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D.P. Carbone
Moderator of
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ISS12 - Immuno–Oncology: A Renaissance in the Treatment of Lung Cancer – MSD Oncology (ID 448)
- Event: WCLC 2016
- Type: Industry Supported Symposium
- Track:
- Presentations: 6
- Moderators:D.P. Carbone
- Coordinates: 12/07/2016, 12:45 - 14:15, Lehar 3-4
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ISS12.01 - Welcome and Opening Remarks (ID 6902)
12:45 - 14:15 | Author(s): D.P. Carbone
- Abstract
Abstract not provided
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ISS12.02 - Immunotherapy Experience in Lung Cancer (ID 6903)
12:45 - 14:15 | Author(s): N. Rizvi
- Abstract
Abstract not provided
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ISS12.03 - The Value of OD-L1 Expression in NSCLC (ID 6904)
12:45 - 14:15 | Author(s): K. Kerr
- Abstract
Abstract not provided
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ISS12.04 - Patient Management (ID 6905)
12:45 - 14:15 | Author(s): T. Newsom-Davis
- Abstract
Abstract not provided
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ISS12.05 - Lung Cancer Landscape: Future Directions (ID 6906)
12:45 - 14:15 | Author(s): D.P. Carbone
- Abstract
Abstract not provided
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ISS12.07 - Closing Remarks (ID 6908)
12:45 - 14:15 | Author(s): D.P. Carbone
- Abstract
Abstract not provided
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PL02a - Distinguished Lecture (ID 480)
- Event: WCLC 2016
- Type: Plenary
- Track:
- Presentations: 1
- Moderators:R. Pirker, D.P. Carbone, F.R. Hirsch
- Coordinates: 12/05/2016, 08:45 - 09:00, Hall D (Plenary Hall)
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Welcome Address (ID 7160)
08:45 - 09:00 | Author(s): H. Fischer
- Abstract
- Presentation
Abstract not provided
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PL03 - Presidential Symposium (ID 428)
- Event: WCLC 2016
- Type: Plenary
- Track:
- Presentations: 10
- Moderators:D.P. Carbone, R. Pirker
- Coordinates: 12/06/2016, 08:35 - 10:25, Hall D (Plenary Hall)
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PL03.01 - Presidential Address (ID 6881)
08:35 - 10:25 | Author(s): D.P. Carbone
- Abstract
- Presentation
Abstract not provided
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PL03.02 - Lung Cancer Staging – Changing the Clinical Practice (ID 6866)
08:35 - 10:25 | Author(s): R. Rami-Porta
- Abstract
- Presentation
Abstract:
Introduction At the time of the 17[th] World Conference on Lung Cancer, the 8[th] edition of the tumor, node and metastasis (TNM) classification of lung cancer will have been published by the Union for International Cancer Control, the American Joint Committee on Cancer and the International Association for the Study of Lung Cancer (IASLC) in their respective staging manuals. The innovations introduced, based on the analyses of the new IASLC database that includes 70,967 evaluable patients with non-small cell lung cancer and 6,189 with small cell lung cancer are described in the table. (1-9) These innovations will lead to some changes in clinical practice that are worth reflecting on. Table. Innovations introduced in the 8[th] edition of the TNM classification of lung cancer.
The T component Tumor size is a much more relevant prognostic factor than in previous editions and is now a descriptor in all T categories. Therefore, tumor size measurement should be carefully performed because small changes in size mean important changes in prognosis. (2) In part-solid tumors, only the solid/invasive part counts to measure tumor size. (7) The fact that adenocarcinoma in situ –Tis(AIS) – and minimally invasive adenocarcinoma –T1mi– have their own coding in the TNM classification will increase their awareness. (7) These, together with the smallest coded solid tumors, those of one cm or less in largest dimension –T1a– can become the base from which to study therapeutic options, such as sublobar resections, stereotactic radiotherapy, radiofrequency ablation; tumor biology, including tumor growth, tumor density and intensity of the standardized uptake value, as well as molecular profile and genetic signatures. Visceral pleural invasion and its two categories (PL1: invasion beyond its elastic layer; and PL2: invasion of the pleural surface) have been confirmed as important prognostic factors. (2) This means that pathologists should intensively investigate the identification of visceral pleural invasion, and, if it is not evident by the standard hematoxylin and eosine stains, elastic stains should be used, as recommended in the 7[th] edition of the TNM classification. (10) The N component Although there will be no changes in the N categories, the analyses for the 8[th] edition have shown that quantification of nodal disease has prognostic implications. This had already been evident in the 7[th] edition, when it was found that the number of involved nodal zones was prognostic. The analyses for the 8[th] edition have considered the number of involved nodal stations and have found that the more nodal stations involved, the worse the prognosis; and that the prognosis of tumors with involvement of multiple N1 stations was similar to that of tumors with single station N2 without concomitant N1 disease (skip metastases). (3) The findings of the 7[th] edition already raised the issue of indicating upfront resection in patients with tumors with single N2 zone involvement, because their prognosis was the same as that of tumors with multiple N1 zones. The question will be raised again in the light of the results of the 8[th] edition. However, in both occasions, the quantification of nodal disease derived from pathological staging of those tumors that had been resected and the resection had been accompanied by a properly performed systematic nodal dissection. This is difficult to replicate at clinical staging, the moment at which therapeutic decisions are made, unless a transcervical mediastinoscopic lymphadenectomy is performed. This lymphadenectomy has been found to be equivalent to that performed at the time of resection, either by thoracoscopic or open surgery, and is the only pre-resection test that can define single station or single zone N2 disease reliably. The M component There is no change in the metastasis within the thoracic cavity (M1a), but single extrathoracic metastases have better prognosis than multiple extrathoracic metastasis in one or in several organs, and different categories have been defined for them: M1b for single and M1c for multiple extrathoracic metastases. (4) The fact that single extrathoracic metastasis have their own category will facilitate the redefinition of oligometastatic and oligoprogressive disease, the establishment of therapeutic protocols with radical intention, and the investigation of all therapeutic modalities to eliminate the advance disease. However, clinical staging will have to be precise and will have to determine the number and the organ location of the metastatic deposits. The stages Some TNM subsets have moved from one stage to another and new stages and sub-stages have been created to accommodate groups of tumors with similar prognosis. (5) As it occurred with the 7[th] edition, the question of how to treat patients whose tumors have changed stage will be raised at multidisciplinary team meetings. Taxonomic changes do not necessarily mean an automatic change in therapy if the clinical trials performed to test therapeutic options did not include the tumors that are now included in the selected stages for study. Therefore, in the absence of results from clinical trials, clinical judgment will have to determine what the best options are for a given patient with a given tumor. Lung cancer with multiple lesions The 8[th] edition will provide a set of rules with the intention to classify lung cancers with multiple lesions in a homogeneous way. (8) It is our responsibility to follow the rules to collect prospective data uniformly and validate the given recommendations with international data. Conclusion The 8[th] edition will help us refine prognosis both at clinical and pathologic staging and stratify tumors in future clinical trials, but will require more attention from us at measuring tumor size, at determining nodal disease, at searching for metastases, and at using clinical judgment to indicate treatment. References 1. Rami-Porta R, Bolejack V, Giroux DJ et al. The IASLC lung cancer staging project: the new database to inform the eighth edition of the TNM classification of lung cancer. J Thorac Oncol 2014; 9: 1618-1624. 2. Rami-Porta R, Bolejack V, Crowley J et al. The IASLC lung cancer staging project: proposals for the revisions of the T descriptors in the forthcoming 8[th] edition of the TNM classification for lung cancer. J Thorac Oncol 2015; 10: 990-1003. 3. Asamura H, Chansky K, Crowley J et al. The IASLC Lung Cancer Staging Project: proposals for the revisions of the N descriptors in the forthcoming 8[th] edition of the TNM classification for lung cancer. J Thorac Oncol 2015; 10: 1675-1684. 4. Eberhardt WEE, Mitchell A, Crowley J et al. The IASLC lung cancer staging project: proposals for the revisions of the M descriptors in the forthcoming 8[th] edition of the TNM classification for lung cancer. J Thorac Oncol 2015; 10: 1515-1522. 5. Goldstraw P, Chansky K, Crowley J et al. The IASLC lung cancer staging project: proposals for the revision of the stage grouping in the forthcoming (8th) edition of the TNM classification of lung cancer. J Thorac Oncol 2016; 11: 39-51. 6. Nicholson AG, Chansky K, Crowley J et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: proposals for the revision of the clinical and pathologic staging of small cell lung cancer in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol 2016; 11: 300-311. 7. Travis WD, Asamura H, Bankier A et al. The IASLC Lung Cancer Staging Project: proposals for coding T categories for subsolid nodules and assessment of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol 2016; 11: 1204-1223. 8. Detterbeck FC, Nicholson AG, Franklin WA et al. The IASLC Lung Cancer Staging Project: summary of proposals for revisions of the classification of lung cancers with multiple pulmonary sites of involvement in the forthcoming eighth edition of the TNM classification. J Thorac Oncol 2016; 11: 539-650. 9. Detterbeck FC, Chansky K, Groome P et al. The IASLC Lung Cancer Staging Project: methodology and validation used in the development of proposals for revision of the stage classification of NSCLC in the forthcoming (eighth) edition of the TNM classification of lung cancer. J Thorac Oncol 2016; 11: 1433-1446. 10. Travis WD, Brambilla E, Rami-Porta R et al. Visceral pleural invasion: pathologic criteria and use of elastic stains. Proposal for the 7[th] edition of the TNM classification for lung cancer. J Thorac Oncol 2008; 3: 1384-1390.Descriptor 8[th] edition T component >/= 1cm T1a >1 – 2cm T1b >2 – 3cm T1c >3 – 4cm T2a >4 – 5cm T2b >5 – 7cm T3 >7cm T4 Brochus <2cm from carina T2 Total atelectasis/pneumonitis T2 Diaphragm inasion T4 Mediastinal pleura invasion - M component Metastases in thoracic cavity M1a Single extrathoracic metastasis M1b Multiple extrathoracic metastases M1c Other innovations in classification Second primaries One TNM for each Separate tumor nodules T3, T4 and M1a Multifocal adenocarcinomas with ground glass opacity/lepidic features Highest T (#/m) and global N and M Pneumonic type adenocarcinoma T3, T4 and M1a
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PL03.03 - Randomised Phase III Study of Osimertinib vs Platinum-Pemetrexed for EGFR T790M-Positive Advanced NSCLC (AURA3) (Abstract under Embargo until December 6, 7:00 CET) (ID 4452)
08:35 - 10:25 | Author(s): V. Papadimitrakopoulou, Y.-. Wu, M. Ahn, S.S. Ramalingam, M.C. Garassino, H.R. Kim, F. Shepherd, H. Akamatsu, W.S. Theelen, C.K. Lee, M. Sebastian, A. Templeton, M. Marotti, S. Ghiorghiu, T. Mok
- Abstract
- Presentation
Background:
Osimertinib is a potent, irreversible, CNS active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for sensitising (EGFRm) and T790M resistance mutations. Osimertinib is indicated for the treatment of patients with locally advanced or metastatic EGFR T790M-positive NSCLC. AURA3 (NCT02151981) is a Phase III, open-label, randomised study assessing the efficacy and safety of osimertinib versus platinum-based chemotherapy plus pemetrexed in patients with EGFR T790M-positive advanced NSCLC, whose tumours progressed on first-line EGFR-TKI therapy.
Methods:
Eligible patients were ≥18 years with documented EGFRm, radiological disease progression following first-line EGFR-TKI and centrally confirmed T790M-positive (by cobas® EGFR Mutation Test) from a tissue biopsy after disease progression. Asymptomatic, stable CNS metastases were allowed. Patients were randomised 2:1 to osimertinib 80 mg orally, once daily or platinum-pemetrexed (pemetrexed 500 mg/m[2] plus either cisplatin 75 mg/m[2] or carboplatin AUC5) every three weeks for up to six cycles; pemetrexed could be continued as maintenance treatment. Primary endpoint was progression-free survival (PFS) by investigator assessment according to RECIST v1.1; sensitivity analysis was by blinded independent central review (BICR).
Results:
A total of 419 patients were randomised to treatment (osimertinib, n=279; platinum-pemetrexed, n=140). Baseline characteristics were generally balanced across treatment groups: female 64%, Asian 65%, never smoker 68%, CNS metastases 34%, EGFR exon 19 deletion 66%. Osimertinib significantly improved PFS compared with platinum-pemetrexed: hazard ratio [HR] 0.30; 95% CI: 0.23, 0.41; p<0.001 (median 10.1 months vs 4.4 months). The result was consistent with PFS analysis by BICR: HR 0.28; 95% CI: 0.20, 0.38; p<0.001 (11.0 months vs 4.2 months). Objective response rate was significantly improved with osimertinib (71%) vs platinum-pemetrexed (31%); odds ratio 5.39 (95% CI: 3.47, 8.48; p<0.001). Median duration of response was 9.7 months (95% CI 8.3, 11.6) with osimertinib and 4.1 months (95% CI 3.0, 5.6) with platinum-pemetrexed. Grade ≥3 causally-related adverse events (AEs) as assessed by the investigator were reported in 6% of patients (n=16) treated with osimertinib and 34% (n=46) treated with platinum-pemetrexed. Most common causally-related AEs in the osimertinib group: diarrhoea (29% [grade ≥3, 1%]), rash (28% [<1%]); in the platinum-pemetrexed group: nausea (47% [3%]), decreased appetite (32% [3%]).
Conclusion:
In patients with EGFR T790M-positive advanced NSCLC following progression on EGFR-TKI treatment, osimertinib demonstrated a superior clinically-meaningful efficacy over platinum-pemetrexed, with a 70% reduction in the risk of disease progression, and well-characterised safety profile, establishing the new standard of care for these patients.
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PL03.04 - Discussant for PL03.02, PL03.03 (ID 7156)
08:35 - 10:25 | Author(s): T. Mitsudomi
- Abstract
- Presentation
Abstract not provided
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PL03.05 - BRAIN: A Phase Ⅲ Trial Comparing WBI and Chemotherapy with Icotinib in NSCLC with Brain Metastases Harboring EGFR Mutations (CTONG 1201) (Abstract under Embargo until December 6, 7:00 CET) (ID 4570)
08:35 - 10:25 | Author(s): Y.-. Wu, J.-. Yang, C. Zhou, J. Feng, S. Lu, Y. Song, C. Huang, G. Wu, Y. Cheng, C. Hu, L. Zhang, G. Chen, L. Zhang, X. Liu, H. Yan, F. Tan, Y. Huang
- Abstract
- Presentation
Background:
Non-small cell lung cancer (NSCLC) with brain metastases （M） had a poor prognosis. Whole brain irradiation (WBI) is a standard of care for this critical medical condition. The median survival is only 4-6 months. Small molecule inhibitors of epidermal growth factor receptor (EGFR) including icotinib achieved very successful results in advanced NSCLC with EGFR mutations. There were no prospective randomized clinical trials to explore the efficacy of EGFR tyrosine kinase inhibitors (TKIs) on brain M.
Methods:
Advanced NSCLC with EGFR sensitive mutations and brain M were randomized to WBI plus chemotherapy (chemo) or icotinib. Patients in WBI arm received radiotherapy with 30Gy/3Gy/10 fractions plus concurrent or sequential doublet chemo of 4-6 cycles. Patients in EGFR TKI arm received icotinib 125mg orally tid until disease progression. Icotinib could be continued beyond progression if clinical benefit was observed by the investigator. Crossover to icotinib from WBI could be permitted. Key inclusion criteria were EGFR mutations and radiologically confirmed brain M with at least 3 lesions. The primary endpoint was intracranial progression-free survival (iPFS) by investigator assessments according to RECIST v1.1. The secondary endpoints included objective response rate (ORR), PFS and overall survival (OS). Safety and tolerability were assessed by measuring adverse events （AEs） (CTCAE v4).
Results:
From Dec. 2012 to June 2015, 176 patients from 17 sites were randomized to WBI+Chemo arm (N=91) or icotinib arm (N=85). The baseline clinicopathologic factors were balanced between the two groups. Median age was 58, PS 1 was 87.2%, non-smoker 70.9%, adenocarcinoma 96.8%, symptomatic brain M were 16.5%. Icotinib significantly improved median iPFS compared with WBI+chemo: hazard ratio [HR] 0.56; 95% CI: 0.36-0.90; p=0.014 (10.0 vs 4.8 months). Median PFS was 6.8 vs 3.4 months, (HR 0.44, 95% CI 0.31-0.63, P<0.001). Median OS had no significant difference between the arms (18.0 vs 20.5 months, HR 0.93, 95%CI 0.60-1.44, P=0.734). Intracranial ORR was significantly improved with icotinib than WBI+Chemo (67.1% vs 40.9%; p<0.001); Overall ORR was 55.0% vs 11.1% (P<0.001). Grade ≥3 AEs assessed by the investigators were reported in 8.2% (N=7) of patients treated with icotinib and 26.2% (N=28) treated with WBI+Chemo. Most common causally related AEs in the icotinib arm were increased liver transaminase & rash; in the WBI+Chemo arm were hematologic toxicity.
Conclusion:
Icotinib demonstrated superior iPFS, PFS and ORR over WBI+Chemo in EGFR mutant advanced NSCLC with brain M, and well-tolerated safety profile. Icotinib would be a treatment option for EGFR mutant patients with brain M (NCT01724801).
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PL03.06 - Discussant for PL03.05 (ID 7154)
08:35 - 10:25 | Author(s): J. Jassem
- Abstract
- Presentation
Abstract not provided
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PL03.07 - First-line Ceritinib Versus Chemotherapy in Patients With ALK-rearranged (ALK+) NSCLC: A Randomized, Phase 3 Study (ASCEND-4) (Abstract under Embargo until December 6, 7:00 CET) (ID 4987)
08:35 - 10:25 | Author(s): G. De Castro Jr, D. Tan, L. Crinò, Y.-. Wu, L. Paz-Arez, J. Wolf, S.L. Geater, S. Orlov, D. Cortinovis, C. Yu, M.J. Hochmair, A.B. Cortot, C. Tsai, D. Moro-Sibilot, R. García Campelo, F. Branle, P. Sen, T. McCulloch, J. Soria
- Abstract
- Presentation
Background:
Here, we report results of ceritinib versus chemotherapy as first-line treatment for advanced ALK+ NSCLC.
Methods:
Untreated ALK+ (IHC confirmed), advanced, nonsquamous NSCLC patients (N=376; median age, 54 years) were randomized (1:1) to ceritinib 750 mg/day (n=189 [59 with brain metastases (BM)]) or chemotherapy (n=187 [62 with BM]; [pemetrexed 500 mg/m[2] plus cisplatin 75 mg/m[2] or carboplatin AUC 5-6] for 4 cycles followed by maintenance pemetrexed), stratified by WHO PS (0 vs 1-2), BM at screening, and prior neo-/adjuvant chemotherapy. Crossover from chemotherapy to ceritinib was allowed at progression (n=80 crossed-over).
Results:
Median treatment exposure was 66.4 weeks for ceritinib and 26.9 weeks for chemotherapy. Median follow-up duration was 19.7 months (randomization to cut-off date). The study met its primary objective, with ceritinib demonstrating statistically significant improvement in BIRC PFS (RECIST 1.1; median, 16.6 [12.6, 27.2] vs 8.1 months [5.8, 11.1], HR=0.55, P<0.001) versus chemotherapy. OS was immature (HR, 0.73 [0.50, 1.08]; P=0.056) with 42.3% of required events at interim analysis. ORR (BIRC, 72.5% vs 26.7%) and DOR (BIRC, median, 23.9 vs 11.1 months) were also higher with ceritinib versus chemotherapy. Among patients with measurable baseline BM and ≥1 postbaseline assessment, intracranial ORR (BIRC neuroradiologist; modified RECIST v1.1) was higher with ceritinib (72.7% [49.8, 89.3] vs 27.3% [10.7, 50.2]) versus chemotherapy (Table). Most common AEs (>50%) with ceritinib were diarrhea (84.7%), nausea (68.8%), vomiting (66.1%), ALT increase (60.3%), and AST increase (52.9%). Overall, 5.3% ceritinib- and 11.4% chemotherapy-treated patients discontinued due to AEs suspected to be drug-related. Figure 1
Conclusion:
First-line ceritinib achieved statistically significant and clinically meaningful improvement in median PFS with an estimated 45% risk reduction in advanced ALK+ NSCLC versus chemotherapy including maintenance. Moreover, ceritinib achieved high and durable systemic responses and high OIRR in patients with measurable BM. Safety profile of ceritinib is consistent with previously reported.
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PL03.08 - Discussant for PL03.07 (ID 7155)
08:35 - 10:25 | Author(s): F. Blackhall
- Abstract
- Presentation
Abstract not provided
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PL03.09 - Phase 3 Study of Ganetespib, a Heat Shock Protein 90 Inhibitor, with Docetaxel versus Docetaxel in Advanced Non-Small Cell Lung Cancer (GALAXY-2) (Abstract under Embargo until December 6, 7:00 CET) (ID 5232)
08:35 - 10:25 | Author(s): R.N. Pillai, D.A. Fennell, V. Kovcin, T.E. Ciuleanu, R. Ramlau, D. Kowalski, M. Schenker, B. Perin, I. Yalcin, F. Teofilovici, V.M. Vukovic, S.S. Ramalingam
- Abstract
- Presentation
Background:
Heat shock protein 90 functions as a chaperone to stabilize oncoproteins. Ganetespib (G), a highly potent Hsp90 inhibitor, has demonstrated efficacy in combination with docetaxel (D) over D alone in the second-line therapy of patients with advanced adenocarcinoma of the lung in a phase 2 study.
Methods:
GALAXY-2 is a randomized (1:1), international, open-label study of D with or without G. Patients with advanced (stage IIIB/IV) non-small cell lung cancer (NSCLC) of adenocarcinoma histology, EGFR and ALK wild-type, diagnosed ≥ 6 months prior to study entry, one prior systemic therapy and ECOG PS 0-1 were eligible. D was given at 75 mg/m[2] on day 1 of three-week cycle; D was given on day 1 with G at 150 mg/m[2 ]on Days 1 and 15 of each cycle. Patients were stratified by performance status (PS), LDH, and geographic region. Primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS) and OS in elevated LDH (eLDH) patients. We report the results of a planned interim analysis at 336 events, which occurred on October 5, 2015, with type I error level set at 0.01 (2 sided stratified log-rank test).
Results:
677 patients were randomized with 335 patients in G+D arm and 337 patients in D arm. Baseline characteristics: females 60%, age < 65 68%; never-smoker 18%; PS 0 36%; eLDH 29%; North America/Western Europe 39%. The median number of cycles delivered was 5 in G+D and 4 in D arm. There was no difference in median OS (mOS) for the two arms: 10.9 months with G+D versus 10.5 months with D alone. The hazard ratio for OS was 1.111 (95% CI 0.899-1.372), which met the early stopping criteria for futility. Median PFS was similar in the two arms: 4.2 versus 4.3 months, G+D and D, respectively (HR 1.161, 95% CI 0.961-1.403). There was no improvement with the addition of G for any secondary endpoint, including survival in the eLDH and EGFR and ALK negative populations, response rate, or progression due to new metastatic lesions. The most common grade 3/4 treatment-emergent adverse event in both arms was neutropenia (31.1% versus 24.3%, G+D and D, respectively).
Conclusion:
The addition of ganetespib to docetaxel did not result in improved efficacy for salvage therapy of patients with advanced stage lung adenocarcinoma.
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PL03.10 - Discussant for PL03.09 (ID 7157)
08:35 - 10:25 | Author(s): D.R. Gandara
- Abstract
Abstract not provided
Author of
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ED01 - Biology of Lung Cancer (ID 263)
- Event: WCLC 2016
- Type: Education Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:R. Rosell, M. Filipits
- Coordinates: 12/05/2016, 11:00 - 12:30, Hall C1
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ED01.01 - Understanding Biology: The Road to Cure? (ID 6421)
11:00 - 12:30 | Author(s): D.P. Carbone
- Abstract
- Presentation
Abstract not provided
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ISS12 - Immuno–Oncology: A Renaissance in the Treatment of Lung Cancer – MSD Oncology (ID 448)
- Event: WCLC 2016
- Type: Industry Supported Symposium
- Track:
- Presentations: 3
- Moderators:D.P. Carbone
- Coordinates: 12/07/2016, 12:45 - 14:15, Lehar 3-4
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ISS12.01 - Welcome and Opening Remarks (ID 6902)
12:45 - 14:15 | Author(s): D.P. Carbone
- Abstract
Abstract not provided
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ISS12.05 - Lung Cancer Landscape: Future Directions (ID 6906)
12:45 - 14:15 | Author(s): D.P. Carbone
- Abstract
Abstract not provided
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ISS12.07 - Closing Remarks (ID 6908)
12:45 - 14:15 | Author(s): D.P. Carbone
- Abstract
Abstract not provided
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MA16 - Novel Strategies in Targeted Therapy (ID 407)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:G. Purkalne, J. Von Pawel
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 2
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MA16.03 - Global RET Registry (GLORY): Activity of RET-Directed Targeted Therapies in RET-Rearranged Lung Cancers (ID 4325)
14:20 - 15:50 | Author(s): D.P. Carbone
- Abstract
- Presentation
Background:
GLORY is a global registry of patients with RET-rearranged non-small cell lung cancer (NSCLC). In order to complement ongoing prospective studies, the registry’s goal is to provide data on the efficacy of RET-directed targeted therapies administered outside the context of a clinical trial. We previously reported results from our first interim analysis (Gautschi, ASCO 2016). Following additional accrual into the registry, updated results are presented here, with a focus on an expanded efficacy analysis of various RET inhibitors.
Methods:
A global, multicenter network of thoracic oncologists identified patients with pathologically-confirmed NSCLC harboring a RET rearrangement. Molecular profiling was performed locally via RT-PCR, FISH, or next-generation sequencing. Anonymized data including clinical, pathologic, and molecular features were collected centrally and analyzed by an independent statistician. Response to RET tyrosine kinase inhibition (TKI) administered off-protocol was determined by RECIST1.1 (data cutoff date: April 15, 2016). In the subgroup of patients who received RET TKI therapy, the objectives were to determine overall response rate (ORR, primary objective), progression-free survival (PFS), and overall survival (OS).
Results:
165 patients with RET-rearranged NSCLC from 29 centers in Europe, Asia, and the USA were accrued. The median age was 61 years (range 28-89 years). The majority of patients were female (52%), never smokers (63%), with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent metastasic sites were lymph nodes (82%), bone (51%) and lung (32%). KIF5B-RET was the most commonly identified fusion (70%). 53 patients received at least one RET-TKI outside of a clinical protocol, including cabozantinib (21), vandetanib (11), sunitinib (10), sorafenib (2), alectinib (2), lenvatinib (2), nintedanib (2), ponatinib (2) and regorafenib (1). In patients who were evaluable for response (n=50), the ORR was 37% for cabozantinib, 18% for vandetanib, and 22% for sunitinib. Median PFS was 3.6, 2.9, and 2.2 months and median OS was 4.9, 10.2, and 6.8 months for cabozantinib, vandetanib, and sunitinib, respectively. Responses were also observed with nintedanib and lenvatinib. Among patients who received more than one TKI (n=10), 3 partial responses were achieved after prior treatment with a different TKI.
Conclusion:
RET inhibitors are active in individual patients with RET-rearranged NSCLC, however, novel therapeutic approaches are warranted with the hope of improving current clinical outcomes. GLORY remains the largest dataset of patients with RET-rearranged NSCLC, and continues to accrue patients.
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OA04 - Epidemiology and Prevention of Lung Cancer (ID 370)
- Event: WCLC 2016
- Type: Oral Session
- Track: Epidemiology/Tobacco Control and Cessation/Prevention
- Presentations: 1
- Moderators:L. Petruželka, S. Shastri
- Coordinates: 12/05/2016, 11:00 - 12:30, Schubert 4
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OA04.05 - Chronic Inflammation, NSAIDS and the Risk of Lung Cancer Death (Abstract under Embargo until December 5, 7:00 CET) (ID 6166)
11:00 - 12:30 | Author(s): D.P. Carbone
- Abstract
- Presentation
Background:
Chronic inflammation appears to heighten the risk of lung cancer and, reciprocally, agents that reduce inflammation have been found to reduce this risk. Nevertheless, few prospective studies have examined associations between lung cancer and the intake of nonsteroidal anti-inflammatory drugs (NSAIDs). In the current study, we examined associations between fatal lung cancer and NSAIDs using prospective data from the Third National Health and Nutrition Examination Study.
Methods:
Baseline data on smoking, NSAIDs and other lifestyle variables were collected for 10,735 participants during 1988-1994, and cause-specific mortality status was ascertained through probabilistic record matching using the National Death Index through 2006. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) to quantify associations between NSAID use and lung cancer death, with adjustment for current smoking and other variables.
Results:
During 18 years of follow-up, 269 individuals died from lung cancer of which 252 (93.6%) reported a history of cigarette smoking. Since all but 17 of the 269 fatal lung cancer cases occurred among current or former smokers, estimates of NSAID effects were ascertained from a sub-cohort of 5,882 individuals who reported a history of past or current cigarette smoking. Multivariate regression models revealed that regular use of ibuprofen reduced the risk of lung cancer death by 48% (HR=0.52, 95% CI=0.33-0.82, P<0.01). Main effects of other compounds tested (aspirin or acetaminophen) were not statistically significant.
Conclusion:
Prospective data from NHANES III showed that among adults with a history of past or current smoking, ibuprofen intake was associated with a substantial (48%) reduction in the risk of dying from lung cancer. Effects of aspirin and acetaminophen were not statistically significant. These results suggest that regular use of certain NSAIDs may be beneficial for high-risk subgroups of smokers as a lung cancer prevention strategy.
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-092 - PRMT5 is a Poor Prognostic Marker for NSCLC and Inhibition of PRMT5 Results in Increased Lung Cancer Sensitivity to Cisplatin and Radiotherapy (ID 6137)
14:30 - 15:45 | Author(s): D.P. Carbone
- Abstract
Background:
Protein arginine methyltransferase 5 (PRMT5), a member of the protein arginine methyltransferase family, has important regulatory function in many cellular processes through epigenetic control of target gene expression. Because of its overexpression in a number of human cancers and its essential role in cell proliferation, transformation and cell cycle progression, PRMT5 has been recently proposed to function as an oncoprotein in cancer cells. In this study, we explore prognostic and predictive value of PRMT5 expression in lung cancer. Impact of PRMT5 inhibition in the setting of radiation therapy and platin-based chemotherapy was investigated.
Methods:
PRMT5 expression levels in lung tumors as well as their paired normal tissue obtained from TCGA public databases were compared. The impact of PRMT5 expression on lung cancer patient survival was investigated by using “Director’s challenge Consortium for the Molecular Classification of Lung Adenocarcoma” and JBR10 datasets. SiRNA designed to target PRMT5 was used to transiently knockdown (KD) PRMT5 expression in several lung cancer cell lines. Clonogenic survival assays of lung cancer cell lines with increasing doses of cisplatin or radiation were performed in cells with normal endogenous PRMT5 expression or in cells after siRNA knockdown. Impact of PRMT5 knockdown in cell cycle, apoptosis, DNA damage response was investigated through cell cycle analysis, Annexin/PI flow cytometry, ɣH2A foci measurements in lung cancer cells with normal or reduced PRMT5 expression.
Results:
PRMT5 expression is significant higher in lung tumors compared to parired normal tissue in TCGA datasets (LUAD and LUSC) with p value ≤0.0001. Patients with high PRMT5 expression portend lower overall survival at 3 years (p=0.02) from director’s challenge lung cancer study. Patients with low PRMT5 expression had significantly better DFS at 5 years (p=0.3) if they received cisplatin while patients with high PRMT5 expression did not benefit from cisplatin treatment (p=0.7). In several lung cancer cell lines, we observed >90% PRMT5 KD in transiently transfected cells at 48 h and 72 h post transfection as verified by western blot analysis. This inhibition of PRMT5 activity achieved by transient KD lead to a significant decrease in colony survival after radiation and cisplatin. There is an increase of cell population in G1 arrest in PRMT5 transient KD cells.
Conclusion:
High PRMT5 expression is associated with worse survival in lung cancer patients. Inhibition of PRMT5 in lung cancer cells results in sensitization to cisplatin and radiotherapy,
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-069 - LKB1 Loss is a Novel Determinant of MEK Sensitivity Due to Alterations in AKT/FOXO3 Signaling (ID 3941)
14:30 - 15:45 | Author(s): D.P. Carbone
- Abstract
Background:
The use of MEK inhibitors for non-small cell lung cancer (NSCLC) has shown little efficacy in clinical trials, even in the case of tumors with mutant KRAS where one might predict good outcomes. From these data, it is clear that the success of MEK inhibitors is going to rely on finding a biomarker that predicts sensitivity to this type of therapy. Our area of interest is finding a way to treat LKB1 mutant tumors and, surprisingly, an in silico screen of drug sensitivity data for NSCLC cell lines determined that four MEK inhibitors were among the top drugs that were significantly associated with LKB1 loss.
Methods:
We determined the effects MEK inhibition by evaluating 23 lung cancer cell lines with known LKB1 status. In addition, we investigated MEK sensitivity by restoring wild-type (Wt) LKB1 in lung cancer cell lines with LKB1 loss in vitro, or by silencing LKB1 in lung cancer cell LKB1-Wt lines both in vitro and in vivo experiments.
Results:
MEK inhibition with trametinib led to a significant reduction in cell viability in LKB1 mutant cell lines when compared to cell lines with wild type LKB1. Transduction of LKB1 resulted in significant MEK resistance in six of the seven LKB1 add-back lines, while silencing LKB1 induced MEK sensitivity in all five LKB1-Wt lines tested. The mechanism behind these observed results appears to be through phosphorylation of AKT and its downstream target FOXO3, which are important determinants of the apoptotic response to MEK inhibition. With LKB1 transduction into mutant cell lines we see an increase in the activating phosphorylation of AKT, a protein involved in survival mechanisms, and an increase in the deactivating phosphorylation of FOXO3, a transcription factor implicated in increased levels of apoptosis.
Conclusion:
Our data suggest that the identification of LKB1 activity may be promising biomarker for the sensitivity to MEK inhibition by regulating activation of AKT-FOXO3 pathway in NSCLC.
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P2.03b-082 - AQP11 as a Novel Factor of Lung Cancer Cell Resistance to Cisplatin (ID 6276)
14:30 - 15:45 | Author(s): D.P. Carbone
- Abstract
Background:
Platinum-based combination treatment is a standard of care treatment for lung cancer patients. Aquaporin 11 (AQP11), a non-ubiquitous member of aquaporins family, is an ER-specific water channel mostly present in epithelial cells and is implicated in the maintenance of ER homeostasis. We demonstrated that the induction of AQP11 expression is a pro-survival factor in normal epithelial cells under the stress and that cispaltin interacts with AQP11, as a non-DNA target, causing AQP11 structural and post-translational modification. This study evaluated the expression of AQP11 in lung cancer cells to determine whether the AQP11 expression correlates with cisplatin resistance and whether AQP11 expression in lung tumor associates with overall survival in patients with lung adenocarcinoma.
Methods:
18 lung cancer cell lines were tested for AQP11 expression using Western blotting. Growth inhibitory effect of cisplatin was examined using MTT assay and IC~50 ~values were determined. AQP11 knockdown cell lines were generated using a lentiviral vector with shRNA targeting AQP11; efficiency of AQP11 blockage was assessed by Western blotting. We analyzed TCGA database to identify connection between AQP11 mRNA expression and overall survival (OS) in lung adenocarcinoma patients.
Results:
All tested cancer cell lines expressed AQP11 and correlation analysis revealed significant association of AQP11 expression with cisplatin resistance (Spearman’s r=0.82, p=0.008). Analysis of stress markers showed that cisplatin-treated cells with higher AQP11 expression had lower stress. Using shRNA, we knocked down AQP11 in cispaltin resistant A549 and HCC827 cells and cisplatin sensitive H460 cells. Resulting knockdown A549 and HCC827 cells became 2.6- to 2.9-fold more sensitive to cisplatin compared to parental and control vector transduced cells. In sensitive H460 cells, knocking down AQP11 did not change sensitivity to cisplatin. Results suggest that high expression AQP11 contributes to cisplatin resistance. TCGA database analysis of previously untreated lung adenocarcinoma, detected 13% tumors with elevated AQP11 mRNA expression (6.18±0.55 vs. 4.28±0.77, p<0.001). Increased AQP11 expression was significantly associated with decreased OS. These patients showed lower median survival rate of 34.47 versus 52.5 months in patients with low AQP11 expression (longrank test p<0.05).
Conclusion:
AQP11 is the cispaltin non-DNA target that may significantly contribute to the development of resistance. High AQP11 level is a pro-survival factor protecting tumor cells from cisplatin-induced stress. High AQP11 expression associates with lower OS in lung adenocarcinoma patients and with cispaltin resistance in lung cancer cell lines. With further validation, AQP11 level might be a predictor of cisplatin resistance and overall survival in lung cancer.
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P2.04 - Poster Session with Presenters Present (ID 466)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.04-027 - Targeting Adenosine A2B Receptor for Modulation of Tumor Microenvironment, Primary Tumor Growth, and Lung Metastasis (ID 6107)
14:30 - 15:45 | Author(s): D.P. Carbone
- Abstract
Background:
Our work addresses two poorly understood areas of tumor metastases; the first is how tumor-conditioned immune cells initiate and drive premetastatic niche evolution and secondary tumor establishment and secondly, how the tumor microenvironment (TME) conditions shape the tumor immune response and function.
Methods:
We have developed a model that is fully capable of addressing these biological questions through in vivo EPR monitoring of the primary TME that allows simultaneous measurements of tumor pO~2~, pH, and inorganic phosphate (Pi) levels, which are parameters implicated in tumor metastasis and demonstrates how the TME contributes to metastasis. In combination, we employ an in vivo immune/tumor cell imaging platform in which mice are fitted with cutaneous window chambers containing syngeneic lung tissue transplant to create a lung metastatic site in which differentially-labeled tumor and immune subsets will be imaged via multiphoton microscopy.
Results:
Our EPR methodology accurately monitors TME changes that occur with tumor growth as well as their modulation by pharmacological inhibition of the A~2B~ adenosine receptor, giving reason to the use of specific A~2B~ receptor inhibitors as anti-tumor and anti-metastatic therapeutics. A~2B~ inhibition prevented the accumulation of Pi in the tumor interstitial space for every tumor model tested, which includes lung adenocarcinoma, breast adenocarcinoma, colon carcinoma, and melanoma. The exact role this plays in tumor initiation and progression is not completely elucidated but correlates with the reduction of tumor lung metastases and tumor growth. Secondly, our window chamber model enables spatiotemporal analysis of pre-metastatic niche enrichment, individual tumor cell recruitment, and subsequent secondary tumor growth with specific focus on metastatic lung disease. To our knowledge, no model exists capable of unifying these aspects of tumor biology and immunity.
Conclusion:
The project will lead to understanding a key process of metastasis and thus allow targeted immunotherapies to block metastasis and thus eliminate, or greatly reduce, the lethal aspect of cancer. Future work will also examine the potential anti-tumor therapeutic strategy of using specific A~2B~ adenosine receptor antagonists for TME modulation. Of which, PBF-1129 is undergoing pre-clinical and IND-enabling studies and demonstrates high anti-tumor efficacy, suggesting the possibility for clinical trials with A~2B~ antagonists for cancer therapy in the nearest future. Lastly, our methodology is targeting a glaring hole in the understanding of tumor metastasis, meaning the forthcoming information from our work holds great promise to identify novel therapeutic strategies aimed at greatly diminishing the chief cause of cancer morbidity.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-019 - A Phase II Study of Atezolizumab as Neoadjuvant and Adjuvant Therapy in Patients (pts) with Resectable Non-Small Cell Lung Cancer (NSCLC) (ID 4642)
14:30 - 15:45 | Author(s): D.P. Carbone
- Abstract
Background:
There is no curative treatment for patients with NSCLC who develop metastatic disease after resection. Trials of neoadjuvant and adjuvant chemotherapy have demonstrated an absolute survival benefit of 5% for patients with stages IB, II, and IIIA disease. Clearly, developing new treatment strategies to improve survival following resection is critical to improving outcomes for this patient population. Immunotherapy with checkpoint inhibitors such as antibodies to PD-1 and PD-L1 has demonstrated superior survival compared to chemotherapy in randomized clinical trials. PD-L1 expression is being investigated as a predictive biomarker for these therapies, but its ability to predict response has varied in published trials. Atezolizumab is a humanized IgG1 monoclonal PD-L1 antibody that was recently evaluated in the POPLAR trial (NCT01903993), a phase II randomized trial of patients with NSCLC who progressed on platinum based chemotherapy. Atezolizumab therapy improved overall survival compared with docetaxel (12.6 months vs. 9.7 months, HR 0.73 [95% CI 0.53 – 0.99]) with a manageable safety profile. Improvement in survival correlated with PD-L1 immunohistochemistry expression of tumor and tumor-infiltrating immune cells.
Methods:
Trial design: This phase II, open-label, single-arm study is designed to evaluate the efficacy and safety of atezolizumab as a neoadjuvant therapy in patients with Stage IB, II, or IIIA NSCLC prior to curative-intent resection. Approximately 180 patients with NSCLC will be enrolled in this study at 15 academic medical centers in the United States. There are two parts to this study: the first/primary part will evaluate the ability of neoadjuvant atezolizumab to produce objective pathologic responses in patients with early stage NSCLC. Atezolizumab 1200 mg IV will be given every 3 weeks for two doses. Surgical resection of tumors following treatment will allow determination of pathologic response rates and potential predictive biomarkers. Part 2 is exploratory and will evaluate atezolizumab adjuvant therapy for up to 12 months in patients who demonstrate clinical benefit (evidence of pathologic response or absence of radiographic progression) in Part 1. After surgical resection, patients may receive SOC adjuvant chemotherapy (with or without radiation) before starting atezolizumab adjuvant therapy in Part 2. The primary objectives are safety and major pathologic response based on surgical resection. Secondary objectives include overall response rate based on PD-L1 status, mutational load, antigen burden, and RNA-sequencing. This trial presents a unique opportunity to evaluate exploratory biomarkers, including pre- and post-treatment biopsy assessment of evolution of immune related markers associated with response.
Results:
Section not applicable
Conclusion:
Section not applicable
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P3.03 - Poster Session with Presenters Present (ID 473)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.03-008 - Hypoxia-Induced Changes in microRNA Levels Contribute to Drug Resistance in a 3D Model of Malignant Pleural Mesothelioma (ID 5867)
14:30 - 15:45 | Author(s): D.P. Carbone
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is an aggressive asbestos-related thoracic cancer. Chemotherapy is the most frequent treatment option but almost every patient will be confronted with recurrence of disease and drug resistance. Previous studies have used 3D spheroid cultures to investigate drug response in MPM. We showed that microRNAs are important players in MPM biology and that they contribute to the response of MPM cells to some chemotherapy drugs. In the current study we aimed to investigate the role of microRNAs in the drug resistance of a 3D spheroid model of MPM.
Methods:
MPM cells were grown in standard 2D culture or as 3D spheroids in low adherence round bottom multi-well plates. The structure of the spheroids was confirmed by conventional and scanning electron microscopy. MicroRNA expression was profiled using TaqMan Low Density Arrays. RT-qPCR and droplet digital PCR were used to validate candidate microRNAs. HIF1a expression was examined in MPM spheroids using immunofluorescence staining. Drug cytotoxicity was investigated in both 2D and 3D cultures using standard proliferation assays, and the effect of drugs on gene expression was analysed. MicroRNA mimics and siRNAs were used to determine the influence of microRNA and HIF1a expression on drug resistance.
Results:
In our adapted model of 3D cell growth, MPM cell lines formed spherical 3D structures, in contrast to the donut shapes reported with other models. MPM cells in these spheroids were more resistant to cisplatin and gemcitabine when compared to cells grown in 2D cultures. Immunofluorescence revealed a hypoxic gradient with high HIF1a expression observed in the centre of the spheroids. Spheroids also exhibited a significant up-regulation of miR-210, miR-21, miR-378a, miR-195 and miR-146b, and down-regulation of miR-320b and miR-1225b. Transfecting MPM cells in 2D culture with miR-210 or miR-21 mimics resulted in increased drug resistance, whereas HIF1a knockdown inhibited spheroid formation and decreased drug resistance. Spheroids displayed higher expression of the ABCG2 drug pump, and ABCG2 was also up-regulated in cisplatin and gemcitabine treated MPM cells.
Conclusion:
Our spheroid model revealed a clear impact of hypoxia on gene expression in MPM cells. Hif1a was highly expressed in the hypoxic centre of the spheroids and is an upstream regulator of the microRNAs we found to be differentially expressed. Pharmacologic and genetic modulation of microRNA and HIF1a levels altered drug resistance in MPM cells, suggesting a link between hypoxia, microRNAs and drug resistance in MPM.
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PL03 - Presidential Symposium (ID 428)
- Event: WCLC 2016
- Type: Plenary
- Track:
- Presentations: 1
- Moderators:D.P. Carbone, R. Pirker
- Coordinates: 12/06/2016, 08:35 - 10:25, Hall D (Plenary Hall)
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PL03.01 - Presidential Address (ID 6881)
08:35 - 10:25 | Author(s): D.P. Carbone
- Abstract
- Presentation
Abstract not provided
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