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Ernest Nadal
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ES21 - Current Strategies to Improve Outcome of Patients with Oligometastatic NSCLC (ID 24)
- Event: WCLC 2019
- Type: Educational Session
- Track: Oligometastatic NSCLC
- Presentations: 5
- Now Available
- Moderators:Ernest Nadal, Francoise Mornex
- Coordinates: 9/09/2019, 15:45 - 17:15, Dublin (1997)
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ES21.01 - Optimal Imaging for Staging of OMD (Now Available) (ID 3269)
15:45 - 17:15 | Presenting Author(s): Klaus L. Irion | Author(s): Bruno Hochhegger
- Abstract
- Presentation
Abstract
The role of imaging in oligometastatic disease in NSCLC:
The current guidelines include a contrast-enhanced CT of the chest and upper abdomen as the baseline imaging investigation of lung cancer patients. A contrast-enhanced CT or MRI of the brain is indicated in patients who present with neurological signs/symptoms1. An additional investigation with PET-CT and MRI could be considered, "but only if their results could alter the treatment strategy"2. Lung cancer patients who are candidates to a radical treatment should be referred to a PET-CT if the initial investigations indicate a potentially curable disease2. Not infrequently, the identification of unsuspected metastasis on the PET-CT changes the initial staging to a stage IV, in a significant number of cases. A radical treatment can be considered for those with oligometastatic disease (OMD), which is defined by the National Cancer Institute as: "a small number of metastatic tumors in one or two other parts of the body"3. Discerning additional lung lesions as benign or malignant can be improved with the use of MRI4,5. Considering the limitations of PET-CT for detecting brain and liver metastases, MRI should be considered to avoid a futile extended radical treatment in this select group of patients5. This presentation will discuss the role of imaging in OMD patients being considered for extended radical treatment.
1. NICE. https://www.nice.org.uk/guidance/ng122/chapter/Recommendations#diagnosis-and-staging
2. Planchard D. et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology (2018) 29(4): iv192–iv237.
3. NCI. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/oligometastasis.
4. Basso Dias A. et al. Fluorine 18–FDG PET/CT and diffusion-weighted MRI for malignant versus benign pulmonary lesions: a meta-analysis. Radiology (2019) 290:525–534
5. Hochhegger B. et al. MRI in lung cancer: a pictorial essay. BJR (2011) 84:1003, 661-668
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ES21.02 - Biological Disease Characterization of OMD (Now Available) (ID 3270)
15:45 - 17:15 | Presenting Author(s): David E. Gerber
- Abstract
- Presentation
Abstract
Variation in the characterization of OMD Trial OMD characteristics OMD timing Iyengar et al (2017) · ≤6 sites of extracranial disease (including primary)
· ≤3 sites in liver or lung
·Up to 2 contiguous vertebral metastases considered a single siteAfter first-line therapy and without progression Gomez et al (2016) · ≤3 metastatic sites
· Any N1-3 thoracic nodes considered a single site
· Satellite lesions counted as separate sitesAfter first-line therapy and without progression Parikh et al (2014) · ≤5 metastatic sites After first-line therapy and without progression Cheruvu et al (2011) · ≤8 metastatic sites At time of initial staging Khan et al (2006) · 1-2 metastatic sites
· Definitive (surgery and/or chemoradiation) treatment of thoracic diseaseAfter treatment of thoracic disease Recent years have seen a marked increase in interest in the concept of oligometastatic disease (OMD) in non-small cell lung cancer (NSCLC). Lacking a precise and consistent definition, OMD is generally considered to represent a relatively favorable clinical state, with more indolent biology, a limited number of disease sites, and potential for prolonged periods of disease control. Discussions of oligometastatic NSCLC area inexorably linked with management considerations, specifically the use of local therapies such as surgery and radiation therapy. There are numerous clinical and biological rationales to support such approaches: (1) disease progression most commonly occurs in original sites of gross disease1; (2) metastatic sites may propagate secondary metastases (parallel progression model)2; (3) solid tumors are composed of faster growing (sensitive) and slower growing (resistant) cell populations (Norton-Simon hypothesis)3; (4) resistance depends on spontaneous mutations and therefore increases with time (Goldie-Coldman hypothesis).4
Nevertheless, several questions regarding the characterization and optimal management of OMD remain (Table 1). Up to how many sites of disease constitute an oligometastatic state? Does a “site” of disease comprise a single lesion or neighboring tumors? Does the anatomic site matter? For instance, brain metastases have historically been considered a more favorable location for definitive treatment of OMD, and their emergence may reflect pharmacokinetic failure rather than molecular evolution.5,6 Additionally, there are likely meaningful clinical differences between OMD states depending on whether they are defined at diagnosis (de novo), after initial exposure to systemic therapy (induced), recurrence, or progression.
OMD may also have a distinct biologic phenotype. The metastatic cascade includes loss of cellular adhesion, increased motility, primary tumor invasiveness, entry into and survival in the circulation, and entry into and colonization of distant organs.7 Tumor dormancy, regulated in part by interferon signaling, may impact the number, location, and timing of metastases.8 Expression of genes that positively regulate the cell cycle may determine whether cancer growth occurs as polymetastasis versus oligometastasis. Ideally, ongoing and future clinical trials will collect biospecimens for discovery and validation of OMD biomarkers, thereby enabling the identification of cases most likely to benefit from OMD treatment paradigms.
References:
1. Rusthoven KE, Hammerman SF, Kavanagh BD, Birtwhistle MJ, Stares M, Camidge DR. Is there a role for consolidative stereotactic body radiation therapy following first-line systemic therapy for metastatic lung cancer? A patterns-of-failure analysis. Acta Oncol 2009;48:578-83.
2. Klein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer 2009;9:302-12.
3. Norton L, Simon R. Tumor size, sensitivity to therapy, and design of treatment schedules. Cancer Treat Rep 1977;61:1307-17.
4. Goldie JH, Coldman AJ. A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 1979;63:1727-33.
5. Hu C, Chang EL, Hassenbusch SJ, 3rd, et al. Nonsmall cell lung cancer presenting with synchronous solitary brain metastasis. Cancer 2006;106:1998-2004.
6. Grommes C, Oxnard GR, Kris MG, et al. "Pulsatile" high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol 2011;13:1364-9.
7. Gupta GP, Massague J. Cancer metastasis: building a framework. Cell 2006;127:679-95.
8. Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nature reviews Immunology 2006;6:836-48.
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ES21.03 - Interpreting the Current Data for Local Consolidative Treatment in the Setting of Oligometastatic Disease: Where Do We Stand? (Now Available) (ID 3271)
15:45 - 17:15 | Presenting Author(s): Daniel Gomez
- Abstract
- Presentation
Abstract
Over the past 15 years, several retrospective and single arm prospective studies suggested a benefit for local consolidative therapy (surgery, radiation therapy, or interventional radiologic ablation) in the setting of oligometastatic disease. More recently, a small number of randomized trials have provided further data regarding the utility of an agressive approach with regard to progression free and overall survival. With the considerable amount of emerging evidence, it can be difficult to aggregate and interpret the major themes across studies. This presentation will discuss the composite data of local consolidative therapy in oligometastases, with a particular focus on high impact non-randomized studies and the limited randomized trials addressing this topic. The presentation will then provide major conclusions that can be the basis for analysis going forward. Attendees will thus be provided with a summary of the current evidence in the oligometastatic disease context and a basis for future directions.
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ES21.04 - Optimal Systemic Treatment of OMD (Now Available) (ID 3272)
15:45 - 17:15 | Presenting Author(s): Hideo Kunitoh
- Abstract
- Presentation
Abstract
A series of randomized trials (1-3), 2 of them specifically conducted for non-small cell lung cancer (NSCLC) patients (2,3), have shown that those with OMD could get clinical benefit from the addition of local ablative therapy to the standard systemic treatment. All 3 trials demonstrated improvement of progression-free survival (PFS), and 2 of them suggested overall survival (OS) benefit (1,2). OS was the primary endpoint of the 2 studies.
In each of the trials, however, the “standard systemic treatment” was not specified; in fact, it was merely described that the systemic therapy was determined by the treating oncologists from a set of “standard-of-care options” (3). It would be easy to imagine that the “standard-of-care options” for OMD in these trials would be no different from those for other stage IV diseases.
For NSCLC, they are cytotoxic chemotherapies according to histologic subtypes, appropriate target-based therapies when the tumors have druggable targets, and, more recently, immune-oncology (IO) drugs when the tumors have potentially predictive markers, such as PD-L1 (4) or tumor mutation burdens (5). The question is, is the optimal systemic therapy of OMD really exactly same with the “standards” of other, more advanced, poly-metastatic stage IV NSCLC?
First of all, let me suppose that the disease is truly oligo-metastatic, meaning there are no other metastatic foci than those which are detected by the image scans. In this scenario, you do not require systemic therapy at all; the disease is “cured” by a series of local ablative therapies, since no other diseases exist.
However, in the vast majority of the patients, this would not be the case. Instead, there should be some other “microscopic” metastases which are undetected by the scans, evade the local therapies, and get relapsed without systemic treatment. By focusing on the “microscopic metastases” status, you could make analogy to post-operative adjuvant therapy.
After the apparently curative surgery, without no “macroscopic” metastases in sight, we usually use conventional chemotherapies for prevention of recurrence. It is hoped that these “cytotoxic” drugs would eradicate the residual cancer cells, leading to true “cures”. The long-tails of the survival curves, with increased number of long-term survivors with the adjuvant chemotherapy (6), show that this theory actually works.
On the other hand, use of target-based drugs as post-operative adjuvant therapy has so far had only limited success (7,8). The PFS is elongated, without OS benefit (7). It appears that the patients do as good with the use of “targeted” drugs after relapse, and those drugs suppress tumors only as long as they are taken (9). In other words, they appear “cytostatic” and unable to “cure” the disease. Results of IO adjuvant trials are not yet available, but the “long-tails” of the survival curves of IO treatment make us hope for strong cytotoxic, “cure-oriented” effect.
Therefore, when you aim at “cure” of the OMD, you should choose cytotoxic chemotherapies and/or IO drugs. However, if you are to “control” the disease and get some OS improvement, target-drugs are strong candidates.
Let me see the topic from another viewpoint. The “local ablative” therapies employed in OMD are surgery and (stereotactic) radiotherapy. Which systemic therapy would make a better partner to which local therapy?
Almost all target drugs are eventually turned ineffective, due to acquired resistance. However, in some cases, you could elucidate the resistance mechanism and conquer it (10), with modification of the target-based “precision” medicine.
At present, investigation of the tumor itself is the most certain method, as expressed in the “tissue is the issue” slogan. Very often, however, tiny pathological specimens obtained from transbronchial or CT-guided biopsies are insufficient for the full molecular analysis. Surgical resection of the tumor has advantages both in terms of curative therapy and supply of ample specimens. It also minimizes the late effect on pneumonitis, which is a rare but dreadful toxicity of target-based tyrosine kinase inhibitors. Taken together, use of surgery would be (more) appropriate when you use target-based drugs in OMD.
On the other hand, there are some clinical data that prior use of radiotherapy is associated with better outcome of IO therapy, implying the so-called “abscopal” effect (11). Investigations are on-going, which are aimed at showing synergistic effect of stereotactic radiotherapy and IO treatment (12,13). This could be applied in the management of OMD.
So, in conclusion, what is the optimal systemic treatment of OMD? It depends on the aim of the therapy, cure vs elongation of PFS/OS, as well as on the choice of main local therapy, surgery vs radiotherapy. Future studies should specify the aim of the clinical investigation, not only to maximize the efficacy of local therapies and benefit to the patients, but to increase the statistical power of the clinical trials.
References
1. Palma DA, et al. Lancet 2019
2. Gomez DR, et al. J Clin Oncol 2019
3. Iyenger P, et al. JAMA Oncol 2018
4. Sacher AG, Gandhi L. JAMA Oncol 2016
5. Goto Y. J Clin Oncol 2018
6. Pignon J-P, et al. J Clin Oncol 2008
7. Kelly K, et al. J Clin Oncol 2015
8. Zhong WZ, et al. Lancet Oncol 2018
9. Pennell NA, et al. J Clin Oncol 2019
10. Jänne PA, et al. New Engl J Med 2015
11. Shaverdian N, et al. Lancet Oncol 2017
12. Luke JJ, et al. J Clin Oncol 2018
13. Miyamoto S, et al. Jpn J Clin Oncol 2019
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ES21.05 - Clinical Trials to Advance the Field of OMD (Now Available) (ID 3273)
15:45 - 17:15 | Presenting Author(s): Thierry Berghmans
- Abstract
- Presentation
Abstract
Oligometastatic disease (OMD) in non-small cell lung cancer (NSCLC) is a complex pathology. Four settings can be displayed where synchronous OMD (sOMD), occurring at the time of initial diagnosis, was the most evaluated in clinical trials. Other potential situations are oligorecurrence (rOMD), developed after optimal local control of a localised tumour, oligoprogression (pOMD) corresponding to a progression in a limited number of metastatic sites, and oligopersistant disease (peOMD) after/on systemic therapy. Several non-randomised phase II studies demonstrated the feasibility adding local ablative therapy (LAT) to systemic therapy in sOMD. Design, number of metastatic sites, type of LAT (chemoradiotherapy [CTRT], surgery, stereotactic radiotherapy [SBRT]) and endpoints largely differed among studies. A first pilot study (1) showed that surgery at the primary and the single metastatic sites after induction chemotherapy (CT) was feasible with 57% complete resection (R0) and 11 months median survival (MST). The same approach was recently confirmed in another prospective study with 71% R0 and 46.5% 5-years survival (2). Later, a phase II study conducted in The Netherlands and recently updated (3) demonstrated, when combining LAT (surgery or radiotherapy) to systemic therapy, MST of 13.5months but more essential, 5 and 6-years survival rates of 7.7% and 5.1% respectively. Other phase II studies, including NSCLC with <6 metastases, confirmed those results whether considering overall survival (4), metabolic response (5) or progression-free survival (PFS) (6).
The first randomised phase II trial (RCT) compared, in sOMD with < 3 metastases non-progressing after CT, LAT (surgery, SBRT, CTRT) plus maintenance to maintenance only. The study closed early after first interim analysis and 49 randomised patients. Updated data confirmed improved PFS (14.2 months vs 4.4 months; p = 0.022) and MST (41.2 months vs 17 months; p = 0.017) favouring the LAT arm. A second small-sized phase II RCT closed early after interim analysis (8). 29 sOMD patients (≤5 metastases) not progressing after CT were randomised between SBRT plus maintenance or maintenance. Also median PFS improved from 3.5 months to 9.7 months (p = 0.01) in the LAT arm.
All these data need confirmation in larger RCT. Four phase III trials are or will be ongoing. SARON (NCT02417662) is comparing standard CT alone to CT plus SBRT in sOMD with ≤ 3 metastases. In the OMEGA trial (NCT03827577), patients with synchronous or metachronous oligometastatic NSCLC (1-3 metastatic lesions) were considered for LAT (surgery or RT) or not in addition to systemic therapy. SINDAS (NCT02893332) is assessing the role of SBRT in addition to tyrosine kinase inhibitor in sOMD EGFR muted NSCLC with ≤ 5 tumoral sites (inclusive primary site; lymph nodes being considered as a metastatic site). Finally, HALT (NCT03256981) is a phase II-III RCT evaluating SBRT for pOMD during targeted therapy in NSCLC harbouring activating mutations.
All these studies are presenting with various designs and primary endpoints, but also differences in staging procedures resulting in major difficulties for definite conclusions on the usefulness of LAT in OMD patients. In order having similar populations among clinical trials, we need that a common definition is used by all investigators. In this way, the EORTC Lung Cancer Group proposed a definition for sOMD based on a consensus from thoracic oncology experts (8). Using common definition and staging assessment, and finding predictive factors for a better patient’s selection should be addressed in future clinical trials.
1. Downey et al. A phase II trial of chemotherapy and surgery for non-small cell lung cancer patients with a synchronous solitary metastasis. Lung Cancer 38:193-7, 2002
2. Endo et al. A prospective study of surgical procedures for patients with oligometastatic non-small cell lung cancer. Ann Thorac Surg 98:258-64, 2014.
3. De Ruysscher et al. PFS and OS beyond 5 years of NSCLC patients with synchronous oligometastases treated in a prospective phase II trial (NCT 01282450) OA07.07 J Thorac Oncol 2018
4. Arrieta et al. Radical consolidative treatment provides a clinical benefit and long-term survival in patients with synchronous oligometastatic non-small cell lung cancer: A phase II study. Lung Cancer. 130:67-75, 2019
5. Petty et al. Long-Term Outcomes of a Phase 2 Trial of Chemotherapy With Consolidative Radiation Therapy for Oligometastatic Non-Small Cell Lung Cancer. Int J Rad Oncol Biol Physics. 102:527-535, 2018.
6. Collen et al. Phase II study of stereotactic body radiotherapy to primary tumor and metastatic locations in oligometastatic nonsmall-cell lung cancer patients. Ann Oncol. 25:1954-9, 2014.
7. Gomez et al. Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients With Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study. J Clin Oncol JCO1900201, 2019.
8. Dingemans et al, MA25.02 Journal of Thoracic Oncology 2018;13:S445-S446
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IBS06 - Multimodality Treatment - Realtime Data from National Registries (Ticketed Session) (ID 37)
- Event: WCLC 2019
- Type: Interactive Breakfast Session
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 07:00 - 08:00, Dublin (1997)
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IBS06.01 - Realtime Data from Europe ETOP / ESTS Database (Now Available) (ID 3331)
07:00 - 08:00 | Author(s): Ernest Nadal
- Abstract
- Presentation
Abstract
Title: Mesothelioma Realtime Data from Europe - ETOP Mesoscape / ESTS Database
Introduction:
Malignant pleural mesothelioma (MPM) is an aggressive malignancy with increasing prevalence and poor prognosis. Despite a still increase in incidence, it remains an orphan disease and studying limited numbers of MPM cases hampers the derivation of solid conclusions.
The combination of two databases including clinical as well as pathological information will allow researchers to improve the knowledge and facilitate decision-making in patients with MPM.
The European Thoracic Oncology Platform (ETOP) Mesoscape project and the European Society of Thoracic Surgeons’ (ESTS) database are designed to address clinical, pathological, and molecular characteristics of mesothelioma patients and their impact on outcome. The joined analysis of both databases is a unique approach to real-time data reflecting the reality of mesothelioma characteristics, treatment and prognosis in Europe.
Materials and Methods:
A decentralized biobank with fully annotated tissue samples is established for ETOP Mesoscape. Selection criteria for participating centers included sufficient number of cases, and documented ethical approval. Patient selection is based on availability of comprehensive clinical data with adequate follow-up, and adequate quantity and quality of formalin-fixed tissue.
The ESTS database is a clinical database with pre-operative, intra-operative and post-operative data. A minimum set of data is captured, including demographic, histology, treatment, staging and follow up data.The characteristics between the two databases are compared using the Fisher’s exact test (for categorical variables) and Mann-Whitney test (for continuous variables), while Kaplan-Meier method (with log-rank test).
Results:
Up to 29 May 2019, the ETOP Mesoscape included information on 497 patients from 10 centers, diagnosed between 1999-2018. In the ESTS database, as of April 2019, 2269 patients are included, diagnosed between 1989-2019.
Patients in both databases are primarily men (84% in the ETOP, 71% in the ESTS), of 0/1 ECOG Performance status (46/46% and 59/29% in ETOP and ESTS respectively), with known previous exposure to asbestos (75% and 93%) and median ages 64 and 67 years old.
Significant differences are detected between the two data sources with respect to gender, exposure to asbestos and age (p-value <0.001).
The primary histology of patients is epithelioid (72% in ETOP and 70% in ESTS), followed by biphasic (22%; 17%) and sarcomatoid (6%; 9%) (not significantly different between the two databases).
Clinical staging is available for 77% of the patients in ETOP, but only for the 28% in the ESTS database. The stage distribution (I/II/III/IV) is 14/29/42/15% in the ETOP and 23/21/41/16% in the ESTS (significantly difference p<0.001).
Among the biomarkers common in both data sources, Calretinin and WT1 are detected in the vast majority of patients tested (Calretinin: 97% in both cases; WT1: 89% and 87% in the ETOP and ESTS database respectively).
For the ETOP cases 90% (of those tested) are CK5/6 positive, 91% D2-40 positive and 97% Pan-CK positive.
Palliative treatment has been administered in 41% of the ETOP cases. Among them, 84% received palliative chemotherapy (with the vast majority 92%, using multiple agents). Palliative surgery was undertaken in 32% (62 of 194 patients with available information) and palliative radiotherapy for 13% of the patients.
Complete resection has been performed in 59% of the ETOP Mesoscape patients. This was combined with induction chemotherapy (81%), while adjuvant chemotherapy and radiotherapy was administered in 4% and 37% respectively.
The surgical approach adopted for the ESTS patients was either video-assisted thoracoscopic surgery (VATS) (59%) or thoracotomy (41%) based on a subset of 887 patients with available information. Post-operation treatment information is available for 620 ESTS patients. Among them, 71% received chemotherapy, 54% underwent surgery and 15% radiotherapy.
Conclusion:
We present the combined results from the ETOP Mesoscape and the ESTS database, one of the largest databases. These two series allow us to report on mesothelioma epidemiology and treatment.
Up to now, the comparison of the baseline characteristics of the patients of the two data sources revealed some statistically significant differences with respect to gender, age, exposure to asbestos and clinical stage.
As tissue from all ETOP Mesoscape patients is preserved locally and is available for detailed molecular investigations, Mesoscape provides an excellent basis to evaluate the influence of molecular parameters on the disease outcome, besides providing an overview of the molecular landscape.
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MA07 - Clinical Questions and Potential Blood Markers for Immunotherapy (ID 125)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:David R Spigel, Roberto Ferrara
- Coordinates: 9/08/2019, 13:30 - 15:00, Vancouver (2003)
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MA07.02 - Early Change of dNLR Is Correlated with Outcomes in Advanced NSCLC Patients Treated with Immunotherapy (Now Available) (ID 2676)
13:30 - 15:00 | Author(s): Ernest Nadal
- Abstract
- Presentation
Background
The [neutrophils/[leucocytes-neutrophils] ratio (dNLR) correlates with immune checkpoint inhibitors (ICI) outcomes in advanced non-small cell lung cancer (aNSCLC) patients. Significance of early dNLR change after the first course of ICI is unknown.
Method
Patients with NSCLC treated with ICI (PD(L)1+/-CTLA4) between Nov. 2012 and Jun. 2018 at 16 EU/US centers were included. A control group treated with chemotherapy (CT) only was also evaluated (NCT02105168). dNLR was collected at baseline (B) and at cycle 2 (C2). Patients were categorized as low vs high dNLR at each timepoint (defined as < vs > 3, as previously done), and the change between B and C2 (good = low at both timepoints, poor = high at both timepoints, mixed = different at each timepoint).
Result
1485 patients treated with ICI were analyzed. PDL1 was negative in 162 (11%), 1-49% in 178 (12%), ≥50% in 201 (14%), and missing in 944 (64%). dNLR at B and C2 did not associate with PD-L1 status.
At baseline, dNLR was high in 509 (34%) patients and associated with worse PFS compared to those patients with low dNLR at baseline (HR 1.56, P<0.0001) and OS (HR 2.02, P<0.0001). At C2, dNLR was high in 484 (34%) and similarly associated with worse outcomes compared to patients with low dNLR at C2 (PFS HR 1.64, P<0.0001; OS HR 2.13, P<0.0001).
Between B and C2, dNLR remained low in 804 (56%, « good ») or high in 327 (23%, « poor ») or changed in 310 pts (22%, « intermediate »). Those with a good dNLR demonstrated mPFS 5.3, mOS 18.6 mo), followed by those intermediate with mixed dNLR (mPFS 3, mOS 9.2 mo), and finally poor dNLR (mPFS 2, mOS 5mo). Outcomes were independant of PD-L1 expression (adjusted HR for PFS 1.94 for intermediate and 3.16 for poor groups, compared to good dNLR group, P<.001; adjusted HR for OS was 2.08 for intermediate and 3.67 for poor groups, P<0.001).A bootstrap tested the stability of OS/PFS prediction (P<0.001).
In the chemo-cohort (n=173), high C1-dNLR (n=81, 47%) was not associated with OS (P=0.84).
Conclusion
dNLR at baseline, at cycle 2, and the change between these two timepoints associated with outcomes in patients treated with immunotherapy independent of PD-L1, but not in patients treated with chemotherapy alone. dNLR is specifically prognostic in the context of immunotherapy.
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MA12 - New Frontiers from Pathology to Genomics (ID 138)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:Prasad S Adusumilli, Francisco Perez Ochoa
- Coordinates: 9/09/2019, 14:00 - 15:30, Melbourne (1991)
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MA12.07 - Integrative Transcriptome Analysis of Malignant Pleural Mesothelioma Reveals a Clinically-Relevant Immune-Based Classification (Now Available) (ID 1680)
14:00 - 15:30 | Author(s): Ernest Nadal
- Abstract
- Presentation
Background
Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasia affecting the lining of the lungs. Immune checkpoint inhibitors in MPM have not been extremely successful, likely due to a poor identification of suitable candidate patients for the therapy. The aims of this study were: to identify immune fractions associated with clinical outcome and classify MPM samples based on their immune contexture; to characterize the immune-based groups at the genomic and transcriptomic levels; and to identify potential therapeutic strategies for each group.
Method
Seven gene-expression datasets of MPM were used to assess the immune microenvironment of 516 samples. The abundance of 20 immune fractions in each sample was inferred using Gene Set Variation Analysis. Identification of clinically-relevant fractions was performed with Cox Proportional-Hazards Models adjusted for age, stage, sex, and tumor histology.
Result
T-Helper 2 (TH2, HR=2.14, p=1.5x10-4) and cytotoxic T cells (CTC; HR=0.57, p=9.1x10-3) were found to be consistently associated with overall survival in multiple datasets. Three immune clusters (IG) were subsequently defined based on TH2 and CTC immune infiltration levels: IG1 (54.5% of samples) was characterized by high TH2 and low CTC levels, IG2 (37%) had either low or high levels of both fractions, and IG3 (8.5%) was defined by low TH2 and high CTC levels. This classification was associated with overall survival independently of tumor histology, with an improving survival from IG1 to IG3 (HRIG2=0.52 (0.39–0.69); HRIG3=0.32 (0.19–0.53); p=8.4x10-8).
IG3 was significantly enriched in epithelioid tumors (90% IG3 vs. 62% IG1, p=0.001) and patients were younger compared to the other groups (60 years IG3 vs. 66 years IG1, p=0.021). These groups showed differential molecular profiles, with IG1 enriched for CDKN2A and IFN-related genes deletions. At the transcriptional level, IG1 samples showed upregulation of proliferation and DNA repair-related gene-sets, while IG3 samples presented upregulation of immune and inflammation-related pathways. Finally, integration of gene expression with functional signatures of in vitro drug response showed that IG3 patients are more likely to respond to immune checkpoint inhibitors, while IG1 patients could be more sensitive to PARP inhibitors.
Conclusion
Analysis of publicly available MPM transcriptome data reveals three major immune-based groups, based on TH2 and CTC composition. These clusters are associated with distinct genomic profiles and clinical outcome. Further validation of this classification is warranted in an independent cohort of MPM.
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MA13 - Going Back to the Roots! (ID 139)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Maurice Perol, Kaoru Kubota
- Coordinates: 9/09/2019, 14:00 - 15:30, Vancouver (2003)
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MA13.03 - Retrospective Study of Intrathecal Therapy for Non-Small Cell Lung Cancer (NSCLC) Patients with Leptomeningeal Carcinomatosis (Now Available) (ID 2086)
14:00 - 15:30 | Author(s): Ernest Nadal
- Abstract
- Presentation
Background
Leptomeningeal carcinomatosis (LMC) is a devastating cancer-related neurological complication with poor prognosis. In EGFR-mutant (mut) NSCLC patients (pts), osimertinib achieves high penetration into cerebral-spinal fluid (CSF) and promising efficacy. However, for EGFR-mut T790M-negative pts treated with prior 1st- and 2nd-generation tyrosine kinase inhibitors (TKI) and for driver negative NSCLC pts, a combination of intrathecal therapy (IT) and systemic therapy (ST) seems to be an appropriate approach. Our purpose is to explore the clinical outcome of IT combined with ST among NSCLC with LMC depending on EGFR status.
Method
NSCLC pts with LMC treated with IT in our institution between 2010 and 2018 were retrospectively studied. After LMC diagnosis, intrathecal methotrexate (scheduled: 12mg twice weekly for 4 weeks, then 12mg weekly for 4 weeks) was given in combination with ST. A Kaplan-Meier survival analysis was performed for overall survival (OS) and progression free survival (PFS).
Result
A total of 39 pts were included. Patient’s clinical characteristics are summarized in table 1. EGFR status was 17 mut (del19: 11pts); 11 wild-type (wt) and 11 unknown (unk). LMC and NSCLC diagnosis were more likely to be synchronous in EGFR wt compared with EGFR mut. The median follow-up from LCM diagnosis was 10.2 months. At the time of this analysis, only 6 pts were alive. Thirty-two pts received ST in combination with IT, 18 (46%) pts chemotherapy (6wt/ 3mut/ 9unk), while 14 (36%) pts an EGFR TKI (1wt/ 13mut). Clinical response (improvement of neurological symptoms and/or KPS) was seen in 11 (65%) EGFR mut pts vs 2 (18%) wt pts (p=0.033). Median OS and PFS for the whole cohort were 23 weeks (95%CI, 8.1 to 37.9) and 10 weeks (95%CI, 7.1 to 12.8) respectively. Median OS was higher for EGFR mut pts compared to wt pts, 38 weeks (95%IC 13.6-62.4) and 19 weeks (95%IC, 4.06-33.9) respectively, however this difference was not statistically significant (p=0.36) probably due to lack of statistical power.
Conclusion
Methotrexate-based IT given concurrently with systemic TKI may confer a higher clinical benefit and a trend toward OS benefit in NSCLC patients with LCM and EGFR activating mutations.
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MA23 - Preclinical Models and Genetics of Malignant Pleural Mesothelioma (ID 353)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:Ramon Palmero Sánchez, Raphael Bueno
- Coordinates: 9/10/2019, 14:30 - 16:00, Copenhagen (1980)
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MA23.02 - CDK4/6 Inhibitors Show Antitumor Effects in Preclinical Models of Malignant Pleural Mesothelioma (Now Available) (ID 1866)
14:30 - 16:00 | Author(s): Ernest Nadal
- Abstract
- Presentation
Background
Novel therapeutic approaches are needed to improve the clinical outcome of patients with malignant pleural mesothelioma (MPM). In the current study, we investigate the antitumor activity of CDK4/6 inhibitors in preclinical models of MPM.
Method
MPM cell lines (H28, H226, H2052, H2452, MSTO-211H) and primary cultures (ICO_MPM1, ICO_MPM2, ICO_MPM3) were treated with abemaciclib or palbociclib for 24 and 72 hours. Cell viability was evaluated by cell counting and crystal violet assays. Cell death and cell cycle distribution were analyzed by flow cytometry and senescence was quantified by β-galactosidase expression. For transcriptomic studies, mRNA expression was assessed through RNA sequencing analysis. Gene set enrichment analysis (GSEA) was used to identify signaling pathways deregulated in MSTO-211H cells treated with CDK4/6 inhibitors. MSTO-211H cells were implanted subcutaneously in athymic mice that were randomly assigned to the following cohorts (n=7): i) vehicle; ii) cisplatin + pemetrexed; iii) palbociclib alone and iv) palbociclib + gemcitabine. Tumors’ size and mice weight was monitored during 4 weeks to evaluate efficacy.
Result
Treatment with abemaciclib or palbociclib at 100nM induced a significant decrease in cell proliferation (mean 50.9% ± 7.6; mean 47.3% ± 9.9, respectively) in distinct MPM cell models, including cells derived from patients who progressed to prior cisplatin and pemetrexed. Both CDK4/6 inhibitors induced G1-phase cell cycle arrest, while cell death was slightly affected (up to 1-5%). At concentrations ranging from 250 to 500nM, the percentage of senescent cells was increased after abemaciclib (15-26%) and palbociclib (18-25%) treatment in all the analyzed cell models. GSEA revealed that CDK4/6 inhibitors promote interferon signaling pathway and MHC presentation. In the in vivo experiment, a significant reduction in tumor growth was observed in response to palbociclib alone or combined with gemcitabine for 4 weeks (vehicle = 1335.8±586.4 mm3; cisplatin + pemetrexed= 726±573.5 mm3; palbociclib = 479±235.7 mm3; palbociclib + gemcitabine = 517±487.4 mm3; p< 0.05).
Conclusion
CDK4/6 inhibitors reduce cell proliferation in culture models of MPM mainly by blocking cell proliferation at G1 and by inducing senescence. Palbociclib alone or combined with gemcitabine reduces in vivo tumor growth of subcutaneously implanted MSTO-211H cells compared to chemotherapy.
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OA13 - Ideal Approach to Lung Resection and Novel Perioperative Therapy (ID 146)
- Event: WCLC 2019
- Type: Oral Session
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Now Available
- Moderators:Tomasz Grodzki, Kenji Suzuki
- Coordinates: 9/10/2019, 11:30 - 13:00, Toronto (1985)
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OA13.05 - NADIM Study: Updated Clinical Research and Outcomes (Now Available) (ID 1670)
11:30 - 13:00 | Author(s): Ernest Nadal
- Abstract
- Presentation
Background
Patients with stage IIIA (N2 or T4N0) are potentially curable but median overall survival is only around 15 months
Method
A Phase II, single-arm, open-label multicenter study of resectable stage IIIA N2-NSCLC in adult patients with CT plus IO as neoadjuvant treatment: 3 cycles of nivolumab (NV) 360 mg IV Q3W + paclitaxel 200 mg/m2 + carboplatin AUC 6 IV Q3W followed by adjuvant NV treatment for 1 year. After completing neoadjuvant therapy, all patients underwent tumor assessment prior to surgery. Surgery was performed during the 3rd or 4th week after day 21 of the 3rd neoadjuvant treatment cycle. The study aimed to recruit 46 patients. The primary endpoint was Progression-Free Survival (PFS) at 24 months. Efficacy was explored using objective pathologic response criteria. Here we present the final data on all study patients that underwent surgical assessment.
Result
At the time of submission, the 46 patients had been included. None of the patients were withdrawn from the study preoperatively due to progression or toxicity. 41 patients had undergone surgery and all tumors were deemed resectable with R0 resection in all cases. Intention to treat analysis shows 35 patients (85%; 95% CI, 71; 94%) achieved major pathologic response (MPR) of which 25 (71%; 95% CI, 54; 85%) were complete pathologic responses (CPR). Downstaging was seen in 38 (93%; 95% CI, 80; 98%) of cases. The median follow-up was 13.8 months (P25; P75: 11.7; 16.6 months) for both the whole series and resected patients, and 12 month PFS was 95.7% (95% CI, 84; 99%).
Conclusion
This is the first multicentric study to test CT-IO in the neoadjuvant setting in stage IIIA. Neoadjuvant CT-IO with nivolumab in resectable IIIA NSCLC yields a complete pathologic response rate that is higher than ever seen previously, together with a promising PFS which may translate into increased overall survival. EudraCT Number: 2016-003732-20. Clinical trial information: NCT 03081689.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 2
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-111 - ATEZO-BRAIN, A Single-Arm Phase II Study of Atezolizumab Combined with Chemotherapy in Stage IV NSCLC Patients with Untreated Brain Metastases (ID 733)
09:45 - 18:00 | Presenting Author(s): Ernest Nadal
- Abstract
Background
Brain metastases (BM) are a frequent complication in non-small cell lung cancer (NSCLC), have significant impact on quality of life and are associated with poor prognosis. Systemic therapies might be an alternative approach to whole brain radiotherapy (WBRT) to avoid cognitive-related adverse events. Immune checkpoint inhibitors (ICI) showed intracranial activity in advanced NSCLC patients with BM. However clinical data about efficacy and safety of immune checkpoint inhibitors in combination with chemotherapy in patients with untreated BM are limited and further research in this setting is needed. We hypothesize that addition of ICI to conventional platinum-based chemotherapy may increase intracranial tumor response and provide clinically relevant benefit in terms of PFS, OS and quality of life to the patients with asymptomatic and non-previously treated BM.
Method
This is an ongoing multicenter, open-label, single-arm phase 2 study (EUDRACT: 2017-005154-11) to evaluate the efficacy and safety of atezolizumab 1200 mg combined with 4-6 cycles of carboplatin AUC 5 and pemetrexed 500mg/m2 every 3 weeks followed by maintenance with atezolizumab 1200 mg plus pemetrexed 500mg/m2 every 3 weeks in stage IV non-squamous NSCLC patients with untreated synchronous BM. Patients should have multiple and measurable BM, adequate performance status and organic function, do not harbor EGFR or ALK genomic alterations, be treatment naïve and do not have any contraindication to receive immunotherapy. Exclusion criteria consist of active neurological symptoms, dexamethasone dose ≥ 4 mg QD, prior treatment with brain radiotherapy, presence of leptomeningeal carcinomatosis, spinal or hemorrhagic metastases in the central nervous system. Primary endpoints are progression-free survival (PFS) at 12 weeks according to RANO-BM and RECIST v1.1 criteria and safety based on CTCAE v4. Both primary endpoints will be assessed in 40 patients in 15 sites using a Bayesian approach. Patients will undergo tumor assessments by body CT scan and brain MRI at baseline every 6 weeks for the first 12 weeks and thereafter tumor assessments will be performed every 9 weeks until disease progression or loss of clinical benefit. Secondary endpoints: intracranial and systemic objective response rate and duration of response. Exploratory endpoints: to assess neurocognitive function and quality of life; to determine time to neurological deterioration and time to need of salvage brain radiotherapy. Enrollment started on August 2018 and currently 12 patients have been included in the study.
Result
Clinical trial in progress
Conclusion
Clinical trial in progress
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P1.01-54 - Somatic Genome Alterations in Lung Cancer Patients Diagnosed with Li Fraumeni Syndrome (Now Available) (ID 1014)
09:45 - 18:00 | Author(s): Ernest Nadal
- Abstract
Background
Li-Fraumeni syndrome (LFS) is a rare hereditary condition that consists of TP53 mutations inherited in autosomal dominant manner that confer high risk of developing cancer, including lung adenocarcinoma (LUAD). EGFR-mutated LUAD were reported in the context of LFS but there is no systematic description of somatic mutations and characteristics of lung cancer (LC) patients with LFS.
Method
We present a retrospective analysis of clinical and molecular characteristics of patients with LFS diagnosed with LC at the Catalan Institute of Oncology from 1999 to 2019. We collected demographical and clinicopathological features, germline and somatic mutational alterations, treatment and progression-free survival (PFS) and overall survival (OS).
Result
A total of 7 patients with LC and LFS were identified in the Genetic Counseling Unit database. They were carriers of germline mutations in TP53. Five of them were classified as pathogenic: c.638G>A; p.(Arg213Gln), c.725G>A; p.(Cys242Tyr), c.742C>T; p.(Arg248Trp), c.844C>T; p.(Arg282Trp) and c.1010G>A; p.(Arg337His) and two of them as likely pathogenic: c.374C>T; p.(Thr125Met) and c.473G>A; p.(Arg158His). Six out of 7 patients were female and 5 out of 7 never smoker. Median age at diagnosis was 38 year-old (range: 29-74). Five patients had stage IV at diagnosis and the most common histologic subtype was LUAD (5). Six patients had first grade family history of cancer with a median of 2 family members (range: 1-4) and 2 patients had prior history of cancer. Tumor somatic profile in LC was obtained in 6 patients, consisting on a ROS-1 rearrangement in one patient and EGFR mutations in 5 patients (exon 19 deletion in 3 patients and missense mutations in 2 patients, p.(Gly719Ala) at exon 18 and p.(Leu858Arg) at exon 21) and in 1 patient was unknown. All patients with mutant EGFR received EGFR tyrosine kinase inhibitors (TKI) with a median PFS of 29 months (95% CI 0-67). Four had partial response and one a complete response to TKI treatment. At disease progression, one patient had small cell transformation and another acquired EGFR T790M mutation. Median lines of treatment were 4 (range 1-6). Two patients are alive at data cut off. Median OS is 47 months (95% CI 32-62).
Conclusion
Patients diagnosed with LC and LFS are enriched with actionable genomic alterations and have an earlier onset of the disease. Clinical outcome of patients with EGFR mutations and LFS did not differ from EGFR mutated LC patients who do not carry TP53 germline mutations.
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P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.03-26 - Genetic and Molecular Profiling of Non-Smoking Related Lung Adenocarcinomas (ID 1701)
09:45 - 18:00 | Author(s): Ernest Nadal
- Abstract
Background
The etiology and many details of the genomic profile and molecular basis of lung adenocarcinomas (LuADs) in nonsmoker patients remain elusive. Further, the scarcity of primary cultures available from non-smoking related lung adenocarcinomas (NSK-LuADs) contributes to hamper our biological understanding of these tumors.
Method
We established patient-derived cancer cell (PDCs) cultures from NSK-LuADs, and performed whole exome sequencing (WES) and RNA sequencing (RNA-seq) analysis to delineate their genomic architecture. For validations, we analyzed independent cohorts of LuADs.
Result
The analysis revealed non-smoker related alterations such as those at the growth factor receptors RET, ALK, EGFR and ERBB2. There were also mutations affecting signal transduction molecules such as AKT1, BRAF and KRAS, and mutations in tumor suppressor genes, including TP53, CDKN2A, RB1, ARID1A, ATM and STK11. We also identified new fusions and recurrent mutations in some genes, one of them, a possible regulator of gene expression, affecting ten percent of the LuADs, thus constituting a potentially relevant tumor suppressor gene. We also report a predominance of RB1-inactivation, mostly complex intragenic rearrangements (homozygous deletions or duplications) in EGFR-mutant tumors. Three EGFR-/RB1-mutant tumors, treated with EGFR-TKIs, and one EGFR-wild type tumor, treated with standard chemotherapy, developed small cell lung cancer and/or squamous cell carcinoma transformation, evident in the re-biopsies and/or PDCs. Finally, we found pathogenic germ-line mutations at genes associated to familiar-cancer syndromes, especially the TP53-associated Li Fraumeni syndrome, affecting ten percent of EGFR-mutant LuADs patients, underscoring a genetic predisposition origin for a subset of NSK-LuADs.
Conclusion
The recurrent gene inactivation found in candidate gene in LuADs heralds a tumor suppressor role which deserves further exploration. The pre-existent inactivation of RB1 predominates in EGFR-mutant tumors and may underlie an extremely ductile nature, albeit additional gene alterations are required to overcome sensitivity to the TKIs. Given their potential clinical and therapeutic implications, testing for RB1-alterations and for the Li-Fraumeni syndrome in EGFR-mutant LuADs patients may need to be incorporated in the clinical settings.
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P1.18 - Treatment of Locoregional Disease - NSCLC (ID 190)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 2
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.18-01 - RELAY EU/US Subset: Ramucirumab Plus Erlotinib Improves Progression-Free Survival in First-Line EGFR Mutation-Positive NSCLC (Now Available) (ID 356)
09:45 - 18:00 | Author(s): Ernest Nadal
- Abstract
Background
Dual blockade of EGFR and VEGFR pathways in EGFR mutation-positive NSCLC augments anti-tumor efficacy versus EGFR inhibition alone. The RELAY (NCT02411448) phase 3 study demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for erlotinib plus ramucirumab versus erlotinib plus placebo in patients with previously untreated EGFR mutation-positive metastatic NSCLC (median PFS 19.4 vs 12.4mo, HR 0.591 (95% CI 0.461–0.760), p<0.0001). Here we report efficacy and safety data of the EU/US subset.
Method
Eligible patients (untreated, metastatic NSCLC with an EGFR exon 19 deletion or exon 21 (L858R) substitution mutation and no CNS metastasis) were randomized (1:1) to receive 150 mg daily oral erlotinib plus 10 mg/kg intravenous ramucirumab (RAM+ERL) or placebo (PL+ERL) Q2W until progressive disease or unacceptable toxicity. Patients were stratified by geographic region (East Asia vs ‘other’, i.e. EU/US). Primary endpoint was investigator-assessed PFS. Other key objectives included safety, ORR, DoR, PFS2, and OS.
Result
In the EU/US, 113 (25.2%) of 449 total patients (58 RAM+ERL, 55 PL+ERL) were randomized between Feb 2016-Feb 2018. Baseline characteristics were balanced between treatment arms: ~60% female, ~52% never-smokers and ~66% Ex19del. RAM+ERL improved PFS and had a longer DoR (Table). PFS2 and OS data were immature. Grade≥3 TEAEs occurring in >5% of patients included (RAM+ERL vs PL+ERL): hypertension (29.8% vs 7.3%), diarrhea (12.3% vs 1.8%), AST increased (7.0% vs 3.6%), ALT increased (7.0% vs 1.8%), dermatitis acneiform (5.3% vs 9.1%), fatigue (5.3% vs 0%), and rash (0% vs 5.5%).
Abbreviations: CI=confidence interval; DoR=duration of response; ERL=erlotinib; HR=hazard ratio; N=total population; n=total responders; NR=no response; ORR=overall response rate; OS=overall survival; PFS=progression-free survival; PL=placebo; RAM=ramucirumab RAM + ERL (N=58) PL + ERL (N=55) Unstratified HR (95% CI) p-value PFS Median, months (95% CI) 20.6 (14.7-26.0) 10.9 (8.3-19.4) 0.605 (0.362-1.010) 0.0523 Censoring rate
52% 38% ORR, % (95% CI)
74.1 (62.9-85.4) 76.4 (65.1-87.6) NA 0.8319 DoR, for responders only n=43 n=42 Median, months (95% CI) 18.0 (12.7-22.0) 10.0 (7.1-17.7) 0.527 (0.296-0.939) 0.0274 Censoring rate
54% 33% PFS2 Median, months (95% CI) NR NR 0.632 (0.304-1.313) 0.2143 Censoring rate 79% 67% OS Median, months (95% CI) NR NR 1.096 (0.465-2.582) 0.8344 Censoring rate 81% 82%
Conclusion
The EU/US subset analysis was consistent with the full ITT population where RAM+ERL demonstrated a statistically significant improvement in PFS over PL+ERL. Efficacy and tolerability were similar to that of the overall RELAY study population. Ramucirumab is an effective and safe addition to standard-of-care EGFR-TKI for treating EGFR mutation-positive metastatic NSCLC.
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P1.18-03 - How to Predict High Grade Radiation Pneumonitis in Non-Small Cell Lung Cancer Patients Treated with Thoracic Radiotherapy (Now Available) (ID 835)
09:45 - 18:00 | Author(s): Ernest Nadal
- Abstract
Background
Predictive factors of radiation pneumonitis (RP) have been studied without conclusive results. The aim of this retrospective study was to identify clinical, inflammatory or dosimetric factors that could predict the development of high grade RP (HGRP).
Method
A retrospective analysis was conducted in patients with non-small cell lung cancer (NSCLC) treated with concurrent chemo- radiotherapy, secuential chemo-radiotherapy or radiotherapy (RT) alone at the Catalan Institute of Oncology from 2012 to 2016 who developed symptomatic RP. Collected variables were: anthropometric values, Neutrophil-Lymphocyte Ratio (NLR), Platelet-Lymphocyte Ratio, lung function, tumor features (histology, localization, staging) and treatment characteristics. RP was classified using RTOG scale. Patients were divided in 2 groups (low-grade [G1-G2], and HGRP [G3-G5]). Multivariate and regression tree analysis were performed.
Result
Sixty-seven patients were identified: 61% had low-grade RP and 39% HGRP. Development of HGRP was only associated with RT total dose (p=0.045). The most relevant predictive factors of HGRP were tumor location in lower lobes, high NLR values and the presence of peripheral vasculopathy. Figure 1 shows, when tumor is located in lower lobes and NLR is > 2.75, the probability of HGRP was 70% vs 50% when NLR <2.75. In other locations with NLR >4.56 the probability to develop a HGRP was 62%. But, when NLR<4.56, the presence of peripheral vasculopathy and its treatment determine the development of HGRP. When vasculopathy was not treated the probability to develop HGRP was 36% vs 0% when it was treated.61% had low-grade RP and 39% HGRP. Development of HGRP was only associated with RT total dose (p=0.045). When cancer is localized in lower lobes and NLR is > 2.75 the probability to develop HGRP was 70% vs 50% when NLR <2.75. In other locations with NLR >4.56 the probability to develop a HGRP was 62%. But, when NLR<4.56, the presence of vasculopathy and its treatment determine the development of HGRP. When vasculopathy was not treated the probability to develop HGRP was 36% vs 0% when it was treated.
Figure 1. Probability to develop HGRP (G3 –G5)
Conclusion
The probability of develop HGRP has been associated with RT dose and the association of cancer location, NLR, presence of vasculopathy and its treatment.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-03 - Landscape of Gene Fusions in Lung Adenocarcinoma Patients with Minimal Cigarette Exposure Identified on Malignant Pleural Effusions (ID 575)
10:15 - 18:15 | Author(s): Ernest Nadal
- Abstract
Background
Gene fusions in lung adenocarcinoma (LuAD) involving tyrosine kinase receptors such as ROS1, ALK or RET are recurrent oncogenic drivers (~10%), enriched in light or never-smokers. Some of them represent emerging and predictive biomarkers for targeted therapies. Here we report the fusions detected in a cohort of metastatic LuAD patients with low tobacco exposure (never or former-smokers).
Method
Patient-derived cancer cell lines (PDC) were successfully established from malignant pleural effusions from 11 patients diagnosed with LuAD. We assessed the genetic and molecular profile by whole-exome sequencing (WES) and RNA sequencing (RNA-seq) in each cell line.
Result
Patients’ characteristics: median age, 58 (39-86); 9 were female. Eight of eleven were never-smokers and three, former-smokers. Seven patients were treatment naïve when pleural effusion samples were collected. A cytological examination of pleural fluid was performed by a lung pathologist and all samples were positive for malignant cells. Known driver mutations in lung primary tumours included one ALK translocation detected by FISH and three EGFR Del19 mutations by targeted sequencing. The three EGFR-mutant LuAD patients progressed to first or second-generation EGFR-TKI and we were able to stablish paired PDC after progressing to tyrosine kinase inhibitors (TKI) in two of them. We identified an acquired FGFR3-TACC3 fusion in one paired PDC after gefitinib progression (T790M-negative), that led to overexpression of FGFR3 concurrent with an enrichment of squamous cell lineage transcripts (e.g. TP63, SOX2) and MDM2 amplification. Among EGFR wild type (wt) patients, two RET rearrangements, CCDC6-RET and KIF5B-RET, and one EML4-ALK fusion -also detected in the primary tumour- were identified in PDC models. In addition, in two of the samples we discovered novel gene fusions that will be described in detail, involving proteins that are not kinases, and thus, their potential role in cancer is still unknown.
Conclusion
In this cohort enriched with never-smoking LuAD patients presenting pleural effusions at diagnosis, the presence of known driver fusions during the disease’s course detected by RNA-Seq was 36% (4/11), including a FGFR3-TACC3 fusion as an acquired resistance mechanism to EGFR-TKI. Further study is ongoing in our PDC models to test the functional role of these fusions in order to facilitate precision medicine.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-10 - Biomarkers of Pathological Response on Neo-Adjuvant Chemo-Immunotherapy Treatment for Resectable Stage IIIA NSCLC Patients (ID 1466)
10:15 - 18:15 | Author(s): Ernest Nadal
- Abstract
Background
PD1/PDL1 treatments have become the main therapy in advanced stages of NSCLC due to its significant increase in overall survival (OS), but recently, combination with chemotherapy in locally advanced stages is showing promising results. Many studies have described peripheral blood immune cells parameters as biomarkers of response to immunotherapy. In our study, we described the effect of neo-adjuvant chemo-immunotherapy treatment in Complete Blood Count (CBC) and Peripheral Blood Mononuclear Cells (PBMCs) phenotype, as well as, the association of these parameters with the degree of pathological response.
Method
Immune cell populations of 46 resectable stage IIIA NSCLC patients treated with neo-adjuvant chemo-immunotherapy from NADIM clinical trial were analysed. Samples were extracted before initiating the neo-adjuvant treatment with nivolumab plus carboplatin and at the third cycle before patients underwent surgery. We classified patients in 3 subgroups of pathological response assessed in the resection specimen: complete response (pCR), major response (<10% viable tumour) and incomplete response (>10% viable tumour, pIR). Wilcoxon and Mann-Whitney U statistic test were used to evaluate differences between pre and post treatment and between pathological responses groups respectively.
Result
From 46 patients, 5 patients did not undergo surgery, so they were excluded from the analysis. Absolute numbers of Leucocytes, Eosinophil, Monocytes, Neutrophils, Haemoglobin and Platelets from hemograms were significantly reduced after neo-adjuvant treatment. However, no changes were observed for Lymphocytes, Basophils, LDH levels or the Lung Immune Prognostic Index (LIPI). Additionally, post-treatment Neutrophil-to-Lymphocyte (NLR), Myeloid-to-Lymphoid lineage (M:L) and Platelets-to-Lymphocytes (PLR) ratios were decreased. Remarkably, from all the CBC absolute numbers and ratios, only PLR variation showed differences between pCR and pIR.
On the other hand, percentages of PBMCs (T cells, B cells, NK cells and macrophages) did not vary after neo-adjuvant treatment, however activation of CD4 T cells and NK cells as well as PD-1 receptor expression on immune cells were downregulated after neo-adjuvant chemo-immunotherapy. Interestingly, these variations correlate with pCR.
Conclusion
In our study, PLR, PD-1 expression, CD4 T cells and NK cells activation are predictive biomarkers of response to treatment. Thus, a higher decrease on PLR post neo-adjuvant treatment is associated to pCR. Moreover, a decrease of PD-1 expression in CD4, CD8 and NK cells, as well as, a reduction of CD4 T cells and NK cells activation after neo-adjuvant treatment, are associated to pCR.
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P2.13 - Staging (ID 315)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Staging
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.13-04 - Molecular Nodal Restaging Based on Embryonic Markers Expression Adds No Relevant Clinical Information in Resected Lung Cancer (ID 1149)
10:15 - 18:15 | Author(s): Ernest Nadal
- Abstract
Background
The relapse rate in non-small cell lung cancer (NSCLC) is high, even in localised disease, suggesting that the current approach to pathological staging is insufficiently sensitive to detect occult micrometastases present in resected lymph nodes. Therefore, we aimed to determine the prognostic value of the expression of embryonic molecular markers in histologically-negative lymph nodes of completely-resected NSCLC.
Method
76 NSCLC patients undergoing radical resection were included. Primary tumours and 347 lymph nodes were studied. The molecular markers finally were selected based on testing of 27 normal lung and 129 lung tumour samples as well as 25 lymph nodes obtained from non-neoplastic diseases. CEACAM5, FGFR2b, and PTPN11 expression levels were evaluated through mRNA analysis using real-time RT-qPCR assay. Statistical analyses included the Kruskal-Wallis test, Kaplan Meier curves, and log-rank tests.
Result
CEACAM5 expression levels were scored as high in 90 lymph nodes (26%). The molecular-positive lymph nodes lead to the restaging of 37 (62%) pN0 patients as molecular N1 or N2 and 5 (31%) pN1 cases were reclassified as molecular-positive N2. Surprisingly, molecular-positive patients (42, 55%) associated with a better OS (overall survival, p=0,04) than molecular-negative patients (34, 45%). FGFR2b overexpression was observed in 41 (12%) lymph nodes leading to the restaging of 17 patients (22%). Again a trend was observed towards a better DFS (disease-free survival) in the restaged patients (p=0,09). PTPN11 expression levels were high in 109 (31%) lymph nodes and led to the restaging of 41 (54%) patients who did not correlate with clinical outcome (p=0,61). The combination of CEACAM5-FGFR2b restaged the same number of patients than CEACAM5 only. Accordingly, high expression levels of CEACAM5 or FGFR2b in the primary tumour were related to better DFS (p<0,06; p<0,02, respectively); PTPN11 did not correlate with prognosis (p=0,37).
Conclusion
Molecular nodal restaging based on expression levels of CEACAM5 and/or FGFR2b, does not add relevant clinical information to pathological staging of NSCLC likely related to the better prognosis of their overexpression in primary tumors.
