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Rebecca S Heist



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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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      MA14.03 - EGFR M+ Subgroup of Phase 1b Study of Telisotuzumab Vedotin (Teliso-V) Plus Erlotinib in c-Met+ Non-Small Cell Lung Cancer (Now Available) (ID 1622)

      15:45 - 17:15  |  Author(s): Rebecca S Heist

      • Abstract
      • Presentation
      • Slides

      Background

      Telisotuzumab vedotin (ABBV-399; teliso-v) is an anti-c-Met antibody conjugated with monomethyl auristatin E, a tubulin polymerization inhibitor. Preliminary activity was reported for the teliso-v + erlotinib combination in c-Met overexpressing (c-MET+) non-small cell lung cancer (NSCLC) patients, with an activating EGFR mutation and for whom prior EGFR TKI failed. We present mature data from the EGFR M+ subgroup of the teliso-v + erlotinib cohort of a phase 1b study (NCT02099058).

      Method

      Teliso-v was administered at 2.4 mg/kg (dose-escalation phase) or 2.7 mg/kg intravenously once every 3 weeks, and erlotinib at 150 mg orally once a day/prior tolerated dose in adult patients with advanced NSCLC. For efficacy analysis, c-Met+ was defined as central lab IHC H-score ≥150 or local lab MET amplification (MET/CEN7 ≥2); EGFR M+ was defined as del19 or L858R by local lab. Pharmacokinetics were assessed. All patients who received teliso-v + erlotinib were evaluated for safety.

      Result

      As of Dec 2018, 42 NSCLC patients received teliso-v + erlotinib; 37 were c-MET+ (36 evaluable: 35 H-score≥150, 1 MET amplified). Median age was 65 years, 25 patients (69%) had ECOG PS 1, 29 (81%) were EGFR M+ (of these: 48% had T790M, 10% had MET amplification, 3% had polysomy, 97% had prior EGFR TKI, 55% 3rd-generation TKI, 69% TKI as last prior therapy, and 62% platinum doublet). All-grade (≥20%) adverse events (AEs) were dermatitis acneiform (38%), diarrhea (36%), peripheral motor/sensory neuropathy (52%; 7% Grade 3), dyspnea, fatigue, hypoalbuminemia (31% each), decreased appetite, nausea (24% each), asthenia, vomiting (21% each). Grade ≥3 (≥10%) AE: pulmonary embolism (14%). Pharmacokinetics of teliso-v for the combination were similar to single-agent teliso-v. The table presents efficacy data.

      Patients with EGFR mutation
      (n=29)

      Objective response rate*, % (95% CI)
      Complete response, n

      34.5 (17.9, 54.3)
      1

      Median duration of response, months
      (95% CI)

      NR
      (2.8, NE)

      Median PFS, months (95% CI)

      NR
      (2.8, NE)

      Median follow-up, months 4
      6-month PFS rate, % (95% CI)

      51 (30, 69)

      Median treatment duration, month (range)
      Teliso-v
      Erlotinib


      3.5 (0.71–10.4)
      5.3 (0.71–25.4)

      Objective response rate by subgroup of interest, n (%)
      Received prior 3rd generation EGFR TKI
      C-met amplified, copy number gain, or polysomy
      EGFR TKI-containing regimen as last-line therapies


      6/16 (37.5)
      5/7 (71.4)
      8/20 (40.0)

      *RECIST version 1.1.

      EGFR, epidermal growth factor receptor; NE, not estimable; NR, not reached; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; TKI, tyrosine kinase inhibitor;

      Conclusion

      These data suggest acceptable safety and promising activity of teliso-v + erlotinib in patients with c-Met+ NSCLC with an activating EGFR mutation and for whom EGFR TKI has failed.

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    MA25 - Precision Medicine in Advanced NSCLC (ID 352)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA25.10 - First-In-Human Phase 1 Study of DS-1062a (TROP2 Antibody-Drug Conjugate) in Patients with Advanced Non-Small Cell Lung Cancer (Now Available) (ID 3854)

      14:30 - 16:00  |  Presenting Author(s): Rebecca S Heist

      • Abstract
      • Presentation
      • Slides

      Background

      DS-1062a is a trophoblast cell-surface antigen 2 (TROP2)-targeting antibody-drug conjugate with Daiichi-Sankyo exatecan derivative (DXd) technology. TROP2 is highly expressed in epithelial cancers, including non-small cell lung cancer (NSCLC), and is associated with poor survival. In preclinical studies DS-1062a showed promising antitumor activity in xenograft mouse models. Updated results from the dose escalation part of a phase 1 study of DS-1062a in patients with advanced NSCLC are reported.

      Method

      This is an ongoing US and Japan dose-escalation/dose-expansion phase 1 study of DS-1062a in patients with unselected NSCLC (NCT03401385). Adult (age ≥20 years [Japan] or ≥18 years [US]) patients with measurable disease per RECIST v1.1 and available tumor for TROP2 measurement were eligible. The primary objectives are to identify the maximum tolerated dose (MTD) and recommended dose for expansion, assess safety and tolerability. Endpoints include safety, efficacy, pharmacokinetics, and molecular and genomic analyses.

      Result

      At most recent data cutoff (April 12, 2019) 39 patients with advanced NSCLC were treated with DS-1062a at doses of 0.27 (n=4), 0.5 (n=5), 1.0 (n=7), 2.0 (n=6), 4.0 (n=6), 6.0 (n=8) and 8.0 (n=3) mg/kg. Overall, patients were exposed to a median (range) of 3.0 (1–10) treatment cycles over a duration of 8.86 (3.0–31.1) weeks. Patient disposition included dose interruption (n=2), reduction (n=1) and discontinuation (n=23; primary reason was progressive disease (PD) per RECIST in 13/23 patients). The majority (87.2%; 34/39) of patients reported ≥1 treatment-emergent adverse event (TEAE), regardless of severity or causality; the most common (in ≥30% of patients) were fatigue (33.3%) and nausea (30.8%). Grade ≥3 TEAEs were reported in 41.0% (16/39) of patients, of which 12.5% (2/16) were considered drug related. Drug-related TEAEs occurred in 59.0% (23/39 [21/23 grade 1 or 2], and serious TEAEs in 25.6% (10/39 [n=8 grade 3 (n=1 grade 5/sepsis/6.0-mg/kg dose; n=1 grade 3/drug-related/maculopapular rash/6.0-mg/kg dose; n=1 grade 2/drug-related/pyrexia/4.0-mg/kg dose) of patients. One DLT (maculopapular rash, grade 3; resolved) occurred with the 6.0-mg/kg dose; the MTD has not been reached. Of tumor-evaluable patients, as of May 23, 2019, 10 partial responses (PR) were observed (7 PRs were observed at the April 12, 2019 datacut), with a clear dose response and good durability: n=1 in the 2mg/kg, n=2 in the 4-mg/kg, n=3 in the 6 mg/kg, and n=4/5 evaluable in the 8.0-mg/kg groups (4 of the PRs remain to be confirmed). Across all dose groups (April 12, 2019 datacut), 16 stable disease (SD), and 11 PD were observed. Systemic DS-1062a exposure increased in an approximate dose-proportional manner; plasma DS-1062a levels and total anti-TROP2 antibody were similar, suggesting DS-1062a stability in circulation. Updated tumor response profile and durability, biomarker analyses and correlation with clinical outcome will be presented, including immunohistochemistry and circulating tumor DNA analysis of baseline and sequential on-treatment samples, and other related markers.

      Conclusion

      DS-1062a was well tolerated and 10 PRs were observed during dose selection in unselected NSCLC patients having progressed on standard of care, including immune checkpoint inhibition in 8 of 10 patients. Updated data will be presented.

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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  |  Author(s): Rebecca S Heist

      • 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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