serious irAE development during treatment with PD-(L)1 inhibitors. The study's findings offer valuable insights into the intricate IFN-induced immune responses associated with irAEs and propose potential predictive markers for their severity.

Summary of Research: Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC.

This is a summary of the original article ?Overall survival with osimertinib in resected EGFR-mutated NSCLC.Ë® Osimertinib blocks the activity of the epidermal growth factor receptor (EGFR) on cancer cells, causing cancer cell death and tumor shrinkage, and is an effective treatment for EGFR-mutated non-small cell lung cancer (NSCLC). The ADAURA study assessed the effects of osimertinib versus placebo in patients with EGFR-mutated (exon 19 deletion or L858R) early stage (IB-IIIA) NSCLC removed by surgery (resected). Previous results from ADAURA demonstrated that patients treated with osimertinib stayed alive and cancer-free (disease-free survival) significantly longer than patients who received placebo. Recent data showed the overall length of time patients were alive after starting treatment (overall survival). In both the primary stage II-IIIA and overall stage IB-IIIA populations, patients in the osimertinib group had a significant 51% reduction in the risk of death compared with the placebo group. The data demonstrated that osimertinib after surgery significantly improved overall survival in patients with resected, EGFR-mutated, stage IB-IIIA NSCLC.

Longitudinal Analyses of Circulating-Tumor DNA for Detection of EGFR Mutation-Positive Advanced Non-Small Cell Lung Cancer Progression During Treatment: Data From FLAURA and AURA3.

INTRODUCTION: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-sensitizing and -resistance mutations may be detected in plasma via circulating tumor DNA (ctDNA). ctDNA level changes reflect alterations in tumor burden and could be a dynamic indicator of treatment effect. This analysis aimed to determine whether longitudinal EGFR-mutation ctDNA testing could detect progressive disease (PD) before radiologic detection. METHODS: This was a retrospective, exploratory ctDNA analysis in two phase 3 trials (FLAURA, NCT02296125; AURA3, NCT02151981). Patients had treatment-naïve (FLAURA) or EGFR-TKI pre-treated (AURA3) advanced non-small cell lung cancer (NSCLC) with EGFR mutations and on-study PD (RECIST), with a baseline ctDNA result and EGFR-mutation ctDNA monitoring beyond Cycle 3 Day 1. Patients received osimertinib versus comparator EGFR-TKIs (FLAURA) or chemotherapy (AURA3). Outcomes included time from ctDNA PD to RECIST PD, and to first subsequent treatment (FST; FLAURA only). RESULTS: ctDNA PD preceded/co-occurred with RECIST-defined PD in 93/146 (64%) patients in FLAURA and 82/146 (56%) in AURA3. Median time from ctDNA PD to RECIST-defined PD (months) was 3.4 and 2.6 in the osimertinib and comparator EGFR-TKI arms (FLAURA) and 2.8 and 1.5 in the osimertinib and chemotherapy arms (AURA3). In FLAURA, median time from ctDNA PD to FST (months) was 6.0 and 4.7 in the osimertinib (n = 51) and comparator EGFR-TKI arms (n = 70). CONCLUSIONS: Among patients with EGFR mutation-positive advanced NSCLC receiving EGFR-TKI or chemotherapy with ctDNA data and RECIST-defined PD, ctDNA PD preceded/co-occurred with RECIST-defined PD in approximately 60% of cases. Longitudinal ctDNA monitoring may detect PD before radiologic PD.

Overall Survival From the EORTC LCG-1613 APPLE Trial of Osimertinib Versus Gefitinib Followed by Osimertinib in Advanced EGFR-Mutant Non-Small-Cell Lung Cancer.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Osimertinib has been established as a standard of care for patients with common sensitizing EGFR-mutant advanced non-small-cell lung cancer (NSCLC) although the sequential approach (first-generation inhibitor gefitinib followed by osimertinib) has not been formally compared. The phase II APPLE trial (ClinicalTrials.gov identifier: NCT02856893) enrolled 156 treatment-naïve patients, and two treatment strategies were evaluated: osimertinib up front or the sequential treatment approach with gefitinib up front followed by osimertinib at the time of progression, either molecular progression (detection of plasma T790M resistance mutation) regardless of the radiologic status or just at the time of radiologic progression. Patients' characteristics were well balanced, except for the higher proportion of baseline brain metastases in the sequential approach (29% v 19%). Per protocol, 73% of patients switched to osimertinib in the sequential arm. Up-front treatment with osimertinib was associated with a lower risk of brain progression versus the sequential approach (hazard ratio [HR], 0.54 [90% CI, 0.34 to 0.86]), but a comparable overall survival was observed between both strategies (HR, 1.01 [90% CI, 0.61 to 1.68]), with the 18-month survival probability of 84% and 82.3%, respectively. The APPLE trial suggests that a sequential treatment approach is associated with more frequent progression in the brain but a similar survival in advanced EGFR-mutant NSCLC.

Malignant Pleural Effusion: A Multidisciplinary Approach.

Malignant pleural effusion (MPE) has become an increasingly prevalent complication in oncological patients, negatively impacting their quality of life and casting a shadow over their prognosis. Owing to the pathophysiological mechanisms involved and the heterogeneous nature of the underlying disease, this entity is both a diagnostic and therapeutic challenge. Advances in the understanding of MPE have led to a shift in the treatment paradigm towards a more personalized approach. This article provides a comprehensive review and update on the pathophysiology of MPE and describes the diagnostic tools and the latest advances in the treatment of this complex clinical entity.

El derrame pleural maligno (DPM) se ha convertido en una complicación cada vez más prevalente en los pacientes oncológicos, empeorando la calidad de vida y ensombreciendo el pronóstico de los mismos. Debido a los mecanismos fisiopatológicos involucrados y a la naturaleza heterogénea de la enfermedad subyacente, esta entidad representa un desafío diagnóstico y terapéutico. Los avances en la comprensión del DPM han originado un cambio en el paradigma del tratamiento hacia un enfoque más personalizado. Este artículo proporciona una revisión exhaustiva y una actualización sobre la fisiopatología del DPM, y describe las herramientas diagnósticas y los últimos avances en el tratamiento de esta compleja entidad clínica.

RET Fusion Testing in Patients With NSCLC: The RETING Study.

Introduction: RET inhibitors with impressive overall response rates are now available for patients with NSCLC, yet the identification of RET fusions remains a difficult challenge. Most guidelines encourage the upfront use of next-generation sequencing (NGS), or alternatively, fluorescence in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (RT-PCR) when NGS is not possible or available. Taken together, the suboptimal performance of single-analyte assays to detect RET fusions, although consistent with the notion of encouraging universal NGS, is currently widening some of the clinical practice gaps in the implementation of predictive biomarkers in patients with advanced NSCLC. Methods: This situation prompted us to evaluate several RET assays in a large multicenter cohort of RET fusion-positive NSCLC (n = 38) to obtain real-world data. In addition to RNA-based NGS (the criterion standard method), all positive specimens underwent break-apart RET FISH with two different assays and were also tested by an RT-PCR assay. Results: The most common RET partners were KIF5B (78.9%), followed by CCDC6 (15.8%). The two RET NGS-positive but FISH-negative samples contained a KIF5B(15)-RET(12) fusion. The three RET fusions not identified with RT-PCR were AKAP13(35)-RET(12), KIF5B(24)-RET(9) and KIF5B(24)-RET(11). All three false-negative RT-PCR cases were FISH-positive, exhibited a typical break-apart pattern, and contained a very high number of positive tumor cells with both FISH assays. Signet ring cells, psammoma bodies, and pleomorphic features were frequently observed (in 34.2%, 39.5%, and 39.5% of tumors, respectively). Conclusions: In-depth knowledge of the advantages and disadvantages of the different RET testing methodologies could help clinical and molecular tumor boards implement and maintain sensible algorithms for the rapid and effective detection of RET fusions in patients with NSCLC. The likelihood of RET false-negative results with both FISH and RT-PCR reinforces the need for upfront NGS in patients with NSCLC.

Multidisciplinary approach for locally advanced non-small cell lung cancer (NSCLC): 2023 expert consensus of the Spanish Lung Cancer Group GECP.

INTRODUCTION: Recent advances in the treatment of locally advanced NSCLC have led to changes in the standard of care for this disease. For the selection of the best approach strategy for each patient, it is necessary the homogenization of diagnostic and therapeutic interventions, as well as the promotion of the evaluation of patients by a multidisciplinary oncology team. OBJECTIVE: Development of an expert consensus document with suggestions for the approach and treatment of locally advanced NSCLC leaded by Spanish Lung Cancer Group GECP. METHODS: Between March and July 2023, a panel of 28 experts was formed. Using a mixed technique (Delphi/nominal group) under the guidance of a coordinating group, consensus was reached in 4 phases: 1. Literature review and definition of discussion topics 2. First round of voting 3. Communicating the results and second round of voting 4. Definition of conclusions in nominal group meeting. Responses were consolidated using medians and interquartile ranges. The threshold for agreement was defined as 85% of the votes. RESULTS: New and controversial situations regarding the diagnosis and management of locally advanced NSCLC were analyzed and reconciled based on evidence and clinical experience. Discussion issues included: molecular diagnosis and biomarkers, radiologic and surgical diagnosis, mediastinal staging, role of the multidisciplinary thoracic committee, neoadjuvant treatment indications, evaluation of response to neoadjuvant treatment, postoperative evaluation, and follow-up. CONCLUSIONS: Consensus clinical suggestions were generated on the most relevant scenarios such as diagnosis, staging and treatment of locally advanced lung cancer, which will serve to support decision-making in daily practice.

Association Between Lung Immune Prognostic Index and Durvalumab Consolidation Outcomes in Patients With Locally Advanced Non-Small-Cell Lung Cancer.

INTRODUCTION: The LIPI, based on pretreatment derived neutrophils/[leukocytes-neutrophils] ratio (dNLR) and LDH, is associated with immune checkpoint inhibitors (ICI) outcomes in advanced non-small-cell lung cancer (NSCLC). We aimed to assess baseline LIPI correlation with durvalumab consolidation outcomes in the locally advanced setting. MATERIAL AND METHODS: Multicentre retrospective study (330 patients) with stage III unresectable NSCLC treated with durvalumab after chemo-radiotherapy between April 2015 and December 2020; 65 patients treated with chemo-radiotherapy only. Baseline LIPI characterized 3 groups: good (dNLR≤3+LDH≤ULN), intermediate (dNLR>3/LDH>ULN) and poor (dNLR>3+LDH>ULN). Primary endpoint was overall survival (OS). RESULTS: In the durvalumab cohort, median age was 67 years, 95% smokers, 98% with a performance status of 0-1; 60% had nonsquamous histology and 16% a PD-L1 expression <1%. Radiotherapy was delivered concurrently in 81%. LIPI was evaluable in 216 patients: 66% good, 31% intermediate, 3% poor. LIPI significantly correlated with median OS (median follow-up: 19 months): 18.1 months vs. 47.0 months vs. not reached in poor, intermediate and good LIPI groups, respectively (P = .03). A trend between objective response rate and LIPI groups was observed: 0% vs. 41% vs. 45%, respectively (P = .05). The pooled intermediate/poor LIPI group was associated with shorter OS (HR 1.97; P = .03) and higher risk of progressive disease (OR 2.68; P = .047). Survivals and response were not influenced in the control cohort. CONCLUSION: Baseline LIPI correlated with outcomes in patients with locally advanced NSCLC treated with durvalumab consolidation, but not in those who only received chemo-radiotherapy, providing further evidence of its prognostic and potential predictive role of ICI benefit in NSCLC.

BRAF mutational status is associated with survival outcomes in locally advanced resectable and metastatic NSCLC.

BACKGROUND: Immunotherapy-based treatments have demonstrated high efficacy in patients with advanced and locally advanced non-small-cell lung cancer (NSCLC). BRAF mutations affect a small but significant fraction of NSCLC. The efficacy of these therapies in this subgroup of patients is unknown. MATERIALS AND METHODS: Plasma and tissue samples from 116 resectable stage IIIA/B NSCLC patients, included in NADIM and NADIM II clinical trials (NADIM cohort), and from a prospective academic cohort with 84 stage IV NSCLC patients (BLI-O cohort), were analyzed by next-generation sequencing. RESULTS: The p.G464E, p.G466R, p.G466V, p.G469V, p.L597Q, p.T599I, p.V600E (n = 2) BRAF mutations, were identified in four (3.45 %) samples from the NADIM cohort, all of which were cases treated with neoadjuvant chemoimmunotherapy (CH-IO), and four (4.76 %) samples from the BLI-O cohort, corresponding to cases treated with first-line immunotherapy (n = 2) or CH-IO (n = 2). All these patients were alive and had no evidence of disease at data cut-off. Conversely, patients with BRAF wild-type (wt) tumors in the BLI-O cohort had a median progression-free survival (PFS) of 5.49 months and a median overall survival (OS) of 12.00 months (P-LogRank = 0.013 and 0.046, respectively). Likewise, PFS and OS probabilities at 36 months were 60.5 % and 76.1 % for patients with BRAF-wt tumors in the NADIM cohort. The pathological complete response (pCR) rate after neoadjuvant CH-IO in patients with BRAF-positive tumors (n = 4) was 100 %, whereas the pCR rate in the BRAF-wt population was 44.3 % (RR: 2.26; 95 % CI: 1.78-2.85; P < 0.001). CONCLUSION: BRAF mutations may be a good prognostic factor for advanced and locally advanced NSCLC patients undergoing immunotherapy-based treatments.

Spatially Preserved Multi-Region Transcriptomic Subtyping and Biomarkers of Chemoimmunotherapy Outcome in Extensive-Stage Small Cell Lung Cancer.

PURPOSE: Transcriptomic subtyping holds promise for personalized therapy in extensive-stage small cell lung cancer (ES-SCLC). In this study, we aimed to assess intratumoral transcriptomic subtype diversity and to identify biomarkers of long-term chemoimmunotherapy benefit in human ES-SCLC. EXPERIMENTAL DESIGN: We analyzed tumor samples from 58 patients with ES-SCLC enrolled in two multicenter single-arm phase IIIb studies evaluating frontline chemoimmunotherapy in Spain: n = 32 from the IMfirst trial and n = 26 from the CANTABRICO trial. We used the GeoMx Digital Spatial Profiler system to perform multi-region transcriptomic analysis. For subtype classification, we performed hierarchical clustering using the relative expression of ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1 (SCLC-Y). RESULTS: Subtype distribution was found to be similar between bothcohorts, except for SCLC-P, which was not identified in the CANTABRICO_DSP cohort. A total of 44% of the patients in both cohorts had tumors with multiple coexisting transcriptional subtypes. Transcriptional subtypes or subtype heterogeneity was not associated with outcomes. Most potential targets did not show subtype-specific expression. Consistently in both cohorts, tumors from patients with long-term benefit (time to progression ≥12 months) contained an IFNγ-dominated mRNA profile, including enhanced capacity for antigen presentation. Hypoxia and glycolytic pathways were associated with resistance to chemoimmunotherapy. CONCLUSIONS: This work suggests that intratumoral heterogeneity, inconsistent association with outcome, and unclear subtype-specific target expression might be significant challenges for subtype-based precision oncology in SCLC. Preexisting IFNγ-driven immunity and mitochondrial metabolism seem to be correlates of long-term efficacy in this study, although the absence of a chemotherapy control arm precludes concluding that these are predictive features specific for immunotherapy.

A Delphi consensus panel about clinical management of early-stage EGFR-mutated non-small cell lung cancer (NSCLC) in Spain: a Delphi consensus panel study

Purpose This Delphi panel study assessed the level of consensus between medical oncologists on the clinical management of patients with early-stage EGFR-mutated non-small cell lung cancer (NSCLC). Methods A modified two-round Delphi approach was used. A scientific committee comprised of medical oncologists developed an online questionnaire. Delphi panel experts rated their level of agreement with each questionnaire statement on a 9-point Likert scale. The questionnaire included 36 statements from 3 domains (clinical management of early-stage NSCLC: 15 statements; role of adjuvant therapy in early-stage NSCLC: 9 statements; and role of adjuvant therapy in early-stage NSCLC with sensitizing EGFR mutation: 12 statements). Results In round 1, consensus was reached for 24/36 statements (66.7%). Nine statements that did not achieve consensus after the first round were evaluated in round 2, and none of them reached consensus. Overall, 84.4% of the panelists agreed that EGFR mutation testing should be done after surgery. Consensus was not achieved on whether the implementation of EGFR mutation testing in resected early-stage NSCLC could limit the use of adjuvant osimertinib. The panelists recognized the rationale for the use of osimertinib in the adjuvant scenario (88%) and 72% agreed that it may change the treatment paradigm in stage IB–IIIA EGFR-mutated NSCLC. Consensus was not reached on the inconvenience of prolonged duration of osimertinib. Conclusions This Delphi study provides valuable insights into relevant questions in the management of early-stage EGFR-mutated NSCLC. However, specific issues remain unresolved. The expert consensus emphasizes the role of adjuvant treatment with osimertinib in this scenario. (AU)

Expert consensus to optimize the management of older adult patients with advanced EGFR-mutated non-small cell lung cancer

Lung cancer (LC) is associated with ageing, with the average age of affected individuals being approximately 70 years. However, despite a higher incidence and prevalence among older people, the older adult population is underrepresented in clinical trials. For LC with Epidermal Growth Factor Receptor (EGFR) mutations, there is no clear association of this mutation with age. Geriatric assessments (GAs) and a multidisciplinary approach are essential for defining the optimal treatment. In this consensus, a group of experts selected from the Oncogeriatrics Section of the Spanish Society of Medical Oncology (Sección de Oncogeriatría de la Sociedad Española de Oncología Médica—SEOM), the Spanish Lung Cancer Group (Grupo Español de Cáncer de Pulmón—GECP) and the Association for Research on Lung Cancer in Women (Asociación para la Investigación del Cáncer de Pulmón en Mujeres—ICAPEM) evaluate the scientific evidence currently available and propose a series of recommendations to optimize the management of older adult patients with advanced LC with EGFR mutations (AU)

SEOM Clinical Guideline update for the prevention of chemotherapy-induced nausea and vomiting (2021)

Among the side effects of anticancer treatment, chemotherapy-induced nausea and vomiting (CINV) is one of the most feared given its high prevalence, affecting up to 40% of patients. It can impair patient’s quality of life and provoke low adherence to cancer treatment or chemotherapy dose reductions that can comprise treatment efficacy. Suffering CINV depends on factors related to the intrinsic emetogenicity of antineoplastic drugs and on patient characteristics. CINV can appear at different times regarding the administration of antitumor treatment and the variability of risk according to the different antitumor regimens has, as a consequence, the need for a different and adapted antiemetic treatment prophylaxis to achieve the desired objective of complete protection of the patient in the acute phase, in the late phase and in the global phase of emesis. As a basis for the recommendations, the level of emetogenicity of anticancer treatment is considered and they are classified as high, moderate, low and minimal emetogenicity and these recommendations are based on the use of antiemetic drugs with a high therapeutic index: anti 5-HT, anti-NK and steroids. Despite having highly effective treatments, clinical reality shows that they are not applied enough, so evidence-based recommendations are needed to show the best options and help in decision-making. To cover all the antiemetic prophylaxis options, we have also included recommendations for oral treatments, multiday regimens and radiation-induced emesis prevention.

Correction to: SEOM Clinical Guideline update for the prevention of chemotherapy-induced nausea and vomiting (2021)

In this article the title was incorrectly given as “SEOM clinical guideline emesis (2021)” but should have been “SEOM Clinical Guideline update for the prevention of chemotherapy-induced nausea and vomiting (2021).”The original article has been corrected.

Efficacy of nintedanib plus docetaxel in patients with refractory advanced epidermal growth factor receptor mutant lung adenocarcinoma

Background Anti-angiogenic agents are reported to exert clinical activity in patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). We evaluated the outcomes of the combination of docetaxel plus nintedanib in refractory NSCLC patients harboring EGFR mutations. Methods We retrospectively analyzed 19 patients with advanced EGFR-mutant NSCLC who had progressed to EGFR tyrosine kinase inhibitors (TKI) and platinum-based chemotherapy receiving docetaxel and nintedanib at 14 Spanish institutions from January 2013 to December 2019. Kaplan–Meier and log-rank tests were used to evaluate progression-free survival (PFS) and overall survival (OS). Results Median age was 58.9 years (range 42.8–81), 73.7% were female. All patients were Caucasian, and 73.7% were never or light smokers. The baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0–1 in 94.7% of patients. All patients had adenocarcinoma. Brain and liver metastases were present in 47.4% and 31.6% of patients, respectively. The most common EGFR mutations were exon 19 deletion (52.6%) and exon 21 L858R mutation (36.8%); 47.4% patients presented the EGFR T790M. 94.8% of the patients had received 2–3 previous treatment lines. Docetaxel was administered at 75 mg/m2/3 weeks to 16 patients, at 60 mg/m2 to 2 patients and at 45 mg/m2 to one patient. Nintedanib was given until disease progression or unacceptable toxicity at 200 mg twice daily except in 2 patients who received 150 mg twice daily and one patient who received 100 mg/12 h. With a median follow-up of 11.4 months (1–38), the median PFS was 6.1 months [95% confidence interval (CI), 4.9–7.3] and the median OS 10.1 months (95% CI 5.9–14.3). The objective response rate (ORR) was 44.4% (23.7–66.8%) and the disease control rate (DCR) 72.2% (49.4–88.5%) (AU)