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Charles M Rudin

Moderator of

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    OA15 - Targeted Agents and Immunotherapy for Small Cell Lung Cancer (ID 152)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 7
    • Now Available
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      OA15.01 - Combination Olaparib and Temozolomide in Relapsed Small Cell Lung Cancer: Updated Results from Phase 1/2 Clinical Trial (Now Available) (ID 1394)

      14:30 - 16:00  |  Presenting Author(s): Anna F Farago  |  Author(s): Beow Yeap, Rebecca S Heist, J Paul Marcoux, Deepa Rangachari, David Barbie, Elizabeth Kennedy, Mari Mino-Kenudson, Alice T. Shaw

      • Abstract
      • Presentation
      • Slides

      Background

      DNA damage repair inhibition is an emerging strategy for treating small cell lung cancer (SCLC). Combining poly(ADP-ribose) polymerase (PARP) inhibition with the DNA alkylating agent temozolomide has shown activity in both preclinical models and early phase clinical trials.

      Method

      This is a single-arm phase 1/2 study combining the PARP inhibitior olaparib (tablet formulation) with temozolomide in patients with SCLC. Key eligibility criteria include histologically or cytologically confirmed incurable SCLC which progressed following ≥ 1 platinum-based chemotherapy. In cohort 1, olaparib and temozolomide are administered orally on days 1-7 of 21-day cycles. After cohort 1 completed enrollment, cohort 2 was added in a protocol amendment, in which olaparib is administered continuously days 1-21 and temozolomide is administered days 1-7 of 21-day cycles. For each cohort, the phase 1 portion is a conventional 3+3 design, with the primary objective to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). The primary objective of the phase 2 dose expansion portion is to determine the objective response rate (ORR). Response assessments are performed every 6 weeks, with treatment continued until progression, unacceptable toxicity, or investigator’s discretion. Treatment post-progression is allowed for patients with ongoing clinical benefit.

      Result

      Between October 2015 and April 2018, 50 patients were enrolled to cohort 1. The median age was 63 (range 39-85), median number of prior therapies was 2 (range 1-7), and 72% were platinum sensitive. The RP2D was olaparib 200 mg PO BID d1-7 and T 75 mg/m2 QD d1-7. The confirmed ORR was 41.7%. After a median follow-up of 7.1 months among 22 surviving patients, the median progression-free survival (mPFS) was 4.2 months, median overall survival (mOS) was 8.5 months, and median duration of response (mDoR) was 4.3 months. The ORR among platinum-sensitive and platinum-resistant patients was 47.1% and 28.6%, respectively, with no significant differences in mPFS, mOS or mDOR. The most common grade 3/4 treatment related adverse events were neutropenia (38%), anemia (28%) and thrombocytopenia (26%). Among 41 pts treated at the RP2D, dose reductions occurred in 44% overall and 64% of those who received at least 3 cycles. Enrollment to the phase 1 portion of cohort 2 began in November 2018 and is ongoing. Updated results from cohorts 1 and 2 will be presented at the meeting.

      Conclusion

      Combination olaparib and temozolomide has an acceptable tolerability profile and shows promising clinical activity in relapsed SCLC. Clinical trials identifier NCT02446704.

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      OA15.02 - Carboplatin-Etoposide Versus Topotecan as Second-Line Treatment for Sensitive Relapsed Small-Cell Lung Cancer: Phase 3 Trial (Now Available) (ID 546)

      14:30 - 16:00  |  Presenting Author(s): Isabelle Monnet  |  Author(s): Nathalie Baize, Laurent Greillier, Margaux Geier, Hervé Lena, Henri Janicot, Alain Vergnenegre, Jacqhy Crequit, Regien Lamy, Jean Bernard Auliac, Jacques Le Treut, Hervé Le Caer, Radj Gervais, Eric Dansin, Anne Madroszyk, Patrick Renault, Gwenaëlle Legarff, Roland Schott, Patrick Saulnier, Christos Chouaid

      • Abstract
      • Presentation
      • Slides

      Background

      Topotecan is currently the only drug approved in Europe in second line setting for small-cell lung cancer (SCLC). This study investigates whether the doublet carboplatin-Etoposide was superior to topotecan monotherapy as second-line treatment in patients with sensitive relapsed SCLC.

      Method

      this open-label, multicenter, phase 3 trial randomized patients with SCLC that responded to first-line platin etoposide doublet treatment but showed evidence of disease relapse or progression at least 90 days after completion of the first-line treatment. Enrolled patients were randomly assigned (1:1) to receive combination chemotherapy (Six cycles of 3-weeks Carboplatin, AUC 5, day 1 and Etoposide 100 mg/Sqm/d 1-3, intra-venous) or oral Topotecan (2.3 mg/Sqm/d 1-5, every 3 weeks). Primary endpoint was progression free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), quality of life and tolerance in the intention-to-treat population, (clinical trialgouv: NCT02738346)

      Result

      178 patients were screened and 164 randomized in 36 centers, with 82 assigned to each treatment group (age: 64.5 ± 7.2 years, men: 72.8%, PS 0/1/>1: 34.7%/56.3%/ 9%. Median PFS was significantly longer in combination chemotherapy group (4.7 months, 95% CI: 3.9-5.5) compare to topotecan group (2.7 months, 95% CI: 2.3-3.2), HR: 0.6, 95% CI 0.4-0.8, p < 0.002. The ORR were significantly more important in the combination chemotherapy than in topotecan arm (ORR 49 % vs 25 %, p < 0,002), but without difference in term of median OS, 7.5 months (95% CI: 5.4-8.7) in combination chemotherapy group versus 7.4 months (95% CI.6.0-9.3) in topotecan arm. Grade 3/4 neutropenia were significantly more common in the topotecan group than in the combination chemotherapy group (35.8% vs 19.7 %, p < 0.001. There is a non-significant trend for more febrile neutropenia in topotecan arm compare to combination arm (13.6 % 6.2 %, p = 0.19, and no difference for grade 3/4 thrombopenia, 35.8 % vs 30.9 %, and anemia, 24.6 % vs 21 %, for topotecan and combination arms, respectively. Two treatment-related deaths occurred in the topotecan arm (febrile neutropenia with sepsis), none in the combination arm. Results of quality of life outcomes will be presented at the meeting.

      Conclusion

      platin - etoposide re-challenge can be considered as a standard second-line chemotherapy for sensitive relapsed SCLC.

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      OA15.03 - Discussant - OA15.01, OA15.02 (Now Available) (ID 3804)

      14:30 - 16:00  |  Presenting Author(s): Mary O'Brien

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA15.04 - Genomic and TCR Intratumor Heterogeneity of Small-Cell Lung Cancer by Multiregion Sequencing: An Association with Survival (Now Available) (ID 1458)

      14:30 - 16:00  |  Presenting Author(s): Jianjun Zhang  |  Author(s): Runzhe Chen, Ying Jin, Jun Li, Jiexin Zhang, Junya Fujimoto, Won-Chul Lee, Xiao Hu, Yamei Chen, Carmen Behrens, Chi-Wan Chow, Edwin Parra, Latasha Little, Curtis Gumbs, Xingzhi Song, Emily Roarty, Jianhua Zhang, Don Lynn Gibbons, John Victor Heymach, J. Jack Lee, William N. William Jr, Bonnie Glisson, Ignacio Wistuba, P. Andrew Futreal, Lauren Averett Byers, Alexandre Reuben, Ming Chen

      • Abstract
      • Presentation
      • Slides

      Background

      Small cell lung cancer (SCLC) is an aggressive cancer. Although sensitive to initial therapy, recurrence is almost inevitable. The molecular mechanisms underlying recurrence are unknown. We have previously demonstrated that complex genomic and T cell receptor (TCR) intratumor heterogeneity (ITH) was associated with increased risks of relapse in non-small cell lung cancers (NSCLC). Genomic ITH and TCR architecture of SCLC and its clinical impact have not been well studied, largely due to lack of tumor specimens as surgery is rarely used to treat SCLC.

      Method

      We performed multiregion whole-exome sequencing and TCR sequencing of 49 tumor samples from 18 resected limited-stage SCLCs to delineate the immunogenomic ITH of SCLC. We compared the results to those in NSCLC and assessed the association of genomic and TCR attributes with patient’s survival.

      Result

      On average, 544 mutations/sample were detected. The median proportion of trunk mutations (mutations identified in all regions within the same tumors) was 80.4% versus 70% in NSCLC (TRACERx, Jamal-Hanjani, NEJM, 2017, p=0.08) and all TP53 and RB1 mutations were trunk mutations, suggesting these mutations were early events during carcinogenesis of this cohort of SCLCs. A higher non-synonymous tumor mutational burden (TMB) was associated with a higher T cell density (infiltration) in the tumor (r=0.46, p=0.005). Compared to the TCR repertoire of NSCLC (Reuben, WCLC, 2017), these SCLC tumors demonstrated significantly lower T-cell density (0.05 versus 0.24, p<0.0001), richness (diversity, 1,043 versus 3,666, p<0.0001) and clonality (reactivity, average 0.02 versus 0.15, p<0.0001) despite similar non-synonymous TMB (average 187 in SCLC versus 176 mutations/sample in NSCLC). Only 0.2% to 14.6% of T cells were detectable across all regions from the same tumors, suggesting substantial TCR ITH. Jaccard index (JI), a parameter quantifying TCR ITH was significantly lower in SCLC than in NSCLC (0.06 versus 0.1, p<0.0001) implying higher level of TCR ITH in SCLC than NSCLC. Interestingly, higher T-cell density, richness or clonality appeared to be associated with lower risk of recurrence numerically. Furthermore, higher TCR JI (less degree of ITH) was associated with significantly longer overall survival (HR=0.15, p=0.04).

      Conclusion

      Limited-stage SCLC tumors have distinct TCR repertoire and genomic ITH architecture. Overall, SCLC may have a more pronounced immunosuppressive microenvironment and higher level of TCR repertoire ITH than NSCLC. Nevertheless, higher degree of T cell infiltration and clonal expansion as well as more homogeneous T cell response may be associated with more favorable clinical outcome in patients with limited-stage SCLC.

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      • Abstract
      • Presentation
      • Slides

      As requested by the author, the abstract for this presentation will not be published

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.

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      OA15.06 - Discussant - OA15.04, OA15.05 (Now Available) (ID 3805)

      14:30 - 16:00  |  Presenting Author(s): Hidehito Horinouchi

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA15.07 - Heine H. Hansen Lectureship Award for Small Cell Lung Cancer (Now Available) (ID 3861)

      14:30 - 16:00  |  Presenting Author(s): Caroline Dive

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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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): Charles M Rudin

      • 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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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-122 - A Clinical Utility Study of Plasma DNA Next Generation Sequencing Guided Treatment of Uncommon Drivers in Advanced Non-Small-Cell Lung Cancers (ID 2997)

      09:45 - 18:00  |  Author(s): Charles M Rudin

      • Abstract
      • Slides

      Background

      Although EGFR and ALK testing in non-small-cell lung cancers (NSCLC) is now considered standard practice, next generation sequencing (NGS) for extended molecular testing of uncommon drivers is often difficult to perform in the community due to factors surrounding tissue adequacy, availability and turnaround time. We set out to prospectively determine the clinical utility of plasma ctDNA NGS in detecting uncommon actionable drivers and their plasma guided treatment response.

      Method

      Patients with advanced NSCLC who were driver unknown after routine EGFR and ALK testing were eligible. Patients were enrolled prospectively at Memorial Sloan Kettering Cancer Center (NY, USA) and Northern Cancer Institute (Sydney, Australia). Peripheral blood (10-20mL) was collected and sent to Resolution Bioscience (Kirkland, WA) for targeted ctDNA NGS using a bias-corrected hybrid-capture 21 gene assay in a CLIA laboratory achieving a mean unique read of at least 3000x and sensitivity above 0.1%. Clinical endpoints included detection of uncommon oncogenic drivers defined as actionable alterations in ROS1, RET, BRAF, MET, HER2, turnaround time, concordance with tissue NGS when available, and plasma guided treatment outcome.

      Result

      614 patients were prospectively accrued. Plasma NGS detected an uncommon oncogenic driver in 7% (45/614) of patients including ROS1, RET fusions, BRAF, MET exon 14 and HER2 exon 20 mutations, of whom 3% (20/614) were matched to targeted therapy producing 12 partial responses. Mean turnaround time for plasma NGS was significantly shorter than tissue NGS (10 vs 25 days, P <0.0001). 399 patients had concurrent tissue NGS results available for concordance analysis; Overall concordance, defined as the proportion of patients for whom an uncommon driver was uniformly detected or absent in both plasma and tissue NGS, was 94.7% (378/399, 95% confidence interval [CI] 92.1 – 96.7%). Among patients who tested plasma NGS positive for uncommon drivers, 87.5% (28/32, 95% CI 71.0-96.5%) were concordant on tissue NGS, and among patients tested tissue NGS positive for uncommon driver, 62.2% (28/45, 95% CI 46.5-76.2%) were concordant on plasma NGS.

      Conclusion

      Plasma NGS uncovered uncommon oncogenic drivers with faster turnaround time than tissue NGS, directly matched patients to targeted therapy and produced clinical responses independent of tissue results. A positive finding of an oncogenic driver in plasma is highly specific and can immediately guide treatment, but a negative finding may still require tissue biopsy. Our findings provide prospective evidence to support a “blood first” approach in molecular diagnostics for the care of patients with NSCLC.

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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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      P1.04-39 - Molecular Characteristics, Immunophenotype, and Immune Checkpoint Inhibitor Response in BRAF Non-V600 Mutant Lung Cancers (ID 1529)

      09:45 - 18:00  |  Author(s): Charles M Rudin

      • Abstract
      • Slides

      Background

      Targeted therapy for Class I BRAF mutant lung cancers (V600) is well described and there is growing literature on their response to immune checkpoint inhibitors (ICI). In contrast, the molecular characteristics, immunophenotype, and response rates of class II and III BRAF mutations are not well defined.

      Method

      Patients with BRAF Class I, II, III mutant and variants of unknown significance (VUS) lung cancers detected on NGS (MSK-IMPACT) from 1/2014-1/2018 were identified. PD-L1 by immunohistochemistry (E1L3N) was evaluated. Tumor mutation burden (TMB; mut/Mb) was determined by MSK-IMPACT. Best objective response to ICI was assessed by RECIST v1.1. Time to treatment discontinuation (TTD) and overall survival (OS) were assessed. Statistical analysis was performed with Fisher’s exact and Kaplan-Meier. BRAF V600 lung cancers were used as a comparator and analyzed separately from BRAF non-V600.

      Result

      6.0% (177/2962) of lung cancers harbored a BRAF-mutation. Median TMB of BRAF non-V600 mutant lung cancers was 10.8 mut/Mb (n=136) overall compared to 4.9 mut/Mb in V600 (n=41; p<0.0001) and 5.9 mut/Mb in BRAF wild-type patients (n=2785; p<0.0001). 69% (127/177) of BRAF-mutant cases were metastatic (29 Class I, 36 Class II, 23 Class III, and 39 VUS). 57% of patients were female, 82% were smokers, and 90% were adenocarcinoma. More smokers were seen in the BRAF V600 group than in the non-V600 group (n = 16 vs 88 respectively, p<0.0001). PD-L1 expression in 49 non-V600 cases with available tissue was 0%, 1-49%, and >50% in 59% (n=29), 31% (n=15), and 10% (n=5) respectively. 7 BRAF V600 cases with PDL1 testing had expression of 0%, 1-49%, and >50% in 2, 3, and 2 cases, respectively. No BRAF V600 cases had concurrent RAS/NF1-alterations compared to 11 non-V600 (p=0.07).

      36 patients with BRAF non-V600 mutations received ICI (nivolumab (n=25), pembrolizumab (n=5), atezolizumab (n=2), ipilimumab/nivolumab (n=4); median line of therapy=2) with an ORR of 22% (8/36). 10 BRAF V600 mutant lung cancer patients received ICI (nivolumab (n=5), pembrolizumab (n=2), atezolizumab (n=1), ipilimumab/nivolumab (n=2); median line of therapy=2) with an ORR of 10% (1/10). There was no difference in ORR between non-V600 and V600 patients that received ICI (p=0.66). TTD in BRAF non-V600 was 3.2 months compared to 1.4 months for BRAF V600 mutant lung cancer patients (HR 0.59, p=0.26). Median TMB in patients with BRAF non-V600 mutations that responded vs those who did not was 13.2 and 10.8 mut/Mb respectively (p=0.92). One response to ICI was seen in a BRAF V600 with TMB of 19.3. OS of BRAF non-V600 patients was 1.7 years compared to 2.5 years in V600 (HR 1.25, p=0.38). OS was higher in BRAF non-V600 lung cancer patients who received ICI (2.4 years) compared to those that did not (1.2 years; HR 0.60, p=0.04).

      Conclusion

      The molecular characteristics and immunophenotype of BRAF non-V600 mutant lung cancers is typified by high TMB and low PD-L1 expression, with reasonably higher response rates and improved OS to later line ICI compared to BRAF V600. Further studies of immunotherapy in this oncogene subset is warranted.

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    P1.12 - Small Cell Lung Cancer/NET (ID 179)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.12-05 - Microenvironment Characterization of Small Cell Lung Cancer Xenografts Implanted in Hematopoietic Humanized Mice (ID 2022)

      09:45 - 18:00  |  Author(s): Charles M Rudin

      • Abstract

      Background

      With the high mutational burden seen in small cell lung cancer (SCLC) there is the theoretical potential to improve SCLC outcome through immunotherapy. Recent immunotherapeutic clinical trials in SCLC have demonstrated promising results. However, to better understand the immune response and the potential role of immunotherapy in SCLC, immunocompetent models are needed. To this end, we have applied a hematopoietic humanized mouse model, Hu-CB-BRGS to investigate the mechanisms underlying SCLC immunotherapy and develop novel strategies to improve therapeutic efficacy.

      Method

      BALB/c-Rag2nulllll2rynullSIRPαNOD (BRGS) pups were humanized through transplantation of cord blood (CB)-derived CD34+ cells. SCLC flank tumors were initiated in BRGS mice using two characterized SCLC cell lines (CDX) and 1 patient derived xenograft (PDX). Upon verification of human T-cell chimerism in the Hu-CB-BRGS mice, SCLC tumors grown in BRGS mice were engrafted into the flanks of Hu-CB-BRGS mice by trocar transfer. Tumor growth was quantified by twice weekly measurement and harvested on reaching 1200 mm3. At harvest, tumor tissue as well as host immune organs (lymph node, spleen) were collected for immunological assessment. Humanized immune system and tumor were evaluated by flow cytometry and immunohistochemistry (IHC).

      Result

      Flank tumors from two CDX tumors (H82 and H187) and one PDX tumor (LX-95) were successfully developed in the Hu-CB-BRGS mice with take rates averaging 82%. SCLC tumor growth rate in Hu-CB-BRGS mice was comparable to that seen in BRGS mice. Although human T cells were well represented in the lymph nodes and spleens of the Hu-CB-BRGS mice, we detected very few tumor infiltrating immune cells in the engrafted SCLC tumors by IHC and flow cytometry as defined by CD45 and CD3, which is consistent with the observations in SCLC patient tumor tissue. Tumor cells, identified by EpCAM expression, expressed low levels of MHC class I, II and PD-L1. PD-1 was expressed by human T cells found in the lymph nodes and spleen of Hu-CB-BRGS mice, while the SCLC xenografts expressed varying levels.

      Conclusion

      We demonstrate that both SCLC PDX and CDX tumors can be grown in the context of a humanized immune system within mouse recipients. SCLC Hu-CB-BRGS mice demonstrate persistence of human immune cells, including T cells and B cells in the immune organs. The xenograft tumor microenvironment included variable human immune infiltrates. The SCLC Hu-CB-BRGS mouse model may be a valuable preclinical platform for testing human specific immune-oncology therapeutics for SCLC patients.

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      P1.12-15 - PET Imaging of [<sup>18</sup>F]PARP Inhibitor as a Pharmacodynamic Biomarker of Talazoparib in Small Cell Lung Cancer PDXs (ID 1794)

      09:45 - 18:00  |  Author(s): Charles M Rudin

      • Abstract

      Background

      Inhibitors of poly-(ADP)-ribose polymerase (PARP) are promising therapeutics for small cell lung cancer (SCLC). We tested whether PARP inhibitor (PARPi) target engagement as measured by a radiolabeled PARP inhibitor ([18F]PARPi) has the potential to predict drug efficacy in vivo.

      Method

      Tumor growth inhibition during daily talazoparib treatment was evaluated in mice engrafted with SCLC patient-derived xenografts to evaluate talazoparib efficacy at multiple doses. Mice were intravenously injected with [18F]PARPi radiotracer at multiple time points after single doses of oral talazoparib to quantitatively assess the extent to which talazoparib could reduce tumor radiotracer uptake and PET/CT activity.

      abstract fig 1.jpg

      Result

      A dose range of talazoparib with differential therapeutic efficacy was established, with significant delay in time to reach 1000 mm3 for tumors treated with 0.3 mg/kg (p=0.02) but not 0.1 mg/kg talazoparib. On PET/CT with [18F]PARPi tumor was among the tissues with the highest radioactivity per gram (1.37 ± 0.15 %ID/g), significantly higher than surrounding lung (0.24 ± 0.05 %ID/g, p = 0.007), bone (0.27 ± 0.05 %ID/g, p = 0.007), and muscle (0.24 ± 0.15 %ID/g, p < 0.002). A reduction in [18F]PARPi uptake after talazoparib dosing was consistent with talazoparib clearance, with reduction in PET activity attenuating over 24 hours. Talazoparib target engagement, measured by maximum tumor PET uptake, increased in a dose dependent manner (3.9% vs. 2.1% ID/g for 0.1 and 0.3 mg/kg at 3 hours post-talazoparib, p=0.003) and correlated with PARP enzymatic activity among individual tumors as measured by total tumor PAR (p=0.04, R=0.62 at 1 hour post-talazoparib).abstract fig 2.jpg

      Conclusion

      [18F]PARPi PET imaging appears to model PARP inhibitor pharmacokinetics, correlates with PARP inhibitor pharmacodynamics as measured by tumor PAR levels, and differs significantly between therapeutic and subtherapeutic doses of talazoparib. PET imaging using [18F]PARPi has the potential to be a powerful tool in treatment monitoring by assessing PARP inhibitor target engagement in real-time.