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Aaron Lisberg
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OA03 - Promising Antibody-Drug Conjugate and Cytotoxic Therapy in NSCLC (ID 100)
- Event: WCLC 2020
- Type: Oral
- Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 10:30 - 11:30, Scientific Program Auditorium
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OA03.03 - Datopotamab Deruxtecan (Dato-DXd; DS-1062), a TROP2 ADC, in Patients With Advanced NSCLC: Updated Results of TROPION-PanTumor01 Phase 1 Study (ID 3407)
10:30 - 11:30 | Author(s): Aaron Lisberg
- Abstract
- Presentation
Introduction
Trophoblast cell-surface antigen 2 (TROP2) is a transmembrane glycoprotein that is overexpressed in NSCLC and other solid tumors. DS-1062 is a TROP2 directed ADC comprising a novel topoisomerase 1 inhibitor (exatecan derivative, DXd), a tetrapeptide-based linker, and a TROP2 directed monoclonal antibody. DS-1062 has demonstrated promising safety and antitumor efficacy in an ongoing phase 1 study in patients with advanced/metastatic NSCLC (NCT03401385); the MTD was declared as 8.0 mg/kg. The study was expanded to include 80 patients at 8 mg/kg and 50 patients each at 4 mg/kg and 6 mg/kg. Updated interim results for 133 patients treated at these doses are reported here.
Methods
Eligible patients were aged ≥18 (US) or ≥20 (Japan) years with advanced/metastatic NSCLC refractory to/relapsed from standard treatment, had measurable disease per RECIST v1.1, and had tumor tissue available for retrospective TROP2 analysis (eligible regardless of TROP2 expression level). Primary objectives are identification of the maximum tolerated dose, safety, and tolerability. Secondary objectives include efficacy (including response by blinded independent central review [BICR]), pharmacokinetics, and incidence of antidrug antibodies.
Results
As of June 15, 2020, 133 patients were treated with ≥1 dose of DS-1062 at 4.0 mg/kg (n = 29), 6.0 mg/kg (n = 24), and 8.0 mg/kg (n = 80). Patients received a median of 4 cycles (range, 1-26) of DS-1062 (1 cycle = 21 days). At study entry, 108 (81%) had received prior immunotherapy and 119 (90%) had received prior platinum-based chemotherapy (preliminary); 126 (95%) had stage IV disease; and 117 (88%) and 15 (11%) had nonsquamous and squamous NSCLC, respectively. In 125 response-evaluable patients (≥1 post baseline tumor assessment or discontinued study treatment), 1 had a confirmed complete response (CR; at 6.0 mg/kg) by BICR, and 32 had partial responses (PRs) by BICR (8 PRs in 29 patients at 4.0 mg/kg, 4 PRs in 20 patients at 6.0 mg/kg, and 20 PRs in 76 patients at 8.0 mg/kg); 29 CRs/PRs were confirmed, and 4 are awaiting confirmation. Among 29 confirmed responders, the probability of having an ongoing response at 6 months was >80% (based on the Kaplan-Meier method). Disease control rate (confirmed CR/PR + stable disease) was 79% (95% confidence interval [CI], 60.3%-92.0%) at 4.0 mg/kg, 75% (95% CI, 50.9%-91.3%) at 6.0 mg/kg, and 79% (95% CI, 68.1%-87.5%) at 8.0 mg/kg. Any-grade treatment-emergent adverse events (TEAEs) were reported in 128 patients (96%); most frequent TEAEs (≥30%) included nausea (50%), stomatitis (44%), alopecia (40%), and fatigue (33%). Sixty-four patients (48%) experienced grade ≥3 TEAEs (most frequently dyspnea [5%]). There were 12 patients (9%) with interstitial lung disease adjudicated by an independent adjudication committee as treatment related (1 [4%] at 6.0 mg/kg [G2] and 11 [14%] at 8.0 mg/kg [7 at G1-2 and 4 at G3-5]). Fourteen patients [11%] discontinued treatment because of TEAEs. At data cutoff, 49 patients (37%) remained on study treatment. Updated results will be presented.
Conclusion
DS-1062 demonstrated encouraging antitumor activity across doses in pretreated patients with prior progression on standard treatment, accompanied by a manageable safety profile.
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OA07 - Immuno-biology and Novel Immunotherapeutics from Bench to Bed (ID 228)
- Event: WCLC 2020
- Type: Oral
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/30/2021, 10:30 - 11:30, Scientific Program Auditorium
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OA07.02 - Chair (ID 4230)
10:30 - 11:30 | Presenting Author(s): Aaron Lisberg
- Abstract
Abstract not provided
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P15 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Novel Immunotherapeutics (Phase I) (ID 154)
- Event: WCLC 2020
- Type: Posters
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P15.08 - Phase I Trial of in situ Vaccination With Autologous CCL21-Modified Dendritic Cells (CCL21-DC) Combined With Pembrolizumab for Advanced NSCLC (ID 1648)
00:00 - 00:00 | Presenting Author(s): Aaron Lisberg
- Abstract
Introduction
Effective immunotherapy options are lacking for patients with advanced non-small cell lung cancer (NSCLC) who progress on a programmed cell death-(ligand)1 [PD-(L)1] inhibitor and for those that are epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement positive after progression on tyrosine kinase inhibitor (TKI) therapy. One potential approach to improve immune checkpoint efficacy in these patient populations is to promote cytolytic T cell infiltration into tumors. This can be accomplished via in situ vaccination with functional antigen presenting cells (APCs) which can take advantage of the full repertoire of tumor antigens and convert the tumor into a lymph node-like environment promoting both local and systemic T cell activation. The chemokine CCL21 promotes co-localization of naive T cells and antigen-experienced dendritic cells (DCs) to facilitate T cell activation. Our preclinical studies and phase I trial of intratumoral (IT) administration of DC genetically modified to overexpress CCL21 (CCL21-DC) revealed augmentation of tumor antigen presentation in situ, resulting in effective T cell responses and systemic antitumor immunity. However, increased PD-L1 expression was observed in a subset of patient tumors, suggesting that tumor-mediated impairment of T cell function may be forestalling a more robust CCL21-DC mediated antitumor response. Similarly, improved PD-(L)1 inhibitor efficacy may be possible with enhanced T cell infiltration and augmented APC function following IT CCL21-DC. Therefore, we are conducting a phase I trial, combining IT CCL21-DC with pembrolizumab in patients with advanced NSCLC that are either (1) EGFR/ALK wild-type after progression on a PD-(L)1 inhibitor or (2) EGFR/ALK mutant after progression on TKI therapy.
Methods
This is a phase I, single institution, non-randomized, dose-escalating, multi-cohort trial followed by dose expansion. A maximum of 24 patients (9-12 escalation + 12 expansion) with stage IV NSCLC will be evaluated who have tumors accessible for IT injection and are either (1) EGFR/ALK wild-type after progression on a PD-(L)1 inhibitor or (2) EGFR/ALK mutant after progression on TKI therapy. Three IT injections of autologous CCL21-DC (days 0, 21, 42) will be concurrently administered with pembrolizumab, followed by q3wk pembrolizumab up to 1 year. Primary objective of dose escalation is safety and determination of maximum tolerated dose (MTD) of IT CCL21-DC (5x106, 1x107, or 3x107) when combined with pembrolizumab. Primary objective of dose expansion is objective response rate (ORR) of CCL21-DC at MTD combined with pembrolizumab. Secondary objectives include adverse event profiling and determination of drug target activity by immune monitoring studies. This trial, NCT03546361, is currently open for enrollment.
