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Oscar Gerardo Arrieta

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    ES01 - What Is the Role of Chemotherapy in the Era of Immunotherapy in Advanced NSCLC? (ID 4)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Advanced NSCLC
    • Presentations: 5
    • Now Available
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      ES01.01 - Chemotherapy is Strictly Additive to Immunotherapy (Now Available) (ID 3149)

      10:30 - 12:00  |  Presenting Author(s): Johan Vansteenkiste  |  Author(s): Els Wauters

      • Abstract
      • Presentation
      • Slides

      Abstract

      Historically, chemotherapy was the only systemic therapy for advanced NSCLC. Over the last decades, effective targeted therapy has been developed. EGFR is the prime target since 20 years now [1], and is followed by an increasing number of targetable rare oncogenic driver mutations. This decade, the phase I trial of nivolumab – including NSCLC patients – started recruitment on July 1, 2011 [2]. Since then, immunotherapy with immune checkpoint inhibition (ICI) has become the third pillar in our therapeutic armentarium, with a very rapid development for relapsed, and thereafter for untreated advanced NSCLC. Most patients with non-oncogene addicted advanced NSCLC will nowadays have both chemotherapy and ICI, either in a concurrent or sequential way. This raises the question whether their interaction is synergistic or additive, favoring the former versus the latter approach. We will look at this from the perspective of adverse events, mechanistic background, and clinical trial outcomes.

      There is not much overlap between the typical and common adverse events (AEs) of chemotherapy or ICI. The former are mostly bone marrow inhibition, nausea/vomiting, mucositis, hair loss and neuropathy. ICIs are well tolerated, with no or mild AEs in most patients, but may induce immune related AEs mostly in skin or endocrine organs, liver, lungs or kidneys. Hence, there is little difference in overall adverse event profiles when the chemotherapy+ICI (chemo+ICI) and chemotherapy+placebo (chemo+PL) arms from randomized trials are compared. In the Keynote-189 trial - an example with the anti-PD-1 agent pembrolizumab – overall grade 3 to 5 AEs were present in 67.2% and 65.8% of patients with chemo+ICI and chemo+PL, respectively [3]. Grade 3 to 5 immune-related AEs, as rated by investigators blinded to the assigned therapy, were 8.9% for chemo+ICI, while 4.5% for chemo+PL. AEs leading to discontinuation of all treatment were 13.8% and 7.9%, respectively. Hence, irAEs acted additive to the overall AE profile. The notable exception in this trial was renal toxicity. There was a low frequency of auto-immune nephritis (1.7%), but there was a 5.2% incidence of acute kidney injury in the chemo+ICI arm, compared to 0.5% in the control arm.

      In the IMpower-133 trial – an example with the anti-PD-L1 agent atezolizumab – overall grade 3 to 5 AEs were present in 67.2% and 63.8% of patients with chemo+ICI and chemo+PL, respectively [4]. All grade immune-related AEs, as rated by investigators blinded to the assigned therapy, were 39.9% for chemo+ICI, and 24.5% for chemo+PL. So, here again a rather additive pattern in AE profile is put forward.

      Chemotherapy has long time been regarded as immunosuppressive and incompatible with immuno­therapy. To improve on the rather low response rate with ICI alone, recent trials focused on the combination of chemo+ICI, trying to exploit the immune modulatory (synergistic) effects of chemotherapy both on the tumor cells and immune cells. The details of this interaction are beyond the scope of this abstract, but a central one is immunogenic cell death (ICD) by chemotherapy. In contrast with necrotic/apoptotic cell death, ICD is characterized by immune-promoting features on dendritic cells and macrophages, by means of inducing calreticulin expression on tumor cells, release of adenosine triphosphate in the extracellular space and of high mobility group box 1 protein from the nucleus of the cancer cell. ICD, however, has been associated with only a limited number of chemotherapeutic agents used in clinical practice, such as doxorubicin, mitoxantrone, oxaliplatin and cyclophosphamide [5]. None of these agents is part of the modern chemotherapeutic armentarium for NSCLC.

      Recent phase III trials with chemo+ICI versus chemo+PL demonstrated a convincing benefit in response rate, progression-free survival (PFS) and overall survival (OS) with the combination (e.g. [3]). Of note, there are no randomized data comparing the combination of chemo+ICI in a concurrent versus a sequential way. Ideally, such a trial should have several arms: one with the concurrent use of chemo+ICI in all PD-L1 tumors; a sequential one with pembrolizumab followed by chemotherapy in PD-L1 >=50% tumors; and one with the sequential use of a chemotherapy and then ICI in PD-L1 <50% tumors. The primary endpoint preferably should be PFS2 in a intention-to-treat analysis.

      In the absence of such data, there is no definitive evidence that one or the other strategy is superior, and we can only make speculations about this question. At the meeting, we will present suggested algorithms based on the comparison of PFS from several recent trials. Especially the PFS2 analysis of the Keynote-024 [6,7] and KN-189 [3,8] trials are helpful in this respect. Even if there are many caveats with this approach, it may be helpful to guide clinical practice between concurrent and sequential treatment strategies.

      References

      1. Vansteenkiste J, Wauters E. Tyrosine kinase inhibition of EGFR: A successful history of targeted therapy for NSCLC since 20 years. Ann Oncol 2018; 29 Suppl 1: i1-i2.

      2. Topalian SL, Hodi FS, Brahmer JR et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366: 2443-54.

      3. Gandhi L, Rodriguez-Abreu D, Gadgeel S et al. Pembrolizumab plus chemotherapy in metastatic non-small cell lung cancer. N Engl J Med 2018; 378: 2078-92.

      4. Horn L, Mansfield AS, Szczesna A et al. First-line atezolizumab plus chemotherapy in extensive-stage small cell lung cancer. N Engl J Med 2018; 379: 2220-9.

      5. Bezu L, Gomes-de-Silva LC, Dewitte H et al. Combinatorial strategies for the induction of immunogenic cell death. Front Immunol 2015; 6: 187.

      6. Brahmer JR, Rodriguez-Abreu D, Robinson AG et al. Progression after the next line of therapy (PFS2) and updated OS among patients with advanced NSCLC and PD-L1 TPS >=50% enrolled in KEYNOTE-024. J Clin Oncol 2017;. 35S, abstr 9000.

      7. Reck M, Rodriguez-Abreu D, Robinson AG et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small cell lung cancer. N Engl J Med 2016; 375: 1823-33.

      8. Gadgeel SM, Garassino MC, Esteban E et al. KEYNOTE-189: Updated OS and progression after the next line of therapy (PFS2) with pembrolizumab (pembro) plus chemo with pemetrexed and platinum vs placebo plus chemo for metastatic non-squamous NSCLC. J Clin Oncol 2019; 37S, abstract 9013.

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      ES01.02 - Chemotherapy Enhances the Efficacy of Immunotherapy (Now Available) (ID 3150)

      10:30 - 12:00  |  Presenting Author(s): Natasha B Leighl

      • Abstract
      • Presentation
      • Slides

      Abstract

      Combination chemotherapy with anti-PD-1 therapy has now become standard of care as first-line therapy in patients with advanced NSCLC. Several trials demonstrate the improvement of combination therapy versus chemotherapy alone, but trials comparing immunotherapy +/- chemotherapy are ongoing (e.g. INSIGNA, CCTG BR.34, Checkmate 9LA, Checkmate 227).

      Several preclinical studies suggest that adding chemotherapy to immunotherapy is additive. Chemotherapy has been shown to disrupt immunsuppressive cell activity, for example regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC) and tumour associated macrophages (TAM) in preclinical studies (reviewed in Yan et al. Frontiers in Immunology, 2018). Chemotherapy may also promote immune responses via induction of tumor cell death, upregulation of MHC Class 1 expression and dendritic cell maturation. Lara et al recently reported activity both preclinically and clinically when combining gemcitabine with anti-PD1 therapy in mesothelioma, despite lack of activity of either as a single agent (Lara et al. Clin Cancer Res 2018).

      A key question in the first-line setting for those eligible for anti-PD1 monotherapy (PDL1 TPS >=50%) is whether the addition of chemotherapy is of benefit. Keynote 024 demonstrates superior survival, progression-free survival and response in this population compared to platinum doublet therapy, with a response rate of 45%. Overall response rates in the Keynote 189 and 407 trials in the subgroup with PDL1 TPS>=50% were 60% and 63% for chemotherapy plus pembrolizumab. Despite consensus that some patients clearly benefit from combination therapy while others likely can receive anti-PD-1 monotherapy, it is unclear how to select patients for each strategy. Ongoing studies are currently examining this question, such as the US cooperative-group-led INSIGNA trial (NCT03793179). In this study, patients with advanced PDL1 TPS>=1% nonsquamous NSCLC will be randomized to receive either (1) pembrolizumab monotherapy followed by pemetrexed/platinum upon progression; (2) pembrolizumab monotherapy and upon progression, the addition of pemetrexed/platinum to pembrolizumab; and (3) pembrolizumab/pemetrexed/platinum followed by maintenance pembrolizumab/pemetrexed with investigator's choice of treatment upon progression. It is hoped that this study will provide answers in how to best select patients for either strategy.

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      ES01.03 - Chemotherapy Directly Targets the Immune System to Improve Efficacy  (Now Available) (ID 3151)

      10:30 - 12:00  |  Presenting Author(s): Daniel SW Tan

      • Abstract
      • Presentation
      • Slides

      Abstract

      Multiple phase III trials support the use of combination chemotherapy with immune checkpoint inhibitors in the first line setting. Yet the exact mechanism of synergy is poorly understood. In this third instalment of three talks dissecting this topic, the focus will be on the impact of chemotherapy on the immune system, ranging from its effect on recognition of tumor antigens, circulating immune cells and/or cytokines, as well as on immune cells in the tumor microenvironment. Elucidating the mechanism of action can delineate more tailored approaches to first line therapy, including the use of single agent checkpoint inhibitors or alternative/ additional combinations that further enhance the immune response.

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      ES01.04 - Immunotherapy, Radiotherapy and Chemotherapy Combination: A Potential New Standard? (Now Available) (ID 3152)

      10:30 - 12:00  |  Presenting Author(s): Maurice Perol

      • Abstract
      • Presentation
      • Slides

      Abstract

      The advent of immunotherapy in lung cancer with immune checkpoints inhibitors (CPIs) has first involved stage IV non-small cell lung cancer (NSCLC), recently in combination with cytotoxic chemotherapy in first-line setting. The rationale to combine chemotherapy with CPIs is theoretically based on the chemotherapy-induced immunogenic cell death triggering an immune response and the modification of the tumor microenvironment (TME) by depletion of immunosuppressive cells. Radiotherapy remains one of the main components of the NSCLC treatment, from early stages with stereotactic ablative radiotherapy (SABR) and locally advanced stage III NSCLC in combination with chemotherapy to stage IV disease for the local palliative treatment of metastatic sites. Radiation therapy (RT) techniques have been considerably improved with image-guidance, and technological developments in linear accelerators, allowing now a very precise delivery of radiation.

      Radiation biology has been mainly concentrated on radiation-induced DNA damage with irreparable double strand break, leading to cell cycle inhibition and cell death. There are also a rationale and a preclinical evidence to expect a synergy between RT and CPIs. RT can also cause immunogenic cell death by direct cytotoxic effects, resulting in the release of tumor-associated antigens (TAAs) and danger signals (DAMPs: damage associated molecular pattern) that can be recognized by toll-like receptors, thus facilitating the presentation of TAAs to CD8+ T cells by MHC I. The dendritic cell activation and up-regulation of interferon pathway also enhance TAAs presentation to immune cells and up-regulate MHC-1 expression on tumor cells. Radiotherapy can therefore act as an auto-vaccine, activating the dendritic cells, broadening up the immune repertoire of T cells and increasing the "visibility" of TAAs. Beside this promotion of priming and activation of cytotoxic T cells, RT upregulates PD-L1 expression in the TME. Nevertheless, the modification of TME induced by RT may be equivocal with on one hand an increase in the CD8+ T cells recruitment by up-regulation of adhesion molecules, but on the other hand, the promotion of immune tolerance via the recruitment of MDSCs and Treg cells. Moreover, RT activates the immunosuppressive TGF-β pathway by reactive oxygen species. In addition to the potential synergism in terms of local control, the RT might also mediate an abscopal effect, describing the tumor regression of lesions distant from the irradiated volume, due to circulating of T cells locally activated by RT. This phenomenon has been experimentally demonstrated in preclinical models and occasionally reported in case reports.

      In stage IV NSCLC, the impact of RT delivered on a metastatic site or on the primary tumor on CPIs anti-tumor effect has been suggested by the retrospective analysis of the Keynote 001 phase I trial of pembrolizumab showing that patients who received radiotherapy before pembrolizumab had a better overall survival (OS) and progression-free survival (PFS) than those patients who did not receive radiotherapy. Many ongoing trials are exploring the possibility to "boost" the activity of CPIs by the addition of local RT, especially SABR; these trials have to face many challenges in terms of treatment timing, radiation dosing, and minimization of the RT toxicity on local and circulating T-cells. The main advance was brought in stage III NSCLC by the Pacific study which evaluated the impact of a treatment consolidation with durvalumab (anti-PD-L1), administered during 1 year after completion of concurrent chemoradiation therapy. This trial was a double-blinded, 2:1 randomized versus placebo study; randomization was authorized between 1 and 42 days after the end of radiation therapy. PD-L1 status was not required for enrollment. The majority of the 713 included patients were male, smokers and received a dose of radiotherapy between 54 and 66 Gy. The addition of durvalumab after concurrent chemo-RTsignificantly improved both PFS (median 17.2 vs. 5.6 months, HR 0.51 95%CI, 0.41-0.63) and OS at the first interim analysis (median not reached vs. 28.7 months, HR 0.68 99.73%CI, 0.469-0.997). The effect of durvalumab was mainly due to a reduction of metastatic relapses, including brain metastases. Subgroups analysis showed a trend toward a greater magnitude of PFS and OS benefit for patients randomized early after completion of radiotherapy (<14 days). The exploratory analysis of the impact of PD-L1 expression on the magnitude of benefit was planned with a cutoff at 25% for tumor cells. Knowing that 37% patients had no PD-L1 assessment, the analysis showed a PFS benefit in both subgroups of patients and no OS benefit for patients with PD-L1<25%. At the request of EMA, an additional unplanned subgroup analysis at the cutoff of 1% showed no PFS benefit and a trend toward a worse survival with durvalumab for the PD-L1<1% tumors, due to an unexpected very good survival for patients randomized in the placebo group in this small subset of patients. While FDA approval of durvalumab was unrestricted, the European label is limited to the PD-L1≥1% tumors, even if the statistical validity of the subgroup analysis is questionable. The risk of pneumonitis after radiation therapy was slightly increased in the durvalumab arm without significant augmentation of grade ≥3 events.

      Pacific was the first study demonstrating the potential for CPIs to obtain a potential synergy with radiation therapy, defining a new standard of care for these patients. However, further already ongoing clinical research will have to address the questions of a similar benefit with sequential chemoradiation therapy and of the optimization of this potential synergy by administering immunotherapy concurrently with thoracic radiotherapy as suggested by preclinical data. Potential long term toxicities must also be carefully assessed. Another area of further development of RT and CPIs combinations actually investigated is the incorporation of immunotherapy after SABR in the treatment of early stage NSCLC.

      The combination of RT and immunotherapy has proven effective in preclinical studies and in stage III NSCLC. A lot of challenges still exist to harness the combination of chemotherapy, RT and CPIs, especially in terms of timing, irradiated volume, fractionation, and dose that likely play a major role in the modulation of the RT different effects on the tumor cells, the immune response and the TME.

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      ES01.05 - Future of Dual Anti-CTLA4 and PD1/PDL1 Blockade (Now Available) (ID 3153)

      10:30 - 12:00  |  Presenting Author(s): David R Spigel

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    EP1.04 - Immuno-oncology (ID 194)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 4
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.04-44 - Exploration of Factors Relating to Paradoxical Immune Response in Patients Treated with Immune Checkpoint Inhibitors for NSCLC (Now Available) (ID 2634)

      08:00 - 18:00  |  Presenting Author(s): Oscar Gerardo Arrieta

      • Abstract
      • Slides

      Background

      Although the introduction of immune checkpoint inhibitors (ICIs) has yielded substantial benefits in terms of survival in the treatment of Non-Small Cell Lung Cancer (NSCLC), the possibility of activation of dormant autoimmune diseases or onset of immune mediated toxicities is a reality. The objective of this study was to explore intrinsic immunological factors associated with poor outcomes.

      Method

      In a retrospective cohort study of 48 patients, without any prior medical history of autoimmunity, treated for advanced/metastatic NSCLC with ICI´s were assessed. Determination of HLA-A*02011 as well as acute phase reactants and antiphospholipid antibodies was performed. Additionally, evaluation of survival in a time to event manner was conducted using the Kaplan Meier method and Cox regressions

      Result

      Median follow-up was 27.3 months, of the included patients 26 were male (54%) with a median age of 62 years old and there were no individuals with and ECOG performance score >1. Median overall survival (OS) was reached at 22.47 months. When analyzing the presence of the HLA-A*02011 serotype, 6 patients tested positive (12.5%). Additionally, all presented with borderline or abnormal B2glycoprotein IgM and IgG, 2Bmicroglubulin and elevated C reactive protein. Four patients (66%) experienced reactive lymphadenopathy during treatment and all suffered some form of venous thromboembolism. When analyzing OS, this group of patients had a significantly worse outcome (6.53 vs 22.47 months, HR= 4.47, [95%CI 1.47 – 13.61], p<0.001) compared with their counterparts. Overall response rate for the whole was superior for the HLA-A*02011 positive patients achieving 41.4% and 33%, p<0.001, respectively.

      Conclusion

      The presence of the HLA-A*02011 could potentially predispose to a paradoxical and pathological activation of the immune system without offering any benefit in terms of tumor control. Larger studies validating these findings are warranted.

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      EP1.04-45 - Relevance of Antibiotic Use on Clinical Activity of Immune Checkpoint Inhibitors in Hispanic Patients with Advanced NSCLC (CLICAP-ABs) (Now Available) (ID 2674)

      08:00 - 18:00  |  Presenting Author(s): Oscar Gerardo Arrieta

      • Abstract
      • Slides

      Background

      The composition of gut microbiota affects antitumor immune responses, as well as preclinical and clinical outcomes following immune checkpoint inhibitors (ICI) in cancer. Antibiotics (ATB) alter gut microbiota diversity and composition leading to dysbiosis, which may influence the effectiveness of ICI.

      Method

      We examined patients with advanced non-small-cell lung cancer (NSCLC) treated with anti-programmed cell death ligand-1 mAb monotherapy alone or in combination in three different countries of Latin America. Those receiving ATB within 30 days of beginning ICI were compared with those who did not. Objective response, progression free survival (PFS) and overall survival (OS) were assessed.

      Result

      18 of 140 (13%) NSCLC patients received ATB. The most commonly used ATB were b-lactam or quinolones for pneumonia or urinary tract infections. In NSCLC patients, ATB was associated with 4 cases of primary PD (28.6% versus 31.5%, P=0.818), non-significant decreased PFS (median 2.66 versus 1.94 months, HR 1.63, [95% CI 0.71-3.72], P=0.247) and significantly deleterious OS (median 12.42 versus 2.04 months, HR 2.3, [95% CI 1.08-4.95], P=0.03). In multivariate analyses, the impact of ATB remained significant for OS.

      Conclusion

      ATB were associated with reduced clinical benefit from ICI in Hispanic patients with NSCLC. Modulation of ATB-related dysbiosis and gut microbiota composition may be a strategy to improve clinical outcomes with ICI.

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      EP1.04-46 - Immunotherapy at Any Line Improves Survival in Hispanic Patients with Advanced Metastatic NSCLC Compared to Chemotherapy (Quijote-CLICaP) (Now Available) (ID 2776)

      08:00 - 18:00  |  Presenting Author(s): Oscar Gerardo Arrieta

      • Abstract
      • Slides

      Background

      Immunotherapy for NSCLMC offers a significant advantage to chemotherapy in selected cases. This benefit starts to disapear as the patients start two progress and requiere change in medication or even chemotherapy. The objective of this study was to compare survival outcomes of patients with advanced or metastatic NSCLC who received immunotherapy at first, second or beyond versus matched patients receiving standard chemotherapy.

      Method

      A retrospective multicenter international cohort study of 296 patients with unresectable/ metastatic NSCLC treated with immunotherapy either as first, second, third or fourth line was conducted. A matched comparison with a historical cohort of first line chemotherapy was conducted.

      Result

      Median age was 64 years (Range 34-90) and 40.2% were female patients. 91.2% of patients had an ECOG performance score ≤ 1. Immunotherapy as first line was given to 39 patients (13.7%), second line to 140 (48.8%), and as third line and beyond to 108 (37.6%). Median overall survival was 19.9 months (95% CI 14.5-22.7 months) and progression-free survival was 3.73 months (95% CI 2.8-4.2). Factors associated with increased survival included treatment as first-line (p < 0.001), type of response (p < 0.001) and PD-L1 status (p = 0.0039). Compared with the historical cohort, immunotherapy proved to be superior in terms of OS (p= 0.05) but not PFS (p= 0.2).

      Conclusion

      Patients who receive immune checkpoint inhibitors as part of their treatment for NSCLC have better OS compared with matched patients treated with standard chemotherapy, regardless of treatment line.

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      EP1.04-47 - Chronic and Severe Non-Lichenoid Oral Ulcers Induced by Nivolumab: Diagnostic and Therapeutic Challenge (Now Available) (ID 2944)

      08:00 - 18:00  |  Presenting Author(s): Oscar Gerardo Arrieta

      • Abstract
      • Slides

      Background

      Due to the widespread use of immune checkpoint inhibitors and the growing research efforts in this area, immune mediated toxicity is well recognized. Nonetheless, few severe cases of oral or upper gastrointestinal tract mucosal involvement have been documented. In this case, report we present the case of a patient who developed severe oral ulcers that were refractory to steroidal support. We also developed a few hypotheses regarding the pathological findings and the implications of microbiomal environment seen in this patient. From a therapeutic point of view, a strategy based on the management given to both Behcet´s disease and Graft versus Host Disease is described.

      Method

      A 93-year-old male was diagnosed with T2N1M0 squamous cell carcinoma of the pharynx with partially involvement of the base of the tongue. Due to comorbid conditions, hypofractionated radiotherapy (40 Gy) plus cetuximab (loading dose of 400 mg/m2 5-7 days before radiotherapy initiation, followed by cetuximab 250 mg/m2 weekly for 5 doses (total 1.650 mg/m2) was administered. A partial response was achieved. Local progression occurred within 12.4 months. The patient received Nivolumab 200 mg IV q15 days. A complete response after 4 months of initiation was observed.

      After 10 cycles, multiple painful erythematous ulcers in the buccal mucosa and tongue were seen. No test evidence of herpes virus, mycotic, Ebstein Barr virus or cytomegalovirus infection was found. Treatment with Nivolumab was halted. He was started on sucralfate, magic mouthwash (oral mucoadhesive) a 14 day course of oral prednisone (1 mg/kg q/day) and topical triamcinolone acetonide, with minimal response. Two weeks later, the patient reported progressive dysphagia, severe pain and rapid weight loss (≈8 Kg). Initial blood tests showed a normal white cell count 8.4×109/L (neutrophils 6.87× 109/L, lymphocytes 0.940×109/L, eosinophils 0.5× 109/L) and platelets at 296.000×109/L. Intravenous methylprednisolone 2 mg/kg/day was started without improvement and increased pain. Due to refractory behavior of the oral ulcers and based on the histological findings, a chronic GVHD reaction was considered.

      Result

      It was hypothesized that the ulcers were caused by a pathologic immune system reactivity against the oral mucosa. Based on this, oral cyclophosphamide was initiated in a metronomic schedule: 50 mg q/day by 21 days in a regimen of 28 days for 2 cycles.

      Additionally, and extrapolating the use of colchicine used for Behcet´s disease ulcers , treatment was initiated with a solution of 1 mg in 150 ml q/8h. Shortly after, an almost complete remission of the lesions and optimal pain control was achieved.

      Simultaneously, metagenomic evaluation of oral microbiome was also performed. High throughput sequencing of bacterial 16S rRNA was used. A significant reduction in bacterial diversity was observed . The bacterial species most commonly found were Prevotella melaninogenica, Veillonella dispar and an enrichment in the concentration of Prevotella melaninogenica and Haemophilus parainfluenzae was noted. At 3 months of follow up the patient maintains an oncologic complete response with no evidence of new ulcers or other ICIs derived complications.

      Conclusion

      In conclusion, treatment of oral lesions as an adverse reaction to ICIs is a therapeutic challenge.

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    EP1.12 - Small Cell Lung Cancer/NET (ID 202)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.12-16 - CD47 Expression and Prognosis in Patients with Small Cell Lung CancerCD47 Expression and Prognosis in Patients with Small Cell Lung Cancer (ID 2935)

      08:00 - 18:00  |  Author(s): Oscar Gerardo Arrieta

      • Abstract

      Background

      CD47 is an integral membrane protein expressed in all cells. CD47 present two opposing roles in cell survival. CD47 can interact with signal-regulatory protein-α (SIRP-a) on macrophages, prevents phagocytic clearance. Besides, CD47 signaling through the thrombospondin-1 limits self-renewal and suppresses expression of the stem cell transcription factors cMyc, Sox2, Oct4, and Klf4 in non-transformed cells. Data on the clinical significance of CD47 expression in patients with small cell lung cancer remain limited.

      Method

      Forty-five naive patients with small cell lung cancer diagnosis were evaluated. Tumor samples obtained by biopsy or surgical resection, were collected for CD47 evaluation. Tumor samples were scored according to the fraction of stained cells at each intensity. The staining intensity of the cell membrane was scored within a scale ranging from 0-3. To determine the prognostic and predictive biomarkers of CD47, patients were stratified according to a cutoff point. This cutoff was optimized as a function of overall survival (OS) using the X-tile and Cutoff Finder software

      Result

      Preliminary results showed that CD47 was present in 26.7% of population. We stratified the CD47 in two cohorts: CD47 positive-negative and a score of CD47>80. The CD47>80 was present mainly in patient with more than 60 years old (35% vs. 8.0%, p=0.024). Longer overall survival was associated with ECOG-PS 0-1 (20.2 vs. 6.9 p=0.001), disease stage IIIB (49.4 vs. 8.0, p=0.020), absent of CNS metastases (14.1-6.8, p=0.016) and absent of pleural effusion (16.2 vs. 6.99, p=0.002). Interestingly, patient with CD47 positive present better OS (10.8 vs. 6.99, p=0.485) but not reaching significance and patient with a score of CD47>80 have better OS (14.0 vs 9.2, p=0.296).

      Conclusion

      Immune checkpoint CD47 expressed on the surface of tumor cells allows them to escape immunosurveillance. We previously reported that high CD47 expression was associated with the presence of somatic EGFR mutations in patients with NSCLC. In these patients, high CD47 expression was an independent prognostic factor of worse progression-free survival. Recent studies have indicated that the signal-regulatory protein (SIRP)α–CD47 pathway regulate a phagocytosis checkpoint in macrophages and other innate immune cells. In contrast, in this report we found that high CD47 expression was associated with <60 years old patient and better overall survival. Previously, studies in small cells lug cancer express high levels of CD47 and the blocking of CD47 enhances phagocytosis inhibits tumor growth. CD47 have a dual role, when interact with SIRPα avoid clearance of cells, but it interacts with thrombospondin 1 inhibits cell cycle progression and induces senescence in endothelial cells. Previous studies have shown that the protein TSP1 is as potent inhibitor of angiogenesis and its antiangiogenic activity is mediated by its receptors, CD36 and CD47. In conclusion CD47 have different function according to the ligand, and is a potential biomarker in cancer

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    EP1.14 - Targeted Therapy (ID 204)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.14-18 - NGS-Molecular Characterization of Lung Adenocarcinomas from Hispanic Patients: Level of Evidence for Therapeutic Actionability (ID 2599)

      08:00 - 18:00  |  Presenting Author(s): Oscar Gerardo Arrieta

      • Abstract

      Background

      Several studies have shown that NSCLC genomic background among Hispanics differs from other populations, therefore genotyping tumors in order to assess their molecular profile is adamantly needed in the current era of targeted therapy. Panel-detected oncodriver mutations can drive therapeutic approaches, and can help classify the information in order to propose strong evidence-based interventions in treatment guidelines. In this study we sought to understand the landscape of genomic drivers in a cohort of patients with lung adenocarcinoma of Hispanic ancestry.

      Method

      Tumor samples were collected from 48 patients with lung adenocarcinoma from march 2017 until march 2019. Samples were submitted for testing to Foundation Medicine and hybrid capture NGS was performed.

      Result

      figura 1_fo.pngfigura 2_fo.pngA total of 282 samples were sent for evaluation, among which 48 (17%) with lung adenocarcinoma were tested by FoundationOne (FO) in tumor tissue. Among the patients included, 54.2% were men and 79.2% were >50 years of age. Most patients had a previous negative report for EGFR and ALK (in tumor tissue). Results for tumor mutation burden (TMB) were obtained from 48 (100%) samples. Median TMB was 4 mutations/Megabase (m/Mb). High TMB (>10 m/Mb) was identified in 9 (18.8%) samples. The most frequently detected alterations were in P53, KRAS and EGFR genes (Figure1). In terms of the level of evidence for therapeutic actionability, level-1 was 33.5 %, level-2 was 12.5%, level-3 14.6% and level-4 37.5%. (Figure 2).

      Conclusion

      Despite an initial assessment of actionable alterations (EGFR and ALK), through a NGS-approach we were able to detect a high amount of genomic alterations linked to a high-level of evidence for therapeutic actionability (33.5%), possibly due to higher sensitivity and a higher number of genes tested in the panel, increasing therapeutic options in this molecular-driven era. This research work was conducted with the support of Roche Foundation Medicine.

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    EP1.15 - Thymoma/Other Thoracic Malignancies (ID 205)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.15-28 - Survival of Thymoma Is Extensive in Latin-American Patients: Results from Over 10 Years of Experience (CLICaP-LATimus) (ID 2936)

      08:00 - 18:00  |  Presenting Author(s): Oscar Gerardo Arrieta

      • Abstract

      Background

      Thymomas are a group of rare neoplasm of the anterior mediastinum. Due to their low incidence, large cooperative studies are required to evaluate outcomes. The objective of this study is to present the results and experience in treatment of this pathology in Latin-America.

      Method

      A retrospective multicenter cohort study was conducted by The Latin-American Consortium for the Investigation of Lung Cancer (CLICaP). Patients with histologically proven thymomas between 1997 and 2018 were included in the analysis. Variables including clinical, pathological and therapeutic outcomes were registered in a centralized manner.

      Result

      A total of 105 patients were included. Median age at diagnosis was 54 years old (20-84), and with 60% (n = 38) of the included patients were female. Only 11% (n=7) of the patients had an ECOG performance score >1. Twenty-four patients (22.9%, 95%CI 14.8-30.9) presented with pulmonary or distant metastatic involvement with a median of 2 metastatic sites. Furthermore, 21.9 % of patients (n=23, 95%CI 13.9-29.8%) concurrently presented myasthenia gravis. Surgery was performed in 55 patients (52.3%, 95%CI 42.8 – 61.9%), comprising of 15 tumorectomies, 37 thymectomies and 5 biopsies achieving an R0 resection rate of 78% (95%CI 67.3-89.1%). Adjuvant treatment in the form of either chemotherapy, radiotherapy or both was offered to 3(5%), 7(12.7%) and 5(9%) patients, respectively. Disease progression was documented in 10 cases (9%, 95%CI3.9-15.1%) of which 6 (60%) were locoregional, 1 (10%) distant progression and 3 (30%) both locoregional and distant. Median overall survival (OS) was estimated at around 139.5 months (95%CI 86.1-NA). Cox regression indicated that OS was significantly improved by resection (139.5 vs 25.7 months, HR 4.17 [95%CI 12.6-17.8 months]).

      Conclusion

      Survival in patients with thymomas continues to be very favorable, especially in patients who receive adequate local control. The benefit of adjuvant treatment in this setting remains unclear.

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      EP1.15-29 - Real World Characterization and Treatment of Patients with Thymic Carcinoma: Lessons from a Latin-American Study (CLICaP-LATimus) (Now Available) (ID 2921)

      08:00 - 18:00  |  Presenting Author(s): Oscar Gerardo Arrieta

      • Abstract
      • Slides

      Background

      Thymic carcinoma is a rare tumor that represents a clinical challenge, especially in resource limited settings. The objective of the present study was to characterize patients who presented this disease in Latin-America.

      Method

      From 2014 until 2018, a multinational Latin-American cooperative retrospective cohort study was performed. Patients with histologically confirmed thymic carcinoma were included. Clinical, pathological and treatment variables were collected across 7 participating nations.

      Result

      A total of 31 patients were included. Median age at diagnosis was 58 years old (34-69), 48% (n=15) of individuals were women with all but 2 patients (6.5%) achieving an ECOG performance score <2. All patients debuted with Stage IV disease; 24 patients (66%, [95%CI 62-92%]) as stage IVa and 7 as stage IVb (33%, [95%CI 7-37%]) with a median LDH level of 396.5 U/L (153-1529 U/L) and a median of 2 metastatic sites. 13 (41.9%, [95%CI 25-59%]) patients received preoperatory treatment consisting of chemotherapy (n=8, 42%) and chemoradiotherapy (n=5, 16%). Among these patients only 4 (12.9%) were subjected to surgery, two of which underwent a tumorectomy and 2 a thymectomy. 28 (90%, [95%CI 79.9-100%]) received palliative chemotherapy either with sunitinib (n=7, 25%) or cytotoxic agents. Median overall survival (OS) was reached at 20.2 months (95%CI 19-NA months). Patients who received preoperative treatment had a significantly prolonged OS (17.6 vs 26 months, HR 2.93 [95%CI 1.04-8.27 months], p = 0.03).

      Conclusion

      Thymic carcinoma constitutes an aggressive disease that is often diagnosed in advanced stages. These results suggest that multimodal treatment can be beneficial even in locally advanced cases. Larger clinical trial validating these conclusions are warranted.

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    EP1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 206)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.16-39 - Prospective Epidemiological Study of Metastatic Non-Small Cell Lung Cancer (NSCLC) in Latin America – LATINO Lung (LACOG 0116) (Now Available) (ID 1405)

      08:00 - 18:00  |  Author(s): Oscar Gerardo Arrieta

      • Abstract
      • Slides

      Background

      Non-small cell lung carcinoma (NSCLC) is the main cause of cancer-related death in Latin America. Nonetheless, there is insufficient information regarding its epidemiology, treatment and outcomes in the region. The goals of this study are to describe disease characteristics, treatment patterns and survival for advanced NSCLC in Latin America.

      Method

      LACOG 0116 LATINO Lung is a prospective cohort study aiming to include approximately 800 patients with advanced stage NSCLC (stage III/IV at diagnosis or distant relapse of early-stage disease) from 24 sites in Brazil, Argentina, Mexico, Colombia and Chile. All consecutive newly diagnosed patients seen at each site will be invited to participate. Data on socioeconomic and demographic characteristics, medical/oncologic history and clinical-pathological characteristics will be collected at baseline. Thereafter, patients will be followed every 6 months for 3 years in order to gather information regarding treatment patterns and sequencing, reasons for treatment discontinuation, response to treatment, disease progression and overall survival. Data will be collected during medical visits or telephone calls and by medical charts review. Primary endpoint is to estimate the overall survival. Descriptive analysis of treatments and outcomes are planned. Multivariable regression methods will be applied to assess possible independent prognostic or predictive factors.

      Result

      As of April 3rd, 2019, 107 patients have been included, all of them within 16 sites in Brazil. Currently, there are 2 sites from Argentina, 2 from Mexico, 3 from Colombia and 1 from Chile awaiting regulatory approval to begin enrollment. Recruitment is planned to last until December 2019, when the estimated sample size will be achieved.figure1.png

      Conclusion

      LACOG 0116 LATINO Lung is the first Latin American lung cancer prospective cohort study that will generate real-world data on NSCLC. The study may identify gaps and inequities in a diverse population of NSCLC in Latin America and consequently raise the need for improvement and individualized approach of lung cancer care in the region.

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    MA07 - Clinical Questions and Potential Blood Markers for Immunotherapy (ID 125)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MA07.08 - The Role of a Cachexia Grading System in Patients with NSCLC Treated with Immunotherapy: Implications for Response and Survival (Now Available) (ID 2046)

      13:30 - 15:00  |  Author(s): Oscar Gerardo Arrieta

      • Abstract
      • Presentation
      • Slides

      Background

      The association between cancer-induced weight-loss (CIWL) and poor clinical outcomes is well established. However, many of these studies were performed in the chemotherapy era. Meanwhile, current standard of care for NSCLC patients has shifted towards the more efficacious immunotherapy agents (IO). IO has improved survival outcomes, nonetheless clinicians face the challenge of identifying who will derive substantial clinical benefit from these more costly agents. Response to IO is influenced by several patient-related factors, including microbiome, medications, and nutritional status.

      Method

      In this study we sought to evaluate the effect of cachexia in survival of NSCLC patients undergoing treatment with IO. Included patients had advanced NSCLC (IIIB, IV), who received IO agents in any line of therapy, and had a good performance status. All the patients were evaluated by the nutritionist specialist and were graded according to a previously documented cachexia scale which takes into consideration body mass index (BMI) and weight loss in order to stratify patients into 5 risk categories (0 [pre-cachexia] - 4 [refractory cachexia]). Primary endpoint was overall survival (OS), secondary endpoints included objective response rate (ORR) and progression-free survival.

      Result

      A total of 181 patients met the inclusion criteria and were included in the analysis. Among these 82 (45%) were classified in the first category (risk grade 0-1 [low risk]), 83 (46%) were classified in the second category (risk grade 2-3[intermediate risk]) and 9% were in the third category (risk grade 4 [high risk]). Patients classified as low-risk had a significantly longer OS compared to those with intermediate or high risk (22.4 months [95%CI: 18.7-26.1] vs. 15.7 [95%CI: 10.8-20.7] vs. 3.9 [0.0-7.8]; p<0.001; Hazard ratio: 1.81 [1.29-2.53]; p<0.001). In the multivariate analysis ORR, hemoglobin and risk category were independent factors associated with OS. Grade of cachexia was also significantly associated with ORR, with low-risk patients having a significantly higher ORR compared to intermediate and high-risk patients (36.6% vs. 17.3% vs. 25%; p=0.021). PFS was also influenced by risk category, with low risk patients having a longer PFS compared with intermediate and high-risk patients. diapositiva1.jpg

      Conclusion

      Cachexia is independently associated with worse OS in NSCLC patients who receive IO, while better nutritional status is related to higher ORR, highlighting a potential role for nutritional assessment in the selection of patients who are candidates for IO. Early assessment of nutritional status in these patients is imperative in order to timely diagnose and treat anorexia-cachexia and improve outcomes.

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    MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MA11.03 - Pembrolizumab Plus Docetaxel Increases Progression-Free Survival Compared with Docetaxel Alone in Previously Treated Advanced Non-Small Cell Lung Cancer Patients (Now Available) (ID 2017)

      14:00 - 15:30  |  Presenting Author(s): Oscar Gerardo Arrieta

      • Abstract
      • Presentation
      • Slides

      Background

      Immunotherapy is now the standard of care for non-small cell lung cancer patients without actionable mutations, due to a clear survival benefit in large phase III trials, further this benefit can be translated into the first-line setting, alone or in combination with chemotherapy. Nonetheless, due to several circumstances many patients do not receive immunotherapy as first-line. The effect of the combination therapy with pembrolizumab plus docetaxel in previously-treated NSCLC patients has not been prospectively assessed.

      Method

      In this phase II clinical trial, we evaluated the effect of a combination therapy with pembrolizumab plus Docetaxel (PD) compared with Docetaxel (D) for the treatment of advanced NSCLC patients who had progressed to previous lines of therapy. Primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety profile.

      Result

      Eighty patients met the inclusion criteria and were enrolled in the study, among which 78 were randomized 1:1. Forty patients were allocated to receive PD, while thirty-eight were allocated to receive D. Baseline characteristics, including sex, age, tobacco index, performance status and EGFR mutation were well-balanced between both arms of the trial. We found a statistically significant difference in terms of ORR (42.5% vs. 15.8%; OR: 3.9 [95%CI: 1.34-11.5]; p=0.01), in patients receiving PD compared with D alone. Further, patients receiving PD had a significantly longer PFS compared with those receiving D monotherapy (9.5 months [95%CI: 4.2-NR] vs. 3.9 [95%CI: 3.2-5.7]; HR: 0.24 [95%CI: 0.13-0.46]; p<0.001). In the multivariate analysis the therapeutic intervention was an independently associated factor with better PFS (Figure). In terms of safety, a total of 22.5% vs. 5.3% of patients experienced any-grade pneumonitis in the PD and D arm of the trial respectively (p=0.048), while 27.5% vs. 16% experienced any-grade hypothyroidism (p=0.20). No new safety signals were identified.

      Conclusion

      Patients who receive the combination therapy have a significantly increased ORR and PFS, with a significant decrease in the hazard of progressing. This work was performed through a grant from MSD (Investigator Initiated Study). The sponsor did not have any role in the acquisition or interpretation of the data.


      pfs_figure 1.png
      Figure. Kaplan-Meier curve for the progression-free survival of patients in the experimental (P+D) vs. the control (D) arm of the trial.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-117 - Pulmonary Function Monitoring in Patients with Oligometastatic NSCLC Who Receive Stereotactic Body Radiation Therapy (ID 2044)

      09:45 - 18:00  |  Author(s): Oscar Gerardo Arrieta

      • Abstract
      • Slides

      Background

      Patients with early and oligometastatic stage Non-small cell lung cancer (NSCLC) who are non-surgical candidates benefit from new radiation treatment modalities, such as stereotactic body radiotherapy (SBRT). Previously we reported the correlation of lung function decline and the presence of lung toxicity related to concomitant chemo-radiotherapy. This work aims to evaluate lung function performance after SBRT in patients with oligometastatic NSCLC.

      Method

      A one-year prospective multicentric study was conducted at the Instituto Nacional de Cancerología in Mexico. Twenty-six patients with stage IV NSCLC with a single metastasis considered non-operable were treated with SBRT. Lung function was assessed at the baseline and at one, six, twelve, twenty-four and fifty-two weeks after SBRT, using forced spirometry with a bronchodilator, a carbon monoxide diffusing capacity (DLCO) test and oxygen saturation (SpO2) measurement. The study was registered in clinicaltrials.gov (NCT01580579).

      Result

      Fourteen patients were evaluated with lung function tests, the results were adjusted for the Mexican population. At baseline, the mean for post-bronchodilator (post-BD) FVC (l) was 2.16 (±1.09), for FEV1 2.25 (±1.06), DLCO (ml/min/mmHg) 20.22 (±8.44) and SpO2 of 94% (±2.81). A reduction of <10% of relative change (max. 294 ml) was observed in lung volume in FEV1 and FVC (l) post-BD follow-up with non-significant results. A statistically significant reduction in DLCO 18% (p=0.03) at week 12 was observed, Fig.1. All patients maintained an oxygen saturation level over 90% during the study. Quality of life reduces significantly at week six after SBRT (p=0.03), while respiratory symptoms were non-considerable in the first 12 weeks after receiving SBRT.figure 1.jpg

      Conclusion

      Although lung function tests showed a reduction trend, no statistically significant differences were found. The magnitude of lung volume reduction had no significant impact on respiratory symptoms, these findings could suggest that there is less damage in the surrounding tissue after SBRT. This research is an ongoing prospective study of one-year follow-up where several patients continue the be monitored; therefore, we expect to strength our findings by the end of the study.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-80 - Immunotherapy-Related Thrombosis: Considerations and Associated Factors in Non-Small Cell Lung Cancer (NSCLC) Patients (ID 2724)

      09:45 - 18:00  |  Presenting Author(s): Oscar Gerardo Arrieta

      • Abstract

      Background

      Widespread use of immune checkpoint inhibitors (ICIs) for the treatment of lung cancer has exposed a large number of patients to these medications, increasing the incidence of rare adverse reactions such as thromboses. The present study elaborates on factors related to the occurrence of these events.

      Method

      In a retrospective cohort study, a total of 48 patients, 24 who experienced thrombosis and 24 matched controls who underwent evaluation after initiation of ICIs therapy for advanced/metastatic NSCLC, were included. Clinical and pathological as well as serum inflammatory and coagulation markers were evaluated.

      Result

      Among the 48 patients, 46% (n=26) were female, median age was 62 years old and all patients had an ECOG performance score of < 2. The median overall survival reached by the cohort was 22.47 months. Among patients who developed thrombosis there were 8 cases of deep venous thrombosis (DVT) (33%), 13 pulmonary embolisms in addition to DVT (62.5%) and 1 case of brain venous sinus thrombosis (4.2%). Apart from expected thrombosis markers such as D dimer, differences in inflammatory and immune related markers between patients who experienced thrombosis and those who did not, were observed. Abnormal values were found in the thrombosis group for B2glycoprotein 1 (33% vs 0%, OR= 4.08, [95%CI 1.65 - 12.1], p= 0.005), B2glycoprotein 1 IgG (29.2% vs 0%, OR= 4.64, [95%CI 1.73 – 16.9], p= 0.007), C Reactive protein (83.3% vs 12.5%, OR= 35, [95%CI 7.9 - 213], p< 0.001), B2microglobulin (62.5% vs 8.3%, OR= 14, [95%CI 3.11-103.7], p = 0.002), Prothrombin time (41.7% vs 4.2%, OR= 2.4, [95%CI 1.64 -3.69], p =0.01) and C Coagulation protein (50% vs 16.6%, OR =1.79, [95%CI 1.53 – 2.91], p <0.001).

      Conclusion

      Abnormalities in antiphospholipid antibodies, C reactive protein, B2microglobulin and coagulation in patients who suffered thrombosis during ICI treatment suggest that this phenomenon could be the result of immune and auto-inflammatory induced intravascular dysfunction.

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      P1.04-81 - Characterization of Hispanic Patients Who Experienced Hyperprogression During Treatment for Advanced NSCLC with Immunotherapy (ID 2922)

      09:45 - 18:00  |  Presenting Author(s): Oscar Gerardo Arrieta

      • Abstract

      Background

      Immunotherapy related hyperprogression is poorly characterized in Latin American patients. In this study we sought to characterize and identify factors associated with the presentation of hyperporgression after initiation of immunotherapy in patients with advanced non-small cell lung cancer (NSCLC).

      Method

      A multicenter international retrospective study on 110 patients was conducted. Clinical variables as well as routine blood studies were recorded before initiation of treatment. Regression analysis was used to find associations. A random forest tree analysis (RFTA) based on continuous and discrete variables was used to subcategorize patients based on occurrence of hyperprogression.

      Result

      Median age was 64 years (Range 34-90) and 59.8 % were male patients. ECOG performance status was >1 on 8.8% of patients. Median overall survival was 12.7 months (95% CI 9.67-14 months) and progression-free survival of 4.27 months (95% CI 3.97-5.0). 44 hyperprogressors were documented (19.8%, [95%CI 14.5-25.1%]). Median time to progression was approximately 5 weeks after initiation of treatment. Factors associated included albumin and hemoglobin levels (p = 0.046 and 0.037 respectively), presence of CNS (p= 0.0009) and bone metastasis (p = 0.004) and weight loss (p= 0.004). RFTA revealed that a leucocyte count over 5.300 cells/dl was present in all hyperprogressors.

      Conclusion

      Hyperprogression is a phenomenon after initiation of immunotherapy which is associated with clinical and paraclinical variables. These associations could be used to withhold certain agents and prevent its occurrence in NSCLC treatment.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-61 - EGFR Inhibitors Plus Bevacizumab Are Superior Compared to EGFR Inhibitor Monotherapy in Advanced EGFR+ NSCLC Patients with BIM Deletions (ID 2697)

      09:45 - 18:00  |  Presenting Author(s): Oscar Gerardo Arrieta

      • Abstract

      Background

      BIM activation is essential for EGFR-TKIs triggered apoptosis in EGFR-mutant Non-small-cell lung cancer (NSCLC). A 2903-bp germline deletion in intron 2 of the BIM gene results in generation of alternatively spliced isoforms that lack the crucial BH3 domain, impairing the apoptotic response to TKIs and conferring NSCLC cells intrinsic resistance to these medications. Patients with both alterations have poor clinical evolution. The current study aimed to investigate the clinical efficacy and tolerability of EGFR-TKIs plus bevacizumab (Bev) versus EGFR-TKIs alone as first-line treatment in advanced NSCLC patients with EGFR mutations and BIM deletions (BIMdel).

      Method

      A retrospective analysis was conducted. BIMdel was detected using polymerase chain reaction (PCR) analysis and direct sequencing of DNA from tumor and peripheral blood cells (PBCs). We also assessed BIM protein expression by immunohistochemistry and BIM mRNA levels by RT-PCR. Clinical characteristics, overall survival (OS), progression-free-survival (PFS), objective response rate (ORR) and treatment-related adverse events were compared in the EGFR-TKIs versus EGFR-TKIs plus Bev groups.

      Result

      32 patients were included; 16 of them received EGFR-TKIs and 18 received EGFR-TKIs plus Bev. The addition of Bev resulted in a significantly higher ORR compared with TKIs alone (94% vs. 44%, p=0.0014). Median PFS was longer with the use of the combination compared with TKIs alone (11.1 vs. 7.77 months; p < 0.001). Median OS tended to be longer in the EGFR-TKIs plus Bev group than in TKIs alone (30.9 vs. 25.4 months; p = 0.06). EGFR-TKIs plus Bev was associated with more grade >3 hematological and thrombotic adverse events. The expression of BIM by immunohistochemistry did not influence PFS and OS, however when stratifying BIM mRNA levels by the median (≥2.2 vs. <2.1) allowed to find a prognostic trend in favor of those with higher BIM mRNA levels (32.2 vs. 25.2 months respectively; p = 0.058).

      Conclusion

      EGFR-TKIs plus Bev conferred a significantly higher ORR and PFS in advanced NSCLC patients with EGFR mutation and BIMdel. Further prospective studies are needed to validate these findings.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-40 - Normalization of Carcinoembryonic Antigen Levels Is Associated with Survival Improvement in Patients with Advanced Non-Small Cell Lung Cancer (Now Available) (ID 2611)

      10:15 - 18:15  |  Author(s): Oscar Gerardo Arrieta

      • Abstract
      • Slides

      Background

      Serum carcinoembryonic antigen (CEA) levels are elevated in approximately 65% of the Non-small cell lung cancer (NSCLC) patients with adenocarcinoma histology. Elevated CEA levels are an independent prognostic factor for overall survival (OS) in early and advanced NSCLC stages. Previous reports from our group suggest that the decrease or increase in CEA serum levels is strongly associated with response and progression to systemic treatment. However, determination of CEA levels is not included in standard guidelines, such as National Comprehensive Cancer Network (NCNN). The aim of this study is to analyze the progression-free survival (PFS) and overall survival (OS) in NSCLC patients with elevated CEA levels at diagnosis and its association with systemic treatment response.

      Method

      We performed a retrospective analysis of patients with advanced NSCLC with an elevated serum level baseline of CEA (>20 ng/ml) that received treatment according to international guidelines. The serum CEA levels were measured every two cycles of platinum-based chemotherapy or a tyrosine kinase inhibitor (TKI) treatment. The change in serum CEA levels in response to treatment and the association with overall survival and progression free survival was evaluated.

      Result

      Between March 2004 and February 2018, 748 patients with diagnosis of advanced NSCLC and CEA levels >20 ng/mL were included in the analysis. Median age was 60.2 years old, 631 patients (84.4%) had adenocarcinoma histology. From 338 patients evaluated for EGFR mutations, 139 (31.3%) harbored an EGFR mutation. The median OS was 23.3 months (95% CI 19.4-26.9) in patients who completely normalized CEA vs 10.0 months (95% CI 8.9-11.2) in patients who did not achieved CEA normalization, with a HR 0.48 95% CI (0.35 -0.67) p <0.0001. The median OS was 15.5 months (95% CI 13.4-17.6) in patients who showed a decrease in CEA levels vs 8.8 months (95% CI 7.5-10.1) in those who did not. Reduction in CEA levels was associated with better OS, either in patients treated with TKI or platinum-based chemotherapy.figure cea .jpg

      Conclusion

      The normalization or decrease of the serum CEA levels is a biological marker that serves as tool associated with OS. Based on these findings and previous reports, CEA determination should be included in the clinical guidelines for NSCLC as response biomarker. Serum CEA levels should be part of the standard follow-up of NSCLC patients.

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    P2.08 - Oligometastatic NSCLC (ID 172)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Oligometastatic NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.08-04 - Stereotactic Ablative Radiation Therapy to Lung Metastases Associates with Better Outcomes in Oligometastatic Lung Cancer: Prospective Study (Now Available) (ID 2919)

      10:15 - 18:15  |  Author(s): Oscar Gerardo Arrieta

      • Abstract
      • Slides

      Background

      Nearly 7% of stage IV Non-Small cell Lung Cancer (NSCLC) patients present oligometastatic disease at diagnosis. These patients can benefit from definitive treatment to primary tumour and loco-ablation of metastases. The use of stereotactic ablative radiotherapy (SABR) has demonstrated high rates of local control and survival improvement in early disease stage. The aim of this study is to evaluate Progression Free Survival (PFS), Overall survival (OS) and toxicity of patients with oligometastatic NSCLC treated with Stereotactic ablative radiotherapy (SABR) to lung metastases.

      Method

      A prospective study was conducted with oligometastatic NSCLC patients. From August 2014 to April 2019, with a median follow up of 13 months, forty-seven patients were enrolled. All patients received systemic therapy according to international guidelines. Then, patients without progression to systemic treatment, received SABR to lung metastases (30-60 Gy in 2-8 fractions) to the thoracic lesion (primary or metastatic) depending on location, size and number of lesions, always keeping BED (Biologically Effective Dose) >100 Gy at isocenter. This study was approved by Ethic and Research comitees at Instituto Nacional de Cancerología (CEI/799)(013/014/ICI).

      Result

      Most patients were women (59.6%), with a mean age of 58.9 years. Although two-thirds of patients were ever smokers (66.0%), most of them were light smokers. The most common histology was adenocarcinoma (87.2%). Contralateral lung was the most common metastatic site (40.4%). Half of the patient harbour at least one mutation, EGFR Exon 19 deletion was the most frequent mutation (38.3%). Patients received chemotherapy and EGFR-TKIs as 1st-line treatment in the 61.1% and 38.9%, respectively. All patients received SABR, response to treatment was as follows: disease control rate was 91.5%, partial response 14.9% and complete response 63.8%. Among those with disease progression, median time to systemic progression after SABR treatment was 5.4 months (95% 2.4-8.9 months). PFS since beginning of any treatment was not reached, since only 18 patients (38.3%) had disease progression. Until now only 4 patients (8.5%) had died, thus OS is not reached. Radiographic pneumonitis was observed in 72.2% (13 patients). Grade 1, 2 and 3 pneumonitis were observed in the 69.2% (9/13), 7.7% (1/13) and 23.1 (3/13) of the patients with pneumonitis.sabr figure.jpg

      Conclusion

      SABR is a suitable and has a moderate toxicity profile. SABR is a therapeutic option for patients with oligometastatic NSCLC. SABR have shown to improve local control and increase progression-free survival. Future clinical trials are required to evaluate SABR against other treatment modalities.

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    P2.09 - Pathology (ID 174)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.09-28 - Prognostic Impact of LKB1 Expression in Advanced Non-Small-Cell Lung Cancer (Now Available) (ID 1528)

      10:15 - 18:15  |  Author(s): Oscar Gerardo Arrieta

      • Abstract
      • Slides

      Background

      LKB1 is a tumor suppressor gene that regulates cell energy homeostasis, cell polarization, and apoptosis. Within lung cancer, LKB1 ranks as the third most common mutation found in lung adenocarcinoma, both alleles are somatically inactivated in 30%. LKB1 mutations are linked to smoking history, moreover, it have been associated with more aggressive clinical phenotype in KRAS-mutant NSCLC patients, according to preclinical models. Additionally, LKB1 has been associated with primary resistance to PD-1 axis inhibitors in lung adenocarcinoma. However, its expression and clinical implication has not been extensively studied. The aim of the study was to evaluate LKB1 expression in patients with advanced NSCLC.

      Method

      In retrospective way patients with advanced NSCLC with and without EGFR mutations from México and Colombia were analyzed. Patients received therapy according EGFR status (TKI anti-EGFR or chemotherapy). Inclusion criteria were a histopathological confirmed diagnosis, adequate tissue to determine the expression of LKB1 by immunohistochemistry through the clone HPA017254 (Sigma®). The primary outcome was overall survival (OS).

      Result

      A total of 87 patients were included in the analysis, 25.3% of them had LKB1 positive expression. Median score intensity was 20%. There was a significant association of LKB1 positive expression with wood-smoke exposure (76.9 vs 23.1%, p=<0.001), EGFR mutation (54.5 vs 45.5%, p=<0.001) compared to LKB1 negative. Global Median OS was 29.7 months. Median OS for LKB1 positive was 33.3 months (CI 95%, 8.9 - 57.6) and 29.5 months (CI 95%, 26.1 - 32-8) for LKB1 negative (p=0.42). After stratifying patients by percentage of LKB1 expression, cut-off of 20% showed a tendency to increase OS in patients with ≥20% expression (figure 1); 49.9 months (IC 95%, 10.6 - 85.2 months) vs 29.5 months (IC 95%, 26.3 - 32.7 months), (p=0.068). Furthermore, a similar trend in OS was observed in patients with ≥50% expression, median OS was not reached compared with 29.5 months (IC 95%, 26.2 - 32.7 months) in patients with <50% expression (p=0.091).

      diaz garcia - figure 1.png

      Conclusion

      We found a trend to higher OS in patients with LKB1 expression >20%. This data should be confirmed in prospective study in order to determine the role of LKB1 as biomarker in NSCLC patients.

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-43 - Cost-Effectiveness of 1st-Line Treatment EGFR-TKIs for Advanced NSCLC Patients Harboring EGFR Mutation in Mexico (Now Available) (ID 1146)

      10:15 - 18:15  |  Author(s): Oscar Gerardo Arrieta

      • Abstract
      • Slides

      Background

      As cancer care costs are rising at an unprecedented rate, it is crucial to provide evidence-based justification for promising but expensive therapeutic approaches such as Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). EGFR-TKIs such as gefitinib, erlotinib and afatinib had become the standard first-line treatment for EGFR gene mutation-positive non-small cell lung cancer (NSCLC) improving progression-free survival (PFS) and overall survival (OS) of these patients. However, the economic impact of them remain unclear. Hence, we aimed to assess healthcare costs during and after progression to treatment and to compare the cost-effectivess and safety of the 1st-line treatment with EGFR-TKIs in patients with advanced non-small cell lung cancer (NSCLC) in Mexico.

      Method

      The health and economic outcomes of three first-line strategies (gefitinib, erlotinib, and afatinib) among NSCLC patients harboring EGFRmutations were estimated and assessed. Costs in the Mexican setting were obtained from local hospital data and public national purchasing sources. The structure used in this analysis was a Markov model with three possible health states: free of progression, progression and death considering a time horizon of 3 and 5 years. The probabilities of transition and the use of resources used to feed the model were retrospectively collected by reviewing medical records of patients who were treated at the Instituto Nacional de Cancerologia (INCan) of Mexico between April 2013 and June 2017. Probabilistic sensitivity analysis (PSA) was conducted with a Monte Carlo simulation.

      Result

      Similar hazards of progression and death were obtained when constrasting afatinib vs. erlotinib, [HR:0.91 (95% CI: 0.59 -2.07) and 0.82 (95% CI: 0.56-2.65), respectively] as well as when contrasting the hazards of progression and death of afatinib vs. gefininib [HR:0.87 (95% CI: 0.87-1.53) and 0.94 (95% CI: 0.74-1.55), respectively]. However, statistically significant differences were identified between the costs of the treatment both the total cost (p<.001) and the daily cost (p <0.001) of treatment. The most expensive treatment was with afatinib, followed by erlotinib and gefitinib. In addition, treatment with afatinib showed the highest cost associated with adverse events. PSA with Monte Carlo simulations showed robustness of estimations.

      diapositiva1.jpg

      Conclusion

      Although equivalent effectiveness and safety of the three arms of the study was found, substantial differences in treatment costs were observed. Nonetheless, we should highlight that patient selection is absolutely critical for cost-efectiveness analyses; as well as longer follow-up of existing data could substantially alter the conclusions of this analysis.

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