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Melissa Johnson
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MA21 - Non EGFR/MET Targeted Therapies (ID 153)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:Benjamin Besse, Michael Thomas
- Coordinates: 9/10/2019, 14:30 - 16:00, Vienna (2016)
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MA21.06 - Preliminary Phase 1 Results of U3-1402 — A Novel HER3-Targeted Antibody–Drug Conjugate—in EGFR TKI-Resistant, EGFR-Mutant NSCLC (Now Available) (ID 1720)
14:30 - 16:00 | Author(s): Melissa Johnson
- Abstract
- Presentation
Background
Treatment options are limited for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) resistant to EGFR tyrosine kinase inhibitors (TKIs), in particular osimertinib. Overall, 57%–83% of NSCLC tumors express human epidermal growth factor receptor 3 (HER3). Because signaling through HER3 is not an established mechanism of resistance to EGFR TKIs, treatment with an anti-HER3 antibody–drug conjugate (ADC) presents an approach to targeting diverse resistance mechanisms in EGFR-mutant NSCLC. U3-1402 is a HER3-targeted ADC with a fully humanized antibody, novel cleavable peptide-based linker, and topoisomerase I inhibitor payload. Here, we present the safety/tolerability and antitumor activity data from the dose-escalation phase of an ongoing, multicenter, phase 1 study (NCT03260491).
Method
Patients had locally advanced or metastatic EGFR TKI-resistant, EGFR-mutant NSCLC. Patients with stable brain metastases were eligible. Dose escalation was based on dose-limiting toxicities (DLTs) guided by a Bayesian logistic regression model. U3-1402 was administered every 3 weeks via intravenous infusion. Pretreatment tumor tissue was required for retrospective HER3 immunohistochemistry analysis. Next-generation sequencing analysis was performed on available tumor tissue. Primary objectives included safety, tolerability, and identification of the recommended dose for expansion (RDE).
Result
As of May 2019, 30 patients were enrolled across 4 doses (3.2 [n=4], 4.8 [n=9], 5.6 [n=12], and 6.4 [n=5] mg/kg). Thirteen patients (43%) have discontinued (progressive disease [n=9], clinical progression [n=1], consent withdrawal [n=2], adverse event [AE; n=1]). All 30 patients received prior EGFR TKIs, of which 28 (93%) received prior osimertinib, and 15 (50%) prior chemotherapy. Activating EGFR mutations were reported in all patients (Ex19del: 57%; L858R: 40%; L861Q: 3%). All 25 evaluable tumors demonstrated HER3 expression (median HER3 membrane H-score, 183 [range, 56–290]). History of central nervous system (CNS) metastases was reported in 15 patients (50%). Treatment-emergent AEs were reported in 29 patients (97%; 13 patients [43%] reported grade 3/4). Two DLTs (grade 3 febrile neutropenia and grade 4 platelet count decrease) were reported in 1 patient (5.6 mg/kg) and 3 DLTs (all grade 4 platelet count decrease) in 3 patients (6.4 mg/kg). Of patients with a history of CNS metastases, 9 have progressed (2 with CNS progression; 3 with both CNS and non-CNS progression). One patient without a history of CNS metastasis progressed with new CNS disease. Of 26 efficacy-evaluable patients, 6 had confirmed partial responses (2 each at 4.8, 5.6, and 6.4 mg/kg), including 2 patients with an EGFR C797S mutation. Median best percentage change in sum of diameters (SoD) was −25.7% (range, −82.6% to 13.3%), including decreases in SoD in patients with CDK4 amplification (–25.7% and –17.8%), HER2 amplification (–28.6%), and both CCNE1 amplification and PIK3CA mutation (–28.8%).
Conclusion
U3-1402 demonstrated tolerable safety and antitumor activity in this ongoing study. Antitumor activity of U3-1402 was seen in cancers with EGFR-mediated and other resistance mechanisms. These findings support the hypothesis that targeting HER3 with U3-1402 may provide clinical benefit to patients with EGFR-mutant NSCLC with diverse mechanisms of resistance. RDE evaluation is ongoing.
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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
- Moderators:Sebastian Defranchi, Karen Kelly
- Coordinates: 9/10/2019, 14:30 - 16:00, Dublin (1997)
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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 | Author(s): Melissa Johnson
- Abstract
- Presentation
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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OA04 - Immuno Combinations and the Role of TMB (ID 126)
- Event: WCLC 2019
- Type: Oral Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:Solange Peters, Martin Reck
- Coordinates: 9/08/2019, 15:15 - 16:45, Copenhagen (1980)
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OA04.08 - Discussant - OA04.05, OA04.06, OA4.07 (Now Available) (ID 3743)
15:15 - 16:45 | Presenting Author(s): Melissa Johnson
- Abstract
- Presentation
Abstract not provided
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PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)
- Event: WCLC 2019
- Type: Plenary Session
- Track:
- Presentations: 1
- Now Available
- Moderators:Giorgio Vittorio Scagliotti, Ramon Rami-Porta
- Coordinates: 9/09/2019, 08:00 - 10:15, Barcelona (2005)
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PL02.08 - Registrational Results of LIBRETTO-001: A Phase 1/2 Trial of LOXO-292 in Patients with RET Fusion-Positive Lung Cancers (Now Available) (ID 964)
08:00 - 10:15 | Author(s): Melissa Johnson
- Abstract
- Presentation
Background
No targeted therapy is currently approved for patients with RET fusion-positive non-small cell lung cancer (NSCLC). LOXO-292 is a highly selective RET inhibitor with activity against diverse RET fusions, activating RET mutations and brain metastases. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion-positive NSCLC in August 2018.
Method
This global phase 1/2 study (87 sites, 16 countries) enrolled patients with advanced RET-altered solid tumors including RET fusion-positive NSCLC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. The phase 1 portion established the MTD/RP2D (160 mg BID). The phase 2 portion enrolled patients to one of six cohorts based on tumor type, RET alteration, and prior therapies. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, CNS ORR, CNS DoR, PFS, OS, safety and PK.
Result
As of 17-June 2019, 253 RET fusion-positive NSCLC patients were treated. The primary analysis set (PAS) for LOXO-292 registration, as defined with the US FDA, consists of the first 105 consecutively enrolled RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy; 58 patients (55%) also received prior anti PD-1/PD-L1 agents. The majority of PAS responders have been followed for ≥6 months from first response. Of the remaining 148 patients, 79 had previously been treated with platinum-based chemotherapy, 55 did not receive prior platinum-based chemotherapy and 14 did not have measurable disease at baseline.
Conclusion
Among PAS patients, the investigator-assessed ORR was 68% (95% CI 58-76%, n=71/105, 2 PRs pending confirmation). Responses did not differ by fusion partner or the type or number of prior therapies, including chemotherapy, anti PD-1/PD-L1 agents and multikinase inhibitors with anti-RET activity. The median DoR was 20.3 months (95% CI 13.8-24.0) with a median follow-up of 8 months; as evidenced by the wide confidence interval, this DoR estimate is not statistically stable due to a low number of events (16 of 69 confirmed responders). The intracranial ORR was 91% (n=10/11: 2 confirmed CRs, 8 confirmed PRs) for patients with measurable brain metastases at baseline.
The ORR in efficacy evaluable treatment naïve RET fusion-positive NSCLC patients was 85% (95% CI 69-95%, n=29/34, 7 PRs pending confirmation). In the safety data set of all 531 patients, 5 treatment-related AEs occurred in ≥15% of patients: dry mouth, diarrhea, hypertension, increased AST and increased ALT. Most AEs were grade 1-2. Only 9 of 531 (1.7%) patients discontinued LOXO-292 for treatment-related AEs.
LOXO-292 had marked antitumor activity in RET fusion-positive NSCLC patients and was well tolerated. These data will form the basis of an FDA NDA submission later this year.
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