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Anna F Farago

Moderator of

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    MS14 - Molecular Subsets and Novel Targeted Approaches to Small Cell and Neuroendocrine Cancers (ID 77)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 5
    • Now Available
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      MS14.01 - Molecular Subsets of Neuroendocrine Tumors (Now Available) (ID 3519)

      11:30 - 13:00  |  Presenting Author(s): Christine Lee Hann

      • Abstract
      • Presentation
      • Slides

      Abstract

      Small cell lung cancer (SCLC) is an aggressive tumor with one of the highest case-fatality rates among cancer. Clinically SCLC is hallmarked by early metastatic behavior and rapid development of therapeutic resistance. Over the past decades multiple research teams have used genomic, epigenomic, transcriptomic and proteomic approaches to further characterize SCLC. Long considered a relatively homogeneous tumor, these data have led to a deeper understanding of SCLC biology and support the concept that there are distinct biologic subsets of SCLC. Complementary work using patient-derived xenografts and genetically engineered mouse models have validated some of this data and these models serve as platforms for novel therapeutic development. These studies support translational efforts in SCLC focused on distinct vulnerabilities in subsets of this disease and the development of predictive biomarkers.

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      MS14.02 - Subclonal Architecture and Genomic Evolution of SCLC (Now Available) (ID 3520)

      11:30 - 13:00  |  Presenting Author(s): Jinghui Wang

      • Abstract
      • Presentation
      • Slides

      Abstract

      Small cell lung cancer (SCLC) accounts for 15-20% of all of lung cancer worldwide and it is a highly aggressive and rapidly progressive tumor with rapid growth speed and strongly associated with smoking. SCLC is divided to limited disease and extensive disease. The staging systems for SCLC are Veterans Administration scheme (VA), the AJCC TNM staging systemand NCCN staging, among of these VA is most commonly used. In recent several decades, chemotherapy combined radiotherapy is the main treatment for SCLC. The overall survival (OS) in patients with limited disease-SCLC and extensive disease were 15-18 months and 10-12 months, respectively. Immunotherapy is becoming a promising treatment for SCLC nowadays.

      Targeted therapy based on genotyping in non-small cell lung cancer is a main treatment. However, targeted therapy in SCLC is not successful and studies on the genomic evolution of SCLC are rare. ctDNA (circulating cell-free tumor DNA) is a good tool for monitoring the genomic changing in patients with malignant tumors, especially for monitoring acquired resistance of targeted therapy. ctDNA and CTCs are useful for genomic evolution of cancer. However, isolation and identification of CTCs are not satisfied in lung cancer, though there are more CTCs in small call lung cancer because of tumor cells are more easily to shed to blood stream in SCLC. ctDNA can provide more accurate genomic landscape of SCLC through overcome heterogeneity.

      We conducted a study that aimed to explore the genomic structure and gene evolution pattern of SCLC using next-generation sequencing and who had been followed by dynamic samples after chemotherapy or/and radiotherapy. We found that TP53 and RB1 are the most common mutations in SCLC, and NOTCH1-4, CREBBP, EG300, MYC, MYCL1, and MYCN are also frequently mutated genes and copy number alterations. We also compared the tissue and blood ctNDA genome and we found that a majority of mutations detected in tumor DNA were also detected in paired ctDNA samples suggesting ctDNA sequencing is sensitive and reliable for detecting mutations in SCLC patients. We used the average VAF (Variant allelic frequencies) of mutations from the major clones as a surrogate for overall ctDNA level. We found higher median ctDNA level was associated with shorter progression-free survival (PFS) and overall survival (OS). Dynamic ctDNA levels are correlated with tumor measurements on imaging suggesting that ctDNA sequencing has the potential for monitoring the clinical course of SCLC. The genomic profiles derived from pre-treatment ctDNA to the genomic profiles from ctDNA at different time points during treatment from post-treatment plasma samples available. Some new mutations that were not exist in pre-treatment blood samples.

      Immunotherapy is an important method for lung cancer. PD-L1 expression and tumor mutation burden (TMB) are two common predictors for immunotherapy. In our cohort, tumor mutation burden is not higher based on the large gene panel. PD-L1 expression is about more than 10% in SCLC. The treatment for SCLC is still highly challenging. TMB based on ctDNA is worth further investigation on predicting SCLC immunotherapy. A previous study showed that SCLC with high TMB had a better response to checkpoint inhibitors. Shedding of ctDNA is a complicated process affected by many factors. With the technique development and increasing understanding of tumor biology, the genome of SCLC will be a useful tool for guiding the treatment and predicting the prognosis of SCLC in the future.

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      MS14.03 - Targeting Transcription (Including Lurbinectedin) (Now Available) (ID 3521)

      11:30 - 13:00  |  Presenting Author(s): Manuel Cobo

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS14.04 - Targeting DNA Damage and Repair (Now Available) (ID 3522)

      11:30 - 13:00  |  Presenting Author(s): Charles M Rudin

      • Abstract
      • Presentation
      • Slides

      Abstract

      Genomic profiling of small cell lung cancer has revealed nearly universal inactivation of the key tumor suppressor genes TP53 and RB1. Loss of these critical regulators of cell cycle entry and DNA damage response together results in selective sensitivity to DNA damaging agents, inhibitors of DNA damage repair, and inhibitors of the remaining late phase cell cycle checkpoints. Multiple preclinical studies and recent clinical data nominate these pathways as potential synthetic lethal vulnerabilities in small cell lung cancer. Recent study has also demonstrated that targeting DNA damage response can activate the anti-tumor immunity and potentiate the response of immune checkpoint blockade antibodies. This talk will review these recent studies, focusing on opportunities and future directions in investigational therapy for patients with small cell lung cancer.

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      MS14.05 - DLL3 Targeting Agents (Now Available) (ID 3523)

      11:30 - 13:00  |  Presenting Author(s): John T Poirier

      • Abstract
      • Presentation
      • Slides

      Abstract

      Delta-like ligand 3 (DLL3) is a single-pass transmembrane Notch ligand that interacts with full-length, unprocessed NOTCH1 in the Golgi apparatus, inhibiting the pathway in cis. DLL3 is selectively overexpressed in the subtype of small cell lung cancer (SCLC) driven by the transcription factor ASCL1 (SCLC-A) that accounts for ~70% percent of SCLC diagnoses (95% CI [60 – 79])1. In one study immunoreactivity was observed in 1,040/1,363 (70.4%) of SCLC specimens, consistent with this incidence2. Overexpression of DLL3 leads to low-level cell surface expression of the protein on the order of 10,000 proteins per cell while expression in normal tissues is restricted to intracellular compartments: the same study demonstrated only low to moderate cytoplasmic or nuclear immunoreactivity in normal adult tissues3. High expression of DLL3 has also been reported in low-grade glioma4,5, neuroendocrine prostate6, and occasionally in other cancer types when neuroendocrine features are present7,8. The exquisitely selective expression of surface DLL3 on cancer cells presents an attractive target for a variety of therapeutic strategies.

      Rovalpituzumab teserine (Rova-T; SC16LD6.5) is an antibody drug conjugate consisting of a monoclonal antibody targeting DLL3, a cathepsin-cleavable linker, and a pyrrolobenzodiazepine (PBD) warhead4. The first-in-human clinical trial of Rova-T in recurrent SCLC demonstrated
      encouraging activity despite often severe side-effects attributable to the PBD warhead9; however, the phase 2 TRINITY study showed a disappointing 16% objective response rate while reporting a similar toxicity profile (NCT02674568). Subsequently, the phase 3 TAHOE study was halted due to shorter overall survival in the treatment arm. An active phase 3 trial of Rova-T in the maintenance setting (MERU) is ongoing (NCT03033511).

      Other DLL3-targeting therapies under active investigation include the bispecific T cell engager (BiTE) AMG 757 (NCT03319940), and a chimeric antigen receptor CAR-T AMG119 (NCT03392064). These agents have shown significant anti-tumor activity in preclinical models of SCLC; however, AMG 119 required direct delivery of the engineered T cells for activity. AMG 757 was therefore the more potent of the two strategies in preclinical models and may therefore be better suited to overcome known barriers to CAR-T activity in solid tumors.

      Alternative strategies remain under exploration including the use of 89Zr-SC16, a PET radiotracer, for in vivo imaging and as a companion diagnostic to optimize the selection of patients for treatment with DLL3-directed therapeutic agents. 89Zr-labeled-SC16 antibody successfully delineated normal tissue from subcutaneous and orthotopic SCLC tumor xenografts. Radiotracer accumulation in tumors was directly correlated with the degree of DLL3 expression and, also correlated with response to SC16LD6.5 therapy in SCLC patient–derived xenograft models.

      1 Rudin, C. M. et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer 19, 289-297, doi:10.1038/s41568-019-0133-9 (2019).
      2 Huang, R. S. P. et al. Delta-like Protein 3 Prevalence in Small Cell Lung Cancer and DLL3 (SP347) Assay Characteristics. Arch Pathol Lab Med, doi:10.5858/arpa.2018-0497-OA (2019).
      3 Sharma, S. K. et al. Non-invasive Interrogation of DLL3 Expression in Metastatic Small Cell Lung Cancer. Cancer Res, doi:10.1158/0008-5472.CAN-17-0299 (2017).
      4 Saunders, L. R. et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med 7, 302ra136, doi:10.1126/scitranslmed.aac9459 (2015).
      5 Spino, M. et al. Cell Surface Notch Ligand DLL3 is a Therapeutic Target in Isocitrate Dehydrogenase-mutant Glioma. Clin Cancer Res 25, 1261-1271, doi:10.1158/1078-0432.CCR-18-2312 (2019).
      6 Puca, L. et al. Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Sci Transl Med 11, doi:10.1126/scitranslmed.aav0891 (2019).
      7 Koshkin, V. S. et al. Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target. Clin Cancer Res 25, 210-221, doi:10.1158/1078-0432.CCR-18-1278 (2019).
      8 Ding, X., Li, F. & Zhang, L. Knockdown of Delta-like 3 restricts lipopolysaccharide-induced inflammation, migration and invasion of A2058 melanoma cells via blocking Twist1-mediated epithelial-mesenchymal transition. Life Sci 226, 149-155, doi:10.1016/j.lfs.2019.04.024 (2019).
      9 Rudin, C. M. et al. Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study. Lancet Oncol 18, 42-51, doi:10.1016/S1470-2045(16)30565-4 (2017).

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Author of

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    MA09 - EGFR & MET (ID 128)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA09.07 - Activity of Larotrectinib in TRK Fusion Lung Cancer (Now Available) (ID 1600)

      15:15 - 16:45  |  Presenting Author(s): Anna F Farago

      • Abstract
      • Presentation
      • Slides

      Background

      Tropomyosin receptor kinase (TRK) fusions involving NTRK1, NTRK2, and NTRK3 occur in a range of tumor types. Larotrectinib, the first FDA-approved highly selective TRK inhibitor, has demonstrated an overall response rate (ORR) of 75% by independent central review across a broad spectrum of tumors that harbor NTRK gene fusions (Drilon et al., NEJM 2018;378:731–9). Here, we report updated data on the patients with lung cancer who have been treated with larotrectinib.

      Method

      Patients with non-small cell lung cancer (NSCLC) in two clinical trials (NCT02122913 and NCT02576431) with TRK fusion cancer were included in this analysis. Larotrectinib (100 mg BID) was administered on a continuous 28-day schedule until withdrawal, unacceptable toxicity, or disease progression. Response was assessed by investigator (INV) and independent review committee (IRC) per RECIST v1.1.

      Result

      As of July 30, 2018, 11 patients with metastatic lung adenocarcinoma were enrolled. Median age was 52 years (range 25–76 years). Eight patients had fusions involving NTRK1 and diverse fusion partners: EPS15 (n=2), TPM3 (n=2), IRF2BP2 (n=2), TPR (n=1), and SQSTM1 (n=1). Three patients had fusions involving NTRK3 (fusion partner: SQSTM1 [n=2] and ETV6 [n=1]). Ten patients had prior systemic therapy (five patients had three or more prior therapies) with best responses on last prior therapy being one partial response, four with stable disease, three progressive disease, and three unknown or unevaluable. Seven patients were evaluable for response to larotrectinib. INV and IRC assessment were in agreement, with one complete response, four partial responses (including one patient with central nervous system [CNS] metastases), and two with stable disease (ORR 71%). Results from four patients not evaluable at the July 30, 2018 data cut-off due to insufficient follow-up are expected in April 2019 and will be presented at the meeting. The median time to response was 1.8 months. One patient with brain metastases had an intracranial near complete response (–95% reduction) to larotrectinib, as well as an extracranial response. The duration of response by IRC ranged from 7.4+ months to 25.8+ months; the median duration of response was not reached. One patient continued receiving treatment post-progression. Two patients discontinued treatment due to disease progression and one withdrew without cause. Larotrectinib was well tolerated, with treatment-related adverse events being predominantly grade 1–2.

      Conclusion

      Larotrectinib is highly active in advanced lung cancer patients harboring NTRK gene fusions, including those with CNS metastases, with a favorable safety profile. These results support the use of larotrectinib in NTRK fusion NSCLC.

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    MA14 - The Adequate MTarget Is Still the Issue (ID 140)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA14.02 - Entrectinib in Patients with ROS1-Positive NSCLC or NTRK Fusion-Positive Solid Tumors with CNS Metastases (Now Available) (ID 1631)

      15:45 - 17:15  |  Author(s): Anna F Farago

      • Abstract
      • Presentation
      • Slides

      Background

      Entrectinib potently inhibits kinases encoded by NTRK and ROS1 genes. It achieves therapeutic levels in the CNS with antitumor activity in intracranial tumor models. We report integrated analysis data (31 May 2018 data cut-off) from three Phase 1/2 entrectinib trials (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]) for a large cohort of adult patients with NTRK fusion-positive solid tumors (NTRK+) or ROS1 fusion-positive NSCLC (ROS1+), with baseline CNS metastases.

      Method

      Patients had locally advanced/metastatic NTRK+ solid tumors or ROS1+ NSCLC by nucleic acid-based assays confirmation. Baseline CNS metastases were identified by CT/MRI. Tumor assessments were performed at baseline, week 4, and then every 8 weeks by blinded independent central review (RECIST v1.1). Primary endpoints were overall response rate (ORR), duration of response (DOR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), intracranial efficacy in patients with CNS metastases, safety.

      Result

      Most patients were treated first-line or after one line of prior therapy; baseline characteristics relating to measurable CNS metastases for patients with NTRK+ solid tumors and ROS1+ NSCLC are presented (Table). Intracranial outcomes for the NTRK+ solid tumors (n=54; 18% NSCLC) and ROS1+ NSCLC (n=53) efficacy evaluable populations are reported (Table). Durability of treatment effect and potential delayed progression in the CNS was observed; time to CNS progression was 17.0 months (95% CI: 14.3–NE) for NTRK+ solid tumor patients and NE (95% CI: 15.1–NE) for ROS1+ NSCLC. In the subset of patients with NTRK+ NSCLC (n=10), 6 patients had CNS metastases at baseline (by BICR); IC-ORR was 66.7% (4/6), 2 CR; IC-DOR was NE. In both the NTRK+ and ROS1+ populations, entrectinib was tolerable with a manageable safety profile; most treatment-related AEs were grade 1–2.

      Conclusion

      Entrectinib induced clinically meaningful durable responses in patients with NTRK+ solid tumors or ROS1+ NSCLC with CNS disease at baseline.

      Funding: This study was funded by F. Hoffmann-La Roche

      table.jpg

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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: 1
    • 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

      • 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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