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H. Koeppen
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MO09 - Mesothelioma I (ID 120)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track:
- Presentations: 1
- Moderators:K. Suzuki, S.G. Armato III
- Coordinates: 10/28/2013, 16:15 - 17:45, Bayside 204 A+B, Level 2
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MO09.01 - Evaluation of tolerability and anti-tumor activity of GDC-0980, an oral PI3K/mTOR inhibitor, administered to patients with advanced malignant pleural mesothelioma (MPM) (ID 1712)
16:15 - 17:45 | Author(s): H. Koeppen
- Abstract
- Presentation
Background
The PI3K-AKT-mTOR signaling pathway is dysregulated in a wide variety of cancers. Pathway activation in mesothelioma may occur through diverse cellular mechanisms, including activation of receptor tyrosine kinases that signal through Ras and PI3K/Akt/mTOR, and loss of PTEN expression. GDC-0980 is a potent and selective oral dual inhibitor of class I PI3K and mTOR kinases that has demonstrated broad activity in various xenograft cancer models.Methods
A phase I dose-escalation study was conducted in 2 Stages: Stage 1 evaluated oral, daily (QD) doses of 2-70 mg GDC-0980 given 21/28 or 28/28 days in a 3+3 dose escalation design. Stage 2 evaluated disease specific cohorts at the recommended phase 2 dose (RP2D), including a MPM cohort at 30 mg GDC-0980 QD 28/28 days. Safety and tolerability of GDC-0980 was assessed as well as pharmacokinetics (PK) and pharmacodynamics (PD) assessment of PI3K pathway inhibition by FDG-PET. Anti-tumor activity was assessed by modified RECIST; CT scans were centrally reviewed retrospectively by a radiologist with MPM expertise. Archival tumor tissue was evaluated for PIK3CA mutation by allele specific PCR or Sanger sequencing and PTEN expression was assessed by immunohistochemistry.Results
33 MPM patients were enrolled: 6 in Stage 1 at 8-70 mg and 27 in Stage 2 at 30mg GDC-0980. Safety and tolerability of GDC-0980 in Stage 1 was similar in MPM compared to other solid tumor patients, with the exception of a Grade 5 pneumonitis that occurred in a MPM patient at 40 mg GDC-0980 QD. Based on Stage 1 tolerability data, a RP2D of 30 mg QD was evaluated in Stage 2 for MPM patients. The most frequent Grade ≥3 drug-related adverse events (AEs) at 30 mg GDC-0980 were rash (19%), with one patient (4%) having to discontinue GDC-0980. Other AEs were fatigue (15%), and hyperglycemia, diarrhea, and colitis (7% each). Reversible Grade 2 pneumonitis was reported for 2 patients (7%). Population PK analysis was used to assess the behavior of GDC‑0980 in MPM patients. Additionally, PK/PD relationships will be discussed for efficacy and safety, including exposure‑response, where appropriate. Archival tissue was analyzed for 29 MPM patients. Two samples had PIK3CA mutations (R88Q and E545G) and one sample showed loss of PTEN expression. PI3K pathway inhibition by FDG-PET responses was observed in 8 of 24 MPM patients with available scans. Anti-tumor activity was observed in both stages. Two patients achieved a partial response (PR) in Stage 1, one patient at 50 mg and one patient with the PIK3CA mutation R88Q at 8 mg GDC-0980. Two PRs were observed at the RP2D of 30 mg in Stage 2. Eleven (41%) MPM patients at the RP2D remained on study for >6 months, and 2 (7%) patients remained on study >12 months.Conclusion
GDC-0980 was generally well tolerated in MPM patients at the RP2D. Anti-tumor activity, evidenced by tumor regression and prolonged disease control, has been observed. PIK3CA mutations and PTEN loss were uncommon.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO19 - Lung Cancer Immunobiology (ID 91)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Biology
- Presentations: 2
- Moderators:Y. Sekido, J. Minna
- Coordinates: 10/30/2013, 10:30 - 12:00, Bayside 201 - 203, Level 2
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MO19.09 - Molecular correlates of PD-L1 status and predictive biomarkers in patients with non-small cell lung cancer (NSCLC) treated with the anti-PDL1 antibody MPDL3280A (ID 1653)
10:30 - 12:00 | Author(s): H. Koeppen
- Abstract
- Presentation
Background
In NSCLC, antitumor immune response may be inhibited by PD-L1 expression. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, aims to restore tumor-specific T-cell immunity by blocking PD-L1 binding to its receptors, PD-1 and B7.1.Methods
Patients with squamous or nonsquamous NSCLC received MPDL3280A IV q3w up to 1 year as part of a phase I dose escalation/expansion study. Objective response rate (ORR) was assessed by RECIST v1.1 and included unconfirmed/confirmed responses. EGFR and KRAS status was initially assessed locally by investigators. Archival tumor tissues were evaluated centrally by IHC for PD-L1 and CD8. A qPCR-based gene expression panel measuring ≈90 immune-related genes was used to characterize the tumor immune microenvironment at baseline and during MPDL3280A treatment.Results
41 NSCLC patients first dosed at 1-20 mg/kg prior to Aug 1, 2012, were evaluable for efficacy with an ORR of 22%. Baseline tumor samples were available for IHC (n=33) and for gene expression analysis (n=29). Of patients with available tissue, 5 were PD-L1 tumor status positive and 28 were PD-L1 tumor status negative. Relationship between PD-L1 status and EGFR/KRAS status is described below (table). Elevated baseline PD-L1 expression was associated with response to MPDL3280A (80% ORR vs 14% ORR for PD-L1negative patients), and PD-L1 expression coordinated with CD8+ T cells. A Th1-type T-cell gene signature (including CD8, Granzyme-B and EOMES) was associated with treatment response. Non-responders exhibited at least a 2-fold higher ratio over CD8 of genes associated with immunosuppression, including RORC, FOXP3, TGFb1 and IL10 compared with responders. On treatment, responding tumors across indications showed increasing PD-L1 expression and a Th1-dominant immune infiltrate, providing evidence for adaptive PD-L1 up-regulation.Conclusion
PD-L1 expression and a Th1 driven T-cell gene signature correlated with response to MPDL3280A in NSCLC, and MPDL3280A therapy led to T-cell reactivation and restored antitumor immunity. Additionally, expression of immune suppressive factors in NSCLC tumors is associated with a lack of benefit from MPDL3280A. These data provide mechanistic insights into immunotherapy and patient selection for MPDL3280A monotherapy. Preliminary observations suggest clinical activity and molecular characteristics may be associated with PD-L1 tumor expression. Updated data will be presented. Table: Relationship between PD-L1 status and EGFR/KRAS mutational statusPD-L1-Positive (n = 5) PD-L1-Negative (n = 28) PD-L1 Unknown (n = 7) Overall (n = 40)* EGFRm, n 1 2 1 4 EGFR WT, n 2 20 4 26 EGFR Unknown, n 2 6 2 10 KRASm, n 1 4 1 6 KRAS WT, n 2 8 3 13 KRAS Unknown, n 2 16 3 21 * 1 patient had missing data. Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO19.10 - Prevalence and prognostic association of PD-L1 protein and immune gene expression in NSCLC (ID 2437)
10:30 - 12:00 | Author(s): H. Koeppen
- Abstract
- Presentation
Background
Programmed Death Ligand 1 (PD-L1, CD274, B7-H1) is an immune checkpoint molecule that binds to the receptors PD-1 and B7.1 on activated T cells. Binding negatively regulates T-cell function in both physiological and pathological conditions. Recent clinical studies have suggested that numerous cancers, including NSCLC, may utilize PD-L1 expression to escape T-cell mediated cytotoxic activity. Inhibition of PD-L1 can restore anti-tumor immunity, leading to clinical responses. A better understanding of PD-L1 expression patterns, co-expression with other immune markers and actionable disease associated biomarkers may provide insight into the future design of cancer immunotherapy trials in NSCLC.Methods
Expression of PD-L1 was measured by immunohistochemistry (IHC) in archival tumors and, in some cases, in paired metastases in 2 FFPE NSCLC tumor tissue collections. Set 1 (N=561) was collected from patients who were eligible for surgery with curative intent from 2003 to 2005 at MD Anderson Cancer Center. The samples from Set 2 (N=300) contained surgically resected NSCLC tissue collected between 2006 and 2011 (UCCC and Norwegian Radium Hospital). PD-L1 expression was analyzed in both malignant and non-malignant cells (e.g., infiltrating immune cells). In addition, a multiplex qPCR assay that measures ≈90 immune-related genes was used to characterize the tumor immune microenvironment in the NSCLC tumor samples. Disease associated biomarkers, including the mutation status of EGFR and KRAS, as well as expression of MET (by IHC) were also evaluated.Results
Prevalence of PD-L1 was comparable between adenocarcinoma and squamous cell carcinoma (≈30% in tumor cells; ≈45% and ≈50%, respectively, in immune cells). PD-L1 prevalence varied depending on the pathological stage, and was higher in Stages I-IIIA than in Stages IIIB-IV. Similarly, the prognostic value of PD-L1 varied by both stage and histology. In adenocarcinoma, tumors with PD-L1–positive tumor cells had a higher frequency of KRAS mutation and high Met expression, and a lower frequency of EGFR mutation compared with PD-L1–negative tumors. In contrast, tumors with PD-L1–positive and PD-L1–negative immune cells had a comparable frequency of high Met expression. Expression of PD-L1 was frequently co-localized with CD8+ T-cell infiltrates. Gene expression profiling revealed differences in the tumor immune environment, including genes associated with cytotoxic T-cells, between adenocarcinomas and squamous cell carcinomas. PD-L1 protein and immune gene expression associations with patient characteristics will be described in further detail.Conclusion
These data provide a comprehensive description of PD-L1 expression in the context of disease biology utilizing large independent cohorts of well-characterized lung cancer tissues. The results highlight the complexity of the tumor immune environment in NSCLC with particular emphasis on the association with factors such as pathological stage, histology and oncogenic mutational status. These analyses may help guide future development of immunotherapy trials in NSCLC.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
