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Sarah B. Goldberg



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    IBS09 - Challenges in Translating Small Cell and Neuroendocrine Tumor Research into Clinical Practice (Ticketed Session) (ID 40)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 07:00 - 08:00, Seoul (2007)
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      IBS09.02 - Immunotherapy for Small Cell and Neuroendocrine Tumors (Now Available) (ID 3342)

      07:00 - 08:00  |  Presenting Author(s): Sarah B. Goldberg

      • Abstract
      • Presentation
      • Slides

      Abstract

      A subset of patients with small cell lung cancer (SCLC) will achieve significant benefit from immunotherapy. Both nivolumab and pembrolizumab have demonstrated responses in patients with advanced SCLC, and atezolizumab in combination with chemotherapy results in an improvement in overall survival (OS) compared to chemotherapy alone. However, the ability to translate findings from the laboratory into patient care has been limited by several challenges.

      Though some patients will have durable response to PD-1 or PD-L1 agents, the majority of patients will not benefit. Combination strategies have been proposed and subsequently tested to potentially improve outcomes. Although ipilimumab was not effective as a single-agent for patients with SCLC, it has been combined with nivolumab in a phase I trial. The combination appears to be promising with response rates and OS that numerically exceeds that of single-agent PD-1 inhibitor therapy, although a randomized comparison trial has not yet been performed. Still, the majority of patients will not respond to the combination of PD-1 and CTLA-4 inhibition. Other immunotherapy targets have been explored pre-clinically though none have proven to be effective in patients to date.

      Another challenge in improving outcomes for patients with SCLC is that predictive biomarkers have been elusive. In contrast to non-small cell lung cancer, SCLCs rarely express PD-L1 on tumor cells and its presence has limited predictive value. However, immune cells in the tumor microenvironment more commonly express PD-L1 and may be predictive of benefit from immunotherapy. High tumor mutation burden (TMB) is also found in the majority of patients with SCLC likely due to the heavy smoking history in most patients with the disease. Patients with SCLC with a high TMB have been shown to have better outcomes with PD-1 inhibitors that those with lower TMB, however even those with the highest TMB have a fairly low chance of response or prolonged survival. Despite PD-L1 expression on immune cells and high TMB in most tumors, frequency of tumor infiltrating lymphocytes (TILs) is typically low in SCLC, possibly explaining the lack of response to immunotherapy in most patients with this disease.

      The benefit of immunotherapy for a subset of patients with SCLC has been proven, yet we are still faced with several challenges to optimize this treatment, including finding effective combination strategies that benefit more patients and developing predictive biomarkers to select those who are most likely to benefit.

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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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      MA11.11 - STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (Now Available) (ID 2898)

      14:00 - 15:30  |  Author(s): Sarah B. Goldberg

      • Abstract
      • Presentation
      • Slides

      Background

      Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread use of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we present updated data on the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy from a large retrospective multi-institution international study.

      Method

      620 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 21 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 468 pts treated with first-line CPP (or >1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 152 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP.

      Result

      Among 468 CPP-treated pts, STK11/LKB1 genomic alterations (N=118) were associated with significantly shorter PFS (mPFS 5.0m vs 6.8m, HR 1.45, 95% CI 1.11 to 1.91; P=0.007) and shorter OS (mOS 10.6m vs 16.7m, HR 1.46, 95% CI 1.04 to 2.07; P=0.031) compared with STK11/LKB1-wt tumors (N=350). The likelihood of disease progression as BOR to CPP differed significantly between the two groups (29.5% vs 17%, P= 0.006). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N=435) (mPFS 5.0m vs 6.9m, HR 1.48, 95% CI 1.12-1.95, P=0.006 and mOS 10.6m vs 16.7m, HR 1.45, 95% CI 1.02-2.05, P=0.036). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not result in significant improvement of PFS (mPFS 5.0m vs 3.9m, HR 0.82, 95% CI 0.63 to 1.07, P=0.14) or OS (mOS 10.6m vs 9.1m, HR 0.93, 95% CI 0.67 to 1.30, P=0.69) compared to CP alone.

      Conclusion

      In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.

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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
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-22 - ORCHARD: A Phase II Platform Study in Patients with Advanced NSCLC Who Have Progressed on First-Line Osimertinib Therapy (ID 1303)

      10:15 - 18:15  |  Author(s): Sarah B. Goldberg

      • Abstract
      • Slides

      Background

      Osimertinib is a third-generation, central nervous system (CNS)-active, irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitising mutations (EGFRm) and EGFR T790M. First-line osimertinib has demonstrated superiority in progression-free survival (PFS) compared with first-generation EGFR-TKIs in patients with EGFRm advanced NSCLC (Soria et al, NEJM 2018). The most common resistance mechanisms to first-line osimertinib identified from plasma samples are MET amplification (15%) and EGFR C797S (7%) (Ramalingam et al, Ann Oncol 2018). Further clinical studies are needed to better understand resistance mechanisms and evaluate post-progression targeted treatment options.

      Method

      ORCHARD is an open-label, multicentre, biomarker-directed, Phase II platform study evaluating the optimal treatment for individual patients with EGFRm NSCLC depending on their underlying resistance mechanism to first-line osimertinib.

      Adult patients with EGFRm locally advanced/metastatic NSCLC and radiological progression on first-line osimertinib monotherapy will be eligible.

      Treatment assignment will be based on molecular characterisation of the tumour at progression from a mandatory tissue biopsy.

      ORCHARD will comprise of three groups assigned by tumour molecular profile (Figure). An adaptive design allows addition of new treatments based on emerging findings. Tumour assessments (RECIST 1.1) will be performed every 6 weeks for the first 24 weeks and every 9 weeks thereafter until progression. An interim analysis of each cohort will be performed when ≈16 patients have reached the second on-treatment RECIST assessment. Based on preliminary signals, the cohort may be stopped or expanded to 30–40 patients for further evaluation.

      The primary outcome is investigator-assessed objective response rate; secondary outcomes include PFS, duration of response, overall survival, and pharmacokinetics of each treatment module, evaluated independently. Exploratory outcomes include tumour and plasma biomarker and resistance analyses, and correlation between biomarker profiles and treatment effect. Safety data will also be reported.

      orchard tip_study design figure.jpg

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    P2.17 - Treatment of Early Stage/Localized Disease (ID 189)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.17-07 - Role of Adjuvant Chemotherapy After Sublobar Resection in Stage I NSCLC (ID 672)

      10:15 - 18:15  |  Author(s): Sarah B. Goldberg

      • Abstract
      • Slides

      Background

      Adjuvant chemotherapy (AC) has been associated with improved survival for several subsets of surgically managed NSCLC (e.g. nodal metastases, tumors >4cm). The surgical practice of removing less than the entire lobe (“sublobar resection”) has been associated with increased risk of NSCLC recurrence, yet the impact of AC in this subset is unknown. Stage I NSCLC patients managed by sublobar resection (SR) in the National Cancer Data Base (NCDB) were studied to evaluate SR as a potential indication for AC.

      Method

      The NCDB was queried for completely resected (R0) stage I NSCLC patients who underwent multi-agent AC after SR (wedge resection or segmentectomy) between 2004 & 2014. Survival was calculated from 30 days after surgery to minimize immortal time bias. Multivariable Cox proportional hazards models adjusting for patient, tumor (including visceral pleura invasion (VPI) and lympho-vascular invasion (LVI)) and treatment characteristics were created and stratified by size (0-1 cm, 1.1-2 cm, 2.1-3 cm and 3.1-4 cm).

      Result

      Of the 12,063 patients identified, 584 (4.84%) received multi-agent AC. AC patients tended to be younger (median age 66 vs 71 years, p<0.001), privately insured (35.13% vs 23.05%, p<0.001), and with high risk pathological features (VPI: 6.47% vs 4.55%, p<0.001, LVI: 10.32% vs 5.70%, p<0.001, high grade: 47.15% vs 34.50%, p<0.001). In patients with tumors measuring ≤3 cm, AC was not significantly associated with a mortality reduction (Table 1). In patients with tumors measuring 3.1-4 cm (N=1,172), AC (N=145, 12.37%) was associated with a lower mortality (HR 0.65, 95% CI 0.48 to 0.87, p=0.003) (Figure 1).

      table 1.jpg

      fig 1.jpg

      Conclusion

      The administration of AC was associated with superior survival in stage I NSCLC patients who underwent SR, but only those with tumors 3.1-4 cm. Additional study to validate SR as an indication for AC in stage I NSCLC patients is indicated.

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