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Aaron Lisberg
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EP1.04 - Immuno-oncology (ID 194)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.04-20 - Phase I Trial of in Situ Vaccination with Autologous CCL21-Modified Dendritic Cells (CCL21-DC) Combined with Pembrolizumab for Advanced NSCLC (Now Available) (ID 1888)
08:00 - 18:00 | Presenting Author(s): Aaron Lisberg
- Abstract
Background
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 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 some patient tumors, suggesting that tumor-mediated impairment of T cell function may be forestalling a more robust 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.
Method
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, 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.
Result
Section not applicable
Conclusion
Section not applicable
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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): Aaron Lisberg
- 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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P1.04 - Immuno-oncology (ID 164)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.04-33 - Deep Phenotyping of Immune Populations Reveals Baseline Predictors of Pembrolizumab Efficacy in NSCLC on KEYNOTE-001 (Now Available) (ID 2292)
09:45 - 18:00 | Author(s): Aaron Lisberg
- Abstract
Background
Medical treatment of lung cancer has irreversibly changed since the development of immune checkpoint inhibitors like pembrolizumab. However, immune biomarkers of efficacy are still lacking. Preliminary data in melanoma showed that a high baseline blood level of classical monocytes was associated with improved outcome in patients treated with programmed cell death-1 (PD-1) inhibitors. This led us to explore the immune landscape of non-small cell lung cancer (NSCLC) patients treated with pembrolizumab on KEYNOTE-001 using high-dimensional mass cytometry.
Method
We analyzed 38 advanced NSCLC patients treated with pembrolizumab on KEYNOTE-001 at UCLA. Mass cytometry (CyTOF) was performed on baseline peripheral blood mononuclear cells (PMBC). We used a panel of 31 antibodies defining major immune populations of myeloid cells (plasmacytoid and myeloid dendritic cells, myeloid-derived suppressor cells, classical and CD16+ monocytes), lymphoid cells (B cells, NK cells, TReg, γδ T-cells, sub-populations of CD4+ and CD8+ T-cells), selected co-stimulatory (CD28, ICOS, 41BB), co-inhibitory molecules (PD-1, PD-L1, TIM3, LAG3, CTLA-4) and cytotoxicity molecules (perforin, granzymeB). Unsupervised clustering combined with predictive regression model (Citrus algorithm, false discovery rate = 1%) was used to detect immune populations differing between patients that experienced an objective response on trial, as assessed by immune-related response criteria (responders) vs those that did not (non-responders). Classical manual gating (FlowJo software) was used to confirm the Citrus results.
Result
Among the 38 patients analyzed via CyTOF, 27 patients had sufficient viable cells for analysis. Citrus algorithm comparing responders (n=7) and non-responders (n=20) revealed significant frequency differences in specific subtypes of three immune populations: monocytes, CD4+ and CD8+ T-cells. Manual gating confirmed that responders (vs non-responders) had increased frequency (%CD45+) of classical monocytes perforin+ granzymeB+ (5.54% vs 2.55%, p=0.029), central memory CD4+ T-cells ICOS+ CD28+ PD1+ (1.29% vs 0.83%, p=0.06) and over-expression of 41BB (mean metal intensity (MMI)=0.15 vs MMI=0.09, p=0.006) and perforin (MMI=108.4 vs MMI=70.7, p=0.004) in effector memory CD8+ T-cells.
Conclusion
Mass cytometry in the blood reveals that a high baseline frequency of activated and cytotoxic monocytes, CD4+ and CD8+ T-cells predicted for pembrolizumab efficacy in advanced NSCLC. Preliminary analyses correlating immune cell populations and overall survival are ongoing and suggest a similar increase in the three immune cell populations found to be higher in responders vs non-responders.
