Virtual Library
Start Your Search
E.S. Santos
Author of
-
+
MA16 - Novel Strategies in Targeted Therapy (ID 407)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:G. Purkalne, J. Von Pawel
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 2
-
+
MA16.12 - Discussant for MA16.09, MA16.10, MA16.11 (ID 6945)
15:32 - 15:44 | Author(s): E.S. Santos
- Abstract
- Presentation
Abstract not provided
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.
-
+
MTE13 - Basic Immunology for the Clinician (Ticketed Session) (ID 307)
- Event: WCLC 2016
- Type: Meet the Expert Session (Ticketed Session)
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 07:30 - 08:30, Schubert 5
-
+
MTE13.02 - Basic Immunology for the Clinician (ID 6563)
08:00 - 08:30 | Author(s): E.S. Santos
- Abstract
- Presentation
Abstract:
Lung cancer remains the number one cause of cancer-related death worldwide. Cancer immunotherapy nowadays has become not only a growing field but also a fascinating area as recent clinical trials have improved both PFS and OS in first line and second line treatment for patients with advanced NSCLC. The idea of immunotherapy in cancer is to modify the host immune system, so cytotoxic T-cells (CTCs) can recognize tumor-associated antigens (TAAs) as abnormal and be destroyed by an immune response. For many decades, we have tried unsuccessfully many vaccines against different lung cancer antigens. It was thought at one point that lung cancer was a non immunogenic tumor very different from melanoma and kidney cancers. Whole-cell vaccines (e.g. belagenpumatucel-L) and antigen-specific vaccines (e.g., CIMAvax, MAGE-A3, L-BPL25) showed just promising results in clinical trials, but failed to significantly improve clinical outcomes [1-4]. The major reason why vaccines failed in lung cancer was due to tumor escape mechanisms from host immune surveillance [5, 6]. One of this mechanisms was recently elucidated, checkpoint pathway. Lung cancer has been found to have high levels of CTLA-4 expression, programmed death-1 (PD-1), PD ligand 1 (PD-L1), B7-H3 and B7-H4 expression on tumor-infiltrating lymphocytes (TILs), and regulatory CD4+ T-cells (Tregs) suggesting that lung cancer is immunogenic. For many years, cancer immunology was centered on the adaptive immune system and T-cell activation. Stimulation of the T-cell response involves antigen presenting cells (APCs), or dendritic cells (DCs), expressing tumor antigens from the tumor microenvironment, which then bind to the T-cell receptor (TCR) on CD4+ or CD8+ T-cells. Meanwhile, B7-1/CD80, or B7-2/CD86 on the APC, bind to CD28 on the T-cell in a costimulatory fashion to stimulate tumor-antigen specific T-cells to proliferate. However, cross talk between APCs and T-cells at the immunological synapse is regulated very closely and can be attenuated. One of this attenuation signal is mediated by CTLA-4, which is also stimulated by CD80 and CD86. Although CTLA-4 and CD28 have the same ligands, CTLA-4 has a much higher affinity for them; hence, T-cell proliferation occurs despite the effects of CTLA-4 because of the intracellular location, short half-life and quick degradation of CTLA-4 [7, 8]. Another example of a tumor immune checkpoint is PD-1 which binds B7-H1/PD-L1 and B7-DC/PD-L2 [9]. By using PD-1 inhibitors, we are able to remove the interaction between PD-1 receptor located in the T-cells and its ligand expressed in the tumor cells which causes inhibitory signaling over the T-cells. Hence, an immune response cannot be mounted. CTLA-4 has been studied in lung cancer in combination with platinum-based doublet (carboplatin/paclitaxel). Outcomes from that study were not enough to grant approval from regulatory entities. However, investigators found better response to CTLA-4 inhibition in patients with squamous cell histology; this population has higher percentage of TILs than their non-squamous counterparts. Why the combined therapy (chemotherapy plus ipilimumab) had limited effect remains unclear. Conversely, studies using PD-1 inhibitors pembrolizumab and nivolumab have shown OS advantage over docetaxel in second line therapy, and more recently, OS and PFS advantage in first line against chemotherapy when tumor cells expressed > 50% of PD-L1 [10]. We also understand that PD-L1 is not the perfect predictive biomarkers so efforts are directed to discover more specific markers which can help us to tailor checkpoint inhibitors in lung cancer. The approval of nivolumab in NSCLC came from two phase III trials CheckMate 017 and CheckMate 057 which studied nivolumab vs docetaxel in second-line for squamous and non-squamous advanced NSCLC, respectively. The CheckMate 017 reached the “trifecta” proving that nivolumab was statistically superior to docetaxel for OS, PFS and response rate (RR). Interestingly, OS benefit was independent of PD-L1 expression. The CheckMate 057 showed OS and RR in favor of nivolumab. There was no difference in PFS between nivolumab and docetaxel in non-squamous NSCLC patients. In this study, PD-L1 expression levels at different cut-off matter for OS. For those patients who had ≥1%, ≥ 5%, and 10%, the hazard ratio (HR) for OS were 0.59 (p < 0.06), 0.43 (p < 0.001), and 0.40 (p < 0.001), respectively. In both studies, nivolumab was well tolerated and had better treatment-related adverse event profile. In case of pembrolizumab, it was KEYNOTE-010 study which proved OS advantage over docetaxel in second line therapy. Herein, pembrolizumab at a dose of 10 mg/kg and 2 mg/kg shown an OS of 12.7 months (HR 0.61; p < 0.001) and 10.4 months (HR 0.71; p < 0.001); OS for docetaxel was 8.5 months. Noteworthy, OS was better in patients whose tumors expressed PD-L1 ≥50%; these patients had an OS of 17.3 and 14.9 months when received pembrolizumab at 10 mg/kg and 2 mg/kg, respectively. Again, grade 3-5 treatment-related AEs were less common for both pembrolizumab doses than for docetaxel. Recently, press release on KEYNOTE-024 phase III study, reported OS in favor of pembrolizumab over platinum-based doublet in first-line therapy for advanced NSCLC patients with PD-L1 expression. The clinical results from KEYNOTE-024 may change the landscape of lung cancer treatment at first-line for advanced NSCLC. Also in development are the PD-L1 inhibitors which affect the interaction between PD-L1 and B7.1 and PD-1 receptor and PD-L2; the later interactions are not affected by PD-1 inhibitors. Atezolizumab and darvulumab have several phase III trials ongoing in first line for advanced NSCLC. Phase II trials for both compounds have shown promising results. The role of PD-L1 as predictive biomarker is still not well defined. PD-L1 expression is a dynamic process and it also varies as part of an adaptive immune resistance exerted by the tumor. There are other possible predictive biomarkers such as higher nonsynonymous mutation burden, molecular smoking signature, higher neo-antigenic burden, DNA repair pathway mutations, high levels of PD-L1 expression, T-helper type 1 gene expression, and others. There is no question that we must continue looking for a better predictive biomarker which can help us to determine the therapeutic benefit of PD-1/PD-L1 inhibitors. References. 1. Nemunaitis J, Dillman RO, Schwarzenberger PO, et al. Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer. J Clin Oncol. 24, 4721–30 (2006). 2. González G, Crombet T, Neninger E, Viada C, Lage A. Therapeutic vaccination with epidermal growth factor (EGF) in advanced lung cancer: analysis of pooled data from three clinical trials. Hum Vaccin. 3(1), 8-13 (2007). 3. Vansteenkiste J, Zielinski H, Linder A, et al. Final results of a multi-center, double-blind, randomized, placebo-controlled phase II study to assess the efficacy of MAGE-A3 immunotherapeutic as adjuvant therapy in stage IB/II non-small cell lung cancer (NSCLC). J Clin Oncol. 25(18S), 7554 (2007). 4. Palmer M, Parker J, Modi S, et al. Phase I study of the BLP25 (MUC1 peptide) liposomal vaccine for active specific immunotherapy in stage IIIB/IV non-small-cell lung cancer. Clin Lung Cancer. 3(1), 49-57 (2001). 5. Gross S, Walden P. Immunosuppressive mechanisms in human tumors: why we still cannot cure cancer. Immunology Letters. 116(1), 7–14 (2008). 6. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 3, 991–8 (2002). 7. Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat immunol 3(7):611-618, 2002. 8. Zang X, Allison JP. The B7 family and cancer therapy: costimulation and coinhibition. Clin Cancer Res 13(18):5271-5279, 2007. 9. Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. CancerI Immunol Immunother 56(5):739-745, 2007. 10. http://www.businesswire.com/news/home/20160616005393/en/Merck%E2%80%99s-KEYTRUDA%C2%AE%C2%A0-pembrolizumab-Demonstrates-Superior-Progression-Free-Survival. Access online September 20, 2016.
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.
-
+
OA10 - EGFR Mutations (ID 382)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
-
+
OA10.07 - Report on Liquid Biopsies from Advanced Lung Adenocarcinoma Patients and Correlation with Their Tumor Biopsy Profiles (ID 4826)
12:05 - 12:15 | Author(s): E.S. Santos
- Abstract
- Presentation
Background:
Liquid biopsy (LBx) has emerged as an alternative tool for the management of advanced lung cancer patients (pts) identifying driver mutations, and hence, improving personalized medicine. There are still controversial issues such as standardization, validation of different technologies, concordance with tissue molecular profile results (TMPR), and others. LBx offers many advantages including non-invasive, bypass tumor heterogeneity, an opportunity for serial measurements to evaluate response or early recurrence, and others.
Methods:
Guardant 360 was analyzed in 100 consecutive stage IV or recurrent lung adenocarcinoma (adeno) pts. Guardant 360 is a panel of 70 genes including single nucleotide variations, amplifications, translocations, and short insertions/duplications/deletions in exons 19 and 20 of the EGFR, and others. Cell-free DNA (cfDNA) is extracted from plasma and genomic alterations are analyzed by massively parallel sequencing of amplified target genes. TMPRs from each subject was obtained or recovered for comparison with their LBx counterparts. TMPRs from this cohort was developed in different CLIA laboratories
Results:
69 pts were females; median age 72 (range, 27-99). 84/100 pts had at least 1 genomic alteration by LBx (range, 1-10). Most common abnormalities found in LBx were: TP53 (37 pts), EGFR (35 pts), NF1 (20 pts), KRAS (12 pts), MET (14 pts). From this 84 pts with + LBx results, 67 pts (80%) had TMPRs for comparison. Main reason for lack of TMPRs: insufficient tumor (19/100; 19%). For comparison between the 2 modalities, we considered all pts with available results in both tests; hence, 81 pts were used to compare tumor biopsy (TBx) vs. LBx. 37 pts out of 81 (46%) had at least 1 similar genomic abnormality found in both TBx and LBx, respectively. Most of the concordance was in EGFR alterations (19/28; 68%). LBx caught 16 additional EGFR genomic aberrations not being identified by TBx. A total of 35 EGFR genomics aberrations were identified in LBx; 16/35 EGFR mutations found in LBx were actionable and 5 of these 16 actionable EGFR mutant cases were only found in LBx not in TBx.
Conclusion:
LBx offers an alternative to identify genomic alterations. Still, insufficient tumor is the major reason for lacking of TMPRs. EGFR mutations are the most common actionable mutations found in LBx; also, it has a high correlation with TBx (68%). LBx identified more gene abnormalities than TBx, and in some cases, the actionable EGFR mutations were found only in LBx sample.
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.
-
+
P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P3.02b-077 - Osimertinib Expanded Access Program for Previously Treated Patients With Advanced EGFR T790M Mutation-Positive NSCLC (ID 4923)
14:30 - 14:30 | Author(s): E.S. Santos
- Abstract
Background:
The US AZD9291 Expanded Access Program (EAP) was conducted to provide compassionate access to osimertinib for previously treated patients with advanced/metastatic, epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC).
Methods:
Patients (≥18 years old) with EGFR T790M mutation-positive NSCLC and a WHO Performance Status of 0–2 who had received ≥1 prior lines of therapy that included an EGFR tyrosine kinase inhibitor (TKI) or progressed during EGFR TKI treatment, were eligible. Patients received osimertinib at 80mg oral, once-daily, until dose reduction, discontinuation or EAP completion following FDA approval (November 2015). Patient demographics, T790M testing, safety and tolerability including serious adverse events (SAEs) were collected. Patient response was collected at investigator discretion, but not mandated by the EAP protocol. For required T790M diagnostics, various testing methods were permitted.
Results:
Osimertinib was provided to 248 EGFR T790M mutation-positive patients through the EAP (May 2015 to November 2015). Of the 244 patients with reported T790M method data, the majority were enrolled based on samples from tissue (n=187) and blood (n=48), whereas others were based on pleural fluid (n=5) or urine (n=4). Use of noninvasive (ie, liquid biopsy) T790M testing varied across the 25 participating sites: 5 sites (20%) enrolled no patients using liquid biopsy, 2 (8%) enrolled all patients based on liquid biopsy, and 18 (72%) enrolled based on different methods. Median age was 65 years old (range, 31–91), 69% of patients were female, and 85% of patients received ≥2 prior cancer treatments. Prior erlotinib therapy was reported in 96% of patients. Starting daily dose of 80mg osimertinib was maintained throughout the study in 238 patients (96%) and reduced to 40mg in 10 patients because of AEs/intolerance. Once commercially available, most patients (n=205; 83%) continued on osimertinib, thus completing the EAP. Reasons for EAP withdrawal prior to conversion included disease progression (7%) or death (5%). A total of 19 (8%) deaths were reported during the EAP, mostly attributed to lung cancer/disease progression and/or respiratory complications (n=16; 84%). Five (2%) patients reported drug-related SAEs, including dyspnea, deep vein thrombosis, femur fracture, increased alanine aminotransferase, and pneumonitis.
Conclusion:
In a real-world setting, US AZD9291 EAP demonstrated that osimertinib was well tolerated in previously treated patients with EGFR T790M mutation-positive NSCLC, and most converted to commercial therapy following FDA approval. This EAP suggests early uptake of non-invasive T790M testing at some centers.
