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C. Butts
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MS 04 - Harnessing the Full Potential of the Immune System (ID 22)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 4
- Moderators:C. Butts, P. Forde
- Coordinates: 9/07/2015, 14:15 - 15:45, Four Seasons Ballroom F3+F4
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MS04.01 - PD1/PDL1 Studies (ID 1860)
14:20 - 14:40 | Author(s): R. Herbst
- Abstract
- Presentation
Abstract not provided
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MS04.02 - Other Immune Inhibitors (ID 1861)
14:40 - 15:00 | Author(s): N.A. Rizvi
- Abstract
- Presentation
Abstract not provided
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MS04.03 - Vaccines (ID 1862)
15:00 - 15:20 | Author(s): J. Vansteenkiste
- Abstract
- Presentation
Abstract:
Cancer immunotherapy in a broad sense is any interaction with the immune system to treat cancer. One approach is non-antigen-specific modulation of the immune system. Historical examples with e.g. BCG, interferon, interleukins, were disappointing in lung cancer. More recently, specific antibodies against the Programmed Death 1 (PD-1) receptor or its ligands (PD-L1) have delivered exciting results, with major patient benefits in randomised controlled trials (RCTs) in relapsing NSCLC {Brahmer, 2015 19949 /id}. Antigen-specific immunotherapy aims at specific priming of immune system to recognize the tumour as foreign, thereby generating specific antibodies and/or cytotoxic T cells. This is “therapeutic cancer vaccination (TCV)”. Conditions for optimal TCV are: 1/ specificity (well-defined target antigen(s) in the tumour, not in other tissues); 2/ selectivity (use in the population expressing the target); 3/ immunogenicity (interaction with antigen leads to effective humoral and/or cellular response); 4/ tumour sensitive to immune kill in order to obtain improvement in patients’ outcome. Better knowledge of tumour immunity has led to encouraging data in phase II RCTs with several TCVs, which then have entered large phase III trials. Examples are the MAGE-A3 vaccine studied in resected early stage NSCLC, the BLP-25 vaccine in locally advanced NSCLC after chemoradiotherapy, and e.g. belagenpumatucel-L and the TG4010 vaccine in advanced stage NSCLC. The MAGE-A3 protein is totally tumour-specific and present in about 35% of early stage NSCLC. In the hypothesis generating double-blind, randomized, placebo-controlled phase II study, 182 patients with completely resected MAGE-A3-positive stage IB-II NSCLC received recombinant MAGE-A3 protein combined with an immunostimulant (13 doses over 27 months) or placebo (2). No significant toxicity was observed. There was a 24% – non-significant – improvement in disease-free survival (DFS, HR 0.76; 95% CI 0.48 to 1.21). The ensuing large phase III study MAGRIT (MAGE-A3 as Adjuvant Non-Small Cell LunG cancer ImmunoTherapy) was reported at the ESMO 2014 meeting (3). MAGE-A3 positive patients with completely resected stage IB-II-IIIA NSCLC and adjuvant chemotherapy as clinically indicated, were randomly 2:1 assigned to receive MAGE-A3 vaccine or placebo. Almost 14,000 surgical patients were screened, 4210 patients were MAGE-A3 positive (33%), and 2312 patients were randomised. The median DFS (primary endpoint) was slightly better with MAGE-A3 (60.5 versus 57.9 months), but the difference was unfortunately not significant (Hazard Ratio, HR, 1.02, 95%CI: 0.89, 1.18, P=0.74). No subgroups with potential benefit could be identified. Based on this disappointing result, further development of the MAGE-A3 vaccine in NSCLC has been abandoned. Mucins like the MUC1 protein are present in many epithelia, but MUC1 expression is altered (mainly by aberrant glycosylation) in many cancer types, including NSCLC. The tandem repeat MUC1-peptide liposomal vaccine BLP-25 has been studied in patients with stage IIIB-IV NSCLC (4). While overall survival (OS) was not significantly different in the total group, a challenging effect was observed in stage IIIB patients (HR 0.524; 95%CI 0.261-1.052). This led to START (Stimulating Targeted Antigenic Responses to NSCLC Trial), a phase III, double blind, RCT comparing maintenance therapy with Tecemotide (n=829) or placebo (n=410) in patients with unresectable stage III NSCLC who did not progress after sequential or concurrent chemo-radiotherapy (5). The primary endpoint – OS – was not significantly different between the vaccine and placebo group (25.6 and 22.3 months). However, pre-planned subgroup analysis showed that the patients treated with concurrent chemoradiotherapy (N=829) had a 10.2-month improvement in OS (30.8 versus 20.6 months, adjusted HR 0.78, P=0.016). The consequential trial was START 2, a similar large RCT in patients who completed concurrent chemoradiotherapy for unresectable stage III NSCLC (NCT02049151). However, this RCT and further development of Tecemotide was abandoned after disappointing results of a smaller trial in Japanese patients with stage III NSCLC and concurrent chemoradiotherapy. Belagenpumatucel-L is a vaccine based on a mixture of allogeneic tumour cells with TGF-β2 antisense blockade as adjuvant. A phase III trial in patients with stage III-IV NSCLC in disease control after first-line therapy was reported at the 2013 ESMO meeting (STOP, NCT00676507) (6). Patients without progression after 1[st] line chemotherapy, were randomly assigned to intradermal belagenpumatucel-L (N=270) versus placebo (N=262)for 24 months. Median OS was 20.3 months with belagenpumatucel-L versus 17.8 months with placebo (HR 0.94, p=0.594). In subgroup analysis of patients randomized <12 weeks after the last chemotherapy, the HR of the median OS was 0.77 (P=0.092). For patients enrolled within 12 weeks and treated with previous radiotherapy, the HR was HR 0.45 (P=0.014). The vaccine was well tolerated with mainly mild local administration side-effects. TG4010 is a vaccine based on a recombinant viral vector (attenuated strain of vaccinia virus) expressing both the tumour-associated antigen MUC1 and interleukin-2. This vaccine is explored in the phase IIB/III RCT TIME trial (NCT01383148). This double-blind, placebo-controlled trial evaluates standard first-line chemotherapy with or without TG4010 in MUC1-positive stage IV NSCLC patients. In the phase IIB part, the predictive value of activated NKs (TrPAL: triple positive activated lymphocytes) was evaluated based on a PFS endpoint, and reported in an interim report at the 2014 ESMO meeting (7). Based on a Bayesian analysis, the predefined endpoint of a HR <1 in the patients with low level of NK cells was met. The PFS was not significantly different between vaccine and placebo (HR 0.78, 95%CI 0.55-1.10]. In subgroup analyses, the effect was more pronounced in patients with non-squamous NSCLC (HR 0.71, 95CI 0.51-0.97) than in squamous histology. Therefore, a decision was made to continue the phase III part of the trial in non-squamous NSCLC only, with OS a the primary endpoint. References 1. Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus docetaxel in advanced squamous cell non-small cell lung cancer. N Engl J Med 2015; on-line May 31. 2. Vansteenkiste J, Zielinski M, Linder A et al. Adjuvant MAGE-A3 immunotherapy in resected non-small cell lung cancer: Phase II randomized study results. J Clin Oncol 2013;31:2396-2403. 3. Vansteenkiste JF, Cho BC, Vanakesa T et al. MAGRIT, a double-blind, randomized, placebo-controlled phase III study to assess the efficacy of the recMAGE-A3 + AS15 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small cell lung cancer (NSCLC). Ann Oncol 2014; 25 Suppl 4: abstract 1173O. 4. Butts C, Murray N, Maksymiuk A et al. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small cell lung cancer. J Clin Oncol 2005;23:6674-6681. 5. Butts C, Socinski MA, Mitchell PL et al. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): A randomised, double-blind, phase 3 trial. Lancet Oncol 2014;15:59-68. 6. Giaccone G, Bazhenova L, Nemunaitis J et al. A phase III study of belagenpumatucel-L therapeutic tumor cell vaccine for non-small cell lung cancer (NSCLC). Eur J Cancer 2013; 47 Suppl 2: abstract LBA 7081. 7. Quoix E, Losonczy G, Forget F et al. TIME, a phase 2B/3 study evaluating TG4010 in combination with first-line therapy in advanced non-small lung cancer (NSCLC). Phase 2B results. Ann Oncol 2014; 25 Suppl 4: abstract 1055PD.
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MS04.04 - Microenvironment as a Target (ID 1863)
15:20 - 15:40 | Author(s): S. Albelda
- Abstract
- Presentation
Abstract:
The traditional approaches to lung cancer therapy have focused on treating the malignant epithelial cancer cells within the tumor. However, it is now realized that in most cases, most of the tumor consists of “supporting cells” that include endothelium, pericytes, fibroblasts, and a variety of innate and acquired (B cells and T cells) immune cells. Thus, targeting these non-tumor cells could be an alternative therapeutic strategy. This concept is already being used in clinical practice. One example is targeting the endothelial cells within the tumor using an anti-VEGF antibody (bevacizumab). Another example are the checkpoint inhibitors (anti-CTLA4 and anti-PD1 antibodies) that target endogenous T cells. However, it may also be possible to attack other targets such as macrophages, Tregs, neutrophils or cancer-associated fibroblasts (CAFs). Tumor-associated macrophages represent one target. These cells take on a tumor-supportive phenotype and produce anti-inflammatory cytokines/chemokines (i.e. TGFbeta, PGE2, IL10, VEGF), arginase (which inactivates T cells), and angiogenic factors. This has led to the hypothesis that changing the state of the macrophage to an anti-tumor phenotype in which immune-activating mediators would be made and antigen-presentation could be enhanced would have direct anti-tumor activities and would allow endogenous T cells to kill tumor cells. Macrophage activation has been attempted for many years using agents such as bacterial endotoxin, TNF, liposomal-encapsulated muramyl tripeptides, lipopeptides or oligonucleotides/agents that activate toll-like receptors. To date, however, this approach has not been very successful, primarily due to lack of specificity for tumor infiltrating macrophages resulting in intolerable systemic toxicity. Our group explored the use of a cell permeable flavonoid compound called DMXAA for this purpose. Administration of DMXAA causes activation of tumor-associated macrophages via multiple pathways with release of cytokines and chemokines resulting in hemorrhagic tumor necrosis, a subsequent inflammatory/immuno-permissive tumor environment, and ultimately attracts CD8 T cells into tumors (Jassar et al. 2005). Although intra-tumoral treatment of both large and small lung cancers in mouse models led to striking tumor regression, there was a major problem in translating this work- DMXAA does not react with human macrophages. Since we did not know how DMXAA was working (i.e. what was the DMXAA receptor that triggered macrophage activation) progress was stalled. This changed recently, when it was discovered that DMXAA worked by binding to a newly described intracellular sensor of cytosolic DNA (working through binding to cyclic dinucleotides) called STING (stimulator of Interferon Genes). STING activates innate immunity by signaling through the TBK/IRF3 axis, NF-kB and STAT6 pathways. Interestingly, it was noted that DMXAA bound well to mouse STING but NOT to human STING (explaining its lack of efficacy in humans). A company (Aduro Biotech) has designed a compound that binds to human STING and thus activates human macrophages like DMXAA activates mouse macrophages. Their lead compound has strong in vivo anti-tumor activity (much like DMXAA) and clinical trials using intra-tumoral injections are about to start (Corrales et al., 2015). Another potential target in the tumor microenvironment is the cancer-associated fibroblasts (CAFs). Fibroblasts and their associated stroma promote tumor growth through multiple mechanisms, including suppression of anti-tumor immunity, supporting angiogenesis, as a depot for growth factors/ cytokines/chemokines, modulating the inflammatory response, and shielding the tumor from infiltrating cells. Our group at Penn has been developing genetically altered T cells that can be targeted to any expressed surface antigen by transducing autologous T cells with a chimeric antigen receptor (CAR). A CAR is composed of a single chain antibody fused to the cytoplasmic sequences from the CD3zeta chain and a co-activating receptor (41BB/CD137). This construct combines antibody specificity with the ability to activate the killing machinery of T cells. Our lead CAR T cell target is CD19 to treat B cell malignancies, however, we are also testing CARs targeted to mesothelin (mesothelioma, lung cancer, pancreas cancer, ovarian cancer) and other solid tumor cell targets. We hypothesized that we could use this approach to eliminate CAFs. To do so, we identified Fibroblast Activation Protein (FAP) as a target antigen for CAFs. In epithelial-derived tumors, FAP is selectively expressed by cancer-associated stromal cells It is highly expressed in the stroma of lung (and many other) cancers, but not in benign tumors or normal adult quiescent tissues (although it is upregulated in wounds and fibrotic tissues). We thus produced T cells expressing anti-mouse FAP CARs. The FAP CAR T cells selectively killed FAP-expressing cells. Immune-competent C57BL/6 mice bearing large established subcutaneous murine lung cancers and human A549 tumors in immune-deficient mice were treated. FAP-CAR T cells reduced the number of FAP+ cells, markedly reduced the amount of tumor matrix and limited tumor growth in all three lung cancer models (Wang et al., 2014; Lo et al., 2015). We hope to move this approach forward to clinical trials in lung cancer and mesothelioma. We will likely combine anti-fibroblast therapy with chemotherapy, vaccines, or other types of immunotherapy. In summary, a new therapeutic paradigm is now emerging based on therapy aimed at the non-malignant host cells, NOT directly targeting the cancer cells. Examples include antibodies targeting endothelial cells and checkpoint inhibitors that target T cells. An advantage of this approach is that stromal cells are more genetically stable compared with tumor cells and they are unlikely to lose their antigen(s) and become invisible to T cells. Another advantage is the same targets could be used in multiple tumors. Future applications will likely include activation or elimination of TAMS, targeting fibroblasts, and deletion of T-regulatory cells. References: Corrales L, et al. Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity. Cell Reports 2015. 11:1-13. Jassar, A., et al. Activated Tumor-Associated Macrophages and CD8[+] T-cells are the Key Mediators of Anti-tumor Effects of the Vascular Disrupting Agent DMXAA in Murine Models of Lung Cancer and Mesothelioma”. Cancer Research 2005. 65:11752-11761. Lo A, et al. Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res. 2015 May 15. [Epub ahead of print] Wang LC, et al. Targeting Fibroblast Activation Protein in Tumor Stroma with Chimeric Antigen Receptor T Cells Can Inhibit Tumor Growth and Augment Host Immunity Without Severe Toxicity. Cancer Immunology Research 2014. 2:154-166.
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ORAL 18 - Non PD1 Immunotherapy and Angiogenesis (ID 114)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 7
- Moderators:C. Butts, K. Reckamp
- Coordinates: 9/08/2015, 10:45 - 12:15, Four Seasons Ballroom F1+F2
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ORAL18.01 - TG4010 Immunotherapy plus Chemotherapy as First Line Treatment of Advanced NSCLC: Phase 2b Results (ID 669)
10:45 - 10:56 | Author(s): E. Quoix, F. Forget, C. Chouaid, Z. Papai, G. Losonczy, E. Felip, M. Cobo, C. Ottensmeier, J.T. Beck, B. Bastien, A. Tavernaro, G. Lacoste, J. Limacher, H. Léna
- Abstract
- Presentation
Background:
TG4010 is an immunotherapy using an attenuated and modified poxvirus (MVA) coding for MUC1 and interleukin-2. Previous Phase 2 trials have demonstrated the efficacy and safety of TG4010 in combination with chemotherapy. In addition, Triple Positive Activated Lymphocytes (TrPAL; CD16+, CD56+, CD69+) was identified as a potential biomarker predictive of efficacy
Methods:
TIME is a double blind, placebo-controlled phase 2b/3 study. The Phase 2b part compared first line chemotherapy combined with TG4010 or placebo and further assessed the predictive value of baseline level of TrPAL. Eligibility criteria included stage IV NSCLC not previously treated, MUC1+ tumor by immunohistochemistry, PS ≤1. TG4010 10[8] pfu or placebo was given SC weekly for 6 weeks (w), then every 3w up to progression in immediate combination with chemotherapy. Patients were randomized using TrPAL cut-off value (normal vs high) that was previously pre-determined in healthy subjects. Primary efficacy endpoint was progression-free survival (PFS) using a Bayesian design to confirm that, with a 95% probability, the true hazard ratio (HR) is <1 in patients with normal TrPAL level. Secondary objectives were response rate (ORR), duration of response, survival, safety and subgroup analyses according to histology and level of TrPAL.
Results:
222 patients (pts) were randomized 1:1. In pts with normal TrPAL the study met the primary endpoint with a Bayesian probability of 98.4% that the PFS HR is <1 in favor of TG4010. In the whole study population, ORR was 39.6% vs 28.8% and duration of response was 30.1w versus 18.7w in the TG4010 and placebo arms respectively. Survival data will be presented at the time of the meeting. Preplanned subgroup analyses showed that PFS was significantly improved in the TG4010 arm in pts with low TrPAL (n=152; HR=0.66 [CI95% 0.46-0.95] p= 0.013) while it was not the case in pts with high TrPAL (n=70; HR=0.97 [CI 95% 0.55-1.73] p=0.463). In addition, PFS was also significantly improved in pts with non-squamous tumors (n=196; HR=0.69 [CI95% 0.51-0.94] p=0.009) as well as in pts with non-squamous tumors and low TrPAL (n=131; HR=0.61 [CI95% 0.42-0.89] p=0.005). In this last group, PFS at 9 months was 37% with TG4010 versus 18% with placebo. Frequency and severity of adverse events were similar in both treatment arms except injection site reactions which were more frequent in the TG4010 arm but all of mild or moderate intensity. Exploratory analysis of the impact of PDL1 expression in the tumor of patients treated with TG4010 in TIME study supports the activity of TG4010 whether the tumor is positive or negative for PDL1 expression.
Conclusion:
These results provide additional data supporting the efficacy of TG4010, particularly in patients with non-squamous tumors and/or a low level of TrPAL at baseline. The Phase 3 part of the TIME study is planned to continue in patients with non-squamous tumors with OS as primary endpoint.
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ORAL18.02 - MUC1-Targeted Dendritic Cell-Based Vaccine Immunotherapy in Patients with Standard Treatments-Refractory Non-Small-Cell Lung Cancer (ID 1193)
10:56 - 11:07 | Author(s): K. Teramoto, J. Hanaoka, N. Tezuka, Y. Daigo
- Abstract
- Presentation
Background:
MUC1, a tumor antigen, has been considered to a promising target antigen for cancer immunotherapy because it possesses a potent immunogenicity. It is processed and presented by antigen-presenting cells in a MHC-unrestricted pattern. Dendritic cell-based vaccine immunotherapy can elicit antigen-specific cytotoxic T lymphocytes in tumor-bearing hosts, and activated cytotoxic T lymphocytes are expected to attack cancer cells. In this study, we evaluated the efficacy of MUC1-targeted dendritic cell-based vaccine immunotherapy in patients with standard treatments-refractory advanced non-small-cell lung cancer (NSCLC).
Methods:
The eligibility criteria of this immunotherapy were as follows: histologic or cytologic evidence of NSCLC that had been proven to express MUC1 abundantly; an Eastern Cooperative Oncology Group performance status of 0-2; advanced stage of diseases refractory for other standard cancer treatments. The dendritic cells were prepared from peripheral blood mononuclear cells with cytokines interleukin-4 and granulocyte macrophage colony stimulating factor, were pulsed with MUC1 peptides, and subsequently administered to patients subcutaneously. The vaccinations were repeated bi-weekly, and assessable patients were received at least 6 vaccinations. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors. Adverse events were graded according to National Cancer Institute Common Toxicity Criteria.
Results:
From June 2005 and March 2015, 42 patients were treated with dendritic cell-based vaccines, and 29 patients (69.0%) with median age of 61 years (range, 49-84 years) were assessable for tumor responses. The cohort consisted of 18 males and 11 females. As their histological types, 24 patients had adenocarcinomas; 4 patients with squamous cell carcinomas and 1 patient with pleomorphic carcinoma. Among these assessable patients, neither complete response nor partial response was obtained. Seventeen patients had progressive disease as the best response, and 11 patients had stable disease, yielding overall disease control rate of 39.2% (95%CI=20.3-55.6). Median survival time after the vaccines was 10.0 months, and 1-year survival rate was 39.6%. Adverse events related to the vaccines were less frequent. Immunological responses were able to be monitored in five patients, showing that MUC1-specific cytotoxic responses of effector immune cells were achieved in all of those patients, and the population of regulatory T lymphocytes in peripheral blood cells was decreased after the vaccines.
Conclusion:
MUC1-targeted dendritic cell-based vaccine immunotherapy is feasible, and has a potential to control the diseases in patients with refractory NSCLC.
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ORAL18.03 - Discussant for ORAL18.01, ORAL18.02 (ID 3335)
11:07 - 11:17 | Author(s): J. Vansteenkiste
- Abstract
- Presentation
Abstract not provided
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ORAL18.04 - Anti-Angiogenic Therapy in Advanced Non-Small Cell Lung Cancer (NSCLC): A Meta-Analysis of Phase 3 Randomized Trials (ID 937)
11:17 - 11:28 | Author(s): J. Raphael, K.K. Chan, S. Karim, H. Lam, K. Delos Santos, S. Verma
- Abstract
- Presentation
Background:
There is a significant unmet medical need for effective and well-tolerated treatment options for advanced NSCLC patients. Angiogenesis is a fundamental step in tumor growth and progression; its inhibition has become an attractive target as anticancer therapy. We conducted this meta-analysis to evaluate the effectiveness of adding anti-angiogenic therapy (AT) to standard of care (chemotherapy, tyrosine kinase inhibitors (TKIs) or best supportive care) in advanced NSCLC
Methods:
The electronic databases Ovid PubMed, Cochrane Central Register of Controlled Trials, Embase, the websites of European Society of Clinical Oncology, the American Society of Clinical Oncology and the Lung Cancer Association were searched to identify all eligible phase 3, randomized, controlled trials with AT for the treatment of advanced NSCLC. Pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and pooled odds ratio (OR) for overall response rates (RR) were calculated. We divided the population into 2 subgroups based on the dose of Bevacizumab administered: 7.5 mg/kg (group 1) and 15mg/kg (group 2)
Results:
Data of 19098 patients (9867 AT; 9231 controls) from 25 phase III trials were analyzed. Compared with the standard of care alone, the addition of AT did not prolong OS (HR 0.98; 95% [CI] 0.96-1.00; p=0.1 and HR 0.97; 95% [CI] 0.94-1.00; p=0.06 for group 1 and 2 respectively). In an exploratory analysis, the addition of AT did not prolong OS for the adenocarcinoma histology and when it was used in the 1[st] line setting. Furthermore, there was no OS benefit regardless of the type of AT therapy i.e. monoclonal antibodies (Mabs) versus oral TKIs. There was a significant improvement in PFS with the addition of AT (HR 0.85; 95% [CI] 0.79-0.91; p<0.00001 and HR 0.81; 95% [CI] 0.75-0.88; p<0.00001 for group 1 and 2 respectively) and overall RR (OR 1.61; 95% [CI] 1.30-2.01; p<0.0001 and OR 1.72; 95% [CI] 1.39-2.14; p<0.00001 for group1 and 2 respectively).
Conclusion:
This is the 1[st] meta-analysis to our knowledge including all phase 3 trials with AT in NSCLC and showing that the addition of AT to the standard of care in advanced NSCLC had no significant effect on OS and only improved PFS and overall RR. The role of AT in advanced lung cancer is still questionable; strong validated biomarkers are eagerly needed to predict which subgroup might benefit the most from such therapy.
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ORAL18.05 - Early Predictive Value of Perfusion-Computed Tomography (pCT) in Advanced NSCLC Patients Treated with Bevacizumab: IMPACT Trial (ID 2268)
11:28 - 11:39 | Author(s): F. Aya, N. Viñolas, M. Sanchez, M. Benegas, O. Reig, A. Sosa, I. Vollmer, A. Arcoha, A. Martinez, M. Boillos, M. Viladot, A. Prat, N. Reguart
- Abstract
- Presentation
Background:
The use of targeted drugs has implied the development of new imaging techniques able to assess in vivo processes as part of antitumor response. Functional imaging techniques may be more appropriate to study changes in vascularization parameters such as blood flow (BF), blood volume (BV) and permeability (PMB) after treatment with antiangiogenics. Perfusion-computed tomography (pCT) could be a useful technique to predict non-small cell lung cancer (NSCLC) (pts) that most benefit from antiangiogenic therapy by assessing early variations of perfusion parameters.
Methods:
IMPACT (NCT02316327) is an ongoing open-label, single arm phase II/IV study to evaluate the predictive value of early perfusion changes in pts diagnosed with advanced non-squamous (ns)-NSCLC treated with bevacizumab in combination with chemotherapy. Patients receive cisplatin (80 mg/m2 i.v. d1), gemcitabine (1250 mg/m2 i.v. d1 and 8) and bevacizumab (B, 7.5 mg/kg i.v. d1) up to 6 cycles each 21 days. Pts with non-progressive disease are allowed to continue with B maintenance until PD or unacceptable toxicity. pCT assessment is done basal (d-1), at d+7 and d+42. The primary endpoint is to evaluate whether early reductions (d-1 vs d+7) in pCT parameters in terms of BF (mL/100mL/min), BV (mL/100mL) and PMB (mL/100mL/min) may predict response to bevacizumab as compared to Objective Response Rate (ORR) in terms of RECIST after 2 cycles (d+42). All perfusion evaluation parameters during treatment are measured in the same single thoracic target lesion. Planned sample size is 20 pts.
Results:
A total of 12 pts with ns-NSCLC have been recruited and data is available for analysis in 8 pts. Mean age is 62 years, 7 males and 1 female. All pts were diagnosed of adenocarcinoma stage IV (63% stage IVb). All tumor samples were negative for EGFR/ALK and 50% positive for KRAS. Mean cycles of chemotherapy were 5 (range 2-6) and 3 (range 0-12) of B maintenance. Target lesions for perfusion were: lung 3 pts (38%), lymph nodes in 4 pts (50%) and pleura in 1 pt (12%). No differences were found in terms of basal BF, BV and PMB depending on perfusion-target chosen. Four pts (50%) achieved partial response (PR), 3 pts (38%) stable disease (SD) and 1 pt (12%) progressive disease (PD). Mean basal perfusion parameters were: BF 61,5 (34,4 - 109), BV 10,4 (3,7 - 22,2) and PMB 17 (5,5 - 27,9). Mean perfusion changes early assessed by pCT at d+7 were: BF 21,7%, BV -49% and PMB -34,4%, decreasing consistently at day +42 (BF -46,8%, BV -45,5% and PMB -53,9%). Mean early variation (d-1 vs d+7) of BF in pts with SD/PD was +1,7% as compared with -45,3% in pts with PR. Mean variation of BF compared with d+42 (d-1 vs d+42) was also greater in pts with PR (-50%). Similar trends were observed in BV and PMB.
Conclusion:
Early response to B as assessed with p-CT may help to select those pts with NSCLC who most benefit from antiangiogenic therapy. Early changes in perfusion parameters can be identified with B treatment. Recruitment is ongoing.
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ORAL18.06 - Effect of Anti-VEGF Therapy on MDSCs' Population in the Peripheral Blood of Non-Small Cell Lung Cancer (NSCLC) Patients (ID 689)
11:39 - 11:50 | Author(s): F. Koinis, E.K. Vetsika, M. Gioulbasani, D. Aggouraki, A. Koutoulaki, L. Vamvakas, D. Mavroudis, V. Georgoulias, A. Kotsakis
- Abstract
- Presentation
Background:
Bevacizumab is an anti-VEGF monoclonal antibody approved for the treatment of non-squamous NSCLC. It is widely accepted that immunosuppressive mechanisms dominate in patients (pts) with solid tumors, including NSCLC. MDSCs are a heterogeneous population of immature cells of myeloid origin, whose expression is induced by VEGF. We recently identified two monocytic and one granulocytic MDSC subpopulation which are significantly increased and functional in the peripheral blood of NSCLC pts.
Methods:
Peripheral blood immune cells from 46 pts with unresectable NSCLC were analyzed by flow cytometry before the initiation of chemotherapy and after 3 cycles. Changes in the frequencies of the three MDSCs subpopulations were correlated with clinical outcome. Isolated MDSCs were co-cultured with T cells in order to confirm their functionality through estimation of IFN-γ secretion.
Results:
At diagnosis, the CD15(-) monocytic MDSCs’ levels were significantly increased in male pts (p=0.03) and in smokers (p=0.01). Overall, chemotherapy had no effect on the frequency of the distinct MDSC subpopulations. However, after 3 cycles of therapy, levels of all three MDSC subpopulations numerically decreased in responders (n=11) compared to non-responders (n=4). In addition, bevacizumab-based chemotherapy regimens significantly reduced the frequency of the granulocytic MDSC subpopulation when compared to the effect of non-bevacizumab based therapy (p=0.02). Lastly, suppression of IFN-γ secretion in vitro, confirmed the inhibitory effect of isolated MDSCs on T-cell cytotoxic capacity.
Conclusion:
These data indicate that although chemotherapy has no effect on the levels of different immunosuppressive MDSC subpopulations, bevacizumab–based regimens seem to exert an effect on the granulocytic MDSC subpopulation. Additional studies are needed in a larger cohort of pts in order to document its impact in the clinical outcome of NSCLC pts.
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ORAL18.07 - Discussant for ORAL18.04, ORAL18.05, ORAL18.06 (ID 3336)
11:50 - 12:00 | Author(s): P. Lara Jr.
- Abstract
- Presentation
Abstract not provided
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Author of
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PLEN 04 - Presidential Symposium Including Top 4 Abstracts (ID 86)
- Event: WCLC 2015
- Type: Plenary
- Track: Plenary
- Presentations: 1
- Moderators:T. Mok, F.R. Hirsch
- Coordinates: 9/09/2015, 10:45 - 12:15, Plenary Hall (Bellco Theatre)
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PLEN04.03 - Randomized Phase III Trial of Adjuvant Chemotherapy with or without Bevacizumab in Resected Non-Small Cell Lung Cancer (NSCLC): Results of E1505 (ID 1608)
11:07 - 11:19 | Author(s): C. Butts
- Abstract
- Presentation
Background:
Adjuvant chemotherapy for resected early stage NSCLC provides modest survival benefit. Bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor, improves outcomes when added to platinum-based chemotherapy in advanced stage non-squamous NSCLC. We conducted a phase 3 study to evaluate the addition of bevacizumab to adjuvant chemotherapy in early stage resected NSCLC. The primary endpoint was overall survival and secondary endpoints included disease-free survival and toxicity assessment.
Methods:
Patients with resected stage IB (>4 centimeters) to IIIA (AJCC 6th edition) NSCLC were enrolled within 6-12 weeks of surgery and stratified by chemotherapy regimen, stage, histology and sex. All patients were to receive adjuvant chemotherapy consisting of a planned 4 cycles of every 3 week cisplatin at 75 mg/m[2] with either vinorelbine, docetaxel, gemcitabine or pemetrexed. Patients were randomized 1:1 to arm A (chemotherapy alone) or arm B, adding bevacizumab at 15 mg/kg every 3 weeks starting with cycle 1 of chemotherapy and continuing for 1 year. Post-operative radiation therapy was not allowed. The study had 85% power to detect a 21% reduction in the overall survival (OS) hazard rate with a one-sided 0.025-level test.
Results:
From July 2007 to September 2013, 1501 patients were enrolled. Patients were 49.8% male, predominantly white (87.9%) with a median age of 61 years. Patients enrolled had tumors that were 26.2% stage IB, 43.8% stage II and 30.0% stage IIIA and 28.2% of patients had squamous cell histology. Chemotherapy options were utilized with the following distribution: vinorelbine 25.0%, docetaxel 22.9%, gemcitabine 18.9% and pemetrexed 33.2%. At a planned interim analysis, with 412 of 676 overall survival events needed for full information (60.9%), though the pre-planned futility boundary was not crossed, the Data Safety Monitoring Committee recommended releasing the trial results based on the conditional power of the logrank test. At the time of interim analysis, with a median follow-up time of 41 months, the OS hazard ratio comparing the bevacizumab containing arm (Arm B) to chemotherapy alone (Arm A) was 0.99 (95% CI: 0.81-1.21, p=0.93). The DFS hazard ratio was 0.98 (95% CI: 0.84-1.14, p=0.75). Completion of treatment per protocol was 80% on Arm A and 36% on Arm B. Statistically significantly increased grade 3-5 toxicities of note (all attributions) included: overall worst grade (67% versus 84%); hypertension (8% versus 30%), and neutropenia (33% versus 38%) on Arms A and B, respectively. There was no significant difference in grade 5 adverse events per arm with 16 (2%) on arm A and 19 (3%) on arm B.
Conclusion:
The addition of bevacizumab to adjuvant chemotherapy failed to improve survival for patients with surgically resected early stage NSCLC.
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