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Christine M Bestvina



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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): Christine M Bestvina

      • 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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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-12 - Ph I Trial of Concurrent or Sequential Ipilimumab, Nivolumab, and SBRT to Multiple Sites in Patients with Stage IV NSCLC  (ID 2903)

      10:15 - 18:15  |  Author(s): Christine M Bestvina

      • Abstract

      Background

      Despite the promise of immunotherapy for the treatment of advanced NSCLC, only a fraction of patients experience significant benefit from immunotherapy alone. Previous studies have shown that SBRT can stimulate innate and adaptive immunity to potentially augment immunotherapy. In addition, SBRT is used in patients with limited metastatic disease as consolidative approach, showing an improvement overall survival when compared to systemic treatment alone. Combining immunotherapy with ablative therapy is being studied by a number of investigators. While many of these pre-clinical and clinical studies are promising, timing of immunotherapy with SBRT has not be formally studied. Further, few of these studies have addressed treatment of multiple sites of disease and little is known about what molecular changes occur in the tumor microenvironment immediately after ablative therapy. This trial is designed to evaluate the safety and efficacy of the combination of nivolumab (N) and ipilimumab (I) plus sequential(S) or concurrent(C) SBRT in patients with stage IV NSCLC.

      Method

      This is a single-center phase I, open-label, two-arm, randomized platform trial. Eligible patients include those with stage IV NSCLC with >2 metastatic lesions that meet criteria for SBRT (0.2 cc to 65 cc of viable tumor, larger tumors able to be partially treated up to 65 cc). Eligible patients are simultaneously accrued on arm I (S) and arm II (C) in a 1:1 ratio. Participants in arm I complete SBRT to 2-4 sites followed by initiation of N/I 1-7 days after completion of SBRT. Participants in arm II are treated with N/I within 24-48 hours of SBRT with required SBRT completion to 2-4 sites within two weeks (prior to the second dose of N). Protocol therapy consists of treatment with N 3mg/kg every 2 weeks and I 1mg/kg every 6 weeks for a maximum of 24 months. The primary endpoint is dose-limiting toxicity defined as a >33% rate of grade ≥3 toxicity. DLT is defined as any grade ≥3 toxicity possibly, likely, or definitely related to SBRT plus N/I (the combination and not the individual components). 
Secondary endpoints include response rate and progression free survival at 6 months, control rate of treated lesions and non-treated lesions, and comparison of efficacy and toxicity between the arms. Biopsies and blood draws performed pre- and post-SBRT will facilitate molecular correlative studies including investigation of changes in the immune microenvironment induced by the two approaches.

      Result

      Current enrollment includes 27 of the 40-80 participants: 15 patients are enrolled on arm 1 (sequential) and 12 patients are enrolled on arm 2 (concurrent). SBRT safety cohorts, to which patients can contribute to more than one, include the following: central lung (n=20), peripheral lung (n=7), abdominal (n=5), osseous (n=9), and liver (n=5). All patients have paired pretreatment and posttreatment biopsies of at least one irradiated lesion. 79% of post-ablative biopsies are suitable for DNA/RNA sequencing.

      Conclusion

      Section not applicable

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-12 - Tyrosine Kinase Inhibitor Resistance Mechanisms in EGFR T790M-Positive Lung Cancer: The University of Chicago Experience (ID 2709)

      10:15 - 18:15  |  Author(s): Christine M Bestvina

      • Abstract
      • Slides

      Background

      Acquired resistance to osimertinib in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) is a poorly understood phenomenon and presents an ongoing challenge. Previously described mechanisms include emergence of mutations at EGFR C797S, MET amplification, transformation to small cell lung cancer, and BRAF mutation. Next-generation sequencing (NGS) of tumors at progression through osimertinib may help to illuminate novel mechanisms of resistance to osimertinib.

      Method

      We surveyed University of Chicago Medicine case records for osimertinib-treated NSCLC patients treated who progressed through therapy. Panels utilized for NGS included, among others, the University of Chicago’s validated panel (the UCM-OncoPlus, surveying greater than 1,100 genes) and Guardant (Guardant Health; Redwood City, CA). Patients were stratified according to presence of EGFR T790M mutation at the initiation of osimertinib therapy.

      Result

      28 patients were identified to have progressed through osimertinib. 23 patients (82.1%) had next-generation performed at the time of progression. Among osimertinib-resistant patients who had NGS, 17 (73.9%) demonstrated at least one resistance mechanism, of which 8 (34.8% of tested patients) were subsequently treated with tyrosine kinase inhibitor-containing regimens or clinical trial of targeted therapy. Mutational profile at progression through osimertinib included: 2 patients (11.8%) with EGFR C797 mutation, 2 patients (11.8%) with MET amplification, 2 patients (11.8%) with RET fusion protein, 2 patients (11.8%) with MET point mutation, 1 patient (5.9%) with EGFR amplification, and 1 patient (5.9%) with small cell transformation. Newly identified resistance mechanisms (n = 1 for each) included mutation to EGFR G724 and L718 residues, ROS1 fusion protein, and in the same patient CBLB Q371* and SMAD4 loss. Of the 23 patients undergoing NGS at progression, 11 (47.8%) harbored EGFR T790M mutations prior to treatment, 3 (27.3%) of whom demonstrated resistance mutations susceptible to additional tyrosine kinase inhibitor therapy.

      Conclusion

      On the basis of these data, we confirm many previously described mechanisms of osimertinib resistance, including EGFR amplification, MET amplification, fusions involving RET, and transformation to small cell lung cancer, as well as novel resistance mechanisms including ROS1 fusion protein. We demonstrate the utility of NGS at the time of progression through osimertinib in our practice, regardless of the patient’s EGFR T790M status. We conclude that re-biopsy and utilization of NGS identifies a significant subset of osimertinib-resistant patients in whom well-tolerated tyrosine kinase inhibitor therapies remain an option and, in the interests of both patient well-being and clinical trial enrollment, should be considered standard practice at progression.

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