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Zyanya Lucia Zatarain Barrón



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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  |  Author(s): Zyanya Lucia Zatarain Barrón

      • 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  |  Author(s): Zyanya Lucia Zatarain Barrón

      • 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  |  Author(s): Zyanya Lucia Zatarain Barrón

      • 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  |  Author(s): Zyanya Lucia Zatarain Barrón

      • 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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    EP1.15 - 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  |  Author(s): Zyanya Lucia Zatarain Barrón

      • 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  |  Author(s): Zyanya Lucia Zatarain Barrón

      • 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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    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): Zyanya Lucia Zatarain Barrón

      • 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  |  Author(s): Zyanya Lucia Zatarain Barrón

      • 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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    P1.04 - 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  |  Author(s): Zyanya Lucia Zatarain Barrón

      • 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  |  Author(s): Zyanya Lucia Zatarain Barrón

      • 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  |  Author(s): Zyanya Lucia Zatarain Barrón

      • 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.