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Jessica Hellyer



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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): Jessica Hellyer

      • 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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    MS04 - New Systemic Adjuvant/Neo-Adjuvant Strategies in Early Stage Lung Cancer: Targeted Therapy and I/O (ID 67)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
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      MS04.03 - Adjuvant PD-(L)1 Checkpoint Inhibitors (Now Available) (ID 3457)

      15:15 - 16:45  |  Author(s): Jessica Hellyer

      • Abstract
      • Presentation
      • Slides

      Abstract

      Advances in adjuvant therapy for early stage, resectable, non-small cell lung cancer (NSCLC) have been slow for many years. Four cycles of post-operative platinum-based chemotherapy remains the standard of care in most of the world, yet this confers a survival benefit of only ~5% at 5 years.1 Early efforts to stimulate adaptive immunity to prevent tumor recurrence via several immunologic interventions including antigen specific cancer vaccines, Bacillus Calmette-Guerin (BCG), adoptive cell transfer and tumor-infiltrating lymphocytes failed to show a benefit in overall survival in a meta analysis of the early trials2,3 In 2018 though positive results from the PACIFIC trial ushered in a new era of immunotherapy with PD-L1 checkpoint blockade in non-operable, stage III non-small cell lung cancer (NSCLC) and established consolidation durvalumab following chemoradiation as the new standard of care.4 These data provided further enthusiasm for ongoing trials of checkpoint inhibitors in early stage, surgically resectable disease.

      Promising preliminary data has been presented from ongoing neoadjuvant PD-(L)1 checkpoint inhibitor trials, many of which contain an adjuvant component. The most exciting results to date have come from the NADIM trial of neoadjuvant carboplatin/paclitaxel/nivolumab followed by adjuvant nivolumab for one year after surgical resection. Analysis of the first 41 patients following surgical resection showed 35 (86%) of patients with a major pathologic response (MPR) (defined as <10% viable tumor cells present) and of those, 25 (71%) had a complete pathologic response (CR).5 The NEOSTAR study of induction nivolumab or nivolumab/ipilumumab and the LCMC trial with neoadjuvant followed by adjuvant atezolizumab in resectable NSCLC patients were both updated at ASCO 2019 with reported MPR in 17%, 33%, and 19% (with 5% CR) of the nivolumab and nivolumab/ipilumumab and atezolizumab intent to treat populations, respectively.6,7 However, immune toxicity was reported in all of these trials and there were some patients who were not able to complete definitive surgery. We also do not know how MPR with immune therapy correlates with disease free survival (DFS) and overall survival (OS).

      Thus there is still a lot of enthusiasm for the post-operative (adjuvant) use of checkpoint inhibitors. There are multiple adjuvant immunotherapy trials currently underway although there are no results reported to date. A branch of the US coopertive network (NCTN) ALCHEMIST trial, ANVIL, is currently enrolling patients with stage IB (>4cm)-IIIA NSCLC who test negative for EGFR and ALK mutations. After completion of surgical resection and standard of care adjuvant therapy (chemotherapy or radiation therapy if indicated), patients are randomized to up to a year of adjuvant nivolumab or observation. These patients are further stratified by stage, histology, adjuvant treatment received and PD-L1 status (≥1% or <1%). Co-primary endpoints are disease free and overall survival.8 IMpower 010 is a randomized, phase III trial of adjuvant atezolizumab vs supportive care in stage IB (>4cm) - IIIA NSCLC patients following surgical resection and cisplatin-based adjuvant chemotherapy with enrollment of 1280 patients. This study does not allow for radiation therapy and mandates that the adjuvant chemotherapy contain cisplatin plus vinorelbine, gemcitabine, docetaxel or pemetrexed. Following completion of 4 cycles of adjuvant chemotherapy, patients are randomized 1:1 to a year of atezolizumab or observation. Primary outcome is disease free survival.9 In KEYNOTE-091 patients with IB/II-IIIA surgically resected NSCLC who have completed standard of care adjuvant therapy will be randomized to one year of pembrolizumab vs supportive care. The target enrollment is 1080 patients. Primary endpoint is disease free survival. Finally, adjuvant durvalumab is being examined in a randomized, phase III prospective, triple-blind, placebo controlled trial of patients with stage IB (>4cm)-IIIA resected NSCLC being lead by the Canadian Cancer Trials Group. Standard adjuvant chemotherapy is permitted, but post-operative radiation is only allowed for N2 disease. Primary endpoint is disease free survival in PD-L1 positive patients and in all randomized patients. The study stratifies across PD-L1 subgroups (≤1%, 1-49% and ≥50%). Target enrollment is 1360 patients.10

      Checkpoint inhibitor therapy has been established as the new standard of care in unresectable and metastatic NSCLC. Many trials are underway with adjuvant and neoadjuvant immunotherapy for early stage lung cancer and preliminary data from the neoadjuvant trials are promising. In a setting where patients have only modestly benefited from chemotherapy, we eagerly await the results of the ongoing adjuvant immunotherapy studies with the hopes of improving outcomes for surgically resectable NSCLC.

      References

      1. Pignon JP, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26(21):3552-3559.

      2. Somasundaram A, Burns TF. Pembrolizumab in the treatment of metastatic non-small-cell lung cancer: patient selection and perspectives. Lung Cancer (Auckl). 2017;8:1-11.

      3. Zhu J, et al. Immunotherapy (excluding checkpoint inhibitors) for stage I to III non-small cell lung cancer treated with surgery or radiotherapy with curative intent. Cochrane Database Syst Rev. 2017;12:CD011300.

      4. Antonia SJ, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018.

      5. Provencio-Pulla M, , et al. Neoadjuvant chemo/immunotherapy for the treatment of stages IIIA resectable non-small cell lung cancer (NSCLC): A phase II multicenter exploratory study—NADIM study-SLCG. Journal of Clinical Oncology. 2018;36(15_suppl):8521-8521.

      6. Cascone T, et al. Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC): Clinical and correlative results from the NEOSTAR study. ASCO 2019.

      7. Kwiatkowski DJ, et al. Neoadjuvant Atezolizumab in Resectable Non-Small Cell Lung Cancer (NSCLC): Interim Analysis and Biomarker Data From a Multicenter Study (LCMC3). ASCO 2019

      8. Chaft JE, et al. EA5142 adjuvant nivolumab in resected lung cancers (ANVIL). Journal of Clinical Oncology. 2018.

      9. Wakelee HA, et al. A phase III trial to compare atezolizumab (atezo) vs best supportive care (BSC) following adjuvant chemotherapy in patients (pts) with completely resected NSCLC: IMpower010. Journal of Clinical Oncology. 2017;35(15_suppl):TPS8576-TPS8576

      10. O'Brien MER, et al. EORTC-ETOP randomized, phase 3 trial with anti-PD-1 monoclonal antibody pembrolizumab versus placebo for patients with early stage non-small cell lung cancer (NSCLC) after resection and standard adjuvant chemotherapy: PEARLS (NCT02504372). Journal of Clinical Oncology. 2016;34(15_suppl):TPS8571-TPS8571.

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    P1.15 - Thymoma/Other Thoracic Malignancies (ID 184)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.15-02 - Role of mTOR Inhibitor Everolimus in the Treatment of Metastatic Thymic Epithelial Tumors (ID 2763)

      09:45 - 18:00  |  Presenting Author(s): Jessica Hellyer

      • Abstract
      • Slides

      Background

      Optimal treatment for metastatic thymic epithelial tumors (TETs) after progression on platinum-based chemotherapy has yet to be determined. There is emerging evidence to support the use of mTOR inhibitor everolimus in this setting including the recent phase II study by Zucali et al. However, patient selection and identifying predictors of response remains a challenge. Here, we describe a single-center experience with everolimus in TETs and molecular markers associated with response to therapy using a computational biological model (CBM).

      Method

      Data on all patients with advanced TETs who were prescribed everolimus at our institution were retrospectively abstracted from the electronic medical record. Time to treatment failure (TTF) and overall survival (OS) were calculated. Solid Tumor Actionable Mutation Panel (STAMP), a targeted next generation sequencing (NGS) panel, was run on each TET and the results were computationally matched to a cohort of genomically similar TET patients from The Cancer Genome Atlas (TCGA). CBM was used to examine key genomic alterations of TETs correlated with response on everolimus. Responders were defined as having TTF > 6 months.

      Result

      Thirteen patients with TETs, including ten thymomas (T) and three thymic carcinomas (TC) treated with everolimus, were included. All patients had been heavily pre-treated with an average of three prior lines of therapy. Three patients discontinued treatment due to adverse events. The average TTF was 10.8 months in T and 2.6 months in TC with median OS of 205 months (T) and 67.8 months (TC). Molecular data was available for 11 of 13 patients and identified mutations in MAP2K, HRAS and NF1 as key molecular features associated with a response to everolimus. CBM accurately predicted response in 9 of 11 genomically similar TCGA tumors to our patient cohort.

      Conclusion

      Patients with previously treated metastatic TETs appear to benefit from everolimus. Molecular testing of these tumors using targeted NGS panel revealed an association with several key genes, which may help to guide patient selection in the future.

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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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      P2.01-73 - Outcome Disparities in American Indian/Alaskan Natives with Advanced Stage Lung Cancer (ID 2679)

      10:15 - 18:15  |  Presenting Author(s): Jessica Hellyer

      • Abstract
      • Slides

      Background

      Although there have been many advances in the treatment of lung cancer, outcomes for American Indian/Alaskan Natives (AI/AN) have remained poor. AI/AN patients present at a younger age, more advanced stage and have higher lung-cancer attributed mortality rates. While disparities in treatment of early stage lung cancer are well described, the pattern of treatment in advanced stage disease and cancer guideline concordance is incompletely understood.

      Method

      Data was obtained from the National Cancer Institute SEER database from 2000-2013, which was linked with Medicare enrollment and claims data from the Centers for Medicare and Medicaid Services. Patients were included if they were characterized as AI/AN by either SEER or Medicare databases and diagnosed with stage IIIB/IV lung cancer. Demographic data and clinical characteristics were abstracted. Metrics were developed to assess adherence with lung cancer treatment guidelines.

      Result

      Out of 238,439 lung cancer patients, 404 patients had advanced stage disease and were coded as AI/AN in SEER. They were propensity matched by age at diagnosis, year of diagnosis and number of lung cancers to a cohort of white advanced stage patients (N=404). The comparison of the patient characteristics across the two race groups shows that AI/AN patients were more likely to have squamous cell histology, live in smaller urban communities, less likely to be married, and less likely to receive surgery or radiation. Only 20.5% of the advanced lung cancer AI/AN population received appropriate therapy within 90 days of diagnosis compared with 29.5% of the propensity matched white cohort (p = 0.004).

      Conclusion

      AI/AN patients are less likely to receive cancer-directed care such as surgery or radiation than the matched white cohort and less likely to receive appropriate therapy within 90 days of diagnosis. Work is ongoing to evaluate adherence to other metrics such as receipt of appropriate diagnostics and treatment as well as trends in survival.

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