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G. Giaccone
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GR 03 - Extensive Small Cell with Excellent Response to 1st Line Rx (PCI, Chest and/or Oligomet RT) and Second Line and Treatment of Thymic Malignancies (ID 16)
- Event: WCLC 2015
- Type: Grand Rounds
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:B.E. Johnson, B. Kavanagh, P. Kosmidis, E. Ruffini
- Coordinates: 9/09/2015, 14:15 - 15:45, 102+104+106
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GR03.04 - Treatment of Thymic Malignancies - Biology and Standard Treatment (ID 1842)
15:20 - 15:30 | Author(s): G. Giaccone
- Abstract
- Presentation
Abstract:
Thymic epithelial tumors (TETs) are rare malignanices of the thymic epitehlial cells. Recent research has identified recurrent mutations in these tumors, using NextGen sequencing (Petrini et al. Nature Gen 2014; Wang et al Sci. Rep. 2015). GTF2i, a general transcription factor has been found to have a high frequency of a unique muation in over 70% of type A and AB, whereas this mutation decreases in frequency in thymic carcinomas. Mutation in GTF2i may represent an oncogenic event in TETs. Common recurrent mutations in known cancer genes have been found more frequenty in thymic carcinomas, where the number of mutations is higher than in more indolent forms of TETs. In particular genes involved in epigenetic regulation have been found recurrently mutated. Presence of P53 mutations was also found to be related to poorer survival, as well as the number of recurrent mutations. The implications of molecular characterization of TETs on treatment are still relatively small, but they represent a first step toeards more targeted treatments. Chemotherapy remains the standard treatment for first line therapy of patients with un-resectable disease, or as neoadjuvant therapy in large tumors before surgery or radiation. The more commonly employed regimes still are represented by the PAC regimen, PE regimen and more recently carbo-taxol. Targeted therapies have been studied in unselected patients and of all of those tested in properly conducted phase II studies, sunitinib appears to be the most effective in thymic carcinoma (25% response rate; Thomas et al. Lancet Oncol 2015). A phase II of pembrolizumab is actively accruing in patients with thymic carcinomas, where PDL-1 expression is relatively high.
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MINI 21 - Novel Targets (ID 133)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:B.P. Levy, D.S. Tan
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 2a-3b
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MINI21.13 - Discussant for MINI21.10, MINI21.11, MINI21.12 (ID 3423)
17:55 - 18:05 | Author(s): G. Giaccone
- Abstract
- Presentation
Abstract not provided
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MINI 37 - SCLC Therapy (ID 165)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:D. Ettinger, G.R. Simon
- Coordinates: 9/09/2015, 18:30 - 20:00, 605+607
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MINI37.01 - Chk1 Inhibition Enhances Cisplatin Cytotoxicity Regardless of p53 Status in Human Small Cell Lung Cancer Cells (ID 947)
18:30 - 18:35 | Author(s): G. Giaccone
- Abstract
- Presentation
Background:
Small cell lung cancer (SCLC) has a poor prognosis and harbors complex genetic alterations including frequent loss-of-function mutations of p53 and Rb, which impair the G1/S checkpoint control. Checkpoint Kinase 1 (Chk1) is a vital serine/threonine specific protein kinase responsible for halting the cell cycle in check after DNA damage. With abrogation of Chk1-mediated cell cycle checkpoint control, cancer cells may enter mitosis with extensive DNA damage leading to mitotic catastrophe and apoptotic cell death. Previous in vitro studies showed that p53 deficient cancer cells benefit from Chk1 inhibition. Here we demonstrate that a combination of Chk1 inhibition and cisplatin causes more growth inhibition and caspase activation in SCLC cell lines compared to cisplatin alone, regardless of p53 status.
Methods:
Chk1 inhibition was achieved by siRNA knockdown (Qiagen) and AZD7762 (Selleckchem) in p53 mutant SCLC cell lines (GLC4, NCI-H82) and p53 intact SCLC cell lines (NCI-H128, NCI-H209). Cell viability was measured by Cell-Titer Glo assay (Promega) after 72hrs of drug treatment. Synergism was defined by combination index (CI)>1 using the Chou-Talalay method. Cell cycle analysis was performed by PI staining and detected by FACS. Western blotting and immunofluorescent staining were used to evaluate caspase activation and other signaling proteins.
Results:
SCLC cell lines were treated with cisplatin 24hrs at each IC50 dosage after Chk1 siRNA transfection. In GLC4 after 2.5uM cisplatin treatment, cell viabilities of control siRNA-treated and Chk1 siRNA-treated cells were 28% and 10.6% (p=0.006, by paired t-test), respectively. Similar significant reduction of cell viability was observed in 1uM cisplatin-treated NCI-H82 cells (44.6% vs. 29.7%; p=0.0632) and in 3uM cisplatin-treated NCI-H128 cells (62.5% vs. 45.3%; p=0.0155), respectively. More cleaved caspase-2 and caspase-3 were noted in Chk1 knockdown plus cisplatin-treated GLC4 cells than in cisplatin alone. The IC50 (72hrs) of single agent AZD7762 (Chk1 inhibitor) treatment was 240nM, 211nM, 266nM and 215nM in GLC4, NCI-H82, NCI-H128 and NCI-H209 respectively. The combination indexes of AZD7762 and cisplatin (both given at around IC50s) calculated by Chou-Talalay method indicated synergism in all these 4 cell lines. Cell cycle analysis revealed that AZD7762 abrogated cisplatin-induced G2/M arrest in GLC4 and G1 arrest in NCI-H128. Inhibition Chk1 by AZD7762 was associated with reduction of CDC25C and CDC2 phosphorylation. Phospho-Histone H3 (mitotic marker) was increased in AZD7762 and cisplatin combined treatment compared to cisplatin alone in a p53 independent fashion. Intriguingly, inhibition of Chk1 by AZD7762 alone in GLC4 cells activated caspase-2.
Conclusion:
Chk1 inhibition both by siRNA knockdown and AZD7762 enhances cisplatin cytotoxicity. The synergism was primarily due to increased apoptosis and abolished cell cycle arrest. Although p53 is frequently mutated in SCLC, growth inhibition was seen in a p53 independent manner. In GLC4, single agent AZD7762 treatment can cause caspase-2 activation through an as yet unidentified mechanism. Our findings suggest that Chk1 is a potential therapeutic target in small cell lung cancer and is synergistic with chemotherapy. The effects of Chk1 inhibitor and its combination with chemotherapy agents in SCLC animal models are currently underway.
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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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ORAL02.07 - Atezolizumab (MPDL3280A) Combined with Platinum-Based Chemotherapy in Non-Small Cell Lung Cancer (NSCLC): A Phase Ib Safety and Efficacy Update (ID 2208)
11:50 - 12:01 | Author(s): G. Giaccone
- Abstract
- Presentation
Background:
Despite advances in treatment for NSCLC, the standard first-line treatment for metastatic disease remains platinum-based doublet chemotherapy with historical overall response rates (ORRs) of ≈30%. Preclinical data suggest that chemotherapy treatment can result in antigen release in the tumor microenvironment, potentially enhancing effects of cancer immunotherapy. Atezolizumab (MPDL3280A) is a human monoclonal antibody that targets the PD-L1/PD-1 immune checkpoint, while leaving the PD-L2/B7.1 interaction intact (which may reduce the risk of autoimmune lung toxicity). As atezolizumab has shown promising activity in advanced NSCLC, we investigated atezolizumab in combination with chemotherapy.
Methods:
A Phase Ib study was conducted to evaluate atezolizumab with chemotherapy in locally advanced or metastatic NSCLC patients who had not received chemotherapy for advanced disease. Pts received atezolizumab 15 mg/kg IV q3w with standard chemotherapy (carboplatin plus either paclitaxel [Arm C], pemetrexed [Arm D; nonsquamous] or weekly nab-paclitaxel [Arm E]) for 4-6 cycles followed by atezolizumab maintenance until progression. RECIST v1.1 was used to assess ORRs (unconfirmed) in pts dosed by Jun 29, 2014 (data cutoff: Sep 29, 2014). PD-L1 expression was centrally evaluated using the SP142 IHC antibody assay.
Results:
37 NSCLC pts were safety evaluable (8 in Arm C; 14 in Arm D; 15 in Arm E). Across these arms, 54% of pts were male, with a median age of 65 y (range, 40-82 y). 81% had non-squamous NSCLC, and 19% had squamous NSCLC. Median safety follow-up was 22.0 wks (range, 0.1-49.4 wks). Across arms, all-Grade AEs regardless of attribution included those commonly associated with chemotherapy, such as nausea (Arms C & D, 50%; Arm E, 73%), fatigue (Arm C, 38%; Arm D, 36%; Arm E, 73%) and constipation (Arm C, 25%; Arm D, 71%; Arm E, 27%). The most common Grade 3-4 atezolizumab-related AEs included anemia (Arms D & E, 7%), neutropenia (Arm C, 13%; Arm D, 7%) and thrombocytopenia (Arms D & E, 7%), with no pneumonitis or autoimmune renal toxicity observed. One potentially atezolizumab-related Grade 5 AE was observed in Arm D (candidemia after prolonged neutropenia). 30 pts were efficacy evaluable, and responses were observed in all arms regardless of PD-L1 expression (Table). Updated clinical data will be presented.Table. RECIST v1.1 Responses in Patients with NSCLC
Arm C: carboplatin + paclitaxel (n = 5) Arm D: carboplatin + pemetrexed (n = 12) Arm E: carboplatin + nab-paclitaxel (n = 13) All Indicated Arms (n = 30) ORR, % 60% 75% 62% 67% 95% CI, % 19%-92% 45%-93% 33%-83% 48%-82% CR, n 0 0 2 2 PR, n 3 9 6 18
Conclusion:
Atezolizumab plus standard first-line chemotherapy was well tolerated in advanced NSCLC pts, with no unexpected toxicities. Clinical activity was promising and supportive of a potential synergy of atezolizumab with chemotherapy. Based on these results, several Phase III studies have been initiated.
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ORAL 40 - Biology 1 (ID 154)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:C. Brambilla, R. Bueno
- Coordinates: 9/09/2015, 16:45 - 18:15, 702+704+706
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ORAL40.07 - Xpo1 Inhibition: A Promising Therapeutic Strategy in Thymic Epithelial Tumors (ID 1230)
17:50 - 18:01 | Author(s): G. Giaccone
- Abstract
- Presentation
Background:
Growing evidence suggests that nuclear–cytoplasmic transport is frequently dysregulated in cancer cells, and is involved in promoting carcinogenesis, cell survival, drug resistance and tumor progression. In particular, enhanced nuclear export is one mechanism by which malignant cells inactivate tumor suppressor proteins (TSPs). Inhibition of XPO1 (CRM1), the main karyopherin involved in the nuclear export of TSPs, restores nuclear localization and function of TSPs in several preclinical models. Selinexor(KPT-330) is an XPO1 inhibitor being tested clinically in solid tumors and hematological malignancies that showed some activity in patients with thymic epithelial tumors (TETs). Here, we describe the activity of selinexor in preclinical models of TETs.
Methods:
Thymoma (IU-Tab1, T1682), thymic carcinoma (Ty82, T1889, MP57) and immortalized normal thymic epithelial cells (TEC84) treated with selinexor or vehicle were assayed by CellTiter-Glo and flow cytometry. Western blot analysis of nuclear and cytoplasmic protein fractions and immunofluorescence assays were used to study the cellular sublocalization of XPO1 cargoes before and after treatment. The effect of selinexor on cell migration was determined using a wound-healing assay. A selixinor-resistant cell line was generated by growing selinexor-sensitive IU-Tab1 cells at increasing concentrations of the drug. Mutational status and copy number of the XPO1 gene was assessed by Q- PCR and Sanger sequencing.
Results:
All TET cell lines were sensitive to selinexor (IC~50~ 90-250 nM) with the exception of T1682 (thymoma type B), which showed intrinsic drug resistance (IC~50~ > 1000 nM). In the sensitive cell lines, selinexor treatment induced G1 (MP57) or G2 (IU-Tab1, Ty82) cell-cycle arrest at 24 hours, and induced apoptosis 2-5 fold over untreated cells by 72 hours. The cytotoxic effects of selinexor were not observed in immortalized normal TEC84 cells at nanomolar concentrations, and required higher concentrations (IC~50 ~800nM) to induce a cytostatic effect. Drug treatment led to increased nuclear concentrations of several TSPs involved in cell cycle regulation (e.g. p21, p27), genomic stability (p53) and induction of apoptosis (FOXO3a) and also reduced the total cellular expression of the oncogenic protein NF-kB. These results were confirmed with siRNA knockdown of XPO1. In addition,selinexor treatment impaired tumor cell migration and had cytotoxic synergistic effect in combination with doxorubicin or etoposide in T1889 and IU-Tab1 cell lines, increasing nuclear accumulation of the XPO1 cargo protein, Topoisomerase IIα. Furthermore, we demonstrated that selinexor-resistant cell line has similar growth rates to their parental cells, however overexpress XPO1 due to gene amplification, confirming the importance of aberrant XPO1 activity in TET survival.
Conclusion:
Our data show the importance of XPO1 in TETs biology and demonstrate activity of selinexor in preclinical models, further supporting the planned Phase II trial in patients with TETs.
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P3.07 - Poster Session/ Small Cell Lung Cancer (ID 223)
- Event: WCLC 2015
- Type: Poster
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.07-003 - A Phase Ib/II Trial of Doxorubicin with Ganetespib, a Novel Hsp90 Inhibitor, in Advanced Solid Tumors, with Dose Expansion in Small Cell Lung Cancer (ID 3105)
09:30 - 09:30 | Author(s): G. Giaccone
- Abstract
Background:
Relapsed/refractory small cell lung cancer (RR-SCLC) has a poor prognosis with median overall survival of only 2-3 months. Objective responses to single agent newer chemotherapy agents range from 14-29%. One of the key mechanisms for the development of acquired resistance of cancer cells to chemotherapy is the induction of a heat shock response. Over-expression of Hsp90 and its co-chaperones in tumor cells results in up-regulation of ATP-dependent transporters such as ABCG2 and RLIP76. Such transporters act as drug-efflux pumps for chemotherapeutic agents including doxorubicin, thus mediating drug resistance. Ganetespib, a next generation Hsp90 inhibitor devoid of liver and ocular toxicities that limit other agents in its class, is now in phase 3 evaluation in NSCLC. Targeting Hsp90, ganetespib affects multiple drug resistance pathways. We recently demonstrated in vitro and in vivo that the addition of ganetespib (G) to doxorubicin (D) can indeed overcome drug resistance (Lai et al., Oncogene 2014). The primary objective of this clinical study is to determine the maximum tolerated dose and the recommended Phase II dose (RP2D) of G + D in subjects with advanced solid tumors. The secondary objectives are to determine the dose limiting toxicities (DLTs) and to assess if there is preliminary evidence of activity for the combination of G + D in RR- SCLC by determining the objective response rate and response duration. We will also aim to establish conditionally reprogrammed cancer cell lines from tumor tissue in subjects with RR-SCLC to allow ex-vivo molecular characterization and drug sensitivity testing.
Methods:
The dose escalation phase will follow a standard 3+3 dose escalation scheme with 2 dose levels of G administered weekly on Days 1, 8 of a 21-day cycle, in combination with fixed dose D at 50 mg/m[2] on Day 1. After 4-6 cycles of the combination, continuation of single agent G is permitted in patients deriving clinical benefit. The RP2D determined at the end of the dose escalation phase will be used to conduct a dose expansion study in subjects with RR-SCLC. Key inclusion criteria are refractory solid tumors (in dose escalation phase) and RR-SCLC (in dose expansion phase), age >18 years, ECOG PS 0-1, adequate organ/marrow function. Key exclusion criteria include LVEF < 50%, lifetime cumulative doxorubicin dose >150 mg/m[2], untreated, symptomatic brain metastases, serious cardiac illness, QTc >470 msec, strong inhibitors or inducers of CYP 3A4 or 2C19. DLTs are defined as grade 4 hematologic toxicities or > grade 3 non-hematologic toxicities including hypersensitivity reactions despite pre-medication and nausea, vomiting and diarrhea despite maximal medical therapy. Response assessment will be done using RECIST 1.1.
Results:
Clinical Trial Status: A total of 6 subjects have been enrolled thus far. With no DLTs observed in 5 subjects who have crossed the DLT evaluation period, the trial continues enrollment.
Conclusion:
Not applicable
