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Anne Marie Clasina Dingemans
Moderator of
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MA01 - Oligometastatic Disease (ID 114)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Oligometastatic NSCLC
- Presentations: 12
- Now Available
- Moderators:Anne Marie Clasina Dingemans, Matthias Guckenberger
- Coordinates: 9/08/2019, 10:30 - 12:00, Copenhagen (1980)
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MA01.01 - Safety of Pembrolizumab Combined with Stereotactic Ablative Body Radiotherapy (SABR) for Pulmonary Oligometastases (Now Available) (ID 2187)
10:30 - 12:00 | Presenting Author(s): Shankar Siva | Author(s): Mathias Bressel, Sherene Loi, Shahneen Sandhu, Ben Tran, Jennifer Mooi, Jeremy Lewin, A Azad, D Colyer, Mark Shaw, Sarat Chander, Katherine Cuff, Simon Wood, Nathan Lawrentschuk, Declan Murphy, David Pryor
- Abstract
- Presentation
Background
Pembrolizumab has demonstrated safety and efficacy in a broad range of tumors. However, safety concerns exist around the combination of pembrolizumab and high dose radiotherapy to the lung, particularly as both have independent risk of pneumonitis. In this interim analysis we assess the safety profile of combination pembrolizumab and SABR to pulmonary oligometastases.
Method
As part of the ongoing prospective dual-institutional RAPPORT clinical trial (clinicaltrials.gov ID NCT02855203), patients with 1-5 oligometastases from renal cell carcinoma were enrolled between Nov 2016- April 2019. All participants had ECOG performance status 0-1, and signed informed consent. Patients with at least 1 lung oligometastasis were included in this analysis. All patients were planned for a single fraction of 20Gy SABR to each lung oligometastasis, followed 5 days (+/-3 days) later by 8 cycles of 200mg i.v. 3-weekly pembrolizumab (total 24 weeks). When SABR dose constraints were not achievable, conventional hypofractionated radiotherapy could be delivered. At least 1 oligometastasis needed to receive SABR. Adverse events (AEs) were recorded using CTCAE V4.03 until 30 days post last dose of pembrolizumab, and late AEs atrributable to SABR for 24 months after SABR.
Result
20 patients with a combined total of 41 lung oligometastases were included in this analysis. The mean age was 61 years, with 15 (75%) male. The number of lung oligometastases were 1 in 9 (45%), 2 in 3 (15%), 3 in 6 (30%), 4 in 2 (10%) patients. SABR was delivered to 39 lung oligometastases (95%) and conventional radiotherapy to 2 oligometastases (5%) using 10 fractions of 3Gy. Twelve patients have completed all eight cycles of pembrolizumab, with five patients having ongoing treatment. Three patients ceased treatment early due to grade 3 pneumonitis (15%) after 3, 6 and 7 cycles of pembrolizumab respectively. These patients had 1, 2 and 1 lung oligometastases, respectively. The worst grade of any treatment related AEs was grade 3 in 4 pts (20%), with 3 attributed to both SABR and pembrolizumab, and 1 atributed to pembrolizumab alone. Three of the four grade 3 events were pneumonitis. A further 3 patients had grade 2 AEs(15%), and 8 patients had grade 1 AEs(40%). There were no grade 4 or 5 adverse events, and five patients (25%) had no treatment related adverse events.
Conclusion
SABR to lung oligometastases in combination with pembrolizumab was well tolerated, with clinically acceptable rates of grade 3 pneumonitis compared to historical rates reported with pembrolizumab monotherapy.
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MA01.02 - Lung Stereotactic Body Radiotherapy and Concurrent Immunotherapy: A Multi-Center Safety and Toxicity Analysis (Now Available) (ID 597)
10:30 - 12:00 | Presenting Author(s): Sibo Tian | Author(s): Jeffrey M Switchenko, Pretesh R Patel, Joseph W Shelton, Shannon E Kahn, Rathi N Pillai, Conor E Steuer, Taofeek Owonikoko, Madhusmita Behera, Walter J Curran, Kristin A Higgins
- Abstract
- Presentation
Background
Radical treatment of metastases with stereotactic body radiotherapy (SBRT) in patients with advanced malignancies is an emerging treatment paradigm. SBRT is increasingly used in patients receiving immune checkpoint inhibition (ICI); however, limited toxicity data for this treatment approach exists. The purpose of this study was to evaluate the safety and tolerability of lung SBRT with concurrent ICI.
Method
Records from a single academic institution were reviewed to identify patients treated with lung SBRT and concurrent (within 30 days) ICI; a contemporaneous cohort receiving lung SABR without ICI were included as a reference cohort. Treatment-related adverse-effects (AE) occurring within 30 days (acute) and 180 days (subacute) of SBRT were graded via CTCAE v5.0.
Result
110 patients were included; 47 received SBRT with concurrent ICI (49 SBRT courses, 61 lesions) between August 2015 and January 2019. 63 received SBRT without ICI (68 courses, 79 lesions). For the SBRT+ICI cohort, median age at treatment was 64 years, median follow-up was 6.7 months. 70% were lung, 15% were melanoma, 6.4% were from head and neck primaries. 90% were treated for metastatic consolidation/oligo-progression, 10% received SBRT for locally advanced/recurrent disease. 65.3% of patients received prior RT. 36.7% received prior lung RT, 40% of which were overlapping. 67% received ICI monotherapy, 16% ICI/chemotherapy, and 16% ICI/ICI combinations. 24.5% received ICI between SBRT fractions; 38.8% received ICI both before and after SBRT. Grade 3 (G3) and any grade pneumonitis rates were 8.2% and 30.6%; there were no G4-5 events. ICI was discontinued due to toxicity in 22.4% of patients. Receipt of ICI/ICI combinations increased the risk of any grade pneumonitis (62.5% vs 24.4%, p=0.04); but not G3 pneumonitis. Risk of G3 pneumonitis was higher in the SBRT+ICI vs SBRT alone cohort (8.2 vs 0%, p=0.03); but not any grade pneumonitis (30.6% vs 29.9%, SBRT+ICI vs SBRT p=0.75). Median time to onset was 3.4 months from end of SBRT in both groups. Risk of G3 and any grade pneumonitis was not predicted by ICI agent, timing of ICI administration, prior RT, prior lung RT, lesion centrality, number of target lesions, or smoking status. Overall acute G3+ AE rates were 2% (SBRT+ICI) and 0% (SBRT). Subacute G3+ AEs occurred in 26.5% (SBRT+ICI) and 2.9% (SBRT) of patients.
Conclusion
Concurrent ICI, especially ICI/ICI combinations, increased the risk of G3 pneumonitis with lung SBRT. However, SBRT+ICI appears safe and tolerable compared to SBRT alone. Strategies integrating SBRT and ICI warrant additional investigation.
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MA01.03 - Interim Safety Analysis of the Phase IB Trial of SBRT to All Sites of Oligometastatic NSCLC Combined with Durvalumab and Tremelimumab (Now Available) (ID 2893)
10:30 - 12:00 | Presenting Author(s): Ticiana A. Leal | Author(s): Joshua M Lang, Zachary Morris, Jens Eickhoff, Anne M Traynor, Toby Campbell, Andrew Baschnagel, Michael Bassetti
- Abstract
- Presentation
Background
Oligometastatic NSCLC represents a unique subset of patients (pts) with limited burden of metastatic disease. Prior early studies have demonstrated that combining local ablative and systemic therapies in pts with oligometastatic disease leads to improved progression-free survival (PFS). The immunostimulatory effects of SBRT and potential synergy with immune checkpoint inhibitors has prompted enthusiasm in combining the two; however, the toxicity is unknown.
Method
In this phase Ib study, a cohort of 21 pts with oligometastatic NSCLC receive SBRT to all sites of disease between 30 and 50 Gy in five fractions and durvalumab 1500 mg IV + tremelimumab 75 mg IV every 4 weeks x 4 cycles in a sequential fashion, followed by durvalumab maintenance until progression, unacceptable toxicity or patient wishes. Eligible patients had 1-6 metastatic extracranial lesions, all of which were suitable for SBRT, ECOG performance status 0-1, no actionable driver mutation, and no prior immunotherapy.The primary endpoint is safety of this combination. The period for evaluating dose-limiting toxicities (DLTs) is from the time of first administration of SBRT until 28 days post completion of the first dose of durvalumab and tremelimumab. Grading of DLTs follows CTCAE version 4.03. A DLT will be defined as any Grade≥ 3 toxicity. Secondary endpoints include PFS and overall survival. Correlative studies of baseline TMB, PD-L1 expression on post-SBRT biopsy and immune biomarkers on circulating tumor cells will be correlated with outcomes. In this interim analysis, we assess the safety of the first nine patients enrolled.
Result
Nine pts enrolled from 2/2018-3/2019. Median follow-up: 2.8 months (range 1.5-8.2 months). Characteristics included: median age 72 years (range 56-81 years), female/male 2/7, squamous/nonsquamous 2/7, median number of sites treated 2, CNS involvement 3/9. Most toxicities were Grade (G) 1/ 2. Severe adverse events (AEs) included: G4 elevated CK (1). Severe immune-related (ir)AEs: G3 rash (1), G3 AST (2), G3 ALT (1), G3 amylase (1), G3 lipase (1). One DLT reported due to grade 3 AST > 7 days (recovered). One additional pt discontinued treatment due to grade 3 irAE. There were no treatment-related deaths. Two patients (22%) died of disease progression.
Conclusion
There were no unexpected safety signals in the first nine patients enrolled. The incidence of grade 3 or greater irAEs was similar to those seen in the treatment of advanced NSCLC, and no additional toxicity is observed with the addition of SBRT to date. The study continues to enroll and results will be updated.
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MA01.04 - Discussant - MA01.01, MA01.02, MA01.03 (Now Available) (ID 3715)
10:30 - 12:00 | Presenting Author(s): Fiona McDonald
- Abstract
- Presentation
Abstract not provided
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MA01.05 - Progress of Accompanying GGN Beyond Pulmonary Resection for Non-Small Cell Lung Cancer (Now Available) (ID 1525)
10:30 - 12:00 | Presenting Author(s): Kanghoon Lee | Author(s): Hyeong Ryul Kim, Seung-Il Park, Dong Kwan Kim, Yong-Hee Kim, Sehoon Choi, Geun Dong Lee, Yong Ho Jeong, Jae Kwang Yun, Yooyoung Chong
- Abstract
- Presentation
Background
The aim of this retrospective study was to review the natural course of synchronous ground-glass nodule (GGN), which was left after the curative resection of non-small cell lung cancer (NSCLC) in other lobe.
Method
Between 2008 and 2017, a prospectively collected retrospective data of 2276 patients who underwent curative resection for NSCLC was reviewed. Among them, GGN was detected in 126 patients beside resected lung. Defined by high-resolution computed tomography (HRCT) or thin-section of computed tomography (CT), twenty patients with nearly solid nodule or GGN with higher CT ratio (> 0.75) was excluded, thereafter the data of 98 patients (4.3%) was included in the study. Demographic data of patients including age, gender, and smoking history were collected for analysis. In addition, risk factor including characteristics of GGN, histopathology and staging of resected tumor, adjuvant treatment, and any other medical history were evaluated for risk factor analysis.
Result
Median duration of follow-up was 36 months (range; 11 – 120). The size of GGN has been decreased in 10 patients (10.2%), stationary 48 patients (50.0%), while an increasing in size of GGN was observed in 40 patients (40.8%). Among them, five patients were recommended reoperation (12.5%), and the other 35 patients were in clinical observation (87.5%). In mutivariate analysis, existence of solid component, smoking history, and multiple GGNs in one lobe were independent prognostic factor.
Conclusion
During the follow-up, 40.8% of GGN showed a growth in size, emphasizing that patients with part-solid GGN and with smoking history should be in careful observation.
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MA01.06 - Prognostic Factors of Oligometastatic Non-Small Cell Lung Cancer Following Radical Therapy: A Multicenter-Analysis (Now Available) (ID 3063)
10:30 - 12:00 | Presenting Author(s): Isabelle Opitz | Author(s): miriam Patella, Loic Payrard, Jean Yannis Perentes, Thorsten Krueger, Rolf Inderbitzi, Hans Gelpke, Sandra Schulte, Maja Diezi, MIchel Gonzalez, Walter Weder
- Abstract
- Presentation
Background
Patients with oligometastatic non-small cell lung cancer (NSCLC) may benefit from radical therapy. We aimed to identify factors related to better prognosis, in a multicenter analysis of patients who underwent surgery of primary tumours, in combination with radical treatment of metastatic sites, and chemo- or chemoradiation.
Method
We retrospectively reviewed the records of oligometastatic patients who all underwent anatomical resection of primary tumor, treated at 4 centers, (August 2001-November 2018). Oligometastasis was defined as ≤5 synchronous metastases in ≤2 organs. Radical metastatic treatment was surgery (n=48), radiotherapy (n=36) or a combination (n=41). Univariate analysis and multivariate Cox proportional hazards model were used for identification of prognostic factors on overall survival (OS) and progression-free survival (PFS). Survival was estimated by Kaplan-Meier analysis. P-value < 0.05 was considered significant.
Result
We treated 125 patients; 72 (58%) were male, aged 60±9.8 years, with 88 (70%) adenocarcinoma, and following pathological (pN) stage: pNx: 1 (1%), pN0: 57 (46%), pN1: 23 (18%), pN2: 44 (35%). Brain metastasis was most common (n=76; 61%) followed by adrenal (n=13; 11%) and bone (n=12; 10%). Systemic therapy was administered in 102 (82%). Median follow-up was 60 months (95%, CI: 41-86).
One-, 2-, 3-, and 5-years OS was 80%, 58%, 49% and 36% respectively. Several patient-related and treatment-related factors showed a correlation with OS at univariate analysis. Multivariate analysis showed that patients ≤60 years (HR 0.47, 95% CI:0.28-0.78, p=0.004), and/or pN0, compared to pN1,2 (HR 0.38, 95% CI: 0.22-0.66, p=0.001), had a significant survival benefit (Figure 1A). Bone metastasis were associated with worse prognosis (HR 2.122, 95% CI: 1.00-4.48, p=0.05).
Twenty-eight patients were ≤60 years with pN0, and had 1- and 5-year survival of 100 and 83%.
PFS at 1-, 2-, 3- and 5-years was 41%, 29%, 25% and 23% respectively. In the multivariate analysis, absence of mediastinal lymphnode involvement (HR: 0.483, 95% CI: 0.305-0.764, p=0.002) and surgical treatment of metastasis (HR: 0.553, 95% CI: 0.347-0.880, p=0.013) remained independently associated with better outcome (Figure 1B). The administration of treatments after first progression was strongly associated with better prognosis (HR: 0.252, 95% CI: 0.076-0.834, p=0.013).
Conclusion
Our experience demonstrates, in a multicenter setting, that radical treatment of selected oligometastatic NSCLC results in excellent 5-year survival. Nodal status correlates with both OS and PFS. Surgical metastasectomy appears to improve PFS, but multimodality treatment, especially in case of recurrence, remains mandatory.
These data might contribute to develop future combined strategies in the era of immunotherapy.
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MA01.07 - Prognostic Factors of Surgical Treatment in Non-Small Cell Lung Cancer (NSCLC) Patients in Oligometastatic Stage-M1b of Disease (Now Available) (ID 312)
10:30 - 12:00 | Presenting Author(s): Dariusz Adam Dziedzic | Author(s): Grabczan Wojciech, Rudzinski Piotr, Renata Langfort, Tadeusz Orlowski
- Abstract
- Presentation
Background
Non-small cell lung cancer in stage IV is rarely the subject of surgical treatment. Most cases are considered as inoperable and qualified for palliative treatment. Long-term results in this group of patients are poor despite systemic oncological treatment. A special group of patients are patients with a single metastasis beyond the lung (grade M1b), in which in some cases surgery may significantly improve the prognosis. The aim of the study was to determine the prognostic factors of surgical treatment of non-small cell lung cancer in stage IVA with a single distant metastasis (oligometastatic stage-M1b)
Method
A retrospective study was based on data from the National Register of Cancer of the Lung conducted by the Polish Group of Lung Cancer. The study included 387 patients (242 men and 145 women) between 41 and 87 years of age (median 60.4 +/- 8.4 years) with established NSCLC and single synchronous metastasis most often to: second lung (55.5%), brain (24.8%) and adrenal glands (14.5%). All patients underwent resection of the pulmonary parenchyma and resection of the metastatic focus. The size of the primary tumor was respectively: 1-2 cm in 16.0%, 2-3 cm in 26.4%, 3-5 cm in 23.5%, 5-7 cm in 12.4% 7-10 cm in 14 , 0% and over 10cm in 7.8%. The features of N0, N1, and N2 were diagnosed in 69.8%, 15.5% and 14.7% of patients respectively. Radical oncology R0, R1 and R2 were obtained in 96.1%, 2.1% and 1.8% of cases respectively. Anatomical resection was performed in 70% and minor resection in 30% of patients. Preoperative chemotherapy was used in 7.5% of cases, and postoperative in 21.2% of patients.
Result
The 5-year survival in the entire M1b group was 27.3%. Multivariate analysis showed that the negative prognostic factors were male gender (HR = 1.56, 95% CI-1.16-2.1, P <0.003), age> 50 (HR = 1.39, 95% CI-0.87-2.22, P <0.002), tumor size (HR = 34.32, 95% CI-2.39-7.82, P <0.001), feature N1 (HR = 1.53, 95% CI-1.02-2.29, P <0.04) and the N2 trait (HR = 2.71; 95% CI -1.8-4.06, P <0.001). Patients undergoing anatomical resection vs lower (HR = 0.5, 95% CI-0.35-0.72, P <0.001) and postoperative preoperative chemotherapy (HR = 0.69, 95% CI-0.48-0.97, P <0.034) have better prognosis. The number of lymph nodes removed during the procedure is also significantly affected - 5-year survival at 1-5 removed nodes was 24.6%, and in the case of 6-10 nodes 32.4%.
Conclusion
Surgical treatment of NSCLC in the M1b stage in a selected group of patients allows for the improvement of long-term results. Negative prognostic factors are gender, age, tumor size and metastases to lymph nodes. The scope of resection in this group of patients should be the same as in the lower stages with the predominance of anatomical resection and mediastinal lymphadenectomy. Post-operative chemotherapy may have a beneficial effect on long-term results.
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MA01.08 - Discussant - MA01.05, MA01.06, MA01.07 (Now Available) (ID 3716)
10:30 - 12:00 | Presenting Author(s): Corey Jay Langer
- Abstract
- Presentation
Abstract not provided
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MA01.09 - Concomitant SBRT and EGFR-TKI Versus EGFR-TKI Alone for Oligometastatic NSCLC: A Multicenter, Randomized Phase II Study (Now Available) (ID 2214)
10:30 - 12:00 | Presenting Author(s): Li Zhang | Author(s): Ping Peng, Yongshun Chen, Guang Han, Rui Meng, Sheng Zhang, Zhengkai Liao, Yujie Zhang, Juejun Gong, Chuangying Xiao, Xiyou Liu, Peng Zhang, Lu Zhang, Shu Xia, Qian Chu, Yuan Chen
- Abstract
- Presentation
Background
NSCLC patients harboring EGFR mutation generally develop resistance to EGFR TKI less than one year. Prior studies indicated that local consolidative therapy is associated with improved outcomes in patient with limited metastatic NSCLC. Radiotherapy is one of the ideal control methods for locally progressed patients, however, the optimal intervention time in order to slow the occurrence of EGFR-TKI resistance for advanced NSCLC patients with EGFR-sensitive mutations is still unclear. Our preliminary clinical and animal studies suggest that early combined radiotherapy prior to EGFR-TKI resistance can significantly improve the prognosis of patients. Our hypothesis is that the optimal intervention time of radiotherapy for EGFR mutation patients is 3 months after the beginning of EGFR-TKI.
Method
This is a prospective, multicenter, randomized controlled study to evaluate stereotactic body radiation therapy (SBRT) as a potential treatment for limited stage IV NSCLC (primary plus up to 3 metastatic sites) with sensitive EGFR mutation. The patients did achieve partial response or stable disease after three months treatment of the first-generation EGFR-TKI would be randomized to TKI combined SBRT (TS) or TKI alone. The primary endpoint was PFS (the time from the beginning of EGFR-TKI treatment to disease progression or death). The secondary endpoint was overall survival (OS) and safety. TKI wasn’t interrupted during the irradiation.
Result
A total of 61 patients were enrolled from Feb, 2017 to Jan, 2019. Median follow up was 22.3 months. Patients who TS (n: 30) had a significantly longer median PFS compared to those with TKI alone (n: 31) (PFS: 17.4 vs. 8.9 months P =0.042). T790M mutation was observed in 57.9% acquired resistance patients for TS group, and 39.3% for TKI alone group. Median PFS of T790M mutated patients was 17.4 months compared to 10.3 months of TKI alone group (P = 0.007). Multivariable analysis revealed that radiation fields were positively associated with PFS, 21.8 months for just primary tumor; 10.6 months for metastatic lesions and 18.3 months for primary and metastatic lesions (P= 0.006). OS data was not yet mature. None experienced >= grade 3 SBRT related toxicities.
Conclusion
A trend of improved long term PFS was noted in patients receiving SBRT for primary tumor combined EGFR TKI at the third month after the beginning of TKI. Moreover, this data suggested that benefit from radiation might be associated with delay the occurrence of T790M mutation. Further studies are required to investigate the molecular mechanisms underlying this association.
Clinical Trial information: NCT03595644
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MA01.10 - Additional Local Consolidative Therapy Showed Survival Benefit Than EGFR-TKIs Alone in Bone Oligometastatic Lung Adenocarcinoma Patients (Now Available) (ID 398)
10:30 - 12:00 | Presenting Author(s): Fang Hu | Author(s): Changhui Li, Jianlin Xu, Jindong Guo, Yinchen Shen, Wei Nie, Xiaoxuan Zheng, Lixin Wang, Hai Zhang, Baohui Han, Xueyan Zhang
- Abstract
- Presentation
Background
Whether epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) plus local consolidative therapy (LCT) has better survival benefit than EGFR-TKIs alone remains controversial in lung adenocarcinoma patients with EGFR mutation and bone oligometastases.
Method
We conducted a retrospective study to assess the effects of LCT on bone oligometastases lung adenocarcinoma patients with EGFR mutation. The primary endpoint was overall survival (OS); The secondary endpoints was progression-free survival (PFS).
Result
A total of 127 lung adenocarcinoma patients with EGFR mutation and bone oligometastases were identified. There were 65 patients received EGFR-TKIs alone (monotherapy group) and 62 patients received EGFR-TKIs plus local consolidative therapy (LCT) (combination group). Addition of LCT was associated with a significantly longer OS (36.3 vs. 21.0 months, P=0.01, hazard ratio [HR]=0.537, 95% confidence interval [CI]:0.360-0.801, p=0.01) and PFS (14.0 vs. 8.1 months, P=0.01, HR=0.613, 95%CI: 0.427-0.879, p=0.01) in the whole cohort (Figure 1). All subgroups showed OS benefit in faver of combination therapy except for PS scores greater than or equal to 2 group, and all subgroups analyzed derived PFS benefit in favor of combination therapy (Figure 2).
Conclusion
In patients with EGFR-mutant lung adenocacinoma and bone oligometastases, LCT plus EGFR-TKIs therapy was associated with significantly longer OS and PFS than EGFR-TKIs therapy alone, indicating that LCT plus EGFR-TKIs therapy might be a better therapeutic option for those patient population.
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MA01.11 - Improving Survival in Lung Cancer Patients with Oligometastatic Disease Progression Using Stereotactic Body Radiation Therapy (Now Available) (ID 1836)
10:30 - 12:00 | Presenting Author(s): Luis Raez | Author(s): Miguel Castillo, Ana Botero, Aaron Falchook, Ignacio Castellon, Brian Hunis
- Abstract
- Presentation
Background
In patients (pts) with stage IV non-small cell lung cancer (NSCLC) receiving systemic therapy, stereotactic body radiation therapy (SBRT) can eliminate oligometastatic disease progression (OMP). This allows NSCLC pts to continue the same systemic therapy, and its is especially important when the therapy is well tolerated as is the case for many pts receiving immunotherapy (IMMUNO) and targeted therapy (TARGET). The purpose of this study is to quantify the progression free survival (PFS) and overall survival (OS) of pts receiving systemic therapy who experience OMP that is treated with SBRT, and subsequently continue the same systemic therapy.
Method
Retrospective review of one hundred pts with metastatic NSCLC undergoing chemotherapy (CHEMO), IMMUNO or TARGET that had OMP defined as less than 4 sites of metastasis and underwent SBRT were evaluated for PFS and OS. PFS1: Time between initiation of systemic therapy and development of OMP. PFS2: Time between OMP treated with SBRT and development of further PD requiring a change in systemic therapy. Pts received IMMUNO for second line and beyond. SBRT doses were determined based on the disease site and dose tolerance of the adjacent organs. SBRT was delivered in 1-5 fractions on consecutive days or every other day. Radiation dose was determined by target volume and adjacent dose-limiting organs.
Result
OMP presented as brain metastasis (BM) in 45 pts and extracranial metastasis (EM) in 55 pts. 34 pts were receiving CHEMO, 34 TARGET and 32 IMMUNO at the time of OMP. Pts with BM that received SBRT were able to continue the same therapy for a period of 6.5-9 extra months due to the control of BM. Pts with EM that have developed PD were able to continue the same therapy an 17-21 extra months due to the ablation of OMP by SBRT. For the entire cohort PFS was: 16.5m for BM and 34m for EM and the OS were: 31m and 53m respectively.
Location of oligometastatic progression (OMP)
Median PFS1
Median PFS2
PFS
Median OS
Extracranial (N=55)
13
21
34
53
chemo
7
17
24
47
Immuno
13.5
20.5
34
49
Target
12
21
33
53
Brain (N=45)
9
7.5
16.5
31
Chemo
5.5
6.5
12
25.5
Immuno
7
8
15
27
Target
11
9
20
47
Conclusion
PFS and OS may be prolonged due to the use of SBRT in pts that develop OMP. This intervention allowed patients to continue with the same systemic treatment. Our CHEMO cohort is composed of long term survivors under therapy and may not represent the average PFS/OS of pts on CHEMO. Prospective trials are needed to verify these results.
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MA01.12 - Discussant - MA01.09, MA01.10, MA01.11 (Now Available) (ID 3717)
10:30 - 12:00 | Presenting Author(s): Tomoyuki Hishida
- Abstract
- Presentation
Abstract not provided
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Author of
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GR01 - Whether and How to Adapt Treatment of NSCLC Oligometastatic Disease to… (ID 29)
- Event: WCLC 2019
- Type: Grand Rounds Session
- Track: Oligometastatic NSCLC
- Presentations: 1
- Now Available
- Moderators:Jin-Soo Lee, Laurie Gaspar
- Coordinates: 9/08/2019, 13:30 - 15:00, Seoul (2007)
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GR01.01 - Definition and Minimal Staging in Oligometastatic Disease (Now Available) (ID 3298)
13:30 - 15:00 | Presenting Author(s): Anne Marie Clasina Dingemans
- Abstract
- Presentation
Abstract
Oligometastatic non-small cell lung cancer (NSCLC) is perceived as a separate entity of metastatic NSCLC with limited metastatic potential and possibility of long term survival when treated with local radical treatment1-3. However, uniform definition of oligometastatic NSCLC does not exist. We showed in a recent systematic review (21 papers) that the number of metastasis, allowed in the definition of oligometastatic NSCLC, varies between 1 and 8, in only 2 out of 21 papers > 5 metastasis were allowed4. This has led to an European Organisation on Research and Treatment of Cancer (EORTC) –Lung Cancer Group (LCG) initiative to formulate a consensus definition of synchronous oligometastatic NSCLC. A pan-European multidisciplinary consensus group was established. Results from the systematic review, a European survey and real patient cases were taken into account when. It was concluded that the definition of synchronous oligometastatic NSCLC is relevant when a radical treatment is technically feasible for all tumor sites with acceptable toxicity, that may modify the disease course leading to long-term disease control. Based on the review, a maximum of 5 metastases and 3 organs is proposed. Mediastinal lymph node involvement is not counted as a metastatic site5.
In addition staging with PET-CT and imaging of the brain is mandatory. This is in line with the advice of the EORTC-imaging group6.
The eligibility criteria of recent and ongoing clinical trials in this setting will be discussed in this presentation.
1. Gomez D, Tang C, Zhang J, et al. Local Consolidative Therapy (LCT) Improves Overall Survival (OS) Compared to Maintenance Therapy/Observation in Oligometastatic Non-Small Cell Lung Cancer (NSCLC): Final Results of a Multicenter, Randomized, Controlled Phase 2 Trial. ASTRO 2018 2018;abstract LBA3.
2. Gomez DR, Blumenschein GR, Jr., Lee JJ, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. The lancet oncology 2016;17:1672-1682.
3. Iyengar P, Wardak Z, Gerber DE, et al. Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA oncology 2018;4:e173501.
4. GiajLevra N, Levra MG, Durieux V, et al. Defining synchronous oligometastatic non-small cell lung cancer: a systematic review. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2019.
5. Dingemans A, Hendriks L, Berghmans T, et al. MA25.02 - Searching for a Definition of Synchronous Oligometastatic (sOMD)-NSCLC: A Consensus from Thoracic Oncology Experts WCLC 2018. Toronto: 2018:abstract MA 25.02.
6. deSouza NM, Liu Y, Chiti A, et al. Strategies and technical challenges for imaging oligometastatic disease: Recommendations from the European Organisation for Research and Treatment of Cancer imaging group. European journal of cancer 2018;91:153-163.
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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): Anne Marie Clasina Dingemans
- 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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MA08 - Pawing the Way to Improve Outcomes in Stage III NSCLC (ID 127)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 1
- Now Available
- Moderators:Simon Ekman, Helena A Yu
- Coordinates: 9/08/2019, 15:15 - 16:45, Tokyo (1982)
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MA08.02 - Durvalumab Impact in the Treatment Strategy of Stage III Non-Small Cell Lung Cancer (NSCLC): An EORTC Young Investigator Lung Cancer Group Survey (Now Available) (ID 608)
15:15 - 16:45 | Author(s): Anne Marie Clasina Dingemans
- Abstract
- Presentation
Background
Stage III NSCLC represents a very heterogeneous population with extremely different treatment modalities including surgery, chemotherapy (CT) and radiotherapy (RT), mostly in combination. The results of the PACIFIC trial have now been reported in full including an overall survival (OS) benefit with durvalumab in addition to concomitant CT-RT. An electronic European survey was circulated to evaluate the impact of durvalumab in the staging and treatment strategy of stage III disease.
Method
A Young Investigator EORTC Lung Cancer Group survey containing 31 questions, was distributed between 31/01/18 and 31/03/19 to EORTC LCG and several European thoracic oncology societies’ members
Result
206 responses were analyzed (radiation oncologist: 50% [n=103], pulmonologist: 26.7% [n=55], medical oncologist: 22.3% [n=46]; 81.5% with >5 years experience in treating NSCLC). Italy (27.7%, n=57), Netherlands (22.8%, n=47), France (13.6%, n=28), and Spain (11.6%, n=24) contributed most. 83.5% (n=172) confirmed that they had access to durvalumab at the time of the survey. 97.6% (n=201) report that treatment decision is made by a multidisciplinary board. Regarding staging, 76.7% (n=158) support the need of a mediastinal pathological staging in case of suspect lymph-nodes, with a preference for EBUS/EUS (61.2%, n=126). 81.6% (n=168) treated more than half of patients with a concomitant CT-RT with the 1st cycle of chemotherapy in 39.7% (n=81). 95.1% consider durvalumab as practice changing, especially given the OS results (77.9%, n=152/195). 30% (n=119/395) will give patients concomitant CT-RT if PD-L1 >1%, and in borderline resectable cases 17.7% (n=70/395) will propose concomitant CT-RT instead of surgery. Durvalumab administration will be given regardless of PDL1 status in 13.1% (n=27) and 28.6% (n=59) would consider the possibility of a rebiopsy after CT-RT in case of negative PD-L1. 38.8% (n=80) foresee some problems with PD-L1 testing in this population due to availability of cytologic or small histologic samples. About 53.8% (n=105/195) normally will start durvalumab within 6 weeks after CT-RT and 48.5% (n=100) would also use durvalumab after sequential CT-RT
Conclusion
Durvalumab results are changing the treatment approach to stage III unresectable (and maybe resectable) NSCLC and planned strict adherence to the patient population as recruited to the PACIFIC study, was not demonstrated. This survey was released after the EMA approval of durvalumab and PD-L1 status seems to play a role in the treatment strategies, but surprisingly almost half of the clinicians will use durvalumab after sequential CT-RT without safety or efficacy data.
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OA08 - Advanced Models and "Omics" for Therapeutic Development (ID 133)
- Event: WCLC 2019
- Type: Oral Session
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Luis M Montuenga, Julie George
- Coordinates: 9/09/2019, 11:00 - 12:30, Interlaken (1988)
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OA08.02 - A Multidisciplinary Multi-Omics Study of Spatial and Temporal Tumor Evolution in Thoracic Cancers with Clinical Implications (Now Available) (ID 2365)
11:00 - 12:30 | Author(s): Anne Marie Clasina Dingemans
- Abstract
- Presentation
Background
In the context of the MESOMICS and lungNENomics projects1, we generated comprehensive molecular profiles of Malignant Pleural Mesothelioma (MPM)2 and pulmonary carcinoids (PCa)3. We showed that a continuous molecular model can better explain the prognosis of MPM than the three histologies, with strong differences in the expression of immune checkpoints and pro-angiogenic genes across samples. We also identified a new entity of PCa (supra-carcinoids) with carcinoid-like morphology yet the molecular and clinical features of LCNEC, which challenges the general believe that PCa have no relationship or genetic, epidemiologic, and clinical traits in common with LCNEC and SCLC. These two studies suggest an important role of heterogeneity in the biology of these tumors.
Method
Much progress has been made in revealing the evolutionary history of individual cancers, in particular using multi-region sequencing. However, most studies focused on a single ‘omic technique, and lacked temporal samples. Here we present the results of an innovative approach to study spatial and temporal tumor evolution based on (i) integration of whole-genome and transcriptome sequencing and EPIC 850K methylation arrays on multiple regions from 12 MPM, and (ii) a novel tumor-derived organoid-based strategy for studying the evolution of PCa.
Figure 1. Multi-omic multi-regional profiling of a MPM patient. A) Somatic Copy Number Variants (CNV), somatic Structural Variants (SV), kernel density plots of (top) somatic single nucleotide variants (SNVs) allelic fractions, (middle) expression normalized read counts, and (bottom) methylation array M-values. B) Projection of the transcriptomic profile of two tumoral regions into the Principal Component Analysis (PCA) space computed from 284 malignant pleural mesotheliomas2C) Expression (z-score of normalized read counts) for two clinically relevant genes with substantial inter-regional differences.
Biorepositories: French MESOBANK; LungNEN Network
Result
In the data analyses of the 12 MPM we detected significant intra-tumor heterogeneity (ITH) in the expression of immune checkpoints and pro-angiogenic genes (see example in Fig. 1). This might explain the modest and variable response to treatment in clinical trials assessing immunotherapies and antiangiogenic drugs. In the case of PCa, we are currently analysing the organoids genomic data and we will present the preliminary data for the temporal evolution of these diseases.
Conclusion
We found that our approach can detect clinically and biologically meaningful ITH. All the computational methods we developed for these evolutionary studies are available to the scientific community4.
1RareCancersGenomics.com
2Alcala et al., under review in Cancer Res
3Alcala et al., under review in Nat Commun
4https://github.com/IARCbioinfoLFC and MF co-supervised this work
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-120 - Immune Checkpoint Inhibitors Versus Second Line Chemotherapy for Patients with Lung Cancer Refractory to First Line Chemotherapy (Now Available) (ID 2662)
09:45 - 18:00 | Author(s): Anne Marie Clasina Dingemans
- Abstract
Background
Anti Programmed Death-ligand (PD1/PD-L1) directed immune-checkpoint-inhibitors (ICI) are widely used to treat patients with advanced non-small cell lung cancer (NSCLC) who progress after first line chemotherapy. The best strategy after early progression under first line has not been specifically studied
Method
We conducted a multicenter, retrospective study including all consecutive NSCLC patients progressing within the first 3 months following introduction of first-line chemotherapy and being treated with second line ICI monotherapy or chemotherapy between March 2010 and November 2017. We analysed the clinicopathological data and outcome under second line chemotherapy vs. second line ICI: progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).
Result
We identified 176 patients with refractory disease, 99 who received subsequent immunotherapy and 77 undergoing chemotherapy. The 2 populations were comparable regarding the main prognostic criteria, median age was 60, main histology was adenocarcimoma (68,2%). Compared to chemotherapy, ICI treated patients had a superior OS (logrank test, p=0.03) (Median [95% CI] OS 4.6 [2.8-6.7] versus 4.2 months [3.4-5.9] and a non-significant improvement in ORR (17.2% and 7.9%, respectively, p = 0.072). PFS was not significantly different (1.9 [1.8-2.1] versus 1.6 months [1.4- ; 2.0] (p=0.125). Poor performance status (ECOG PS≥2) and a higher number of metastatic sites (≥3) were associated with poorer prognosis. KRAS-mutated patients did not seem to benefit more from ICI than chemotherapy.
Table 1 Multivariable analysis of characteristics associated
n= 175
OS
PFS
Variable
HR [CI 95%]
p value
HR [CI 95%]
p value
Treatment
0.045
0.040
Chemotherapy (ref)
1.00
1.00
Immunotherapy
0.70 [0.49 ; 0.99]
0.71 [0.51 ; 0.98]
Number of metastatic location before 2nd line
0.005
0.011
0-1-2 (ref)
1.00
1.00
3 or +
1.64 [1.16 ; 2.31]
1.52 [1.10 ; 2.10]
Performance Status
0.038
0 -1
1.00
2 - 3 - 4
1.46 [1.02 ; 2.09]
Figure 1 : Kaplan Meier curves for Overall Survival for ICI group and CT group
Conclusion
ICI appears to be the preferred second-line treatment for patients who are refractory to first line chemotherapy
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P2.12 - Small Cell Lung Cancer/NET (ID 180)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.12-23 - Radiological Features of SCLC-Like and NSCLC-Like Large Cell Neuroendocrine Carcinoma (LCNEC) (ID 1587)
10:15 - 18:15 | Author(s): Anne Marie Clasina Dingemans
- Abstract
Background
Large cell neuroendocrine carcinoma (LCNEC) can be divided in two pathological subtypes: the SCLC-like LCNEC with RB1 mutations/loss of RB1 staining and the NSCLC-like LCNEC with preserved RB1 staining. The radiological presentations of NSCLC and SCLC are different, with SCLC mainly presenting with bulky disease and a central tumor. Here, we investigated if a distinction between SCLC-like and NSCLC-like LCNEC can be made based on radiological features.
Method
A survey was developed with chest CT-scans and X-rays of patients with pathological confirmed stage-IV LCNEC (N=52). For reference, images of 10 SCLC and 10 NSCLC patients were randomly included. The survey was distributed among oncology pulmonologists in the Netherlands. Responders could score images as ‘SCLC-like’, ‘NSCLC-like’ or ‘not possible to determine (nptd)’. Cases were considered as SCLC-like if no more than 1 responder scored NSCLC-like and no more than 67% scored ‘nptd’. A similar approach was used to classify NSCLC-like cases. Images not fulfilling both approaches were regarded not applicable (NA).
Result
The survey was completed by 23 pulmonologists with >5 years of experience, of which 12 had >15 years of experience. 90% NSCLC reference CT-scans were correctly classified, in contrast to only 30% correctly classified SCLC CT-scans (Table). For 36/52 LCNEC RB1 immunohistochemical status was known; 9/36 were RB1 positive and 27/36 RB1 negative. In RB1 positive LCNEC 6/9 scans were allocated to the NSCLC-like group. In RB1 negative LCNEC 2/27 scans were allocated to the SCLC-like group and 17/27 to the NSCLC-like group. If the scan was assessed as SCLC-like, RB1 was negative in 100% of cases. However, in cases assessed as NSCLC-like, only 26% was RB1 positive. No distinction between SCLC-like and NSCLC-like LCNEC could be made based on X-rays (Table).
Conclusion
In LCNEC, a CT-scan assessed as SCLC-like is highly predictive for RB1 negative status, whereas a NSCLC-like CT-scan can be both of the RB1 negative and positive subtype. During WCLC results including RB1 status of all 52 LCNEC will be presented.
