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J.W. Goldman
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MS 26 - Genomic Alterations and Drug Targets in Small Cell Lung Cancer (ID 44)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 5
- Moderators:D. Beer, J.W. Goldman
- Coordinates: 9/09/2015, 14:15 - 15:45, Mile High Ballroom 2c-3c
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MS26.01 - Genomic Alterations (ID 1963)
14:15 - 15:45 | Author(s): J.C. Yang
- Abstract
- Presentation
Abstract:
Genomic Alterations and Drug Targets in Small Cell Lung Cancer Over the past 15 years, we have made a lot of advances in the treatment of non small cell lung cancer (NSCLC). However, the treatment paradigm for small cell lung cancer (SCLC) remains the same as 30 years ago, e.g., concurrent chemoradiotherapy for limited stage SCLC and chemotherapy for extensive stage SCLC. The successful introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for the treatment of lung cancer patients has helped us understand the underlying genomic alterations in responding patients and the biology of tumor cells harboring EGFR mutations. In contrast to the successful story of EGFR TKIs in NSCLC treatment leading to the discovery of EGFR mutations in responding patients, the discovery of EML4-ALK fusion in NSCLC has led to the successful treatment of crizotinib in patients harboring this mutation. Crizotinib was designed to inhibit cMET but was developed successfully as an ALK inhibitor for those patients. Further genomic analysis of lung adenocarcinoma patients disclosed that some specific recurrent mutations in EGFR, HER2, KRAS, NRAS, BRAF, cMET, EML4-ALK, ROS1, RET fusions etc. were found in patients. However, each patient only harbored one mutation. Specific inhibitors are very effective in the treatment of lung adenocarcinoma patients harboring corresponding targeted mutations. Thus, driver mutation or oncogene addiction hypothesis was built through genomic analysis of lung adenocarcinoma patients and clinical observations of successful targeted therapy treatment. Several targeted therapies have been tested in a small scale of advanced stage SCLC patients. None of the studies showed any signal of anticancer activity in years. Thus, radiotherapy and chemotherapy remain the effective treatment for SCLC. Current technique allowed us to examine cancer genome in detail. The information can be used to predict clinical usage of certain targeted therapy. Genomic analysis of SCLC may open a door for us to understand the basic differences between NSCLC and SCLC and ponder the ineffectiveness of targeted therapy in SCLC. Genomic alterations of SCLC cells were first described in 1980s by observation of chromosome aberrations. Frequent deletion of 3p was first observed by Peng-Whang J et al. The most frequent reported genetic alterations in SCLC cells were inactivting mutations of TP53, RB1, PTEN, mutations in PIK3CA, EGFR and KRAS, amplification of myc family, EGFR and BCL2 as well as loss of RASSF1A, PTEN and FHIT. Those genomic alterations were examined through small series of samples and target gene examinations. Systemic approach to explore the multitude and magnitude of genomic alterations in SCLC was only possible with recent next generation sequencing technology and the application of bioinformatics to analyze the vast amount of data generated from the samples. Rudin et al. have collected 36 primary human SCLC and normal tissue pairs and 17 matched SCLC and lymphoblastoid cell lines and examined the exome, transcriptome and copy number alterations. In 4 primary tumors and 23 SCLC cell lines, the authors identified 22 significant mutated genes. In the exome of 42 SCLC tumor normal tissue pairs, they identified 26406 somatic mutations. 30% of them resulted in protein alterations. An average of 175 protein-altering single nucleotide variants was calculated per patient. G-to-T transversions were the predominant mutation, followed by G-to-A and A-to-G transition mutations signify that these mutations were related to tobacco smoke carcinogens. In the whole genome analysis of one patient, 286 protein-altering changes were found. Frequent altered genes included genes encoding for kinases, G-protein-coupled receptors and chromatin-modifying proteins. The authors found that SOX2 mutation or amplification was frequently found in its series. SOX2 expression may play some crucial roles in SCLC cells, such as maintenance of pluripotency of stem cells property. In addition, the authors also discovered several non-recurrent fusion genes from RNA-seq data. The roles of these fusion proteins in SCLC are less well understood. But some of those fusion proteins seem to result in activating kinases. Peifer M et al. sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes. They discovered inactivation of TP53, RB1 and recurrent mutations in CREBBP, EP300 and MLL genes. Additional findings included mutations in PTEN, SLIT2, EPHA7 and FGFR1 amplification. They concluded that histone modification is a major feature of SCLC. Both comprehensive genomic studies disclosed similar gene alterations such as TP53 and RB1 are the important signatures of SCLC genomic alterations. However, an individual analysis pointed out at different angles, for example, SOX2 or histone modification. The different results of two series reflected that only a limited number of samples were tested, interpatient heterogeneity may be huge and more genomic studies should be performed in the future. When major genomic alterations were compared among lung adenocarcinoma, squamous cell carcinoma and SCLC, alterations of TP53, CDKN2A, PIK3CA and PTEN were commonly found in all three types of lung cancer. FGFR1 and SOX2 alterations were found in SCLC and squamous cell carcinoma, whereas KEAP1 alterations was detected in both squamous cell carcinoma and adenocarcinoma. Recently, transformation from adenocarcinoma to SCLC was detected in a minority of patients with EGFR mutations who have received EGFR TKIs and developed resistance. Typical EGFR mutations can be found in untreated SCLC patients, especially in east Asian ethnic patients. Occasionally mixed SCLC and adenocarcinoma were described under light microscopy. Some of those patients harbor EGFR mutations. Unfortunately, EGFR TKI was usually not effective in the treatment of such patients, it suggested that alterations of the transcriptional factors contributed SCLC phenotype being more dominant and only chemotherapy was effective to control the progression of the disease. The heterogeneous nature of genomic alterations in SCLC suggested that targeted therapy may be difficult to be successful in SCLC treatment. None of the altered genes seems to be the dominant driver. On the other hand, RB1 and myc, genes altered easily that are not the good targets for current targeted therapy. Thus, genomic analysis of SCLC further indicated that the combination of targeted therapy may not be useful. It may have to combine targeted therapy and chemotherapy to obtain better anti-cancer activity. However, patient selection may be needed according to the genomic findings and pathway predictions. The hyper mutational genomic background was a good predictor for immune checkpoint inhibitor therapy. However, in a recent report in American Society of Clinical Oncology Meeting suggested that only a low response rate was noted in SCLC treated with immune checkpoint inhibitors. More genomic, immune studies and clinical trials are needed to advance the treatment of SCLC in the future.
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MS26.02 - The MYC/MAX and the SWI/SNF Networks: Biological Understanding and Therapeutic Applications (ID 1964)
14:15 - 15:45 | Author(s): M. Sanchez-cespedes
- Abstract
- Presentation
Abstract:
The SWI/SNF chromatin-remodeling complex modifies the structure of the chromatin by the ATP-dependent disruption of DNA–histone interactions at the nucleosomes to activate or repress gene expression. The widespread occurrence of alterations at genes encoding different components of the SWI/SNF complex reveals an important new feature that sustains cancer development and offers novel potential strategies for cancer therapeutics. We discovered that in lung cancer the SWI/SNF component, BRG1 (also called SMARCA4), is genetically inactivated in about thirty per cent of non-small cell lung cancers (NSCLC), and that its inactivation occurs in a background of wild type MYC (either C, L or N). Here, we also report our discovery of tumor-specific inactivation of the MYC-associated factor X gene, MAX, in about ten percent of small cell lung cancers (SCLC). This is mutually exclusive with alterations at MYC and BRG1. We also demonstrate that BRG1 regulates the expression of MAX through direct recruitment to the MAX promoter, and that depletion of BRG1 strongly hinders cell growth, specifically in MAX-deficient cells, heralding a synthetic lethal interaction. Furthermore, MAX requires BRG1 to activate neuroendocrine transcriptional programs and to up-regulate MYC-targets, such as glycolytic-related genes. Finally, we observed genetic inactivation of the MAX dimerization protein, MGA, in lung cancers with wild type components of the SWI/SNF or MYC pathways. Our results provide evidence that an aberrant SWI/SNF-MYC network is essential for lung cancer development. Altogether, the genetic observations coupled with the functional evidence demonstrate that an aberrant SWI/SNF-MYC network is essential for lung cancer development, and opens novel therapeutic possibilities for the treatment of SCLC patients with MAX-deficient tumors. In healthy adults and during embryonic development, the complex is involved in the control of cell differentiation and in the specification of different tissues. The effect of the SWI/SNF complex on some of these processes is, at least in part, related to its involvement in regulating hormone-responsive promoters. Components of the SWI/SNF complex bind to various nuclear receptors, such as those of estrogen, progesterone, androgen, glucocorticoids and retinoic acid, thereby adapting the gene expression programs to the demands of the cell environmental requirements. Retinoic acid (RA) and glucorticoids (GC) are well known modulators of cell differentiation, embryonic development and morphogenesis. Their role in promoting cell differentiation makes it possible to use GC and RA therapeutically to treat some types of cancers. GC are part of the curative treatment of acute lymphoblastic leukemia while RA is the therapeutic agent for some neuroblastomas and acute promyelocytic leukemia, which both carry the PML–RARa gene fusion. GC are also used as a co-medication in the therapy of solid tumors, because of their effectiveness in treating the malignancy, or due to their less severe side effects in cancer treatment, such as electrolyte imbalance, nausea and emesis. However, most solid tumors, including lung cancers, are refractory to GC- and RA-based therapies. Underlying some cases of refractoriness to GC and RA is a dysfunctional SWI/SNF complex, for example due to alterations at BRG1. On the other hand, compounds that modulate the structure of the chromatin are currently used to treat cancer. These include histone deacetylase (HDAC) inhibitors, in hematological malignancies and cutaneous T-cell lymphomas, and inhibitors of DNA methylation such as azacytidine for myelodysplasic syndrome. HDACs and DNA methylation inhibitors promote gene transcription by increasing DNA accessibility through the inhibition of histone deacetylation and DNA methylation, respectively. These drugs have been tested in lung cancer patients in two studies, in which they showed no major responses. However, in a phase I/II trial, the combination of the two inhibitors produced a median survival of the entire cohort that was significantly longer than those of the existing therapeutic options. Here, we aimed to determine whether there could be a therapeutic use for GC plus RA (GC/RA) in combination with the epigenetic drugs azacytidine and SAHA (A/S) for treating lung cancers carrying BRG1 inactivation or MYC amplification. We found that in vitro, GC/RA treatment reduced growth, triggered pro-differentiation gene expression signatures and downregulated MYC, in MYC-amplified but not in most BRG1-mutant lung cancer cells. The co-administration of A/S enhanced all these effects, accompanied by sustained reductions in genome-wide DNA methylation. In vivo, treatments with GC/RA improved overall survival of mice implanted with MYC-amplified cells and reduced tumor-cell viability and cell proliferation. Thus, we propose that the combination of retinoids, corticoids and epigenetic treatments of lung tumors with MYC amplification constitute a strategy for therapeutic intervention in this otherwise incurable disease. REFERENCES Collins SJ. The role of retinoids and retinoic acid receptors in normal hematopoiesis. Leukemia 2002; 16, 1896–905. Liu SV, Fabbri M, Gitlitz BJ, Laird-Offringa IA. Epigenetic therapy in lung cancer. Front Oncol 2013; 3, 135. Medina PP et al. Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell lines. Hum Mut 2008; 29, 617-22a. Pottier N et al. The SWI/SNF chromatin-remodeling complex and glucocorticoid resistance in acute lymphoblastic leukemia. J Natl Cancer Inst 2008; 100, 1792-803. Rodriguez-Nieto S et al. Massive parallel DNA pyrosequencing analysis of the tumor suppressor BRG1/SMARCA4 in lung primary tumors. Hum Mut 2011; 32, E1999-2017. Romero OA et al. The tumour suppressor and chromatin-remodelling factor BRG1 antagonizes Myc activity and promotes cell differentiation in human cancer. EMBO Mol Med 2012; 4, 603-16. Romero OA et al. MAX inactivation in small cell lung cancer disrupts MYC-SWI/SNF programs and is synthetic lethal with BRG1. Cancer Discov 2014; 4, 292-303. Romero OA, Sanchez-Cespedes M. The SWI/SNF genetic blockade: effects in cell differentiation, cancer and developmental diseases. Oncogene 2014; 33, 2681-9. Rutz HP. Effects of corticosteroid use on treatment of solid tumours. Lancet 2002; 360, 1969–70. Wilson GB,Roberts CWM. SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer 2011; 11, 481-92.
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MS26.03 - Targeting ASCL1 in Neuroendocrine Lung Cancers via a MAPK-Regulated Double-Negative Feedback Loop (ID 1965)
14:15 - 15:45 | Author(s): J. Minna, A. Augustyn, S. Earnest, P. Dospoy, J. Johnson, M. Cobb
- Abstract
- Presentation
Abstract:
ASCL1 is a lineage-specific transcription factor responsible during development for the formation of pulmonary neuroendocrine cells. ASCL1 is highly expressed in the majority of neuroendocrine lung tumors including small cell lung cancer (SCLC) and non-small cell lung cancer with neuroendocrine features (NSCLC-NE). Others have shown that SCLC survival depends on continued ASCL1 expression while we showed that ASCL1 is also required for the survival of NSCLC-NEs; that ASCL1 down-stream targets predict for poor survival in NSCLC patients; and that BCL2 is a therapeutically actionable ASCL1 target gene (PNAS 2014;111(41):14788-93). Thus, we are trying to target ASCL1 and its “druggable” downstream genes by developing ASCL1 based ChIP-Seq datasets in SCLC and NSCLC-NE tumors. We have now discovered a way to reliably regulate ASCL1 protein expression through “upstream” targeting. Phorbol 12-myristate 13-acetate (PMA) is an agonist of the MAPK pathway via specific activation of Protein Kinase C. Treatment of ASCL1(+) HCC1833 cells for 24 hours with nM quantities of PMA resulted in a robust down-regulation of ASCL1 mRNA and protein. Tumor cell death was apparent and apoptosis confirmed via induction of cleaved PARP. ASCL1 down-regulation was associated with activation of the MAPK pathway, measured by increased protein levels of phosphorylated ERK (pERK), and decreased ASCL1 mRNA expression was found to be at least partly due to mRNA degradation. These data indicate that activation of the MAPK pathway in high-grade neuroendocrine tumors has potential for therapeutic intervention and also provides a reason for the previously unexplained low levels of MAPK activation (pERK) in SCLC. Unexpectedly, we also found that siRNA mediated knockdown of ASCL1 resulted in activation of the MAPK pathway. In addition, pERK was significantly induced with ASCL1 knockdown even when we also knocked down MEK1 (MEK1 knockdown by itself completely eliminated pERK expression). The MAPK pathway depends on active phosphorylation/dephosphorylation and this is regulated in part by dual-specificity phosphatases (DUSPs). Using our ASCL1 ChIP-Seq data, we identified a conserved ASCL1 binding site in the promoter region of DUSP6. DUSP6 mRNA was found to be dramatically elevated in ASCL1(+) lines HCC1833 and H889, while by contrast there was little or no DUSP6 expression in ASCL1(-) SCLC lines H82 and H526, and knockdown of ASCL1 resulted in a decrease of DUSP6 protein suggesting transcriptional regulation. This led us to try a DUSP6 allosteric inhibitor (E/Z-BCI, Sigma-Aldrich) which induced pERK, decreased ASCL1 protein expression, and inhibited soft agar colony forming ability of H889 SCLC cells. In conclusion: Our data indicate that the MAPK pathway regulates ASCL1 expression, where activation of pERK signaling is correlated with decreased ASCL1 mRNA and protein. In addition, ASCL1 in turn, actively down-regulates the MAPK pathway. Our hypothesis is that high-grade neuroendocrine lung cancers down-regulate the MAPK pathway in order to maintain ASCL1 expression, which promotes cell survival and maintenance of the neuroendocrine lineage. This points to a double-negative feedback loop involving the MAPK pathway, ASCL1, and at least one DUSP. Targeting components of the MAPK pathway regulating ASCL1 expression is thus a new therapeutic avenue for high-grade neuroendocrine lung cancers. (Lung Cancer SPORE P50CA70907, NIH 1F30CA168264, CPRIT).
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MS26.04 - FGFR1 Co-Activation Networks in Lung Cancer (ID 1966)
14:15 - 15:45 | Author(s): L. Heasley
- Abstract
- Presentation
Abstract:
FGFR1 is a therapeutic target under investigation in multiple solid tumors and clinical trials of FGFR-specific and selective tyrosine kinase inhibitors (TKIs) are underway. Our recent studies have demonstrated a role for unmutated FGFR1 as a driver in lung cancer cell lines of all histologies including small cell lung cancers (SCLCs), head and neck squamous cell carcinomas (HNSCCs) and mesotheliomas. Although potent in vitro growth suppression of lung cancer cell lines is observed in response to multikinase inhibitors such as ponatinib as well as FGFR-specific TKIs (AZD4547, BGJ398), the in vivo inhibitory effects of these drugs on xenografts propagated in immune deficient mice are more modest and short-lived in our hands. Thus, while treatment with single FGFR TKIs represents a logical entry point to personalized therapy of cancers bearing over-expressed FGFR1, we hypothesize that intrinsic mechanisms involving rapid kinome reprogramming events limit the therapeutic efficacy of these TKIs. In fact, ample precedent exists to support the signaling of receptor tyrosine kinases (RTKs) within "co-activation networks" where multiple RTKs engage multiple signal pathways to bring about robust and flexible activation of signal cascades. We deployed RNAi-based functional genomic screens to identify protein kinases controlling the intrinsic sensitivity of FGFR1-dependent lung cancer and HNSCC cells to ponatinib, a multi-kinase FGFR-active inhibitor. Mammalian Target of Rapamycin (MTOR) was identified and validated as a synthetic lethal kinase with ponatinib in H157 and H1299 cells. In other FGFR1-expressing cell lines (Colo699, H520 and H1703), MTOR was an essential protein kinase as evidenced by high sensitivity to MTOR-targeting shRNAs and pharmacological inhibitors. Despite wide ranging MTOR dependencies observed among the FGFR1-dependent cell lines, synergistic in vitro growth inhibition was a general observation when FGFR inhibitors where combined with pharmacological inhibitors of MTOR or AKT. At the molecular levels, FGFR inhibitors potently inhibited MEK/ERK activity while MTOR inhibitors reduced the activity of TORC1 (p70S6K, S6) and TORC2 (AKT Ser473)-specific targets. In combination, FGFR TKIs and MTOR inhibitors simultaneously eliminated MEK/ERK and MTOR signaling. Xenografts generated from the FGFR1-dependent lung cancer cell lines, Colo699 and H1581, exhibited only modest sensitivity to monotherapy with the FGFR-specific TKI, AZD4547. However, consistent with the in vitro findings, combination treatment with AZD4547 and the MTOR inhibitor, AZD2014, afforded significantly greater tumor growth inhibition and prolonged survival. The data support the existence of a signaling network wherein unmutated FGFR1 drives the ERK pathway and distinct receptors under investigation activate the MTOR/AKT pathway to induce full transformation. Combining MTOR inhibitors with FGFR-specific TKIs may yield greater clinical efficacy in FGFR1-driven lung cancers.
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MS26.05 - Drug Screening Targets (ID 1967)
14:15 - 15:45 | Author(s): C. Lee Hann
- Abstract
- Presentation
Abstract not provided
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Author of
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MINI 02 - Immunotherapy (ID 92)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:P. Forde, S.J. Antonia
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F3+F4
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MINI02.09 - ERK Activation Mediates Increased PD-L1 Expression in KRAS Mutated Premalignant Human Bronchial Epithelial Cells (ID 1620)
10:45 - 12:15 | Author(s): J.W. Goldman
- 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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MINI 03 - PD1 Axis Inhibition and EGFR (ID 101)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:L. Gandhi, Y. Ohe
- Coordinates: 9/07/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
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MINI03.01 - Prior TKI Therapy in NSCLC EGFR Mutant Patients Associates with Lack of Response to Anti-PD-1 Treatment (ID 2172)
16:45 - 18:15 | Author(s): J.W. Goldman
- Abstract
- Presentation
Background:
Programmed cell death-1 (PD-1) inhibitors have shown significant potential to induce durable responses in non-small cell lung cancer (NSCLC). Although responses have been seen in patients (pts) whose tumors harbor epidermal growth factor receptor (EGFR) mutations (EGFRm), data to date with inhibitors of PD-1, or its ligand PD-L1, suggest that responses are less frequent in EGFRm NSCLC. Studies in which EGFRm pts receive EGFR tyrosine kinase inhibitors (TKIs) and PD-1 inhibitors in sequence or concurrently are being conducted. However, based on the high response rate with EGFR TKIs in EGFRm pts, PD-1 inhibition does not precede the EGFR TKIs in these study designs.
Methods:
We evaluated data from our experience at UCLA as part of the KEYNOTE-001 clinical trial, in which pts received pembrolizumab 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks. Early in the trial, an amendment excluded EGFRm, EGFR TKI naïve pts, however a subsequent amendment allowed such pts if their mutation was non-sensitizing to approved EGFR TKIs. Although the trial employed central radiographic assessment by RECIST v1.1 (available to the sponsor but not the sites), clinical decisions and the assessment we describe were based on investigator-assessed immune-related response criteria. Groups were compared using Fisher’s exact test. Western blot was performed using standard techniques, exposing human non-small cell lung cancer cell lines HCC-827, H1975, Calu3 and H460 to erlotinib or afatinib at 1µM or control using the antibody PD-L1 mAb #1368 (Cell Signaling) and α-tubulin antibody #2144 (Cell Signaling).
Results:
We enrolled 29 EGFRm pts. 2 of 3 EGFR TKI naïve pts experienced a partial response (PR) compared to 1 of 26 enrolled after a prior EGFR TKI (p<0.001). 18 of these 29 pts had a 9 week scan. Of these, PR was seen in both EGFR TKI naïve pts (one L858R mutation and one exon 20 insertion) compared to 1 of 16 enrolled after a prior EGFR TKI (p<0.001). Of note, a similar trend of increased responses in EGFR TKI naïve pts was not seen in EGFR wild type pts. In vitro experiments using erlotinib and afatinib showed unchanged PD-L1 levels in cell lines not inhibited by the EGFR TKI used, but reduced PD-L1 in EGFRm cell lines inhibited by the TKI. Of note, the only responder among the EGFR TKI-treated EGFRm pts was one of only 4 of the 16 scanned post-TKI pts who had a non-sensitizing mutation. So, 0 of 22 EGFRm pts with a sensitizing mutation responded after an EGFR TKI.
Conclusion:
A retrospective analysis in EGFRm NSCLC showed a strong correlation between response and lack of prior EGFR TKI treatment. PD-L1 levels decrease in response to an EGFR TKI in cell lines sensitive to the TKI. Immunohistochemistry evaluating the presence and location of relevant proteins and immune effector cells are ongoing as is whole exome sequencing. These results have implications for the design of clinical trials of PD-1 inhibitors in EGFRm pts. Supported by: 1K23CA149079, One Ball Matt Memorial Golf Tournament, Kasdan Family
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MINI03.10 - Rociletinib in NSCLC Patients with Negative Central Testing for T790M in TIGER-X (ID 951)
16:45 - 18:15 | Author(s): J.W. Goldman
- Abstract
- Presentation
Background:
Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC). Rociletinib has demonstrated efficacy against activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. New insights into mutEGFR NSCLC suggest clonal heterogeneity – activating EGFR mutations are truncal (present in all tumor clones) and T790M is a dominant branch mutation with variable clonal frequency between patients and over time. The extent of this clonal heterogeneity may relate to rociletinib efficacy. Here we present preliminary findings to evaluate this hypothesis from an ongoing Phase 1/2 clinical trial.
Methods:
TIGER-X (NCT01526928) is a Phase I/II open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with metastatic or unresectable locally advanced EGFR mutation-positive NSCLC with progressive disease after ≥1 EGFR tyrosine kinase inhibitor (TKI). Screening included mandatory tumor biopsy and T790M testing. For Phase 1, patients could be T790M negative, positive or unknown. For Phase 2, T790M negative patients (by validated central testing) could have a contemporaneous local T790M+ result.
Results:
As of March 2015, 36 patients were enrolled in TIGER-X who were T790M central negative by cobas® or Qiagen therascreen® and evaluable for efficacy. Sensitivity analysis indicated that the 2 assay platforms were comparable for T790M detection. 69% (25/36) were T790M negative centrally but positive locally; 4/36 (11%) were negative by both central and local testing; and 7/36 (19%) were centrally negative with no local result. Median number of previous TKIs was 1 and median number of previous therapies was 2; 81% (29/36) were treated with a TKI as their most recent prior therapy. In central negative/local+ patients the ORR was 40% (10/25). In central negative/local negative patients the ORR was 25% (1/4). The most common treatment emergent adverse events in this subset (all grades) were fatigue, diarrhea, nausea and hyperglycemia.
Conclusion:
These preliminary findings suggest that patients who test negative for T790M using a sensitive tissue test may still benefit from treatment with rociletinib. In part, this clinical activity may be driven by T790M tumor heterogeneity, demonstrated by the discordant T790M results described. In addition, inhibition of IGF-1R/IR by the previously reported (Soria 2014) rociletinib metabolite M502 may also be driving some of the activity observed. This possible explanation is important, since the response rates reported herein are higher than described for other T790M inhibitors in T790M-negative patients. Furthermore, TKI re-treatment effect is unlikely to be a major driver of these results, since the majority of patients came on study directly after progression on another EGFR TKI. To further explore these findings, the open-label TIGER-2 (NCT02147990) and the randomized Phase 3 TIGER-3 (NCT02322281) studies include T790M negative patients.
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MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:G.J. Riely, M.C. Garassino
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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MINI16.03 - Dose Optimization of Rociletinib for EGFR Mutated NSCLC (ID 967)
16:45 - 18:15 | Author(s): J.W. Goldman
- Abstract
- Presentation
Background:
Rociletinib (CO-1686) is a novel, oral, irreversible mutant selective tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC). Rociletinib has demonstrated efficacy against activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. A maximum tolerated dose was not identified in Phase 1 with 1000 mg BID the highest dose studied. Here we assess the efficacy and safety of the three doses of rociletinib (500 mg BID, 625 mg BID and 750 mg BID) selected for Phase 2 study.
Methods:
TIGER-X (NCT01526928) is a Phase 1/2 open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with advanced EGFR mutant NSCLC progressing after ≥1 EGFR tyrosine kinase inhibitor (TKI). Efficacy is assessed using RECIST. Safety is evaluated using standard adverse event (AE) reporting.
Results:
As of April 2015, a total of 231 central T790M positive patients were evaluable for efficacy and 343 for safety (any T790M). All patients were enrolled in the USA (85%), Europe (9%) and Australia (6%). Baseline characteristics were similar in each dose group. The median number of prior therapies was 2. 85% had EGFR TKI as their most recent prior therapy and 10% had a history of diabetes/hyperglycemia. Immature ORRs are 53% (500 mg BID), 52% (625 mg BID) and 43% (750 mg BID), with disease control rates of 89% (500 mg BID), 87% (625 mg BID) and 82% (750 mg BID). The most common ≥grade 3 treatment-related AE was hyperglycemia [16% (500 mg BID), 25% (625 mg BID) and 35% (750 mg BID)] which was managed with oral hypoglycemic agents. Only one patient discontinued the study for hyperglycemia. Grade 3 QTc prolongation was uncommon, occurring in 2% (500 mg BID), 7% (625 mg BID) and 10% (750 mg BID) of patients, and demonstrated a relationship to dose. There were no clinically relevant cutaneous toxicities with 7 cases of grade 1 rash and 4 cases of grade 1 stomatitis (no dose relationship) and no paronychia.
Conclusion:
All 3 Phase 2 doses of rociletinib are active and well tolerated in a Western patient population with advanced NSCLC. The lack of cutaneous toxicities confirms the selectivity of rociletinib for mutant forms of EGFR and is an important contributor to QOL and maintaining dose intensity (Lacouture et al. 2011). Overall, the adverse event frequency appears to be related to dose, but antitumor activity does not, thus the risk/benefit profile may be optimal at the lowest dose studied.
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MINI16.04 - Activity of Rociletinib in EGFR Mutant NSCLC Patients with a History of CNS Involvement (ID 965)
16:45 - 18:15 | Author(s): J.W. Goldman
- Abstract
- Presentation
Background:
Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) with activity against the activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. TIGER-X (NCT01526928) is a Phase I/II open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with advanced EGFR mutation-positive NSCLC with progressive disease after ≥1 EGFR tyrosine kinase inhibitor (TKI). An overall response rate of 67% has previously been reported in this trial for T790M positive patients treated with the 500 and 625 mg BID doses (Soria 2014). Here we provide preliminary data on the activity of rociletinib in the subgroup of patients with a history of CNS disease.
Methods:
Patients with a history of CNS disease were permitted if asymptomatic and stable, as defined by steroid requirements. The primary activity endpoint was RECIST overall response rate. However, patients who developed progressive disease (PD) while on study treatment were allowed to continue therapy with rociletinib if deemed clinically beneficial by the investigator.
Results:
As of 16 March 2015, a total of 401 patients received therapeutic dose levels of rociletinib (500, 625 and 750 mg BID) including 170 (42%) patients with a history of CNS metastases. Based on this interim analysis, the RECIST overall response rate among these patients with a history of CNS disease is 41%. To date, 42 patients with a history of CNS disease have continued therapy with rociletinib post-progression. Of those who continued for at least 14 days the average treatment duration beyond PD was 89 days (range: 14 - 336 days). Twenty-two of the 42 patients with a history of CNS disease with PD also received brain radiation and continued rociletinib treatment for an average of 120 days (range: 22 – 336 days) after PD. Rociletinib is held on radiation days only. Progression-free survival data for these subgroups is not yet mature. The three most common adverse events in the patient population with a history of CNS disease are similar to those found in the general TIGER-X patient population: hyperglycemia, diarrhea and nausea.
Conclusion:
In patients with a history of CNS disease, a factor associated with poor prognosis, rociletinib is active with a RECIST response rate of 41%. Local CNS radiation has been administered safely with rociletinib held on radiation days and continued afterwards. Prolonged use of rociletinib post CNS radiation suggests ongoing systemic benefit is still experienced by these patients. The role of rociletinib in NSCLC patients with CNS involvement is being further explored in the ongoing TIGER clinical development program.
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MINI 35 - Biology (ID 161)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:T.A. Boyle, M.G. Kris
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 2c-3c
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MINI35.15 - Discussant for MINI35.11, MINI35.12, MINI35.13, MINI35.14 (ID 3555)
18:30 - 20:00 | Author(s): J.W. Goldman
- Abstract
- Presentation
Abstract not provided
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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: 1
- Moderators:E.B. Garon, H.J. Ross
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F1+F2
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ORAL02.05 - 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)
10:45 - 12:15 | Author(s): J.W. Goldman
- 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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ORAL 31 - PD1 Axis Inhibition (ID 143)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:J. Weiss, B. Luey
- Coordinates: 9/09/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
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ORAL31.05 - High Intratumoral T Cell Infiltration Correlated with Mutational Load and Response to Pembrolizumab in Non-Small Cell Lung Cancer (ID 2728)
16:45 - 18:15 | Author(s): J.W. Goldman
- Abstract
- Presentation
Background:
Responses to PD-1 blockade have been induced in approximately 20% of advanced non-small cell lung cancer (NSCLC) patients with progressive disease after standard therapy [Garon, NEJM 2015]. One challenge is to understand how the immune response was initiated in responding patients. Tumor mutational burden has been associated with response to PD-1 checkpoint inhibitors in NSCLC [Rizvi, Science, 2015]. In addition, studies in melanoma patient-derived tumor specimens revealed that responses to PD-1/L1 blockade rely on pre-therapy tumor infiltration of activated T effector cells [Tumeh, Nature, 2014]. We hypothesize that clonal T cell infiltration is correlated with tumor mutational load and clinical response with PD-1 blockade.
Methods:
We studied tumor specimens in NSCLC patients treated with pembrolizumab at UCLA on the KEYNOTE -001 clinical trial. All patients signed informed consent for the trial as well as separate specimen acquisition protocols. Responses were classified by the investigators according to irRC. DNA was extracted and whole exome sequencing was performed at the UCLA Immunogenetics Core. DNA from the same patient’s PBMC or other non-cancerous tissue was sequenced for baseline comparison. Immunohistochemistry (IHC) was done for CD8 (Clone C8/144B, Dako), CD4 (Clone SP35, Cell Marque) and PD-L1 (Clone SP142, Spring Bioscience).
Results:
We report results from 27 patients (14 responders, and 13 nonresponders). Significantly higher density of pre-dosing CD8+ cells (percentage of CD8+ nucleated cells) in the tumors of the responding patients was observed (mean of 17.7% in responders vs 5.6% in non-responders, p=0.02 by unpaired t test) suggestive of a pre-existing immune response. Mutational load in 5 patients (3 responders and 2 nonresponders) showed a trend towards correlation with response (mean of 19 nonsynonymous somatic mutations per MB in responders vs 6 in nonresponders, p=0.33). Interestingly, a strikingly significant correlation between mutational load and CD8 expression was observed (R[2]=0.96, p=0.003). In addition, pre-dosing tumor PD-L1 expression demonstrated a trend towards correlation with response (mean of 72.1% in responders vs 51.5% in nonresponders, p=0.07) but not with CD8 tumor infiltration (R[2]=0.05, p=0.28). No significant association of CD4+ T cell tumor infiltration with response (mean of 37.4% CD4 + cells in responders vs 27.0% in nonresponders, p=0.32) was observed.
Conclusion:
We observed strong correlation of pre-dosing intratumoral T cell infiltration with response and mutational load in NSCLC patients treated with pembrolizumab. Our results have direct implications for the design and interpretation of ongoing and planned immunotherapy studies for NSCLC and evaluation of potential predictive biomarkers to select patients most likely to benefit.
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ORAL 37 - Novel Targets (ID 146)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:S.S. Ramalingam, E. Thunnissen
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
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ORAL37.04 - Comprehensive Genomic Profiling (CGP) of Advanced Cancers Identifies MET Exon 14 Alterations That Are Sensitive to MET Inhibitors (ID 3156)
16:45 - 18:15 | Author(s): J.W. Goldman
- Abstract
- Presentation
Background:
Amplifications and activating mutations in the c-MET proto-oncogene are known oncogenic drivers that have proven responsive to targeted therapy. Mutations causing skipping of MET exon 14 are also oncogenic, but less well characterized. We undertook comprehensive genomic profiling (CGP) of a large series of advanced cancers to further characterize MET exon 14 alterations.
Methods:
DNA was extracted from 40 microns of FFPE sections from 38,028 advanced cancer cases. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of >500x using three versions of the FoundationOne test. Hybridization capture baits for the MET gene were identical for all three versions of the test. Base substitution, indel, copy number alteration, and rearrangement variant calls were examined to identify those nearby to the splice junctions of MET exon 14. These genomic alterations were then manually inspected to identify those likely to affect splicing of exon 14, or delete the exon entirely.
Results:
221 cases harboring MET ex14 alterations were identified. These patients had a median age of 70.5 years (range 15-88), with 97 males and 124 females. The cases were lung carcinoma (193), carcinomas of unknown primary (15), brain glioma (6), and one each of adrenal cortical carcinoma, hepatocellular carcinoma, histiocytic sarcoma, renal cell carcinoma, rhabdomyosarcoma, skin merkel cell carcinoma, and synovial sarcoma. The majority were stage IV. Identification of this alteration has lead to treatment with MET inhibitors such as crizotinib, and to durable partial responses or better exceeding 3 months in histiocytic sarcoma (1), sarcomatoid lung carcinoma (1), and nsclc (1+). Multiple patients (5+) have initiated treatment on either crizotinib or MET inhibitors in clinical development, and additional outcome data will be reported. One patient with locally advanced unresectable disease harbored a MET exon 14 skipping alteration. On initiation with treatment with an MET inhibitor, symptomatic relief was observed in 3 days, radiographic response was observed at two weeks, and resection was performed 8 weeks after initiation of the MET inhibitor.
Conclusion:
MET exon 14 alterations define a hereto unrecognized population of advanced cancer cases, particularly in NSCLC. Multiple case reports demonstrate that these alterations confer sensitivity to multiple small molecule MET inhibitors. This finding expands the population of advanced NSCLC patients who can derive benefit from MET-targeted therapies.
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-080 - Treatment Rationale and Study Design for the Phase 3 JUNIPER Study: Abemaciclib vs Erlotinib in Patients with Stage IV NSCLC and KRAS Mutation (ID 1438)
09:30 - 17:00 | Author(s): J.W. Goldman
- Abstract
Background:
Abemaciclib (LY2835219) is a potent, selective small molecule inhibitor of CDK4/6, which has been shown to inhibit cell cycle progression by preventing the phosphorylation and functional inactivation of the Rb tumor-suppressor protein. Cell cycle dysfunction due to abnormalities in the CDK4/6 pathway occurs in NSCLC. KRAS mutant xenografts predict for greater sensitivity to CDK4/6 inhibitors. In a phase 1 study with abemaciclib (Goldman ASCO 2014), 16 patients with KRAS mutant tumors (N=29) had a response of stable disease (SD) or better (disease control rate [DCR]=55.2%), and 9 patients with KRAS wild-type tumors (N=24) had a response of SD or better (DCR=37.5%).
Methods:
JUNIPER (NCT02152631) is a randomized, phase 3 study of abemaciclib (200 mg orally q12hrs) + best supportive care (BSC) versus erlotinib (150 mg orally q24hrs) + BSC in patients with stage IV NSCLC whose tumors have detectable KRAS mutations and who have progressed after platinum-based chemotherapy and one other prior therapy or who are not eligible for further chemotherapy. About 550 patients will be randomized to abemaciclib or erlotinib 3:2 ratio using following factors: number of prior chemotherapy regimens (1 vs. 2), ECOG PS (0 vs. 1), gender (male vs. female) and KRAS mutation (G12C vs. others). This design has 80% power to detect overall survival (OS) hazard ratio (HR) of 0.75 (type I error 0.045) and progression-free survival (PFS) HR of 0.67 (type I error 0.005). Erlotinib was chosen as the control arm, as it is the only agent indicated for both 2nd and 3rd line therapy in advanced NSCLC. Treatment will continue until disease progression or unacceptable toxicity occurs, with assessments every 28 days, followed by short-term and long-term follow-up. Primary objectives are to compare OS and PFS of the treatment arms. Enrollment began December 2014. If the primary objectives are achieved, this study will provide results on an alternative treatment option, abemaciclib + BSC, for patients with NSCLC whose tumors have detectable KRAS mutations, currently a patient population with few treatment options.
Results:
Not applicable
Conclusion:
Not applicable
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 3
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-085 - Abemaciclib in Combination with Single Agent Options in Stage IV NSCLC, a Phase 1b Study (ID 125)
09:30 - 17:00 | Author(s): J.W. Goldman
- Abstract
Background:
Abemaciclib, a cell cycle inhibitor selective for CDK4/6, demonstrated acceptable safety and early clinical activity in metastatic NSCLC, given orally as monotherapy on a continuous schedule. Combinations of abemaciclib showed greater activity compared with monotherapy in KRAS-mutant NSCLC preclinical models. Primary aim of study NCT02079636 was safety/tolerability of combination therapy with abemaciclib; secondary aims included pharmacokinetics and antitumor activity.
Methods:
In this open-label 3+3 dose-escalation study with expansion cohorts, eligibility included stage IV NSCLC, measurable or nonmeasurable disease (RECISTv1.1), ECOG PS ≤1, and 1-3 prior therapies. Abemaciclib was combined with pemetrexed (Part A, nonsquamous, 500 mg/m[2] IV day 1), gemcitabine (Part B, 1250 mg/m[2] IV days 1 and 8), ramucirumab (Part C, 10 mg/kg IV day 1, or 8 or 10 mg/kg IV days 1 and 8) (Q21), or LY3023414 (dual PI3K-mTOR inhibitor) (Part D, 100 mg, 150 mg or 200 mg orally Q12H). In escalation, patients were dosed continuously until progression with abemaciclib at 100 mg (Part D), 150 mg or 200 mg orally Q12H.
Results:
As of February 27, 2015, 70 patients (Parts A-C) received ≥1 dose; 15 patients at 150 mg and 55 patients (including all 39 patients in expansion) at 200 mg Q12H abemaciclib. The MTD was established at 200 mg Q12H abemaciclib for Parts A-C. See Table 1 for treatment-emergent adverse events (TEAEs). Stable disease was observed in 13/23 patients in Part A; 7 unknown, 4/24 patients in Part B; 10 unknown, and 7/23 patients in Part C; 12 unknown. In Parts A-C, 18/70 (26%) patients started ≥4 cycles (Part A=9, Part B=3, Part C=6). Three confirmed PRs were observed: Part B, 1 patient with squamous histology (unknown mutation status), Part C, 1 patient with nonsquamous histology (KRAS mutation positive; EGFR mutation negative), and 1 patient with squamous histology (unknown mutation status). Updated analyses will be presented including Part D and longer term follow-up for Parts A-C through approximately June 2015. Table 1. TEAEs related to treatment (≥20% in ≥1 part)% All grades (% Gr3/4) Part A (n=23) Part B (n=24) Part C (n=23) Diarrhea 65 (4) 50 (17) 52 (9) Fatigue 57 (9) 63 (8) 17 (4) Nausea 35 (0) 50 (4) 48 (9) Neutropenia 61 (61) 50 (33) 17 (4) Anemia 57 (26) 33 (17) 9 (0) Thrombocytopenia 39 (9) 38 (8) 17 (13) Decreased appetite 30 (0) 25 (0) 22 (0) Vomiting 9 (0) 21 (0) 35 (0) Blood creatinine increased 30 (0) 8 (0) 17 (4) Leukopenia 30 (22) 17 (8) 9 (4)
Conclusion:
Abemaciclib combined with single-agents with acceptable toxicity. Safety findings observed in Parts A and B are consistent with AEs expected when combining myelosuppressive compounds with abemaciclib, resulting in an increased myelosuppressive effect. In Part C, safety findings are consistent with those of single-agents. Tumor responses were observed in Parts B and C.
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P2.01-092 - A Phase IB Dose-Escalation Study of Pemetrexed and AUY922 in Previously Treated Metastatic Non-Squamous, Non-Small Cell Lung Cancer (ID 2164)
09:30 - 17:00 | Author(s): J.W. Goldman
- Abstract
Background:
Despite advances in targeted therapy, treatment options for metastatic NSCLC progressing after initial therapy remains limited. HSP90 is an ATP-dependent molecular chaperone that plays a vital role in protein stabilization. Some HSP90 client proteins are key regulators in cell proliferation and survival. Many mutant oncoproteins are more dependent on HSP90 for proper folding and stability compared to their wildtype counterparts. AUY922 potently inhibits HSP90, showing preclinical activity in a wide range of cancer cell lines, including NSCLC (1). Phase I clinical trials established 70 mg/m[2] as the dose for further development (2). A single agent phase II trial demonstrated clinical activity of AUY922 in NSCLC, particularly molecular subsets with driver mutations in the known HSP90 client proteins, epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) (3). Pemetrexed is a folate antimetabolite chemotherapeutic approved for use in advanced non-squamous, NSCLC. In pre-clinical models, mRNA for dihydrofolate reductase (DHFR), a target of pemetrexed, reliably decreased in response to AUY922 exposure (1). These findings suggest that the combination of AUY922 and premetrexed in NSCLC is worthy of investigation.
Methods:
Adult patients with previously treated stage IV non-squamous, NSCLC, measureable disease per RECIST 1.1, ECOG performance status < 2, and life expectancy > 3 months are eligible for this open label phase Ib clinical trial (NCT01784640). A standard 3 x 3 design will evaluate 3 cohorts, all with pemetrexed at the standard 500 mg/m[2] dose, plus: AUY922 40 mg/m[2], 55 mg/m[2], and 70 mg/m[2] qwk. Enrollment of the 70 mg/m[2] qwk cohort has been open since November 2014 and is currently ongoing. After the optimal dose for further evaluation is determined, an additional 20 patients will be enrolled at that dose. This expansion phase will focus on patients with EGFR mutations and ALK gene rearrangements. The primary endpoint is safety and tolerability of AUY922 combined with pemetrexed in patients with previously treated non-squamous NSCLC. [Funding by Novartis, K23CA149079, Wolfen Family, One Ball Matt Memorial Golf Tournament]. References 1) Garon EB et. al. Mol Cancer Ther. 2013 2) Sessa C et. al. Clin Cancer Res. 2013 3) Garon EB et. al. ASCO 2012
Results:
Not applicable
Conclusion:
Not applicable
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P2.01-096 - Randomized, Double-Blind, Placebo-Controlled Trial of Evofosfamide (TH-302) in Combination with Pemetrexed in Advanced ns-NSCLC (ID 659)
09:30 - 17:00 | Author(s): J.W. Goldman
- Abstract
Background:
Tumor hypoxia is associated with chemo- and radioresistance and is a prevalent characteristic in tumors of patients with non-small cell lung cancer (NSCLC). Evofosfamide (previously known as TH-302) is a hypoxia-activated prodrug designed to release the bis-alkylating DNA crosslinker bromo-isophosphoramide mustard (Br-IPM) when reduced in severe hypoxia. In a Phase 1/2 study (NCT00743379) that included a single arm evofosfamide in combination with pemetrexed in 18 patients with relapsed/refractory non-squamous NSCLC, median PFS was 7.0 months and median OS was 14.9 months. Response in 15 evaluable patients: 6 partial responses (4 confirmed), 6 stable disease and 3 progressive disease. The most common adverse events were fatigue, anemia, stomatitis and nausea.
Methods:
An international, multicenter, randomized, double-blind, placebo-controlled trial was initiated to evaluate evofosfamide in combination with pemetrexed versus placebo and pemetrexed as a potential second-line treatment for patients with non-squamous NSCLC (NCT02093962). Approximately 440 patients will be enrolled with histologically confirmed stage IIIB or IV NSCLC with non-squamous histology, measurable disease according to RECIST 1.1, and ECOG performance status 0-1. Eligible patients have recurrent or progressive disease after one prior platinum-based non-pemetrexed chemotherapy treatment for advanced disease with or without maintenance. EGFR-activating and ALK rearrangements status must be known, and if identified, patients must have received a targeted kinase inhibitor. Evofosfamide (400 mg/m[2]) or matched placebo is administered by IV infusion over 30 - 60 minutes on Day 1 and Day 8 of a 21-day cycle. Pemetrexed (500 mg/m[2]) is administered by IV infusion 2 to 4 hours after evofosfamide administration on Day 1. Overall survival (OS) is the primary endpoint; secondary endpoints include safety, progression-free survival and RECIST response rate. The study design has 85% power to detect a 40% improvement in OS with a one-sided alpha of 0.025. The first patient was enrolled in June 2014; recruitment is ongoing.
Results:
not applicable
Conclusion:
not applicable
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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: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-087 - A Phase I Study of Exemestane with Carboplatin and Pemetrexed in Postmenopausal Women with Metastatic, Non-Squamous Non-Small Cell Lung Cancer (ID 2171)
09:30 - 17:00 | Author(s): J.W. Goldman
- Abstract
Background:
Lung cancer is the most common cause of cancer-related deaths in the US, with adenocarcinoma being the most common histologic subtype. Aromatase, a critical rate-limiting enzyme in estrogen biosynthesis, is notably expressed in NSCLC cells. Retrospective studies show that high NSCLC aromatase levels are associated with worse clinical outcome, particularly in postmenopausal women (Weinberg et al., Cancer Res, 2005; Mah et al., Cancer Res, 2007; Garon et al., J Thoracic Oncol, 2013). Estrogens are known survival factors in lung and promote expression of nucleotide excision repair enzyme ERCC1 that is implicated in resistance to platinum-therapy. In NSCLC cells, ERCC1 transcript expression is blocked by exemestane, an aromatase inhibitor (AI), enhancing cisplatin-induced apoptosis. In preclinical NSCLC xenograft models, exemestane exerts synergistic antitumor activity combined with cisplatin and results in prolonged tumor suppression (Marquez-Garban et al., Ann NY Acad Sci, 2009). These data provide a rationale to assess an AI in the clinic.
Methods:
Based on our preclinical studies, we are conducting a phase IB, open-label, single-center study in postmenopausal, treatment-naïve (except prior single-agent tyrosine kinase inhibitor use) women with metastatic, non-squamous NSCLC (NCT 01664754). We plan to enroll 12-15 participants divided into two dose-escalation cohorts of exemestane. All participants receive standard chemotherapy with pemetrexed (500 mg/m[2]) and carboplatin (AUC 6), both given intravenously every 3 weeks. Cohort 1, which added exemestane 25 mg orally daily, has completed enrollment without any dose-limiting toxicities. Cohort 2, for which enrollment started in December of 2013, evaluates exemestane at 50 mg orally daily. Our primary aim is to evaluate safety and tolerability of the indicated regimen. Secondary objectives are tumor response rate, quality of life, pharmacokinetics/pharmacodynamics, and correlative studies of biomarkers (such as blood estrogens, tumor ERs, aromatase, and apoptosis) with tumor response.
Results:
Not applicable
Conclusion:
Not applicable
