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W. Pao
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MO01 - Lung Cancer Biology - Techniques and Platforms (ID 90)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Biology
- Presentations: 1
- Moderators:S. Lu, P. Waring
- Coordinates: 10/28/2013, 10:30 - 12:00, Bayside 204 A+B, Level 2
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MO01.07 - Inhibition of the IGF-1R signaling pathway potentiates responses to ALK inhibitors in both ALK TKI naive and ALK TKI resistant lung cancer (ID 1660)
10:30 - 12:00 | Author(s): W. Pao
- Abstract
- Presentation
Background
Oncogenic fusions involving the gene encoding the anaplastic lymphoma kinase (ALK) define a new clinically relevant molecular subset of lung cancer. The majority of patients with ALK+ lung cancer are highly responsive to ALK tyrosine kinase inhibitor (TKI) therapy, however, the efficacy of these ALK inhibitors is limited by the development of acquired resistance. Additional strategies using rationally selected therapeutic agents/combinations of agents are needed to both delay and overcome acquired resistance to ALK inhibition. Based upon an intriguing clinical observation from a patient with ALK+ lung cancer who had an ‘exceptional response’ to an IGF-1R monoclonal antibody (MAb), we report a novel therapeutic synergism between ALK inhibitors and IGF-1R inhibitors.Methods
A series of experimental approaches including cell culture models, in vitro assays, and a study of patient tumor samples prior to and at the time of acquired resistance to ALK TKI therapy were employed to test the hypothesis that IGF-1R can be targeted therapeutically to enhance anti-tumor responses in ALK+ NSCLC.Results
Across multiple different ALK+ lung cancer cell lines, including a novel ALK+ cell line developed from a patient prior to ALK TKI therapy, IGF-1R inhibitors (TKIs and MAbs) sensitized ALK+ lung cancer cells to the effects of ALK blockade as assessed by standard cell viability assays. Similar to IGF-1R, ALK fusions co-immunoprecipitated with the adaptor protein, IRS-1, and treatment with ALK inhibitors decreased IRS-1 protein levels. Furthermore, siRNA mediated knock-down of IRS-1 impaired the proliferation of ALK+ lung cancer cells and enhanced the anti-tumor effects of ALK inhibitors. The IGF-1R pathway was activated in cell culture models of ALK TKI resistance, and combined ALK/IGF-1R inhibition in the resistant cells blocked reactivation of downstream signaling and markedly improved therapeutic efficacy in vitro. Finally, IGF-1R and IRS-1 levels were increased in biopsy samples from a patient with advanced ALK+ lung cancer post crizotinib therapy.Conclusion
Collectively, these data support a role for the IGF-1R/IRS-1 signaling pathway in both the ALK TKI sensitive and ALK TKI resistant states and suggest that this rationally selected combination of inhibitors may be an effective strategy to attempt to delay or overcome acquired resistance to therapeutic ALK inhibition. Intriguingly, the ‘second generation’ ALK TKI, LDK-378, which has demonstrated an overall response rate of 70% in patients with both crizotinib naïve and crizotinib resistant ALK+ lung cancer, can inhibit both ALK and IGF-1R in vitro. We speculate, based on these data, that this surprising response rate may be due to LDK-378’s ability to simultaneously inhibit both targets.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO21 - Prognostic and Predictive Biomarkers V - EGFR (ID 98)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:D.C. Lam, S.M. Lee
- Coordinates: 10/30/2013, 10:30 - 12:00, Bayside Auditorium A, Level 1
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MO21.12 - AZD9291: an irreversible, potent and selective tyrosine kinase inhibitor (TKI) of activating (EGFRm+) and resistance (T790M) mutations in advanced NSCLC (ID 2289)
10:30 - 12:00 | Author(s): W. Pao
- Abstract
- Presentation
Background
The first generation EGFR TKIs gefitinib and erlotinib provide significant clinical benefit in patients with advanced EGFR mutant NSCLC but many patients ultimately develop disease progression due to acquired resistance. The EGFR T790M mutation is the most common mechanism of acquired drug resistance, detected in more than 50% of gefitinib/erlotinib resistant patients. Current therapeutic strategies are limited for NSCLC patients with EGFR T790M.Methods
AZD9291 is an oral, irreversible, third generation inhibitor of both EGFR activating (EGFRm+) and resistance mutations (T790M). The mechanistic and functional activity of AZD9291 was characterised in vitro across a number of cell lines harbouring various EGFR-mutations or wild type EGFR. Efficacy of AZD9291 was further evaluated across a number of different EGFR-mutant xenograft and transgenic models in vivo. One open label, dose escalation phase I study of AZD9291 (NCT01802632) is ongoing to determine the safety and tolerability [primary measure], pharmacokinetics and preliminary efficacy profiles of AZD9291, in patients with advanced NSCLC who have progressed following EGFR TKI. Sequential cohorts of 3-6 patients with advanced NSCLC who have had at least one prior regimen containing an EGFR TKI agent (with confirmed EGFRm+ status or Jackman criteria), were treated with AZD9291 once daily. Other key inclusion criteria were PS 0-1, measurable disease, and no prior history of ILD. RECIST assessments were scheduled 6 weekly. Dose escalation can occur after ≥ 3 patients complete both single dose and the first 21-day cycle of AZD9291 multiple dosing with no DLT.Results
AZD9291 potently inhibits EGFR phosphorylation in EGFRm+ (PC9; 14nM) and EGFRm+/T790M (H1975; 13nM) cell lines in vitro, whilst demonstrating much less activity against wild-type EGFR lines (LoVo; 400nM). Consistently, AZD9291 showed significantly more potent inhibition of proliferation in mutant EGFR cell lines compared to wild-type in vitro. In addition, AZD9291 treatment caused profound growth regression across multiple EGFRm+ (PC9; 250% growth inhibition) and EGFRm+/T790M (H1975; 132% growth inhibition) tumour models in vivo, at doses as low as 5mg/kg after 14 days. Tumour growth inhibition was associated with profound inhibition of EGFR activity and key downstream signaling pathways. Chronic long-term treatment of in vivo PC9 and H1975 xenograft tumours with AZD9291 led to a complete and sustained macroscopic response. In the phase I study, clinical activity with RECIST responses have already been observed at the starting dose level of 20mg once daily, with good tolerability, no reported events of EGFR wild-type rash, and only grade 1 diarrhoea (based on preliminary data, unvalidated and subject to change).Conclusion
Preclinical data demonstrates that AZD9291 is a potent and effective inhibitor of both EGFR activating (EGFRm+) and resistance mutations (T790M) whilst sparing wild-type EGFR and, early clinical data have been promising. Taken together, these data support the further clinical investigation of AZD9291 in advanced EGFR mutant NSCLC.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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PL03 - Presidential Symposium Including Top Rated Abstracts (ID 85)
- Event: WCLC 2013
- Type: Plenary Session
- Track:
- Presentations: 1
- Moderators:M. Boyer, K. Fong
- Coordinates: 10/29/2013, 08:15 - 09:45, Plenary Hall, Ground Level
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PL03.07 - Treatment with Therapies Matched to Oncogenic Drivers Improves Survival in Patients with Lung Cancers: Results from The Lung Cancer Mutation Consortium (LCMC) (ID 2444)
08:15 - 09:45 | Author(s): W. Pao
- Abstract
Background
Detecting and targeting the oncogenic drivers EGFR and ALK have transformed the care of patients with lung adenocarcinomas. The LCMC was established to use multiplexed assays to test tumors for alterations in 10 genes and provide the results to clinicians to select treatments and clinical trials matched to the driver detected.Methods
Fourteen LCMC sites enrolled patients with metastatic lung adenocarcinomas and tested their tumors in CLIA laboratories for activating mutations in 10 oncogenic driver genes.Results
Tumors were tested from 1,007 patients for at least one gene and 733 for all 10 genes. An oncogenic driver was found in 466 (64%) of fully-genotyped cases. Among these 733 tumors, drivers found were: KRAS 182 (25%), sensitizing EGFR 122 (17%), ALK rearrangements 57 (8%), “other” EGFR 29 (4%), two genes 24 (3%), HER2 19 (3%), BRAF 16 (2%), PIK3CA 6 (1%), MET amplification 5 (1%), NRAS 5 (1%), MEK1 1 (<1%), AKT1 0. For cases with any genotyping, we used results to select a targeted therapy or trial in 275 (28%). Among 938 patients with follow-up, the median survivals were 3.5 years for the 264 with an oncogenic driver treated with genotype-directed therapy, 2.4 years for the 318 with an oncogenic driver with no genotype-directed therapy, and 2.1 years for the 360 with no driver identified (p<0.0001).Conclusion
Individuals with lung cancers with oncogenic drivers receiving a corresponding targeted agent lived longer than similar patients who did not. An actionable driver was detected in 64% of tumors from patients with lung adenocarcinomas; more than one was present in 3%. Multiplexed testing aided physicians in choosing therapies and targeted trials in 28% of patients. This paradigm for care and research will expand as genotyping becomes more efficient with Next-Gen platforms, additional drivers are identified (i.e.ROS1 and RET), and more targeted drugs become available in the pharmacy and through clinical trials. Supported by HSS NIH NCI 1RC2CA148394-01. Trial Registered with Clinicaltrials.gov: NCT01014286.
