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S.J. Antonia
Moderator of
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MINI 02 - Immunotherapy (ID 92)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 14
- Moderators:P. Forde, S.J. Antonia
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F3+F4
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MINI02.01 - Pulmonary Large Cell Carcinoma and Solid Adenocarcinoma Are Highly Mutated with Frequent Expression of PDL1 (ID 2257)
10:45 - 10:50 | Author(s): D.H. Hwang, A. Perry, F. Kuo, S.J. Rodig, L. Sholl, J.L. Hornick
- Abstract
- Presentation
Background:
Large cell carcinoma (LCC) is an uncommon lung tumor that arises predominantly in smokers and shares many features of solid adenocarcinoma (ADC). 40% of LCC/solid ADC harbor mutations in KRAS; EGFR and ALK alterations are rare in this tumor type. The majority of these tumors, however, lack one of the commonly queried oncogenic driver alterations, thus therapeutic options are limited for patients with this tumor type. Immunomodulatory therapies, including targeting PDL1, have shown promise in a variety of tumor types. Tumor neo-antigens, including those induced by smoking, are associated with mutational burden and may predict susceptibility to cytolytic immune response; in addition, high PDL1 expression in non small cell lung carcinoma has been associated with response to anti-PDL1 drugs. Given the high prevalence of smoking in patients with LCC and solid ADC, we hypothesize that these tumors may be amenable to immunomodulatory therapy and sought to define the frequency of PDL1 expression in tumors lacking an oncogenic driver mutation.
Methods:
This study was restricted to 27 LCC and solid ADC known to be negative for KRAS, EGFR, ALK and ROS1 alterations. Hybrid capture targeted next generation sequencing (NGS) on an Illumina HiSeq 2500 was performed using a cancer genomic assay to detect mutations, copy number variations (CNVs) and structural variants. The assay captures exonic sequences of 275 cancer genes and 91 introns across 30 genes for rearrangement detection. Findings were compared to an institutional cohort of 732 consecutive lung tumors sequenced on the same platform. Immunohistochemistry for PDL1 was performed using a rabbit monoclonal antibody (Cell Signaling Technologies) at 1:100 dilution following pretreatment with citrate buffer/pressure cooker and detected using the Envision + polymer system (DAKO). Immunostaining was considered positive in the tumor component or the inflammatory component if ≥5% of the cells showed membranous staining.
Results:
Of the 27 tumors tested, 26 were resected from smokers. NGS revealed an average of 14.9 mutations per case for LCC/solid ADC cohort versus 8.1 mutations in the overall cohort of lung tumors (p<0.0001). 11 cases (41%) were positive for PD-L1. 7 cases (26%) showed strong, diffuse staining (≥70% of cells) for PD-L1. The inflammatory component was positive for PD-L1 in 25 cases (93%). Two cases with strong expression of PD-L1 by immunohistochemistry (>90% of cells) showed focal amplification of CD274 by NGS.
Conclusion:
LCC and solid ADC are strongly associated with a smoking history and harbor a significantly higher average mutational burden than other lung tumors. 41% of LCC/solid ADC are positive for PDL1 by immunohistochemistry with 26% showing very strong PDL1 expression and nearly all cases showing some degree of positivity in the associated inflammatory infiltrate. In some cases, high PDL1 expression is associated with focal amplification of CD274, the gene encoding PDL1. These findings suggest that LCC/ solid ADC is likely to have smoking-associated neo-antigen expression and that PDL1-directed immunotherapies may be a promising therapeutic approach in this otherwise poorly-characterized lung tumor.
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MINI02.02 - Programmed Cell Death Ligand (PD-L1) Expression in Stage II and III Lung Adenocarcinomas and Nodal Metastases (ID 1519)
10:50 - 10:55 | Author(s): H. Uruga, E. Bozkurtlar, T. Huynh, A. Muzikansky, A. Hata, J.F. Gainor, E. Mark, J.A. Engelman, M. Lanuti, M. Mino-Kenudson
- Abstract
Background:
Inhibition of PD-L1 can lead to reactivation of tumor immunity and assist in cancer therapy. PD-L1 expression in tumor cells has been reported to correlate with clinicopathological parameters and prognosis in a variety of cancers including lung adenocarcinomas (ADC). However, it has not been well studied whether PD-L1 expression is altered along with tumor progression. In addition, little is known about the role of PD-L1 expression in predicting response to chemotherapy in ADC. Thus, we sought to compare PD-L1 expression in the main tumor and lymph node metastases of stage II and III ADC, and correlate PD-L1 expression with survival in patients who underwent adjuvant chemotherapy.
Methods:
The study cohort consisted of 109 ADC who underwent curative resection without neoadjuvant therapy and were diagnosed to have stage II or III disease. Of those, 60 cases received platinum-based adjuvant therapy and were followed at our institution. Immunohistochemistry for PD-L1 (E1L3N, 1:200, CST) was performed on sections of the primary tumor and/or metastatic lymph nodes and the primary tumor sections were also stained with CD8 (4B11, RTU, Leica Bond). Membranous staining of any intensity present in 5% or more of the tumor cells was deemed positive for PD-L1 expression. CD8+ tumor infiltrating lymphocytes (TILs) were evaluated using a 4-tier grading system (0-3). The PD-L1 expression in the primary tumor was correlated with that in lymph node metastases as well as clinicopathological parameters, including CD8+ TILs, and recurrence free survival (RFS).
Results:
Of the 109 cases, 53 (48.6 %) exhibited PD-L1 expression in the primary tumor, which was significantly associated with smaller tumor size, lower pT stage, nodal disease, solid-predominant pattern, the presence of tumor islands, necrosis and lymphovascular invasion, and increased CD8+ TILs (grade 2-3). Upon multivariate analysis, only increased CD8+ TILs remained significant (p=0.039). As for the primary – lymph node correlation, PD-L1 expression was seen in 57.6% of 59 N1 nodes, 53.1% of 32 N2 nodes, and 100% of one N3 node available for evaluation. The PD-L1 expression status was the same between the primary tumor and nodal metastases in the majority (76.3 % of N1 nodes, and 75.0% of N2; p<0.001 and p=0.005, respectively), and the upregulation of PD-L1 expression (positive expression was present in nodal metastasis with negative primary) was seen in only small fractions of the cohort (6.8% of N1 nodes and 9.3% of L2 nodes). Interestingly, PD-L1 expression in the primary tumor was associated with longer RFS in patients who underwent platinum-based adjuvant therapy (mean 84 months vs. 41 months in PD-L1 negative patients, p=0.016), but not in those without adjuvant therapy.
Conclusion:
PD-L1 expression in the primary tumor was associated with prominent CD8+ TILs as well as several adverse clinicopathological parameters including nodal disease, but PD-L1 expression in the nodal metastasis was similar to that in the primary tumor in the majority of cases. Although the evaluation was limited due to a small size of the cohort, PD-L1 expression in the primary tumor appears to be predictive of response to platinum-based adjuvant therapy.
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MINI02.03 - Overexpression of CD47, Decrease of Apoptosis and Phagocytosis of Neutrophils in Advanced Non-Small Cell Lung Cancer Patients (ID 2265)
10:55 - 11:00 | Author(s): L. Barrera, O. Arrieta Rodriguez, R. Morales-Flores, A. Garcia-Vicente, E. Montes-Servín, F. Salinas-Parra, A. Ramirez-Tirado
- Abstract
- Presentation
Background:
Lung cancer is the leading cause of cancer death worldwide and most of the patients are diagnosed with advanced disease. Inflammatory components play a key role in tumor progression and survival. Neutrophils are increased in blood of patients with lung cancer and they are associated with poor clinical outcomes. CD47 is a protein which control cell communication, apoptosis, adhesion and proliferation and it has been found increased in cancer and related with phagocytosis evasion mechanism.The aim of this study was to evaluate CD47 expression levels on peripheral neutrophils, also assess the phenotype, apoptosis, activation state, reactive oxygen species production of neutrophils between patients with Non-Small Cell Lung Cancer (NSCLC) and healthy subjects.
Methods:
Fifty NSCLC patients (stage IIIB and IV) naive to treatment and 25 healthy subjects were analized for: CD47 peripheral blood expression, neutrophils phenotype and activation state, evaluation of apoptosis and phagocytosis by flow cytometry. Reactive oxygen species (ROS) production by circulating neutrophils upon stimulation with PMA was assessed by flow cytometry. For the phagocytosis assay, PMNC were labeled with CMFDA and were cultured in RPMI for 24 hrs. To obtain apoptotic target cells, 24h PMNC were labeled with Annexin-V. For the evaluation of phagocytosis, the neutrophils from NSCLC patients were co-cultured with THP-1 cells. The percentage of phagocytosis was assessed by flow cytometry.
Results:
Our results showed a lower percentage of total CD47 in peripheral blood cells in NSCLC patients compared to controls [P=0.042]. Mean Fluorescence Intensity (MFI) of CD47 was higher in patients [P<0.001]. The percentage of CD66b+ cells characterized as neutrophils was higher in patients as well as their MFI of CD47 [P< 0.001]. MFI of CD66b was higher in patients [P< 0.0178]. This would be related with a more activated state. We found that a higher disease stage (IIIB vs. IV) associated with a higher MFI of CD47 [P=0.020]. Plasma pro-inflammatory cytokines, was increased in patients compare to controls IL-6 (P<0.002), IL-8 (P<0.001), IL-12p70 (P<0.008), TNF (0.010) and IFN-g (P<0.001). MFI of CD47 >1635.5 was associated with a higher median Overall survival (P= 0.007). We found a decrease of AnnexinV+/7AAD+ in neutrophils of patients [P=0.0317]. Caspases 3 and 7 were found decreased in neutrophils of patients [P= 0.049]. Oxygen species (ROS) production of neutrophils upon PMA stimulation was increased in patients [P=0.029], suggesting it might play a role in immune effector function. Phagocytosis of apoptotic neutrophils by differentiated THP-1 cells was decrease in cancer patients cells (P=0.0445). Mean fluorescence Intensity of CD47 was increased after 24 hrs in patients [P=0.0408]. This result suggests that neutrophils from patients avoid being engulfed and this may be associated with overexpression of CD47.
Conclusion:
Taken together, these findings suggest that these are altered mechanisms by which neutrophils evade anti-tumor immune response and their increased expression of CD47 is a potential therapeutic target for NSCLC.
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MINI02.04 - Sequential Assessment of DNA Damage Response and PD-L1 Expression in Circulating Tumor Cells of Lung Cancer Patients during Radiotherapy (ID 2511)
11:00 - 11:05 | Author(s): S.H. Lin, J. He, M. Edelman, T. Xu, H. Gao, J. Reuben, Y. Qiao, H. Liu, P. Amstutz, S. Hahn, R.U. Komaki, Z. Liao, C. Tang, D. Adams
- Abstract
- Presentation
Background:
Recent evidence suggests that PD-L1 expression can be induced with radiotherapy and may be a mechanism for resistance to radiotherapy and immunotherapy. Sequentially assessing PD-L1 expression on cancer associated cells in circulation during treatment regimens may be a way to assess the efficacy of radiotherapy and immunotherapy in clinical trials. For this feasibility study, we evaluated the association of RAD50 induction, and PD-L1 expression, on CTCs and Cancer Associated Macrophage-Like Cells (CAMLs) in lung cancer patients (pts) before and during radiotherapy to determine expression changes of these markers.
Methods:
Eleven pts with stage I-IV lung cancer were included in this pilot study. Three pts received Stereotactic Body Radiation Therapy (SBRT) for stage I disease and 8 other pts received chemoradiation for stage II-IV disease. Baseline blood samples (7.5 ml) were drawn prior to the start of radiotherapy (T0) and a second blood sample was drawn at a follow up visit during radiotherapy; or for three pts, after completing SBRT (T1); for a total of 22 samples. Blood was processed using CellSieve™ microfiltration (Creatv Microtech), stained for cytokeratin 8, 18 & 19 and CD45, and imaged. Using the QUAS-R (Quench, Underivatize, Amine-Strip and Restain) technique to remove fluoresce signal, all cells were restained for RAD50-AlexaFluor550 and PD-L1-AlexaFluor 488, along with DAPI nuclear stain. The RAD50 foci numbers within nuclear regions were quantified. PD-L1 pixel intensity was measured by the ZenBlue software and grouped into 4 IHC groups: 0-negative (pixel average 0-215), 1-low (pixel average 216-300), 2-medium (pixel average 301-750), and 3-high (pixel average 751+).
Results:
There was at least one cytokeratin positive cell (i.e. CTC or CAMLs) found in each of the samples. Specifically CTCs were found in 82% of T0 and 64% of T1 samples, and CAMLs were found in 91% of T0 and 100% of T1 samples. RAD50 foci ranged from 0-16 per cell, with an average of 0.69 at T0 that increased to 3.46 at T1 (p=0.002) during radiotherapy. Distinctively, there were 6 pts with greater than 2 fold RAD50 foci increase at T1 and 5 pts with ≤ 2 fold induction. PD-L1 expression ranged from 34-2004 pixel intensity, with an average of 170 at T0 and 336 at T1 (p=0.08). Interestingly, 4 pts had no PD-L1 expression at T0 but an increase to 2 to 3+ at T1, 4 pts with low/no PD-L1 expression remained low at T1, and 3 pts had high PD-L1 expression that remained high or decreased at T1. There was no correlation between RAD50 induction and PD-L1 expression.
Conclusion:
Both RAD50 foci and PD-L1 expression were quantifiable in both CTCs and CAMLs, and had variable responses to radiotherapy +/- chemotherapy. These data suggest that sequential tracking of CTCs or immune-related cells from the primary lung tumor is feasible using microfiltration and potentially can serve as predictive biomarkers for cancer therapy.
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MINI02.05 - Discussant for MINI02.01, MINI02.02, MINI02.03, MINI02.04 (ID 3299)
11:05 - 11:15 | Author(s): D.P. Carbone
- Abstract
- Presentation
Abstract not provided
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MINI02.06 - Humanized Immuno-Mouse for Study of Anti-PD-1 Therapy in KRAS-Mutated Lung Cancer Patient Derived Xenotransplant (PDX) (ID 3104)
11:15 - 11:20 | Author(s): M. Wang, J.W. Riess, J. Keck, K. Palucka, L. Shultz, M. Cheng, D. Cai, C. Bult, D.R. Gandara, P.C. Mack
- Abstract
- Presentation
Background:
Preclinical modeling of immunotherapeutics in PDX-bearing mice has been limited by the absence of a relevant immune microenvironment, as a highly immunosuppressive environment is often required for the implanted tumor to grow. Checkpoint inhibitors including anti-PD-1 and anti-PD-L1 antibodies (mAbs) are promising new treatments in non-small cell lung cancer (NSCLC). The creation of a PDX model system that supports human tumor growth and recapitulates the relevant genomics in NSCLC while providing the immune microenvironment necessary for anti-PD-1 and anti-PD-L1 mAb activity is critical for validation of combination checkpoint inhibitor strategies in NSCLC.
Methods:
Hematopoietic CD34+ progenitor stem cells (CD34+ HPC) were engrafted into the tail vein of sublethally irradiated NSG mice. A KRAS G12D PDX was assayed for PD-L1 expression by FACS (Biolegend; clone 29E. 2A3, San Diego CA) and implanted into Hu-CD34 NSG mice with > 25% Hu-CD45+ cells 12 weeks post CD34+ HPC injection. Multilineage engraftment of immune cell subsets was assayed in peripheral blood, spleen and tumor by FACS (CD45, CD3, CD4, CD8, CD19). PDX were treated with vehicle Q5D x 6, pembrolizumab (Merck, Whitehorse Station PA) 5 mg/kg Q5D x 6, and combination pembrolizumab and docetaxel (Hospira, Lake Forest) 10 mg/kg Q7D x4 at the same single agent dosages. Body weight and tumor growth were assessed twice weekly.
Results:
Hu-CD45+ cells were detected in peripheral blood, spleen and tumor by flow cytometry on single cell suspension. The majority of Hu-CD45+ cells were T-cells: CD3CD4+ (mean blood 50%, spleen 53%, tumor 52%) and CD3CD8+ (mean blood 14%, spleen 15%, tumor 39%). KRAS G12D tumor had 89% surface expression of PD-L1. No significant change in Hu-CD45+ cell composition was noted between the different treatment groups. Pembrolizumab both alone and in combination with docetaxel showed activity in KRAS G12D PDX with substantial tumor growth inhibition and decreased mean tumor volume at day 24 post-treatment.
Conclusion:
Multilineage engraftment of relevant immune cell subsets for PD-1 inhibition is present in the humanized immune-mouse (Hu-CD34 NSG). PD-1 inhibition in a KRAS G12D Hu-CD34 NSG with high PD-L1 expression demonstrated substantial tumor growth inhibition both alone and in combination with chemotherapy. Additional studies are underway exploiting the Hu-CD34 NSG mouse model for study of anti-PD-1/PD-L1 therapies in KRAS mutant and other important molecular subsets of NSCLC.
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MINI02.07 - Preclinical Rationale for a Phase I/II Study of Pembrolizumab (P) and Vorinostat (V) in Immune Therapy Naïve and Pretreated Stage IV NSCLC (ID 734)
11:20 - 11:25 | Author(s): N. Tchekmedyian, H. Zheng, A.A. Beg, E. Haura, D. Chen, S.J. Antonia, J. Gray
- Abstract
- Presentation
Background:
The WHO estimated that 1.6 million people died of lung cancer in 2012. Nivolumab, an anti-PD-1 immune checkpoint inhibitor, was FDA approved on March 4, 2015 for platinum-refractory, metastatic, squamous-cell NSCLC, based upon a RR to single agent nivolumab of ~15% and improved OS. Combinatorial strategies may enhance these outcomes. Increased tumor expression of T cell chemokines, such as CCL5 and CXCL10, is associated with a better response to immunotherapy. Furthermore, expression of T cell chemokines is strongly and positively associated with increased T cell infiltration and improved patient survival. Therefore, enhancement of expression of T cell chemokines may augment response to PD-1 blockade immunotherapy.
Methods:
FDA-approved oncology agents were utilized from the Approved Oncology Drugs Set (97 agents) from the Developmental Therapeutics program of NCI. LKR cells were plated in 96-well plates, and a viability assay was performed 48 hours after drug administration (Cell Counting Kit-8, Dojindo Laboratories). Mice were bred and housed in the animal facility at Moffitt Cancer Center. Cells were harvested in logarithmic growth phase after being cultured for less than 2 weeks. 1x10[6] LKR or 344SQ cells were injected s.c. and tumors were monitored for growth by measurements 2-3 times per week. Romidepsin was injected i.p. (2mg/kg) on days 14,16, and 18 after tumor inoculation. Anti-PD-1 was injected i.p. (300μg/mouse) on days 15, 17, and 19 after tumor inoculation. Relative tumor size between treatment groups was analyzed using the t test with Welch’s correction.
Results:
Histone deacetylase inhibitors (HDACi), including vorinostat, emerged as the only class of agents in a 97-drug screen capable of inducing expression of multiple T cell chemokines, including CCL5, CXCL9, and CXCL10, in mouse and human lung cancer cell lines and primary tumors. HDACi’s ability to induce T cell chemokine expression was dependent on both JAK-STAT and NF-kB pathways. HDACi (romidepsin) treatment of mice bearing LKR tumors did not substantially cause tumor shrinkage but significantly reduced growth (p<0.0001; final tumor volume). This effect of HDACi was completely T cell dependent. LKR tumor cells had low cell surface expression of PD-L1 but which was substantially increased by IFN-g. PD-1 blockade with mAb reduced tumor growth but rarely induced rejection. However, when PD-1 blockade was combined with HDACi, 9 out of 11 mice demonstrated complete tumor rejection. HDACi anti-tumor response correlated with T cell chemokine induction in tumors and greater presence of tumor-infiltrating lymphocytes (TILs). We next used a mouse tumor model (344SQ) that was relatively resistant to anti-PD-1 treatment. PD-1 blockade combined with HDACi significantly reduced growth of these tumors compared to untreated (p=0.0003), anti-PD-1 alone (p=0.01), or HDACi (p=0.004) alone treated mice.
Conclusion:
HDACi not only enhanced anti-tumor response against PD-1 blockade sensitive tumors (LKR), but also induced response against PD-1 blockade resistant tumors (344SQ). HDACi induces JAK-STAT and NF-kB dependent chemokine expression and may induce tumor-infiltrating lymphocytes. Thus, a Phase I/randomized Phase II clinical trial of vorinostat, an orally active, small molecule HDACi, plus pembrolizumab, an anti-PD-1 humanized monoclonal IgG4-kappa antibody, is planned in patients with immune therapy naïve and pre-treated metastatic NSCLC.
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MINI02.08 - Bidirectional Cross-Talk between CD14+ Monocytes and Human Lung Cancer Cell Lines Results in Different Phenotypic and Functional Outcomes (ID 2497)
11:25 - 11:30 | Author(s): E. Schenk, A. Mansfield, A. Dietz
- Abstract
- Presentation
Background:
Myeloid cell infiltration of the tumor microenvironment is associated with decreased overall survival in multiple tumor types, including lung cancer. This myeloid cell infiltration represents a tissue component of the heterogeneous group of cells termed myeloid derived suppressor cells (MDSC), which can inhibit the endogenous anti-tumor response, direct angiogenesis, and promote tumor progression. In several studies of patients with non-small cell lung cancer (NSCLC), there is wide variation in the presence of myeloid cells in the tumor with increasing levels peripheral blood MDSC associated with poor survival. We have previously shown that CD14+ monocytes can be converted by the tumor microenvironment to an immune suppressive phenotype in non-Hodgkin lymphoma and glioblastoma. In this work, we expand on our earlier observations to include recruitment of CD14+ cells by lung cancer cell lines and their conversion to an immune suppressive phenotype. While most models of myeloid cells in the microenvironment describe the effects of these cells on non-malignant systems, we show that myeloid cells may have profound direct effects on the tumor.
Methods:
Human lung cancer cell lines were cultured and supernatants collected for ELISA. CD14+ cells were isolated from the peripheral blood of healthy volunteers using anti-CD14 immunomagnetic beads. Lung cancer cell lines and CD14+ cells were cocultured under a variety of low serum conditions with or without cisplatin. Changes in CD14+ cell HLA-DR expression and tumor cell survival were measured by flow cytometry. CD14+ cell migration through a permeable transwell membrane was measured in real time with live cell imaging.
Results:
Under normal culture conditions, 7 of 8 human lung cancer cell lines secreted detectable levels of CCL2, a major chemoattractant for monocytes, ranging from 30 to 10,000 pg/ml of CCL2 found in culture supernatants. CD14+ cells more robustly migrated towards cell lines with higher production of CCL2. The coculture system showed a differential impact on monocytes by the tested lung cancer cell lines which either reliably upregulated or downregulated CD14+ cell expression of HLA-DR. In 3 of 8 lung cancer cell lines, CD14+ cell HLA-DR was downregulated in a manner expected to promote local immune suppression. Under serum starvation conditions, one lung cancer cell line showed improved survival when cocultured with CD14+ cells. Similarly, coculture with CD14+ cells enhanced tumor survival of two cell lines after exposure to cisplatin.
Conclusion:
The studied lung cancer cell lines differ in the degree of CD14+ cell recruitment, CD14+ cell HLA-DR expression after coculture, and level of conferred survival benefit under stressful conditions. Taken together these results suggest that the variable myeloid involvement in lung cancer patients can be modeled using lung cancer lines. In addition, we have identified that for some tumors, monocytes confer a significant survival advantage that is not associated with immune or angiogenic responses. Future work is needed to explore the impact of CD14+ cells on lung tumor invasiveness, angiogenesis, and the mechanisms underlying these pro-tumor effects.
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MINI02.09 - ERK Activation Mediates Increased PD-L1 Expression in KRAS Mutated Premalignant Human Bronchial Epithelial Cells (ID 1620)
11:30 - 11:35 | Author(s): M. Lee, J. Yanagawa, S. Wu, T. Walser, G. Wang, J.W. Goldman, E.B. Garon, G. Zeng, S. Sharma, J. Minna, D.P. Carbone, S.M. Dubinett, J.M. Lee
- Abstract
- Presentation
Background:
Immune checkpoint pathways including the PD-1/PD-L1 pathway are involved in tumor evasion from the immune system. Elevated PD-L1 expression in tumor cells inhibits tumor-infiltrating T cell function and may be associated with poor prognosis in lung cancer patients. There is increasing interest in developing immunotherapies that block the immunosuppressive effects of checkpoint pathways such as PD-L1, and identifying patients who may benefit from PD-L1 blockade. Activating KRAS mutations are common driver mutations in non-small cell lung carcinoma. Patients with mutated KRAS demonstrate less benefit from adjuvant chemotherapy and resistance to tyrosine kinase inhibitors. The effect of cancer cell driver mutations on immune checkpoint immune regulation is poorly understood. While recent clinical trials have suggested better response to PD-1 blockade in KRAS mutation subjects, it is unclear if this clinical finding is directly driven by KRAS regulating the PD-1/PD-L1 pathway with resultant improved efficacy to anti-PD-L1 immunotherapy or if the presence of a KRAS mutation is merely a surrogate marker of the overall mutational load and tumor immunogenicity. KRAS mutations are known to activate the RAF-MEK-ERK pathway. We hypothesize that KRAS mutation directly regulates the PD-1/PD-L1 pathway through ERK activation.
Methods:
Immortalized human bronchial epithelial cells (HBEC-vector control), KRAS–mutated (KRAS[v12]) HBEC cells (HBEC-KRAS), p53 knockdown HBEC cells (HBEC-p53), and p53 knockdown/KRAS mutated cells (HBEC-p53/KRAS) were used to assess mRNA and/or surface protein expression levels of immune checkpoints including Lag-3, Tim-3, PD-L1 and PD-L2 by real time-qPCR (RT-qPCR) and flow cytometry, respectively. HBEC-vector and HBEC-KRAS cells were treated with MEK (ERK kinase) inhibitor (PD0325901) at 1µM for 24hrs and evaluated for mRNA and surface protein expression of PD-L1. The premalignant HBEC cell lines were used instead of human lung cancer cell lines in order to assess the role of KRAS mutation in isolation without other mutations.
Results:
PD-L1 and PD-L2 mRNA levels increased 2.4 fold (p<0.001) and 3.6 (p<0.001) fold in comparing HBEC-KRAS to HBEC-vector (wild-type) cells, while Lag-3 and Tim-3 mRNA expression levels were unchanged. Based on mean fluorescence intensity on flow cytometry, cell surface PD-L1 protein expression level was 2.2 and 1.6 fold higher in HBEC-KRAS and HBEC-p53/KRAS, respectively, compared to HBEC-vector cells. There was no increase in surface PD-L1 expression in HBEC-p53 cells compared to HBEC-vector control, suggesting that p53 mutation did not alter PD-L1 expression in HBEC-p53/KRAS cells. With MEK inhibition, PD-L1 mRNA levels decreased 10 and 11 fold in HBEC-vector and HBEC-KRAS cells, respectively. Analogously, PD-L1 surface protein levels were reduced 2.7 fold in HBEC-vector and HBEC-KRAS cells, respectively. These findings suggest that ERK activation mediates intrinsic expression and KRAS mutation mediates over-expression of PD-L1 mRNA and protein.
Conclusion:
Here, we demonstrate that PD-L1 expression is elevated in premalignant KRAS mutated human bronchial epithelial cells, and ERK activation mediates constitutive and KRAS mutation driven up-regulation of PD-L1 in these cells. Our findings suggest that KRAS mutation may directly regulate the PD-1/PD-L1 immune checkpoint pathway. Further understanding of KRAS driven molecular pathways that modulate immune checkpoints may elucidate therapeutic targets for potential combinational drugs to PD-L1 inhibition.
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MINI02.10 - Discussant for MINI02.06, MINI02.07, MINI02.08, MINI02.09 (ID 3300)
11:35 - 11:45 | Author(s): I.I. Wistuba
- Abstract
- Presentation
Abstract not provided
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- Abstract
- Presentation
Background:
As one of the novel therapy strategies, PD-L1 has been shown the function of down-regulating T-cell activation through receptor PD-1. Moreover, prognosis of cancer patients are based not only on tumor-related factors but also on host-related factors, particularly systemic inflammatory response. As significant indicators of patients’ inflammation status, circulating monocyte count, neutrophil ratio and lymphocyte ratio were proved as predictors of prognosis in various cancers. Squamous non-small cell lung cancer (NSCLC) revealed to be divergent clinical and molecular phenotypes compared with non-squamous NSCLC. Significantly, combining application of appropriate biomarkers in prognosis prediction is emerging its high importance in cancer research.
Methods:
Chart review was performed on 1286 consecutive patients, 156 of these patients were enrolled in the final analysis. Patients with squamous NCSLC were randomly assigned (2:1) centrally by computer into training group and validation group. Monocyte ratio, Neutrophils to Lymphocytes Ratio, PD-L1 immunostaining score and PD-1-positive stained tumor-infiltrating lymphocytes counts were assessed by Fisher’s linear discriminant analysis to discriminate if OS would exceeding 5 years. The final model was used to calculate the discriminant score in each study participant. And this prediction model was validated in a second set of squamous NCSLC patients. We internally validated the model using a cross-validation procedure.
Results:
4 independent predictors of OS were identified by using FLDA with stepwise variant-selection. The clinical classifying model was described by the following equation: Y = −1.212 + 0.211 × NLR ratio + 0.437 × monocyte ratio - 0.390 × PD-L1 + 0.035 × PD-1 (eigenvalue 0.673, canonical correlation 0.634, P < 0.001). In this equation, PD-L1 represented PD-L1 immunostaining score; and PD-1 represented PD-1 positive TILs counts. For the training set of 104 leave-one-out-cross-validated cases, 27 of 29 OS > 5 years (93.1% sensitivity) and 61 of 75 OS <= 5 years (81.3% specificity) were correctly classified with an overall accuracy of 84.6% (88 of 104) and an AUC of 0.938 [P < 0.001, 95% confidence interval (CI) 0.864–1] Next, the predicting model consisting of the 4 predictors (NLR ratio, monocyte ratio, PD-L1 and PD-1) were applied to the validation set of 52 patients (14 OS > 5 years and 38 OS <= 5 years). A survival prediction for 38 of the 52 patients (73.1%) with an AUC of 0.908 (P < 0.001, 95% CI 0.806–1) was achieved. Also, 12 of 14 OS > 5 years (85.7% sensitivity) and 26 of 38 OS <= 5 years (68.4% specificity) were correctly identified.
Conclusion:
The analysis of a set of immunological markers could effectively and reproducibly classify patients with squamous NCSLC according to their overall survival. Further prospective validation in larger independent cohorts of patients with similar or different regimens is warranted to fully assess its predictive power. The 4-immunological-marker model offers a novel tool for survival prediction and could have important clinical implications for the consideration of differential treatment strategies in patients with squamous NCSLC, thus providing a framework for future individualized therapy.
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MINI02.12 - Distribution of Immune Markers and Their Association with Overall Survival and Time to Progression in Non-Small-Cell Lung Cancer (NSCLC) (ID 3108)
11:50 - 11:55 | Author(s): A.T. Kuykendall, F. Khalil, E. Haura, S.J. Antonia, M. Schabath, D. Gabrilovich, B. Creelan
- Abstract
- Presentation
Background:
Inducible nitric oxide synthase (iNOS) and reactive nitrosylation are important mediators of tumor immunosuppression by myeloid-derived suppressor cells (MDSCs). However, the role of CD33+ peritumoral PMN-MDSCs in these pathways remains unclear. We conducted a retrospective cohort study of NSCLC subjects treated with surgery, with the primary objective to determine the association of MDSC biomarkers with time to progression (TTP) and overall survival (OS).
Methods:
Inclusion criteria: Surgically treated NSCLC of all stages at a single institution between 1996 and 2010. Somatic mutations tested by PCR. Anti-human antibodies optimized for immunohistochemistry. Samples scored by blinded pathologist based on intensity and percentage of peritumoral cells. Peritumoral nitrotyrosine (NT) and iNOS used Allred scoring. Time to progression (TTP) defined as time from resection to progression event or censored at last evaluation. Overall survival (OS) defined as time from resection to death.
Results:
Of 458 tumor samples, 366 lung primaries, 38 soft tissue metastases, and 39 brain metastases. Demographics: median age 67 yrs, 54% female, 96% Caucasian. Of 151 tested for somatic mutations, 36% KRASm, 8.6% EGFRm, 25% p53m, respectively. Histology: adenocarcinoma 76%, squamous 10%. Higher % CD3+ tumor infiltrating lymphocytes (TILs) and CD33+ myeloid cells were observed in tumors than normal tissue (p < .0001 and p = .002, respectively). More CD3+ TILs observed in soft tissue metastases than primary lung tumors (p < .0001). No difference in iNOS expression between tumor and normal lung tissue. More CD3+ TIL was observed in p53 mutant tumors (p=.03). iNOS was positively correlated with CD3+ TIL (p < .001) and CD73+ epithelial cells (p <.001), but not CD33+ myeloid cells. NT expression correlated with the absence of CD3+ TIL (p = .02), consistent with its putative immunosuppressive activity. Median TTP: 10.4 months; 320 (69.7%) events. Median OS: 35.4 months; 353 (77.1%) events. Expectedly, presence of CD3+ TIL was associated with favorable OS; HR 0.5 [0.4 – 0.7], p < .0001, and TTP; HR 0.7 [.5 – .9], p =.009. CD33+ myeloid cells were associated with favorable OS; HR 0.6 [0.5-0.8], p = .0002. Presence of peritumoral iNOS trended toward favorable OS; HR 0.81 [0.6-1.0], p = .07. Peritumoral iNOS was not associated with TTP. Figure 1
Conclusion:
Increased presence of TILs in p53 mutant tumors has been reported in other cancers, and may be related to somatic mutational load. An inflamed tumor phenotype was associated with improved overall survival. Unexpectedly, iNOS was positively correlated with both CD3+ infiltration and overall survival.
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- Abstract
- Presentation
Background:
Cancer development and biology is influenced by the host immune system. Emerging data indicate that the context of immune cell infiltrates within the tumor is associated with cancer prognosis. Both the activation state and type of immune cells present can provide mediators that either promote or inhibit tumor growth. While the presence of activated cytotoxic T lymphocytes (CTL) may correlate with better patient survival, the presence of tumor associated macrophages and effector lymphocytes that lack cytotoxic properties may promote tumor growth. Thus, in established tumors, a balance between pro and anti-tumor mediators are present, but as advanced tumors rarely regress without therapeutic intervention, this balance is likely skewed towards tumor-promoting inflammation. In attempts to gain insight into the immune networks that regulate tumorigenesis, we used genome wide gene expression datasets of primary lung cancer tissues to identify and functionally validate immune related genes that are associated with patient survival.
Methods:
Gene expression analysis was conducted on microarray datasets from 128 early-stage NSCLC resected tumor samples. Limiting analysis to immune-related gene sets curated by NIAID ImmPortal, we identified a minimum gene set using MAximizing R Square Algorithm (MARSA) that selected for the greatest separation between good and poor prognostic patient subgroups. The prognostic value of this gene signature was validated in nine additional independently published microarray datasets of NSCLC. From the gene signature, we functionally characterized the potential role of the soluble protein LAIR2 in immune regulation of lung cancer.
Results:
We identify a 9-gene signature that separate patients into high and low-risk subgroups for 5-year cancer-free survival (hazard ratio 10.26, 95% confidence interval 4.32-24.34, p<0.0001). The prognostic accuracy of this signature was validated in additional NSCLC datasets (total 1095 patients without adjuvant treatment). Amongst the 9-genes, the gene encoding the soluble protein LAIR2 was highly expressed within the high-risk patient subgroup. Functionally, we found that addition of recombinant LAIR2 resulted in increased NK cell expression of cytotoxicity receptors and secretion of pro-inflammatory cytokines in the presence of lung cancer cell lines.
Conclusion:
By limiting gene expression analysis to immune related genes, we identify a 9-gene prognostic immune signature in resected early stage NSCLC patients. The signature identifies a role for the soluble protein LAIR2 in the modulation of immune cell activation during lung cancer development and may suggest that LAIR2 induce a pro-inflammatory microenvironment which promote tumorigenesis and poor patient outcome.
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MINI02.14 - Discussant for MINI02.11, MINI02.12, MINI02.13 (ID 3469)
12:00 - 12:10 | Author(s): V. Papadimitrakopoulou
- Abstract
- Presentation
Abstract not provided
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MINI 02 - Immunotherapy (ID 92)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 2
- Moderators:P. Forde, S.J. Antonia
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F3+F4
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MINI02.07 - Preclinical Rationale for a Phase I/II Study of Pembrolizumab (P) and Vorinostat (V) in Immune Therapy Naïve and Pretreated Stage IV NSCLC (ID 734)
11:20 - 11:25 | Author(s): S.J. Antonia
- Abstract
- Presentation
Background:
The WHO estimated that 1.6 million people died of lung cancer in 2012. Nivolumab, an anti-PD-1 immune checkpoint inhibitor, was FDA approved on March 4, 2015 for platinum-refractory, metastatic, squamous-cell NSCLC, based upon a RR to single agent nivolumab of ~15% and improved OS. Combinatorial strategies may enhance these outcomes. Increased tumor expression of T cell chemokines, such as CCL5 and CXCL10, is associated with a better response to immunotherapy. Furthermore, expression of T cell chemokines is strongly and positively associated with increased T cell infiltration and improved patient survival. Therefore, enhancement of expression of T cell chemokines may augment response to PD-1 blockade immunotherapy.
Methods:
FDA-approved oncology agents were utilized from the Approved Oncology Drugs Set (97 agents) from the Developmental Therapeutics program of NCI. LKR cells were plated in 96-well plates, and a viability assay was performed 48 hours after drug administration (Cell Counting Kit-8, Dojindo Laboratories). Mice were bred and housed in the animal facility at Moffitt Cancer Center. Cells were harvested in logarithmic growth phase after being cultured for less than 2 weeks. 1x10[6] LKR or 344SQ cells were injected s.c. and tumors were monitored for growth by measurements 2-3 times per week. Romidepsin was injected i.p. (2mg/kg) on days 14,16, and 18 after tumor inoculation. Anti-PD-1 was injected i.p. (300μg/mouse) on days 15, 17, and 19 after tumor inoculation. Relative tumor size between treatment groups was analyzed using the t test with Welch’s correction.
Results:
Histone deacetylase inhibitors (HDACi), including vorinostat, emerged as the only class of agents in a 97-drug screen capable of inducing expression of multiple T cell chemokines, including CCL5, CXCL9, and CXCL10, in mouse and human lung cancer cell lines and primary tumors. HDACi’s ability to induce T cell chemokine expression was dependent on both JAK-STAT and NF-kB pathways. HDACi (romidepsin) treatment of mice bearing LKR tumors did not substantially cause tumor shrinkage but significantly reduced growth (p<0.0001; final tumor volume). This effect of HDACi was completely T cell dependent. LKR tumor cells had low cell surface expression of PD-L1 but which was substantially increased by IFN-g. PD-1 blockade with mAb reduced tumor growth but rarely induced rejection. However, when PD-1 blockade was combined with HDACi, 9 out of 11 mice demonstrated complete tumor rejection. HDACi anti-tumor response correlated with T cell chemokine induction in tumors and greater presence of tumor-infiltrating lymphocytes (TILs). We next used a mouse tumor model (344SQ) that was relatively resistant to anti-PD-1 treatment. PD-1 blockade combined with HDACi significantly reduced growth of these tumors compared to untreated (p=0.0003), anti-PD-1 alone (p=0.01), or HDACi (p=0.004) alone treated mice.
Conclusion:
HDACi not only enhanced anti-tumor response against PD-1 blockade sensitive tumors (LKR), but also induced response against PD-1 blockade resistant tumors (344SQ). HDACi induces JAK-STAT and NF-kB dependent chemokine expression and may induce tumor-infiltrating lymphocytes. Thus, a Phase I/randomized Phase II clinical trial of vorinostat, an orally active, small molecule HDACi, plus pembrolizumab, an anti-PD-1 humanized monoclonal IgG4-kappa antibody, is planned in patients with immune therapy naïve and pre-treated metastatic NSCLC.
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MINI02.12 - Distribution of Immune Markers and Their Association with Overall Survival and Time to Progression in Non-Small-Cell Lung Cancer (NSCLC) (ID 3108)
11:50 - 11:55 | Author(s): S.J. Antonia
- Abstract
- Presentation
Background:
Inducible nitric oxide synthase (iNOS) and reactive nitrosylation are important mediators of tumor immunosuppression by myeloid-derived suppressor cells (MDSCs). However, the role of CD33+ peritumoral PMN-MDSCs in these pathways remains unclear. We conducted a retrospective cohort study of NSCLC subjects treated with surgery, with the primary objective to determine the association of MDSC biomarkers with time to progression (TTP) and overall survival (OS).
Methods:
Inclusion criteria: Surgically treated NSCLC of all stages at a single institution between 1996 and 2010. Somatic mutations tested by PCR. Anti-human antibodies optimized for immunohistochemistry. Samples scored by blinded pathologist based on intensity and percentage of peritumoral cells. Peritumoral nitrotyrosine (NT) and iNOS used Allred scoring. Time to progression (TTP) defined as time from resection to progression event or censored at last evaluation. Overall survival (OS) defined as time from resection to death.
Results:
Of 458 tumor samples, 366 lung primaries, 38 soft tissue metastases, and 39 brain metastases. Demographics: median age 67 yrs, 54% female, 96% Caucasian. Of 151 tested for somatic mutations, 36% KRASm, 8.6% EGFRm, 25% p53m, respectively. Histology: adenocarcinoma 76%, squamous 10%. Higher % CD3+ tumor infiltrating lymphocytes (TILs) and CD33+ myeloid cells were observed in tumors than normal tissue (p < .0001 and p = .002, respectively). More CD3+ TILs observed in soft tissue metastases than primary lung tumors (p < .0001). No difference in iNOS expression between tumor and normal lung tissue. More CD3+ TIL was observed in p53 mutant tumors (p=.03). iNOS was positively correlated with CD3+ TIL (p < .001) and CD73+ epithelial cells (p <.001), but not CD33+ myeloid cells. NT expression correlated with the absence of CD3+ TIL (p = .02), consistent with its putative immunosuppressive activity. Median TTP: 10.4 months; 320 (69.7%) events. Median OS: 35.4 months; 353 (77.1%) events. Expectedly, presence of CD3+ TIL was associated with favorable OS; HR 0.5 [0.4 – 0.7], p < .0001, and TTP; HR 0.7 [.5 – .9], p =.009. CD33+ myeloid cells were associated with favorable OS; HR 0.6 [0.5-0.8], p = .0002. Presence of peritumoral iNOS trended toward favorable OS; HR 0.81 [0.6-1.0], p = .07. Peritumoral iNOS was not associated with TTP. Figure 1
Conclusion:
Increased presence of TILs in p53 mutant tumors has been reported in other cancers, and may be related to somatic mutational load. An inflamed tumor phenotype was associated with improved overall survival. Unexpectedly, iNOS was positively correlated with both CD3+ infiltration and overall survival.
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MINI 14 - Pre-Clinical Therapy (ID 119)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:L. Fernandez-Cuesta, A.F. Gazdar
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 2c-3c
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MINI14.07 - Bavituximab Activates CD8+ TILs in a 3D Ex Vivo System of Lung Cancer Patients Derived Tumors With Negative PD-L1 Expression (ID 2162)
11:20 - 11:25 | Author(s): S.J. Antonia
- Abstract
- Presentation
Background:
Bavituximab is a chimeric monoclonal antibody that targets the membrane phospholipid phosphatidylserine (PS) exposed on endothelial cells and cancer cells in solid tumors. Bavituximab blocks PS-mediated immune suppression and activates cytotoxic T lymphocyte anti-tumor responses.
Methods:
Tissues from consented patients with adenocarcinoma of the lung were extracted at the time of surgical resection and disaggregated to characterize expression of immune checkpoint proteins such as PD-1, CTLA-4, LAG3, TIM3, BTLA and adenosine A2A receptor on both CD4+ and CD8+ tumor infiltrating cells by flow cytometry (FACS) and stained for PD-L1, CD68, and CD163 via immunohistochemistry (IHC). 3D tumor microspheres were prepared and treated ex vivo with an IgG control, F(ab)’2 version of bavituximab, bavituximab, docetaxel, anti-PD-1 or PD-L1 and combinations of bavituximab, anti-PD-1 or PD-L1 and docetaxel for 36 hours within an intact tumor microenvironment. A multiplex human cytokine assay was used to simultaneously analyze the differential secretion of cytokines. Additionally, a NanoString platform containing probes to quantitate 770 immune function genes was used to determine potential positive or negative associations between expression of immune function genes and TIL activation by treatment. In a few cases, the expanded TILs were tested in PDX models using the consented patient’s tumor.
Results:
Bavituximab induces activation of TILs in 3D ex vivo tumor microsphere models of lung cancer, as demonstrated by a significant increase in IFN-ɣ, TNF-a, and GM-CSF secretion. FACS, IHC, and NanoString gene function analysis read out assays revealed that this effect was associated with low PD-1 expression on CD8+ cells, negative PD-L1 expression in the stating biopsy tissue, and a conversion of the M2 to M1 macrophage phenotype.
Conclusion:
These data support the use of bavituximab as an immunomodulatory treatment in adenocarcinoma of the lung by enhancing the activation of CD8+ TIL derived from patients' tumors with negative PD-L1 expression; correlating with increased cytokine production by lymphoid cells and repolarization of myeloid cells from an immunosuppressive to an immune active state.
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ORAL 02 - PD1 Axis Immunotherapy 2 (ID 87)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 4
- Moderators:E.B. Garon, H.J. Ross
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F1+F2
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ORAL02.01 - Phase 3, Randomized Trial (CheckMate 017) of Nivolumab (NIVO) vs Docetaxel in Advanced Squamous (SQ) Cell Non-Small Cell Lung Cancer (NSCLC) (ID 736)
10:45 - 10:56 | Author(s): S.J. Antonia
- Abstract
- Presentation
Background:
Treatment options for patients with advanced SQ NSCLC who fail platinum-based doublet chemotherapy (PT-DC) are limited. NIVO, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor, demonstrates activity across NSCLC histologies and is approved in the US for treatment of metastatic SQ NSCLC with progression on or after platinum-based chemotherapy. We report results from a randomized, open-label, global phase 3 study (CheckMate 017; NCT01642004) comparing NIVO vs docetaxel in patients with previously treated SQ NSCLC and disease progression during/after one prior PT-DC regimen.
Methods:
Patients (N=272) were randomized 1:1 to receive either NIVO 3 mg/kg every 2 weeks (Q2W; n=135) or docetaxel 75 mg/m[2] Q3W (n=137) until disease progression or discontinuation due to toxicity or other reasons. For NIVO patients, treatment after initial progression was permitted at the investigator’s discretion, per protocol criteria. The primary objective was overall survival (OS). Secondary objectives included investigator-assessed objective response rate (ORR; per RECIST v1.1), progression-free survival (PFS), efficacy by PD-L1 expression (PD-L1 testing not required for enrollment), patient-reported outcomes (PRO), and safety. PRO analyses are presented in a separate abstract.
Results:
Treatment with NIVO led to 41% reduction in risk of death (hazard ratio [HR]=0.59; 95% CI: 0.44, 0.79; P=0.00025) and improved ORR (20% vs 9%; P=0.0083) and PFS (HR=0.62; 95% CI: 0.47, 0.81; P=0.0004) vs docetaxel (Table). Twenty-eight patients were treated with NIVO beyond initial progression, nine of whom demonstrated a non-conventional pattern of benefit (ie, reduction in target lesions with simultaneous appearance of new lesions, initial progression followed by tumor reduction, or no further progression for ≥2 tumor assessments). Across pre-specified cut-points (1%, 5%, and 10%), PD-L1 expression was neither prognostic nor predictive of benefit. OS HRs favored NIVO across most predefined patient subgroups. Grade 3–4 drug-related adverse events (AEs) were reported in 7% (9/131) of NIVO and 55% (71/129) of docetaxel patients. Grade 3–4 drug-related select AEs are shown below (Table). No deaths were related to NIVO vs 3 docetaxel-related deaths. Figure 1
Conclusion:
CheckMate 017 achieved its primary objective, demonstrating clinically superior and statistically significant OS with NIVO vs docetaxel in patients with advanced, previously treated SQ NSCLC. Benefit was seen regardless of PD-L1 status. The safety profile of NIVO 3 mg/kg Q2W is favorable vs docetaxel and consistent with prior studies. AEs were manageable with established guidelines. NIVO represents a new standard of care in this patient population. Updated OS and safety data will be presented.
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ORAL02.03 - Longer-Term Follow-Up of a Phase 2 Study (CheckMate 063) of Nivolumab in Patients with Advanced, Refractory Squamous Non-Small Cell Lung Cancer (ID 828)
11:07 - 11:18 | Author(s): S.J. Antonia
- Abstract
- Presentation
Background:
Patients with advanced, refractory squamous (SQ) non-small cell lung cancer (NSCLC) have historically poor outcomes and limited treatment options. Nivolumab (NIVO), a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, has activity across NSCLC histologies and is FDA-approved for treatment of metastatic SQ NSCLC with progression on or after platinum-based chemotherapy. We report efficacy, safety, and biomarker analyses from a phase 2, single-arm study of NIVO in patients with SQ NSCLC who progressed during/after prior platinum-based doublet chemotherapy and ≥1 additional systemic regimen.
Methods:
Patients (N=117) received NIVO 3 mg/kg every 2 weeks until progressive disease (PD)/unacceptable toxicity; treatment beyond PD was permitted per protocol. The primary endpoint was independent radiology review committee (IRC)-assessed objective response rate (ORR), per RECIST v1.1. Additional objectives included investigator-assessed ORR, progression-free survival (PFS), overall survival (OS), safety, ORR by patient subgroups, efficacy by tumor PD-L1 expression (PD-L1[+]: ≥5% tumor cells expressing PD-L1), and blood-based biomarker analyses (measurement of circulating microRNA and cytokines).
Results:
IRC-assessed ORR was 15% (95% CI: 9, 22), with a minimum of 11 months follow-up. Median duration of response was not reached (range, 2+–12+ months); 76% (13/17) of patients had ongoing responses. Objective responses were observed across patient subgroups and regardless of PD-L1 expression (Table). Four of 22 patients treated beyond PD demonstrated a non-conventional pattern of benefit (ie, persistent reduction in target lesions in the presence of new lesions, regression following initial progression, or no further progression for ≥2 tumor assessments); OS for these patients was 6.6, 11.6+, 12.9+, and 13.5+ months. The 1-year OS rate was 41% (95% CI: 32, 50) and median OS was 8.2 months (95% CI: 6.1, 10.9). The 1-year PFS rate was 20% (95% CI: 13, 29); median PFS was 1.9 months (95% CI: 1.8, 3.2). Peripheral increases in serum IFN-γ-stimulated cytokines, including CXCL9 and CXCL10, were observed, and preliminary microRNA analyses identified altered gene expression following NIVO treatment. Grade 3–4 treatment-related adverse events occurred in 17% of patients, including fatigue (4%), diarrhea (3%), and pneumonitis (3%). Pneumonitis was manageable with corticosteroids; median time to resolution was 3.4 weeks (range, 0.7–13.4). Two treatment-related deaths (1 hypoxic pneumonia, 1 ischemic stroke) occurred in patients with multiple comorbidities and concurrent PD. Figure 1
Conclusion:
NIVO demonstrated clinically meaningful efficacy and an acceptable safety profile in patients with advanced, refractory SQ NSCLC. Updated 18-month OS, safety, and biomarker analyses will be presented.
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ORAL02.05 - Safety and Efficacy of First-Line Nivolumab (NIVO; Anti-Programmed Death-1 [PD-1]) and Ipilimumab in Non-Small Cell Lung Cancer (NSCLC) (ID 786)
11:28 - 11:39 | Author(s): S.J. Antonia
- Abstract
- Presentation
Background:
Combined blockade of the PD‐1 and cytotoxic T‐lymphocyte‐associated antigen‐4 (CTLA‐4) immune checkpoint pathways has shown improved responses, encouraging survival rates, and a manageable safety profile in advanced melanoma. NIVO, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, has activity across NSCLC histologies and is approved in the US for treatment of metastatic squamous (SQ) NSCLC with progression on or after platinum-based chemotherapy. This phase 1 study evaluated the safety and efficacy of first‐line therapy with NIVO plus ipilimumab (IPI), an IgG1 CTLA‐4 checkpoint receptor blocking antibody, in chemotherapy‐naïve patients with advanced NSCLC.
Methods:
Patients (N=49) received NIVO plus IPI at the 1+3 mg/kg or 3+1 mg/kg combination dose, respectively (one SQ and one non‐SQ cohort per dose level), every 3 weeks for 4 cycles, followed by NIVO 3 mg/kg every 2 weeks until progression or unacceptable toxicity. Objective response rate (ORR; RECIST v1.1) was evaluated overall and by baseline tumor PD‐1 ligand 1 (PD‐L1) expression (PD‐L1[+]: ≥5% tumor cells expressing PD‐L1). Response was assessed at weeks 10, 17, and 23, and every 3 months thereafter until progression.
Results:
Median follow‐up for all patients was 50 weeks. Across histologies, confirmed ORR was 13% (3/24) for NIVO1+IPI3 and 20% (5/25) for NIVO3+IPI1. Two of 3 and 4/5 responders in the NIVO1+IPI3 and NIVO3+IPI1 arms, respectively, achieved a response by first scan. Median duration of response was not reached (NR) in either group, and responses were ongoing in 67% (2/3) and 60% (3/5) of patients treated with NIVO1+IPI3 and NIVO3+IPI1, respectively. Two patients in the NIVO3+IPI1 group exhibited an unconventional “immune-related” response with 56% and 64% maximum reductions in target lesions and simultaneous appearance of new lesions. The 24-week progression-free survival (PFS) rates and median PFS were 44% and 16.1 weeks, respectively, for NIVO1+IPI3 and 33% and 14.4 weeks, respectively, for NIVO3+IPI1. One-year overall survival (OS) rates and median OS were 65% and NR, respectively, for NIVO1+IPI3 and 44% and 47.9 weeks, respectively, for NIVO3+IPI1. Thirty-eight of 49 treated patients were evaluable for PD-L1 expression; objective responses were observed in PD‐L1[+] (19%, 3/16) and PD‐L1[-] (14%; 3/22) patients. Across arms, grade 3–4 treatment-related adverse events (AEs) were reported in 25 patients (51%); grade 3 pneumonitis was reported in 3 (6%) patients. Treatment‐related AEs led to discontinuation in 18 patients (37%); 15 (31%) patients discontinued treatment during induction. Treatment‐related deaths (n=3) were due to respiratory failure, bronchopulmonary hemorrhage, and toxic epidermal necrosis.
Conclusion:
Treatment with NIVO plus IPI was associated with durable responses and encouraging survival regardless of tumor PD-L1 expression. The safety profile was managed using established safety guidelines. Updated OS and results from additional doses and schedules will be presented.
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ORAL02.06 - Evaluation of PD-L1 Expression in Metachronous Tumor Samples and FDG-PET as a Predictive Biomarker in Ph2 Study (FIR) of Atezolizumab (MPDL3280A) (ID 2207)
11:39 - 11:50 | Author(s): S.J. Antonia
- Abstract
- Presentation
Background:
PD-L1 expression on tumor-infiltrating immune cells (IC) and/or tumor cells (TC) can inhibit antitumor immunity. Atezolizumab (MPDL3280A) is an anti-PDL1 antibody that has shown efficacy across multiple tumor types. The efficacy and safety of atezolizumab in the Phase 2 FIR study has been reported previously (Spigel et al, ASCO 2015). Efficacy appeared to correlate with PD-L1 expression on IC and/or TC, with higher ORRs observed in patients with the highest expression of PD-L1, indicating that PD-L1 may be a predictive biomarker for response to atezolizumab. FIR was also designed to address questions of potential heterogeneity and changes in tumor PD-L1 expression in metachronous tissue samples, as well as the utility of using FDG-PET as a biomarker for response to atezolizumab in PD-L1–selected patients with NSCLC.
Methods:
FIR is a 3-cohort, single-arm, Phase 2 study of atezolizumab in PD-L1–selected patients with stage IIIB/IV NSCLC. Cohort 1 included chemo-naive patients, Cohort 2 included ≥ 2L patients without a history of brain metastases, and Cohort 3 included ≥ 2L patients with asymptomatic treated brain metastases. PD-L1 expression was centrally assessed by immunohistochemistry (IHC) using the SP142 antibody assay in archival and/or fresh tumor biopsies or resections and scored as IC0, 1, 2 or 3 and TC0, 1, 2 or 3. Patients with PD-L1 IC2/3 or TC2/3 tumors were enrolled and received 1200 mg atezolizumab IV every 3 weeks (last patient entered Jun 27, 2014). Responses were measured by RECIST v1.1, modified RECIST and FDG-PET using EORTC criteria. Exploratory objectives included the evaluation of potential predictive biomarkers, including the comparison of PD-L1 expression in matched archival and fresh tumor specimens, as well as the utility of FDG-PET in assessing response to immune checkpoint blockade.
Results:
From 1009 screened patients, 95 paired archival and fresh tumor samples were obtained. In these samples, the agreement of PD-L1 expression between fresh and archival tissue at the TC3 or IC3 cutoff was 88% when the same type of tissue procurement method was used (resection or biopsy), compared with 65% when different methods of procurement were used. To date, FDG-PET response has been centrally assessed in 71 of the 138 patients enrolled in FIR. Patients with metabolic response by EORTC criteria on 6-week scans had a higher ORR per RECIST v1.1 (72% [13/18]) than metabolic non-responders (ORR 4% [2/53]).
Conclusion:
There was a high agreement in TC3 or IC3 PD-L1 expression between archival and fresh tumor specimens. This work demonstrates that intra-patient heterogeneity in PD-L1 expression is low in metachronous tissues, indicating various types of tumor samples, including fresh or archival, can be reliably used to assess PD-L1 expression. In addition, FDG-PET has potential as an early on-treatment measure of response to atezolizumab. Further analyses will be presented. (NCT01846416)
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P2.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 213)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.03-006 - Survival Rates after Surgery for Stage-3A (N2) Non-Small Cell Lung Cancer with Induction versus Adjuvant Chemotherapy+/-Radiation Therapy (ID 3151)
09:30 - 09:30 | Author(s): S.J. Antonia
- Abstract
Background:
We compared survival of stage-3A non-small cell lung cancer (NSCLC) patients (pts) after surgery without or with induction versus adjuvant chemotherapy + radiation therapy (chemo+XRT).
Methods:
We retrospectively analyzed pts with clinical stage-3A (cStage3A) NSCLC and who had surgery without or with induction chemo+XRT or who were pathologic stage-3A (pStage3A) and had adjuvant chemo+XRT. Kaplan-Meier survival curves were compared for these 3 groups, with significant differences at p<0.05 by Chi Square test, with Log Rank (Mantel-Cox), Breslow (Generalized Wilcoxon), and Tarone-Ware pairwise comparisons.
Results:
From 1/1986 to 12/2010, there were 300 NSCLC pts who were cStage3A at surgery. Another 52 pts were not cStage3A at surgery, but were then pStage3A. Of these 352 pts, 192 had curative resection, with 56 pts having surgery alone (SURG), 43 pts having surgery after induction therapy (NEOADJ), and 93 pts having surgery then adjuvant therapy (ADJ). Kaplan-Meier survival for SURG was worse than that for either NEOADJ (p=0.03) or ADJ (p=0.005), while NEOADJ and ADJ had similar survival (p=0.90). Median survival was 18+3 mon (95%CI: 12-24 mon) for SURG, 37+6 mon (95%CI: 25-50 mon) for NEOADJ, and 41+5 mon (95%CI: 31- 51 mon) for ADJ. Survival for NEOADJ chemo-alone pts was better than for SURG pts (p=0.031), while that of NEOADJ chemo+XRT pts was similar to SURG survival (p=0.488). Survival for ADJ chemo-alone pts was better than for SURG pts (p=0.007), while that of ADJ chemo+XRT pts was similar to SURG survival (p=0.163).
Conclusion:
Stage-3A NSCLC pts have improved survival with either induction or adjuvant therapy compared to surgery alone. Patients with induction or adjuvant chemo alone, but not those with induction or adjuvant chemo+XRT, have improved survival compared to surgery alone.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-086 - A Phase I Dose-Escalation Study of Pirfenidone Combined with Standard First-Line Chemotherapy in Advanced-Stage Lung NSCLC (ID 712)
09:30 - 09:30 | Author(s): S.J. Antonia
- Abstract
Background:
Approximately 1.6 million people are diagnosed with lung cancer annually, of which 85% of cases are NSCLC. Due to limited efficacy of current conventional chemotherapy, the majority of patients face poor prognosis; thus, combining chemotherapy with agents targeting the tumor microenvironment may be a novel approach to improving survival outcomes. Pirfenidone (5-methyl-1-phenyl-1H-pyridine-one), an agent demonstrating activity against fibroblasts and growth-promoting cytokines (TGF-β1, fibroblast growth factor [FGF], epidermal growth factor [EGF], and platelet-derived growth factor [PDGF]), has demonstrated clinical efficacy in IPF but has not yet been studied in lung cancer. We propose a proof-of-concept trial testing a novel combination of pirfenidone plus standard first-line chemotherapy in the treatment of advanced-stage NSCLC. Pirfenidone Pirfenidone has demonstrated activity against growth-promoting cytokines such as TGF-β1, FGF, EGF, and PDGF. A recent Phase III clinical trial of pirfenidone compared to placebo in patients with IPF demonstrated improved lung function, exercise tolerance, and progression-free survival (PFS) with an acceptable side-effect profile. To date, pirfenidone has not been studied in cancer, but its anti-fibroblast properties may play an important role in the tumor microenvironment. Our hypothesis is that pirfenidone (by targeting CAFs) in combination with standard chemotherapy will act synergistically and proffer a more potent strategy for NSCLC treatment. Data Generated in Dr Antonia’s Lab at Moffitt Cancer Center Using low doses of pirfenidone (0.5 mg/ml), we observed a small decrease in cell proliferation (20%), also noted with low doses of cisplatin (10%). When both drugs were used, we observed a synergistic decline in proliferation (60%). An in vivo model was performed to verify this data: nude mice were inoculated with a combination of A549 cells and CAF cells at a 1:1 ratio. Treatment with pirfenidone and cisplatin began as soon as tumors were palpable. Cisplatin- or pirfenidone-treated mice had a larger tumor size than mice treated with the combination, and on the final day (43 days after start of treatment), the combination showed statistically significant improvement compared to controls. This led to our hypothesis that similar tumor regression may occur in NSCLC patients.Figure 1
Methods:
Phase I, single-center, dose-escalation study. Phase I trial, followed by an expansion of 20 pts with non-squamous and 10 pts with squamous cell lung cancer. Primary Objectives: Determine safety, tolerability, and MTD of pirfenidone plus chemotherapy in pts with advanced NSCLC, and obtain the preliminary ORR. Secondary Objectives: Determine OS and PFS of pts treated with pirfenidone plus standard first-line chemotherapy.
Results:
Not applicable
Conclusion:
Not applicable
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P3.01-090 - Phase 3, Double-Blind, Placebo-Controlled Study of MEDI4736 after Chemoradiation in Stage III, Locally Advanced, Unresectable NSCLC (PACIFIC) (ID 1263)
09:30 - 09:30 | Author(s): S.J. Antonia
- Abstract
Background:
Non-small cell lung cancer (NSCLC) accounts for 85–90% of all lung cancer cases. Approximately 35% of patients with NSCLC have Stage III disease at the time of diagnosis. Platinum-based, concurrent chemoradiation therapy is the standard treatment for patients with locally advanced, unresectable NSCLC. However, most patients progress despite treatment, and 5-year overall survival (OS) is only ~15%. Therefore, there is a significant unmet need for novel, effective therapeutic approaches to prolong survival. Immunotherapies that block checkpoints used by tumor cells to dampen immune responses are a promising new treatment option. Encouraging clinical activity against several tumor types has been seen for anti-PD-L1/PD-1 monoclonal antibodies (mAbs). MEDI4736 is a human IgG1 mAb that blocks programmed cell death ligand-1 (PD-L1) binding to programmed cell death-1 and CD-80 with high affinity and selectivity, preventing PD-L1-mediated inhibition of T-cell activation. It has been engineered to harbor a triple mutation in the fragment crystallizable domain, which removes antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. Evidence of clinical activity for MEDI4736 in NSCLC has been observed in a Phase 1 study (Study 1108, NCT01693562), with initial data indicating that PD-L1 expression is associated with a higher objective response rate (ORR). Chemotherapy and radiotherapy upregulate the expression of tumor PD-L1, which could increase sensitivity to PD-L1-directed therapy. Based on this rationale, the PACIFIC study (NCT02125461) will evaluate the efficacy and safety of MEDI4736 in patients with locally advanced, unresectable NSCLC (Stage III) whose disease has not progressed following platinum-based, concurrent chemoradiation therapy.
Methods:
In this Phase 3, randomized, double-blind, multicenter, international study, ~700 patients will be randomized 2:1 to receive MEDI4736 (10 mg/kg IV) or placebo every 2 weeks for up to 12 months. Eligible patients must have previously received ≥2 cycles of platinum-based concurrent chemoradiation with no subsequent disease progression, have received a total dose of radiation of ≥60 Gy, and have archival tissue available. Patients treated with sequential chemoradiation therapy for locally advanced disease and those with metastatic disease are excluded. Randomization must occur within 42 days of radiation. Co-primary endpoints are OS and progression-free survival (PFS) (RECIST v1.1). Secondary endpoints include OS at 24 months, proportion of patients alive and progression-free at 12 and 18 months, time to second progression, objective response rate, duration of response, health-related quality of life, safety/tolerability, pharmacokinetics and immunogenicity of MEDI4736. Patients who achieve and maintain disease control up to 12 months will enter follow-up. Patients will be recruited at approximately 300 sites across Australia, Asia, Europe, North and South America and South Africa. Recruitment is ongoing.
Results:
Not applicable
Conclusion:
Not applicable
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-081 - Molecular Evidence of Viral DNA in Non-Small Cell Lung Cancer (NSCLC) and Normal Lung (ID 726)
09:30 - 09:30 | Author(s): S.J. Antonia
- Abstract
Background:
Although 20% of human cancers are caused by infections, only suspicion exists for a microbial cause of lung cancer. This study investigated potential infectious agents in the etiology of non-small cell lung cancer (NSCLC) in both frozen tumor of the major cell types and non-neoplastic lung using several molecular methods.
Methods:
Nucleic acids were extracted from 30 frozen NSCLC [10 squamous cell (SCC), 10 adenocarcinomas (ADC), 10 bronchioloalveolar (BAC)] and 10 non-neoplastic lung tissue specimens. All specimens were screened for microbial DNA on a pan-microbial detection array containing 135,000 DNA probes and controls to detect all sequenced viral and bacterial pathogen species. Additionally, SCC specimens were evaluated by PCR for the presence of 27 subtypes of human papillomavirus (HPV) and an independent panel of 17 known or suspected oncoviruses.
Results:
RESULTS: Using the pan-microbial microarray, several species of retroviral DNA were observed in 100% of SCC, 60% of ADC, and 10% of BAC (Table 1). Among the SCC specimens, HPV DNA was found in 60%, with 30% containing one or more high-risk HPV types, but the oncovirus panel was negative. No consistent viral DNA was detected in non-neoplastic lung specimens by the pan-microbial microarray.
Table 1. Viral DNA Found in Human Lung Cancer Specimens: Pan-Microbial Array ResultsLung cancer cell type HPV (human papillomavirus, type 57) HBV (hepatitis B virus) HTLV-2 (human T- lymphotropic virus 2), a Delta-retrovirus Bovine leukemia virus (a Delta-retrovirus, similar to HTLV-1) Y53 Sarcoma virus (an Alpha-retrovirus) STLV-1, 2, or 6 (simian T-cell leukemia viruses, Delta-retroviruses) Squamous cell ca. n=10 6 (60%) 9 (90%) 7 (70%) 8 (80%) 0 8 (80%) Adenoca. n=10 1 (10%) 2 (20%) 0 0 6 (60%) 1 (10%) Bronchioloalveolar ca. n=10 0 0 0 0 1 (10%) 0 Normal lung, n=10 0 0 0 0 0 0
Conclusion:
High-risk HPV types were detected in many squamous cell lung cancers and, retroviral DNA was found in the majority of NSCLC but not in non-neoplastic lung. Of the 24 naturally-occurring animal cancers with a known etiology including lung adenocarcinoma in sheep, all are induced by retroviruses. Results from this initial discovery trial encourage further study of the viral contribution to human lung oncogenesis.
