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Devalben Patel



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    MA18 - Modelling, Decision-Making and Population-Based Outcomes (ID 920)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 201 F
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      MA18.09 - Predictors of Health Utility Scores (HUS) in Advanced EGFR-Mutated NSCLC. (ID 13087)

      14:25 - 14:30  |  Author(s): Devalben Patel

      • Abstract
      • Presentation
      • Slides

      Background

      Advanced NSCLC patients with EGFR mutations (EGFRm) are currently treated with first - to third-generation tyrosine kinase inhibitors (TKIs). In the advanced setting, quality of life is an important goal; we therefore evaluated determinants of HUS in this population.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In a prospective, observational study, patients with advanced EGFRm NSCLC completed EQ-5D surveys at outpatient visits generating HUS (range 0-1). Patients were allowed to enrol at any point in their disease course. Baseline clinical characteristics and outcome data were extracted from chart review. Patient imaging was reviewed and health states (stable/progressing) at each encounter recorded. Univariable analyses conducted using ANOVA and multivariable regression analyses with generalized estimating equations identified factors associated with HUS.

      4c3880bb027f159e801041b1021e88e8 Result

      From November 2014 to July 2017, 782 encounters (follow-up visits) were collected for 244 patients. Median age at first encounter was 64 years (range:29-96); 54% were female and 54% Asian. Median time from diagnosis of stage IV NSCLC to first encounter was 23 months (range:0-67). The median number of HUS collected per patient was 2 (range:1-14). For patients with multiple visits the median time between completed questionnaires was 1.8 months (1-18). 105 patients (43%) presented with or developed brain metastases during the study period. In a univariable analysis, regardless of treatment line, mean HUS (mHUS) on osimertinib was 0.85 (standard deviation (SD):0.15) (n=33 patients; 114 encounters) compared to mHUS=0.80 (SD:0.17) on gefitinib (n=147, 351 encounters); mHUS=0.72 (SD:0.16) on chemotherapy (n=32, 76 encounters); and mHUS=0.79 (SD=0.15) on other TKIs (n=49, 133 encounters); p<0.001. In a multivariable analysis, disease progression (p=0.04) and ECOG performance status >0 (p<0.001) were associated with lower HUS. In contrast, treatment with osimertinib (when compared to a reference group of first-generation TKIs, gefitinib/erlotinib) was associated with improved HUS (p=0.01), while line of therapy and number of metastatic sites of disease were not associated with HUS. In addition, brain metastases had no significant impact on HUS (p=0.33).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Progressive disease and worse performance status associate with lower HUS in patients with EGFRm NSCLC. Patients treated with osimertinib had the highest HUS when compared with a reference group of first-generation EGFR TKIs regardless of line of therapy. These results may help in the choice of EGFR-TKI, especially in patients with a poor performance status.

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    MA27 - Novel Drugs and PDX Models (ID 931)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 206 BD
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      MA27.01 - Establishment of PDX From Tumors Characterized by EGFR Mutations or ALK Fusion Genes from Resections, Biopsies and Pleural Fluids (ID 12144)

      13:30 - 13:35  |  Author(s): Devalben Patel

      • Abstract
      • Presentation
      • Slides

      Background

      Patient-derived xenograft (PDX) models allow for cancer tissue expansion, providing an effective method to evaluate tumor biology and mechanisms of response or resistance. Our study aims to establish models in patients enriched for lung adenocarcinoma (LUAD) with EGFR mutations or ALK fusion genes which respond initially to oral targeted therapy, but typically develop resistance and disease relapse within 2 years. The PDXs will be evaluated for their potential to model therapy outcomes, to determine resistance mechanisms and to evaluate novel therapy strategies to overcome resistance.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From August 2015 to January 2018, we collected 109 samples from patients with EGFR- or ALK-driven LUAD and from never-smoker LUAD patients with unknown mutation status. Five samples with low tissue viability (i.e. necrotic) or very low tumor content (<100 malignant cells) were excluded. Adequate samples were implanted into the subcutaneous tissue of NOD-SCID mice. At this time, 16 samples have reached the study endpoint (tumor growth ≥1.5cm3) and 60 showed no tumor-growth following implantation (median follow-up: 8m). Results are currently pending for 18 models.

      4c3880bb027f159e801041b1021e88e8 Result

      Samples were collected from surgical resections (31, 36%), CT-guided biopsies (12, 14%), EBUS (19, 22%) and pleural fluid effusions (24, 28%). Most patients were female (51/86, 59%), never smokers (62/85, 73%), and had stage III or IV cancer (55/79, 70%). Mutations in EGFR and ALK were found in 55/81 (68%) and 12/84 (14%) primary cancers, respectively. Early-passage xenograft engraftment (XG) was observed in only 16 (19%) PDXs, including 9/55 (16%) EGFR- and 1/12 (8%) ALK-mutant cancers. The phenotype and molecular changes (EGFR and ALK) were consistent within the PDX model and its corresponding patient sample. Samples collected from surgical-resection specimens showed a trend towards higher engraftment rates (p=0.084). Conversely, the presence of EGFR or ALK mutations showed a trend towards non-engraftment (noXG, p=0.075). Patient smoking status and tumor stage did not influence engraftment rate. To identify reasons for no tumor-growth, we conducted histological analysis in the subcutaneous fat-pads (nodes in the implant sites) of 28 noXG mice. Interestingly, we identified small non-palpable foci of carcinoma in 8 animals (4 EGFR+ and 2 ALK+).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Environmental or molecular factors may impair engraftment rates of EGFR+ and ALK+ LUAD samples in PDX models. Nevertheless, these models recapitulate the primary disease and could be useful for population-based drug-screening studies.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    OA11 - Thymic and Other Thoracic Tumours: Targeted Therapies, Biomarkers and Neo/Adjuvant Radiotherapy (ID 919)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 205 BD
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      OA11.06 - Two BRM Promoter Polymorphisms Do Not Predict Susceptibility or Prognosis of Thymoma (ID 12745)

      14:25 - 14:35  |  Author(s): Devalben Patel

      • Abstract
      • Presentation
      • Slides

      Background

      Brahma (BRM) is a critical protein subunit in chromatin remodeling, and insertions/deletions at its two polymorphic promotor sites (BRM-741 and BRM-1321) have been reported as susceptibility and/or prognostic markers in lung, head and neck, esophageal, pancreatic, and liver cancers. There is also early evidence of potential association with immune-related diseases such as ulcerative colitis and rheumatoid arthritis. As epigenetic silencing of BRM can be pharmacologically reversed, BRM polymorphisms in cancer might have therapeutic implications. Thymoma is a unique cancer in that it has immunological disease associations. We evaluated whether BRM-741 and BRM-1321 polymorphisms influence overall risk, survival, and time-to-progression of thymoma.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Thymoma cases and matched healthy controls were recruited in a comprehensive cancer centre. Study participants’ peripheral blood samples were collected and genotyped for BRM promoter polymorphisms. Multivariable logistic regression assessed risk of thymoma in case-control analyses. Association of BRM variants with overall survival (OS) and time-to-progression or recurrence (TTP) was assessed by multivariable Cox regression.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 237 cases of histologically diagnosed thymoma and 948 age- and gender-matched healthy controls, thymoma patients had median age of 53 (range: 17-84) years; 121 (51%) were male; 76 (32%) had a history of myasthenia gravis. Median follow-up time was 7 years. 79% of patients were recurrence- and progression-free at 10-year follow-up (95% CI: 74-86%), and 81% of patients were alive at 10 years post-diagnosis (95% CI: 75-87%). Frequency of homozygous variants for either gene was not significantly different between thymoma cases and controls: homozygous BRM-741genotype (OR=1.0; 95%CI:0.6-1.8; P=0.95), homozygous BRM-1321 (OR=0.59; 95%CI:0.3-1.0; P=0.07) or double homozygous variants in both loci (OR=0.69; 95%CI:0.3-1.4; P=0.29). No association between BRM-741/BRM-1321 and OS and TTP was detected (For homozygous BRM-741, OS P=0.74, TTP P=0.93; for homozygous BRM-1321 OS P=0.39, TTP P=0.93). Consistently, there was also no association between double homozygous variants and OS and TTP (Double homozygous, OS P=0.64, TTP P=0.48). Heterozygous variants were also not associated with either risk or outcome.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Results of this study do not support use of BRM promoter polymorphisms as susceptibility or prognostic markers for thymoma. Molecular biologic mechanisms of risk and prognosis remain elusive in malignant thymoma.

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-42 - Real-World Evaluation of Tolerability in Older Adult Patients (≥75 Years Old) with EGFR-mutated NSCLC (ID 13289)

      16:45 - 18:00  |  Author(s): Devalben Patel

      • Abstract
      • Slides

      Background

      NSCLC patients carrying EGFR mutations are diagnosed across a wide age distribution. Although EGFR tyrosine kinase inhibitors (TKIs) are generally well tolerated, there remains a paucity of real-world data on toxicity and health utility scores (HUS) in older patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A longitudinal observational study evaluated health-related quality of life (HRQoL) using HUS through the EQ-5D questionnaire, and common EGFR-TKI toxicities using PRO-CTCAE in NSCLC outpatients carrying EGFR mutations. Patients were classified into two groups: older (>75 years) and younger (<75 years). Patient characteristics and outcomes were extracted from chart review; patients were classified as having stable or progressive disease according to imaging findings. HUS and PRO-CTCAE results were compared descriptively.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 240 patients and 774 encounters, 52 patients (22%; comprising 157 encounters) were aged ≥ 75 years. Gender and race were similarly distributed in both age groups: 63% of older patients and 70% of younger (<75 years) were female; 56% of older patients and 53% of younger patients were Asian. Use of gefitinib in older patients was much higher than other drugs: among 147 patients who received gefitinib, 27% (40 patients) were older, compared to 15% (5/33) for osimertinib and 15% (3/20) for erlotinib. Of patients receiving afatinib (n=11) and chemotherapy (n=32), none were ≥ 75 years. The following table describes HUS and PRO-CTCAE results by treatment and age group for stable patients.

      Older Adults (75 years)

      Younger Adults (<75 years)

      N

      HUS, mean (SD)

      PRO-CTCAE*, median [IQR]

      N

      HUS, mean (SD)

      PRO-CTCAE*, median [IQR]

      Stable on gefitinib

      34

      0.83 (0.20)

      4.5 [0,16]

      77

      0.80 (0.15)

      4 [0,15]

      Stable on osimertinib

      5

      0.80 (0.23)

      13.5 [0,17]

      22

      0.87 (0.12)

      0 [0,13.5]

      Stable on erlotinib

      3

      0.82 (0.08)

      0 [0,9]

      11

      0.80 (0.14)

      0 [0,16]

      *Higher PRO-CTCAE indicates more severe toxicities/symptoms.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In a real-world evaluation, patients 75 years or older comprised almost a quarter of all patients with EGFR-mutant advanced NSCLC. Afatinib and chemotherapy were not used at all in this population. Gefitinib was used most commonly, with similar toxicities and health utilities between older and younger patients. Osimertinib and erlotinib were used too infrequently in this study for conclusive age comparisons.

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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.13-11 - PRO-CTCAE Toxicities in Advanced NSCLC Patients with EGFR Mutations: A Real World Assessment (ID 12998)

      16:45 - 18:00  |  Author(s): Devalben Patel

      • Abstract
      • Slides

      Background

      The Patient Reported Outcomes of the CTCAE (PRO-CTCAE) tool has not been evaluated in a real-world study of EGFR-mutation positive patients treated with TKIs/chemotherapies. We evaluated its role in capturing clinically-significant toxicities.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A longitudinal observational study evaluated common EGFR-TKI toxicities using PRO-CTCAE, measured on a five-point scale (1=no symptoms to 5=very severe symptoms) in outpatients with EGFR-mutated (EGFRm) advanced NSCLC.

      4c3880bb027f159e801041b1021e88e8 Result

      Toxicity information was collected for 709 follow-up visits (encounters) from 232 patients. Median age was 64 (range:29-96), 161 (69%) were female and 124 (53%) were Asian. 85 (37%) already had brain metastases at first encounter. 485 encounters were observed from patients stable on treatment, and 187 from patients progressing or with documented progression on their current treatment. 24 patients were treated with osimertinib (97 encounters, 97% in second/subsequent-line), 136 with gefitinib (324 encounters, 95% in first line therapy), 42 were receiving other EGFR-TKIs (118 encounters, 53% in second/subsequent-line), and 29 with chemotherapy (73 encounters, 96% second/subsequent-line). The table below summarizes the treatment-related PRO-CTCAE toxicities self-graded as moderate-to-very-severe by EGFRm patients.

      Proportion of patients reporting highest grade of toxicity as grade 3-5, by PRO-CTCAE

      Gefitinib

      Osimertinib

      Other EGFR TKI

      Chemotherapy

      Diarrhea

      17%

      18%

      24%

      8%

      Constipation

      12%

      4%

      12%

      16%

      Decreased appetite

      10%

      7%

      14%

      26%

      Nausea

      6%

      3%

      4%

      24%

      Vomiting

      1%

      2%

      3%

      16%

      Fatigue

      18%

      12%

      23%

      42%

      Numbness and Tingling

      6%

      7%

      10%

      16%

      Skin Rash

      23%

      12%

      20%

      9%

      Visual Disorders

      (includes dry eye)

      4%

      0%

      3%

      4%

      Total PRO-CTCAE Score, MEDIAN [IQR]

      4 [0,16]

      0 [0,15]

      6 [0,17]

      10 [0,21]

      8eea62084ca7e541d918e823422bd82e Conclusion

      Osimertinib therapy had the most favorable self-reported toxicity profiles of all the therapies in EGFRm patients, followed by gefitinib. Chemotherapy generated the greatest toxicities. The use of PRO-CTCAE was well-accepted by patients in a clinical setting. This confirms trial data supporting favorable toxicities with osimertinib compared to other therapies for EGFRm NSCLC patients.

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    P2.06 - Mesothelioma (Not CME Accredited Session) (ID 955)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.06-23 - Association of Two BRM Promoter Polymorphisms and Tobacco Exposure with Malignant Pleural Mesothelioma (MPM) Risk and Survival (ID 12738)

      16:45 - 18:00  |  Author(s): Devalben Patel

      • Abstract

      Background

      Brahma (BRM) is a critical ATPase subunit of the SWI/SNF chromatin remodeling complex. Homozygous 6-7bp insertion variants at two polymorphic promotor sites (BRM-741/BRM-1321) cause epigenetic suppression of BRM expression and they have been reported as susceptibility and/or prognostic markers in many malignancies, including non-small cell lung cancer. As epigenetic silencing of BRM can be reversed pharmacologically, targeting BRM polymorphisms has significant therapeutic potential. We evaluated BRM-741/BRM-1321 polymorphisms’ association with risk and prognosis of malignant pleural mesothelioma (MPM). While the effect of tobacco in MPM remains controversial, its interaction with genetic polymorphisms in MPM is largely unknown. We evaluated associations between BRM polymorphisms-tobacco exposure and MPM.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      MPM and age-distribution matched asbestos-exposed controls were recruited as part of an asbestos-exposure surveillance program. Participants were genotyped for BRM polymorphisms. Multivariable logistic regression assessed risk of MPM in case-control analyses. Association of BRM variants with overall survival (OS) was assessed by multivariable Cox regression. Secondary subset analyses were performed, stratified by smoking status.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 265 MPM cases, 146 (55%) were ever-smokers; 51 (19%) were female; median age was 66 (range:21-84) years. Median OS was 18 months; median follow-up time was 15 months. Compared to 795 controls, there were no significant associations of BRM with risk (P>0.10, all comparisons). In contrast, compared to the wild-type genotype, the homozygous variant of BRM-741 and BRM-1321 were associated with lower OS, with adjusted hazard ratio (aHR)=2.56 [95%CI:1.7-3.8] and 2.07 [95%CI:1.4-3.1], respectively. Compared to patients carrying the double wild-type, patients homozygous at both loci had lower OS (aHR=2.70 [95%CI:1.7-4.4]).

      There was a significant differential effect of BRM polymorphisms on risk of MPM, by smoking status (interaction P<0.001): among ever-smokers, BRM homozygous variants in BRM-741, BRM-1321, or both conferred lower risks (adjusted odds ratios, aORs were between 0.18-0.28; each P<0.001), while for never-smokers, there was significantly greater risk conferred by carrying the homozygous variants (aORs between 2.7-4.4). Likewise, a similar differential effect by smoking status was seen in prognosis (interaction P<0.001): there was no association between BRM polymorphisms and OS in ever smokers (P>0.1, all comparisons), but in never-smokers, the aHR of carrying homozygous variants of BRM-741, BRM-1321 or both were 7.7 [95%CI:3.8-16], 4.0 [95%CI:2.1-7.7], and 8.6 [95%CI:3.7-20], respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Never-smokers who develop malignant pleural mesothelioma have an increased chance of carrying BRM homozygous variants in their germline DNA, which results in substantially worse prognosis. In contrast, in smokers, there may be a protective effect, with no difference in overall survival.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.15 - Treatment in the Real World - Support, Survivorship, Systems Research (Not CME Accredited Session) (ID 964)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.15-10 - Determinants of Health Utility Scores (HUS) in Patients with ALK Rearranged Non-Small Cell Lung Cancer. (ID 14025)

      16:45 - 18:00  |  Author(s): Devalben Patel

      • Abstract
      • Slides

      Background

      Despite an increasing number of available treatment options for patients with advanced ALK-rearranged (ALKr) NSCLC, the goals of care remain to improve survival whilst maintaining quality of life. With rapidly changing management and prognosis, understanding the impact of treatments on quality of life becomes important. We evaluated factors affecting health utility scores (HUS) in this generally younger cohort of patients with NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      An ongoing prospective observational/real-world cohort study at the Princess Margaret Cancer Centre is enrolling patients with advanced NSCLC. Patients are asked to complete the EQ5D questionnaire at each outpatient visit. During the period from November, 2014 to March, 2018, patients with ALKr who participated were analyzed. Baseline clinical characteristics, oncological treatment, and outcomes were extracted from chart review. Factors associated with HUS were identified using ANOVA.

      4c3880bb027f159e801041b1021e88e8 Result

      272 encounters (follow-up visits) in 43 ALK+ patients were analysed. The median age at diagnosis was 56 years (range: 31-79 years). Half the patients in our sample were female (49%), and the majority were never-smokers (84%); 44% of the cohort were Asian. During the study period, 24 patients (56%) presented with or developed brain metastases. The median number of HUS collected per person was 4 (range: 1-20). Among patients who were stable on treatment, there were no statistically significant differences in mean HUS (mHUS) between different ALK inhibitors: mHUS [SD, standard deviation] were: mHUS of crizotinib=0.82 [0.08] (n=25, 92 encounters); mHUS of ceritinib=0.79 [0.14] (n=17, 102 encounters); and mHUS of other ALK inhibitors=0.80 [0.17] (n=12, 25 encounters), which included mHUS of alectinib=0.79 [0.20] (n=8, 10 encounters). The number of previous lines of treatment did not impact HUS (p=0.85). Patients stable on treatment who received prior whole brain radiation (n=14) had lower mHUS compared to those who never had WBRT (mHUS=0.78 [0.14] vs. 0.84 [0.10]; p=0.05), which may partly explain differences in mHUS by sex (64% of patients who had received WBRT were female vs 41% who did not receive WBRT): males=0.84 [0.10] vs females=0.78 [0.14], p=0.04. In 11 stable patients who had received radiation to bone metastases mHUS was 0.75 [0.16] vs. 0.84 [0.09] in those who did not (p=0.006).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In this study, mean HUS were similar across different ALK inhibitors. Female patients and those receiving whole brain radiation or radiation to bone had lower HUS. This highlights specific factors that influence health-related quality of life in this subset of patients with advanced NSCLC

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