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David E. Gerber



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    ES21 - Current Strategies to Improve Outcome of Patients with Oligometastatic NSCLC (ID 24)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Oligometastatic NSCLC
    • Presentations: 1
    • Now Available
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      ES21.02 - Biological Disease Characterization of OMD (Now Available) (ID 3270)

      15:45 - 17:15  |  Presenting Author(s): David E. Gerber

      • Abstract
      • Presentation
      • Slides

      Abstract

      Variation in the characterization of OMD
      Trial OMD characteristics OMD timing
      Iyengar et al (2017)

      · ≤6 sites of extracranial disease (including primary)

      · ≤3 sites in liver or lung

      ·Up to 2 contiguous vertebral metastases considered a single site      		 After first-line therapy and without progression
      Gomez et al (2016)

      · ≤3 metastatic sites

      · Any N1-3 thoracic nodes considered a single site

      · Satellite lesions counted as separate sites      		 After first-line therapy and without progression
      Parikh et al (2014) · ≤5 metastatic sites After first-line therapy and without progression
      Cheruvu et al (2011) · ≤8 metastatic sites At time of initial staging
      Khan et al (2006)

      · 1-2 metastatic sites

      · Definitive (surgery and/or chemoradiation) treatment of thoracic disease      		 After treatment of thoracic disease

      Recent years have seen a marked increase in interest in the concept of oligometastatic disease (OMD) in non-small cell lung cancer (NSCLC). Lacking a precise and consistent definition, OMD is generally considered to represent a relatively favorable clinical state, with more indolent biology, a limited number of disease sites, and potential for prolonged periods of disease control. Discussions of oligometastatic NSCLC area inexorably linked with management considerations, specifically the use of local therapies such as surgery and radiation therapy. There are numerous clinical and biological rationales to support such approaches: (1) disease progression most commonly occurs in original sites of gross disease1; (2) metastatic sites may propagate secondary metastases (parallel progression model)2; (3) solid tumors are composed of faster growing (sensitive) and slower growing (resistant) cell populations (Norton-Simon hypothesis)3; (4) resistance depends on spontaneous mutations and therefore increases with time (Goldie-Coldman hypothesis).4

      Nevertheless, several questions regarding the characterization and optimal management of OMD remain (Table 1). Up to how many sites of disease constitute an oligometastatic state? Does a “site” of disease comprise a single lesion or neighboring tumors? Does the anatomic site matter? For instance, brain metastases have historically been considered a more favorable location for definitive treatment of OMD, and their emergence may reflect pharmacokinetic failure rather than molecular evolution.5,6 Additionally, there are likely meaningful clinical differences between OMD states depending on whether they are defined at diagnosis (de novo), after initial exposure to systemic therapy (induced), recurrence, or progression.

      OMD may also have a distinct biologic phenotype. The metastatic cascade includes loss of cellular adhesion, increased motility, primary tumor invasiveness, entry into and survival in the circulation, and entry into and colonization of distant organs.7 Tumor dormancy, regulated in part by interferon signaling, may impact the number, location, and timing of metastases.8 Expression of genes that positively regulate the cell cycle may determine whether cancer growth occurs as polymetastasis versus oligometastasis. Ideally, ongoing and future clinical trials will collect biospecimens for discovery and validation of OMD biomarkers, thereby enabling the identification of cases most likely to benefit from OMD treatment paradigms.

      References:

      1. Rusthoven KE, Hammerman SF, Kavanagh BD, Birtwhistle MJ, Stares M, Camidge DR. Is there a role for consolidative stereotactic body radiation therapy following first-line systemic therapy for metastatic lung cancer? A patterns-of-failure analysis. Acta Oncol 2009;48:578-83.

      2. Klein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer 2009;9:302-12.

      3. Norton L, Simon R. Tumor size, sensitivity to therapy, and design of treatment schedules. Cancer Treat Rep 1977;61:1307-17.

      4. Goldie JH, Coldman AJ. A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 1979;63:1727-33.

      5. Hu C, Chang EL, Hassenbusch SJ, 3rd, et al. Nonsmall cell lung cancer presenting with synchronous solitary brain metastasis. Cancer 2006;106:1998-2004.

      6. Grommes C, Oxnard GR, Kris MG, et al. "Pulsatile" high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol 2011;13:1364-9.

      7. Gupta GP, Massague J. Cancer metastasis: building a framework. Cell 2006;127:679-95.

      8. Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nature reviews Immunology 2006;6:836-48.

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    MA06 - Challenges in the Treatment of Early Stage NSCLC (ID 124)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
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      MA06.02 - NSCLC Surgery Outcomes Between Facility Types and Association with Guideline Directed Surgical Quality of Care Metrics  (Now Available) (ID 2245)

      13:30 - 15:00  |  Presenting Author(s): David E. Gerber

      • Abstract
      • Presentation
      • Slides

      Background

      Non-small cell lung cancer (NSCLC) treatment outcomes differ between facility types. Surgical outcome differences may be related to modifiable factors and likelihood of receiving guideline centered care, which could be improved with new policy initiatives. We therefore analyzed the National Cancer Database (NCDB), to determine the variables related to different outcomes between facility types.

      Method

      The NCDB is a cancer registry curated by the Commission on Cancer that captures demographic and clinical data for an estimated 80% of NSCLC patients in the United States. A retrospective analysis of the NCDB was performed from 2004-2013 for Stage 1, 2 and 3a NSCLC patients treated with surgery. We compared overall survival between academic comprehensive cancer programs (ACAD) and community cancer programs (CCP) and four surgical quality metrics; lobectomy or greater vs sublobectomy, positive vs negative margin status, whether regional lymph node (LN) surgery was performed and number of nodes removed (less that 10 or equal to or greater than 10), in addition to 16 other demographic and clinical variables known to affect NSCLC survival. Kaplan-Meier estimates, log-rank test, multivariate Cox proportional hazard models and propensity score matching were used to evaluate survival differences while adjusting the effects of covariates. Quality of matching was checked using Wilcoxon rank sign test, chi-square test, and multivariate logistic regression models.

      Result

      The total cohort was 75,976 patients. After propensity matching for clinical and demographic variables, median overall survival (OS) for Stage 1, 2 and 3a was 76, 51 and 36 months for ACAD and 67, 43 and 32 months for CCP respectively (p<0.002 for all). Overall, selection of lobectomy or greater was the same between facility types (p=0.645), but ACAD were more likely to have negative margins (92.3% vs 89.8%, p<0.00001), perform LN dissection (89.5% vs 84.3%%, p<0.00001) and remove greater than 10 LN (37.4% vs 23.1%%, p<0.00001). After contrast matching for the surgical quality metrics, OS for Stage 1, 2 and 3a was 73, 49 and 34 months for ACAD and 67, 43 and 32 months at CCP respectively, with a non-significant P value for Stage 3a sub-cohort. Analysis revealed that the four key surgical quality measures explained 38% of the OS difference in median survival (p<0.00001).

      Conclusion

      In this large cohort of Stage 1, 2 and 3a NSCLC patients treated surgically, OS was higher at ACAD compared to CCP, which was in part explained by differences in surgical quality metrics. In the era of discussions of nationalized healthcare, policymakers will need to consider the differential treatment outcomes at different centers and consider consolidating treatment for NSCLC at high performing centers or improving the quality care measures of low performing centers.

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    OA07 - Precision Medicine Involves Biology and Patients (ID 132)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      OA07.05 - High-Grade Chemotherapy-Induced Peripheral Neuropathy (CIPN):  An Analysis of ECOG-ACRIN Lung Cancer Clinical Trials (Now Available) (ID 1431)

      11:00 - 12:30  |  Author(s): David E. Gerber

      • Abstract
      • Presentation
      • Slides

      Background

      High-grade (CTCAE grade ≥3) CIPN implies severe symptoms and limitation of self-care activities of daily living (ADL). To date, studies characterizing the incidence of and factors associated with CIPN have been conducted almost exclusively in breast cancer populations. As such, they generally evaluate only women and lack assessment of platinum-based chemotherapy. We therefore examined the incidence and factors associated with high-grade CIPN among patients treated on ECOG-ACRIN advanced non-small cell lung cancer (NSCLC) clinical trials.

      Method

      We included two completed trials in the analysis: E1594 (comparison of 4 chemotherapy regimens: cisplatin-paclitaxel, cisplatin-gemcitabine, cisplatin-docetaxel, carboplatin-paclitaxel) and E4599 (carboplatin-paclitaxel ± bevacizumab). We identified patients who developed treatment-related grade ≥3 CIPN. Multivariable logistic regression modeling was performed to estimate adjusted odds ratios. For the treatment variable, the reference group ended up combining the cisplatin+paclitaxel and cisplatin+docetaxel arms since their results were not significantly different from one another. Body-mass index (BMI) was categorized by median value (25.2 kg/m2).

      Result

      Among 1,989 total patients, 167 (8.4%) developed grade ≥3 CIPN. Incidence was highest for the carboplatin-paclitaxel regimen (9.9%) and lowest for cisplatin-paclitaxel (4.5%) (P=0.006). Grade ≥3 CIPN was associated with BMI (9.9% for ≥25.2 kg/m2 vs 6.9% for <25.2 kg/m2; P=0.02) and sex (6.9% for men vs 10.4% for women; P=0.006). There was a non-significant trend toward association with age (10.4% for ≥70 years versus 7.8% for <70 years; P=0.08). In multivariate analysis, chemotherapy regimen, sex, and BMI remained independently associated with grade ≥3 CIPN.

      Conclusion

      Carboplatin-paclitaxel chemotherapy, female sex, and high BMI are associated with the development of high-grade CIPN. Given the clinical severity of this condition and the potential for long-term persistence, consideration of risk-based monitoring and treatment selection may be warranted.

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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
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      OA14.04 - Five-Year Outcomes From the Randomized, Phase 3 Trials CheckMate 017/057: Nivolumab vs Docetaxel in Previously Treated NSCLC (ID 894)

      11:30 - 13:00  |  Author(s): David E. Gerber

      • Abstract
      • Slides

      Background

      Historically, outcomes for advanced non-small cell lung cancer (NSCLC) have been poor, with 5-year survival rates < 5% with conventional chemotherapy. Nivolumab, a programmed death-1 (PD-1) inhibitor, was approved in 2015 for patients with previously treated advanced NSCLC based on two randomized phase 3 trials, CheckMate 017 (NCT01642004; squamous) and CheckMate 057 (NCT01673867; non-squamous), which demonstrated improved overall survival (OS) vs docetaxel. We report 5-year pooled efficacy and safety from these trials, representing the longest survival follow-up for randomized phase 3 trials of an immune checkpoint inhibitor in advanced NSCLC.

      Method

      Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG performance status (PS) ≤ 1, and progression during or after first-line platinum-based chemotherapy, were randomized 1:1 to nivolumab 3 mg/kg Q2W or docetaxel 75 mg/m2 Q3W until progression or unacceptable toxicity. After completion of the primary analyses, patients in the docetaxel arm no longer receiving benefit could cross over to receive nivolumab. OS was the primary endpoint for both studies.

      Result

      At 5-year follow-up, 50 nivolumab patients and 9 docetaxel patients were alive. Baseline characteristics of 5-year survivors in both arms were similar to the overall population and patients who survived < 1 year, except for a higher percentage of patients with ECOG PS 0 or tumor programmed death ligand-1 (PD-L1) expression ≥ 1% on nivolumab and ECOG PS 0 and Stage IIIB NSCLC on docetaxel. Nivolumab continued to show long-term OS and progression-free survival (PFS) benefit vs docetaxel with 5-year OS rates 13% vs 3% (HR, 0.68 [95% CI, 0.59–0.78]) and PFS rates 8% vs 0% (0.79 [0.68–0.92]). OS benefit with nivolumab vs docetaxel was observed across subgroups including patients with tumor PD-L1 expression < 1%, baseline liver and adrenal metastases, neutrophil-to-lymphocyte ratio < median, lactate dehydrogenase ≥ upper limit of normal or no baseline proton-pump inhibitor use. Among patients with an objective response to nivolumab (20%) or docetaxel (11%), 32% remained in response at 5 years vs none on docetaxel, with a median duration of response of 19.9 vs 5.6 months, respectively. Of the 5-year nivolumab vs docetaxel survivors, 36% vs 0% were on study drug, 20% vs 67% received subsequent immunotherapy (on or off study), and 10% vs 0% were off study drug, progression free, with no subsequent therapy. No new safety signals were observed with longer follow-up. Between 3 and 5 years’ follow-up, 8 of the 31 (26%) nivolumab-treated patients reported a treatment-related adverse event, 1 (3%) grade 3–4. The most common select adverse events (events with a potential immunological cause) were related to skin, in 4 (13%) patients, none of which were grade 3–4.

      Conclusion

      CheckMate 017 and 057 are the first phase 3 trials to report 5-year outcomes for a PD-1 inhibitor in previously treated advanced NSCLC, demonstrating a greater than 4-fold increase in 5-year OS rates with nivolumab (13%) over docetaxel (3%). Nivolumab remained well tolerated with no new safety signals.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-71 - Tumor Burden Is Not Associated with Efficacy of Immune Checkpoint Inhibitors in Advanced Lung Cancer (ID 2454)

      09:45 - 18:00  |  Presenting Author(s): David E. Gerber

      • Abstract

      Background

      Tumor bulk has long been cited as an impediment to efficacy of certain immunotherapeutic agents, such as vaccines. However, the association between tumor burden and efficacy of immune checkpoint inhibitors (ICI) is unknown.

      Method

      We prospectively enrolled patients with diverse cancer types treated with immune checkpoint inhibitors on a registry trial. Demographic, disease, and treatment data were collected on patients with advanced non-small lung cancer (NSCLC). Imaging studies (predominantly computed tomography) were reviewed, and tumor dimensions were recorded according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Associations between tumor number and dimensions, and radiographic response, progression-free survival (PFS), and overall survival (OS) were determined using log-rank tests, cox proportional-hazard regression, and logistic regression.

      Result

      Eighty-nine patients treated with ICI (without concurrent or sequential chemotherapy or radiation therapy) were included in the analysis. Median baseline sum of largest diameters (BSLD) was 6 cm; median baseline largest single diameter was 3 cm; median number for both target and non-target lesions was 2. There was no significant difference between cases with BSLD ≤6 cm and >6 cm for response rate (OR=1.06; P=0.94) (Figure 1), PFS (HR 0.99; 95% CI, 0.60-1.64; P=0.97), or OS (HR 0.99; 95% CI, 0.59-1.68; P=0.98) (Figure 2). No significant differences were observed for these endpoints when cases were considered according to largest single diameter, number of target lesions, or number of non-target lesions.wclc -- tumor burden figure 1.jpgwclc -- tumor burden figure 2.jpg

      Conclusion

      Although tumor burden was considered a potential mediator of efficacy of vaccines and other early immunotherapies, it does not appear to impact outcomes from ICI.

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    P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.16-01 - Complications Associated with Lung Biopsies in Patients with Lung Cancer: A Population Based Analysis (ID 2934)

      09:45 - 18:00  |  Presenting Author(s): David E. Gerber

      • Abstract

      Background

      The discovery of molecular biomarkers that guide management of lung cancer has led to increasing frequency and amounts of tissue required for repeat lung biopsies.This has coincided with increased emphasis on patient safety and reporting on adverse events over the past two decades. The safety of repeat lung biopsies in patients with lung cancer has only been studied in small cohorts. We analyzed hospital-acquired adverse events for patients with lung cancer undergoing lung biopsies in the National Hospital Discharge Survey (NHDS) database from 2001- 2010.

      Method

      NHDS collects clinical information on patients discharged from non-Federal short-stay United States hospitals. Demographics, diagnoses, procedures, and mortality data were extracted using ICD-9 codes. The Agency for Healthcare Research and Quality (AHRQ) Patient Safety Indicators (PSIs) were utilized to identify hospital-acquired adverse events. Weighted analyses were performed using SAS version 9.4.

      Result

      An estimated 540,747 patients with lung cancer underwent lung biopsy during the study period and were included in the analysis; 61% were >65 years, 46% female, 65% white. Biopsy approaches included bronchoscopic (60%), percutaneous (33%), and surgical (7%). The number of lung biopsies increased over the study period, from 51,221 in 2001, to 63,239 in 2010 (P<0.001). Overall, 159,683 (30%) patients suffered ≥1-PSI event during their hospitalization, including an 11% incidence of pneumothorax. Incidence of PSI varied by biopsy type: bronchoscopic (26%), percutaneous (34%), surgical (39%). The proportion of patients experiencing ≥1 PSI event increased from 24% in 2001, to 38% in 2010 (P<0.001). Patients with ≥1 PSI experienced higher in-hospital mortality (14.5% vs 3.2%, adjusted odds ratio, 5.9, 95% CI 3.9 – 8.9; P<0.001), and prolonged length-of-stay (11.6 vs 8.1 days; P<0.001).

      Conclusion

      The frequency of lung biopsies performed in lung cancer patients has increased in recent years, as has the rate of documented complications in this selected inpatient cohort. The increased rate of complications may be due to increased attention to and reporting of adverse events in this era focusing on patient safety, which has implications for policy makers and funding authorities. Investigators, sponsors, patients and regulatory authorities should be aware of the risks associated with repeat biopsies as they design, oversee, and analyze clinical trials. Non-invasive assessment of tumor biology, such as cell-free DNA, may help mitigate these risks.

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      P1.16-41 - Timing, Sites, and Correlates of Lung Cancer Recurrence: The Missing Pieces in National Datasets (ID 2523)

      09:45 - 18:00  |  Presenting Author(s): David E. Gerber

      • Abstract

      Background

      Because national datasets do not collect relevant data, few studies have analyzed the timing, sites, and correlates of lung cancer recurrence. We therefore employed an institutional tumor registry to obtain information on this critical, intermediary disease outcome.

      Method

      From the UT Southwestern Tumor Registry, we identified cases or primary and/or recurrent lung cancer diagnosed January 1, 2000, to December 31, 2017. For cases with recurrent disease, we recorded site, timing, and case characteristics (including gender, age, race, histology, and primary treatment). Associations between these factors were evaluated using univariable and multivariable random-effect logistic regression models. We estimated time to recurrence using Kaplan-Meier methods. We used univariable and multivariable marginal Cox regression models were to assess the association between time to recurrence and case characteristics.

      Result

      A total of 1,619 stage 1-3 lung cancer cases from 1,549 patients were analyzed. Of these, 466 patients (30%) had recurrent lung cancer. In multivariable analyses, both race (P=0.02) and primary treatment (P<0.001) significantly correlated with recurrence. Among recurrent cases, patient age (P=0.02) and TNM staging (P=0.001) significantly correlated with timing of recurrence. The most common type of first recurrence was distant disease, most frequently central nervous system (94/162, 58%). The development of distant recurrent disease was associated with race (P=0.01), histology (P=0.004), and primary treatment (P=0.03).

      Conclusion

      In this single-center analysis of early stage and locally advanced in lung cancer, approximately one-third of cases develop recurrent disease, most commonly at distant metastatic sites. Central nervous system was the most frequent site of distant recurrence, accounting for more than half of cases. Race, TNM stage, and primary treatment were associated with the timing and site of recurrent disease. These findings have potential relevance to post-treatment clinical and radiographic surveillance.