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Helena A Yu
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ES02 - Management of Oncogene Addicted Patients with Stage III NSCLC (ID 5)
- Event: WCLC 2019
- Type: Educational Session
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 4
- Now Available
- Moderators:Carlos Camps, Helena A Yu
- Coordinates: 9/08/2019, 10:30 - 12:00, Vancouver (2003)
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ES02.01 - Biomarker Testing in LA Disease (Now Available) (ID 3155)
10:30 - 12:00 | Presenting Author(s): Helena A Yu
- Abstract
- Presentation
Abstract
Routine biomarker testing in metastatic lung cancer has led to enormous improvements in outcomes for our patients with metastatic lung cancers. Oncogene testing has allowed us to identify the 50% of patients with metastatic lung cancer that are eligible for targeted therapies1. Consistently, targeted therapy for EGFR, ALK, ROS1, RET, BRAF have demonstrated superior progression-free survival compared to standard cytotoxic chemotherapy2. Identification of these genomic biomarkers has provided additional treatment options for our patients that are more effective and less toxic than standard treatments. In addition, serial biomarker testing allows us to also identify mechanisms of resistance to targeted therapy which can then inform subsequent treatment decisions. PDL1 testing is also routinely performed in the metastatic setting and assists us in identifying patients that may benefit from immunotherapy alone instead of first-line combination immunotherapy and chemotherapy treatment3. PDL1 testing allows us to predict likelihood of response to immunotherapy and selects patients that we can de-escalate treatment; patients with high PDL1 expression derive benefit from treatment with immunotherapy alone. Routine utilization of biomarker testing in metastatic lung cancer is easily the most importance advancement in this field to date.
Current recommendations
Biomarker testing for patients with locally advanced lung cancers is currently not recommended in the NCCN guidelines or any expert guidelines. This is likely because the current management for locally advanced lung cancers do not incorporate the use of biomarkers. Patients currently receive adjuvant durvalumab after concurrent chemoradiation for stage 3 disease irrespective of PDL1 status. Currently, adjuvant targeted therapies after definitive resection or radiation are not recommended in the NCCN or other cancer care guidelines.
Oncogene testing
The risk of recurrence for early stage lung cancers remain high. After surgical resection, adjuvant chemotherapy for high risk stage 1B, stage 3 and stage 4 and post-operative radiation for patients with mediastinal lymph node involvement are both recommended are they improve survival. Despite this, there is a large subset of patients that will have recurrent disease. Because of their demonstrated superiority over chemotherapy in the metastatic setting, there is great interest in assessing whether adjuvant targeted therapies would improve outcomes in the locally advanced disease setting. EGFR mutant lung cancer is the largest oncogene subset in which the bulk of previous studies have been done. However, all studies to date have been subsets of larger unselected patients (RADIANT study) or single arm studies (SELECT study). These smaller studies have shown a disease-free survival benefit but have been underpowered to demonstrate a survival benefit. There are several well-designed large studies ongoing that will definitively demonstrate whether adjuvant EGFR inhibitors improve overall survival. The ALCHEMIST study is a phase 3 randomized cooperative group study assessing erlotinib versus observation for patients with stage IB-IIIA resected lung cancers; accrual is ongoing. The ADAURA study is a randomized phase 3 study where patients with stage IB-IIIA resected lung cancers are randomized to osimertinib versus placebo for 3 years with a primary objective of DFS and a secondary objective of overall survival. These studies will help answer the question as to whether adjuvant targeted therapy should be utilized.
PDL1 testing
In stage 3 lung cancers, more than 60 percent of patients will ultimately die of their lung cancer4. Adjuvant durvalumab has improved outcomes with a clear improvement in overall survival but many patients still recur and ultimately die of their disease. An unplanned subset analysis of the PACIFIC study suggests that patients with PDL1 0% expression may not derive benefit from durvalumab. Further assessment will be needed to ascertain whether PDL1 expression can be used to select patients who would derive benefit from adjuvant durvalumab. Due to their efficacy in the metastatic setting, there are a significant number of studies looking at immunotherapy as both neoadjuvant and adjuvant treatment for locally advanced disease. Just as we utilize PDL1 as a biomarker that helps select appropriate therapies in the metastatic setting, I see similar use of PDL1 in the future in the locally advanced setting.
Future directions
As personalized medicine infiltrates our care of patients with lung cancers, we will need biomarker results for patients with locally advanced lung cancer to better tailor and personalize their care. In particular, if the EGFR TKI studies demonstrate improved overall survival with adjuvant EGFR TKI, we will certainly need to incorporate biomarker testing as standard of care for locally advanced disease. In addition, because a significant portion of patients recur, already having molecular test results available which were done on their surgical sample, makes their care later more stream-lined. We also need to assess whether PDL1 is a useful biomarker to select patients for immunotherapy in the adjuvant setting. Results from ongoing clinical trials will provide definitive answers.
Works cited:1. Jordan, E.J., et al. Prospective Comprehensive Molecular Characterization of Lung Adenocarcinomas for Efficient Patient Matching to Approved and Emerging Therapies. Cancer discovery 7, 596-609 (2017).
2. Sequist, L.V., et al. Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2013).
3. Reck, M., et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. The New England journal of medicine 375, 1823-1833 (2016).
4. Pisters, K.M., et al. Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline. Journal of clinical oncology 25, 5506-5518 (2007).Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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ES02.02 - Management of EGFR LA Disease (Now Available) (ID 3156)
10:30 - 12:00 | Presenting Author(s): Keunchil Park
- Abstract
- Presentation
Abstract
Management of EGFR mutation(+) Locally Advanced Non-Small Cell Lung Cancer
Keunchil Park, MD, PhD
Division of Hematology-Oncology, Samsung Medical Center,
Sungkyunkwan University School of Medicine, Seoul, Korea
The standard of care for the locally advanced non-small cell lung cancer(LA-NSCLC) is concurrent chemoradiotherapy(CCRT). Recently, the addition of consolidation immune checkpoint inhibitor following CCRT demonstrated improved outcome and is now recommended as the new standard of care for this heterogeneous group of LA-NSCLC patients. In advanced/metastatic setting EGFR mutation (+), NSCLC cancer patients define a unique subset with a dramatic response to the EGFR TKIs. Currently, molecular profiling of tumor tissue for EGFR mutations (as part of multiplex testing) is a routine procedure at the time of initial diagnosis of patients with recurrent or metastatic NSCLC. For advanced or metastatic EGFR mutant NSCLC patients EGFR TKI therapy is the treatment of choice and the median overall survival is > 30 months.
Despite the great success of EGFR TKI in metastatic NSCLC, the role of EGFR TKIs in LA-NSCLC is less well defined and controversial. Early clinical trials in unselected NSCLC patients failed to demonstrate the benefits of EGFR-TKIs as an adjuvant treatment. The first prospective randomized phase III trial to investigate the role of EGFR TKI in earlier stage NSCLC includes the SWOG 0023 study (J Clin Oncol 2008;26:2450-6) which failed to support the role of maintenance gefitinib (versus placebo) following definitive chemoradiation in unresectable stage III NSCLC. The CALGB 30106 phase II study also failed to show the benefits of adding gefitinib to sequential or concurrent chemoradiotherapy in unresectable stage III NSCLC (J Thorac Oncol 2010;5:1382-90). And the randomized prospective placebo-controlled adjuvant gefitinib trial in unselected patients with stage IB–IIIA resected disease (BR.19) was prematurely closed (J Clin Oncol 2013;31:3320-6). Another randomized double-blind trial in adjuvant NSCLC with tarceva (RADIANT) in patients with completely resected state IB to IIIA NSCLC whose tumors expressed EGFR protein by immunohistochemistry or EGFR amplification by fluorescence in situ hybridization did not show prolonged DFS (J Clin Oncol 2015;33:4007-14).
The prognostic or predictive value of EGFR mutation in early stage NSCLC patients is not well defined. In a retrospective single institutional analysis (J Thorac Oncol. 2012;7: 1815–1822), patients with resected stage I–III lung cancers and EGFR mutation have a lower risk of death compared to patients without EGFR mutation. There was a trend toward improvement in DFS among individuals with resected stages I to III lung adenocarcinomas harboring mutations in EGFR exon 19 or 21 who received adjuvant EGFR TKI therapy (J Thorac Oncol 2011;6:569–575).
There have been recently reported several prospective trials of adjuvant EGFR TKI in early stage NSCLC patients enriched with EGFR mutation.
CTONG1104 study (ADJUVANT), a randomized, open-label, phase III trial of adjuvant gefitinib for 24 months versus intravenous vinorelbine plus cisplatin for 4 cycles in patients with completely resected (R0), stage II–IIIA (N1–N2), EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg) NSCLC, demonstrated that adjuvant gefitinib compared to cisplatin-based chemotherapy significantly increases disease-free survival, diminishes toxic effects, and improves HRQoL in patients with completely resected stage II–IIIA EGFR-mutant NSCLC (Lancet Oncol 2018; 19: 139–48).
In the phase II SELECT trial, adjuvant erlotinib for 2 years in patients with resected stage IA to IIIA EGFR-mutant NSCLC after standard adjuvant chemotherapy with or without radiotherapy (J Clin Oncol 2019;37:97-104) showed an improved 2-year DFS. Patients rechallenged with erlotinib after recurrence experienced durable benefits.
There are also some neoadjuvant trials of EGFR TKI for locally advanced NSCLC.
RTOG 1306, a randomized phase II study of individualized combined modality therapy for stage III NSCLC (12-weeks of either erlotinib hydrochloride or crizotinib followed by chemoradiation therapy in stage III NSCLC with EGFR TK mutations or EML4- ALK fusion). The primary objective was to assess whether patients with unresectable LA-NSCLC treated with EGFR or ALK TK targeted agents based on molecular characteristics have a longer progression-free survival than those treated with standard care therapy alone. The study was, however, unfortunately prematurely terminated due to poor accrual (NCT01822496).
CTONG 1103 is an open-label, randomized trial that compared the efficacy and safety of erlotinib versus gemcitabine plus cisplatin neoadjuvant therapy in patients with exon 19 or 21 EGFR mutations and untreated resectable stage IIIA-N2 NSCLC. The study did not meet the primary end point of ORR with 42 days of neoadjuvant erlotinib, but the secondary end point PFS was significantly improved (J Clin Oncol 37. © 2019; published at jco.org on June 13, 2019: DOI https://doi.org/10.1200/JCO.19.00075)
There are also several ongoing clinical trials of EGFR TKIs in resected stage IB - IIIA NSCLC with activating EGFR mutations.
The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) is a prospective randomized double-blind placebo-controlled trial to investigate the benefits of the addition of molecularly targeted agents after standard postoperative chemotherapy in patients with resected NSCLC (Clin Cancer Res:2015; 21(24); 5439–44). It is worth noting that the primary objective for the ALCHEMIST adjuvant trials is overall survival (OS).
ADAURA, a randomized phase III trial (osimertinib vs. placebo in patients with stage IB-IIIA NSCLC, following complete tumor resection with or without adjuvant chemotherapy; NCT02511106) has been designed to assess the efficacy and safety of adjuvant osimertinib versus placebo in patients with resected stage IB-IIIA EGFR mutation-positive (Ex19Del or L858R) NSCLC. The primary efficacy objective is DFS.
In brief, many neoadjuvant/adjuvant EGFR TKI trials in earlier stage of NSCLC have demonstrated its safety and feasibility with an improved DFS esp. in EGFR mutation(+) LA-NSCLC. However, the real question should be “Can we improve the ‘overall survival’ and thus ultimately the ‘cure rate’ of locally advanced NSCLC with EGFR mutation?” In order to address this issue, there remain several critical questions to be answered, e.g., who is most likely to benefit from adjuvant EGFR TKI, what is the optimal duration of adjuvant TKI, what is the best regimen, etc. Whether the earlier introduction of EGFR targeted therapy in less advanced NSCLC would lead to improved ‘Cure Rate’ remains to be seen in future prospective trials in a larger number of EGFR mutation(+) patients.
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ES02.03 - Management of Other Non EGFR Oncogene Addicted Tumors (Now Available) (ID 3157)
10:30 - 12:00 | Presenting Author(s): Charu Aggarwal
- Abstract
- Presentation
Abstract
Stage III non-small cell lung cancer accounts for heterogeneous group of diseases, due to differences in tumor size, location number of nodes involved, and lymph node station involved. Stage III non-small cell lung cancer comprises 2 distinct stages, stage IIIA and IIIB disease that have different prognosis, and are usually treated differently. Approximately 15% of all patients with newly diagnosed non-small cell lung cancer present with stage III disease. Options for stage III non-small cell lung cancer include surgery, with lobectomy or pneumonectomy depending on the tumor stage, and lymph node involvement. Chemotherapy may be administered in the neoadjuvant, concurrent or adjuvant setting. Radiation therapy can be given in a concurrent, sequential approach, or may be administered in the postoperative fashion. Combination approaches are often used, and due to the significant need of multi-modality therapy, treatment decisions are usually made in a multidisciplinary setting. The optimal therapeutic approach for patients with stage IIIA non-small cell lung cancer remains controversial. For subset of patients with T3 to T4 N0-1 disease, and superior sulcus location, surgery remains a viable and preferred option. However, the optimal treatment for patients with stage III A, with bulky lymph node involvement, or multi station lymph node involvement including N2 disease, remains an area of ongoing controversy. Tri-modality approaches using preoperative chemotherapy, or upfront chemoradiation therapy followed by surgery have been evaluated (1). For patients with surgically unresectable, or medically inoperable disease, concurrent chemoradiation therapy has been established as the standard of care for patients spanning the spectrum of stage IIIA and IIIB disease.
Recently, the PACIFIC trial demonstrated an improvement in progression free survival and overall survival with the administration of durvalumab as consolidation therapy (regardless of PDL-1 status) for patients who had not progressed after 2 or more cycles of definitive concurrent platinum-based chemoradiation therapy (2, 3). This approach represents a new paradigm in the management of unresectable NSCLC, and has now been adopted as standard of care.
Management of Stage III patients with non EGFR oncogene addicted tumors is an area of active research. ALK or ROS directed oral tyrosine kinase inhibitors (TKIs) are not typically administered in the adjuvant setting outside of a clinical trial. There are several trials evaluating the use of targeted therapies. ALINA, is one such trial, that is a phase III study of alectinib versus chemotherapy as adjuvant therapy in patients with stage IB–IIIA anaplastic lymphoma kinase-positive ALK positive NSCLC (4). Another study is comparing adjuvant alectinib versus adjuvant platinum-based chemotherapy in patients with ALK positive NSCLC, here the alectinib is administered for 2 years (NCT 03456076). The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing (ALCHEMIST) trial is actively enrolling patients with operable NSCLC and will perform genetic screening of their tumors. Patients with EGFR mutation or ALK gene rearrangement in their tumor will be randomized to placebo versus erlotinib or crizotinib, respectively (NCT02194738). We await the results of these trials prior to routine incorporation of molecularly directed therapy in the management of locally advanced disease.
References:
1. Albain KS, Swann RS, Rusch VW, Turrisi AT, 3rd, Shepherd FA, Smith C, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009;374(9687):379-86. Epub 2009/07/28. doi: 10.1016/S0140-6736(09)60737-6. PubMed PMID: 19632716; PubMed Central PMCID: PMC4407808.
2. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. The New England journal of medicine. 2017;377(20):1919-29.
3. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. 2018; 379:2342-2350
4. Solomon BJ, Ahn JS, Barlesi F et al. ALINA: A phase III study of alectinib versus chemotherapy as adjuvant therapy in patients with stage IB–IIIA anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC). J Clin Oncol 37, 2019 (suppl; abstr TPS8569)
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ES02.04 - Concurrent, Sequential and Combination Immunotherapy Regimens in LA-NSCLC (Now Available) (ID 3158)
10:30 - 12:00 | Presenting Author(s): Mariano Provencio
- Abstract
- Presentation
Abstract
Immunotherapy in Oncogenic-Addicted Stage III Patients
At diagnosis of non small cell lung cáncer (NSCLC), at least 40% of patients are diagnosed at an advanced stage and a third locally advanced disease (stage III). The results of stage IIIA with induction treatment of clinical practice outside the clinical trial show a median survival of 22 months and a 3-year survival rate of 34%. Concurrent definitive chemoradiation has been established as the standard of care for unresectable stage IIIB (N3 disease) NSCLC, with a median overall survival (OS) of approximately 17 months. Strategies that have been investigated include induction chemotherapy, immunotherapy (IO), concomitant chemoradiotherapy, intensified radiotherapy and adjuvant treatment.
The role of IO in NSCLC with oncogenic-addicted tumors is so far unclear. In EGFR-mutation positive patients there seems to be a worse effect of IO compared to those patients without actionable mutations,; nevertheless, no safe conclusions can be drawn due to the lack of randomized trials addressing this clinical issue. The available information from second lines with IO in patients with actionable mutations, is currently found in 2 meta-analyses[1].
These meta-analyses show OS benefit between EGFR wild-type vs mutated patients with a Hazard Ratio (HR) of 0.67, p< 0.001, consistent in all the trials. There was no OS advantage for those with EGFR mutant tumors, with a HR of 1.11, p=0.54.
Of note, data from other studies were not included in these meta-analyses. Study CA209-012 showed patients with EGFR mutation, overall response rate (ORR) 14% mutated vs 30% in wild type and PFS at 24 weeks: 14% vs 51% respectively[2].
In KEYNOTE-001, best ORR based on mutation status was 15.8% in patients with EFGR mutation vs 37.1% without mutation, and 60% were unknown. Overall PD-L1 subgroups, EGFR mutated patients had lower ORR than patients with EGFR-wild type tumors. ORR was 20 % in TPS > 50% and 0% in patients with TPS<1% vs 12.7% in EGFR wild type[3]. An update of this study, and median OS in patients with EGFR mutation was 6 months (mo) (95%CI, 4.4-8.8) and 12 mo (95%CI, 9.2-14.3) in patients wild-type[4].
In the Immunotarget Cohort study, patients with EGFR-mutation had response rates of 12% and PFS of 2.1 mo and with a positive correlation in patients with high expression of PDL1 and response.
The BIRCH[5] study, also not included in the meta-analyses, provides us with similar information, with higher response rates in patients with higher expression of PDL1 (31% vs 23%), even achieving similar PFS to wild type patients (7.6 vs 7.7 mo) or OS with 28.5 mo (20.1, NE) in mutant vs 20.1 mo (15.5, 31.1) in wild-type. The phase II ATLANTIC trial testing durvalumab as third-line treatment included the largest cohort of EGFR mutant patients treated with IO after progression of TKI and chemotherapy. According to PD-L1 expression (< 25% or ≥ 25%), durvalumab achieved a response rate (RR) of 3.6% and 14.1%, a similar median PFS 1.9 months and a median OS of 9.9 months and 13.3 months, respectively[6].
Despite improvements in the treatment of stage IV NSCLC with the introduction and dissemination of checkpoint inhibitors, very little progress has been made in the treatment of stage III. The PACIFIC trial was the first study to show a clear benefit for the approach. Patients were enrolled regardless of PD-L1 expression, and those with EGFR mutations were also eligible. The subgroup of patients with EGFR mutations did not clearly benefit from durvalumab maintenance. These patients were equally represented in the durvalumab (6%) and placebo (5.9%) arms. The HR was 0.76 in this setting, and whether because of a small sample size or true lack of efficacy, the findings were not significant (95% CI, 0.35–1.64).
In NADIM Study, a Phase II, with neoadjuvant chemotherapy and immunotherapy in stage III, unprecedented pCR rates observed (around 70%) and with down-staging around 90%. We did not include patients with actionable mutations, and we do not have information about other trials using chemo and IO. In KN 189 using combination of chemo and IO in stage IV, no sensitizing EGFR or ALK alteration were included. In the ImPOWER 150 study[7] comparing the use of bevacizumab plus atezolizumab plus carboplatin, plus paclitaxel versus carboplatin plus paclitaxel plus bevacizumab in first-line stage IV, provides interesting results in PFS, with a HR of 0.41 (95% CI: 0.22-0.78), in patients with common mutations (already treated with TKIs) in the arm with atezolizumab plus chemo better than the control arm.
In the light of these results, we may conclude that other biomarkers such as a tumor mutational burden (TMB) could be used in the future, but low TMB is especially significant among the oncogenic alterations strongly related with never-smokers, such as EGFR mutation and ALK rearrangements. Therefore, these data suggest a role for actionable mutations testing in the stage III setting and for additional trials specifically targeting EGFR-mutant patients and stage III disease.
[1] Lee CK, Man J, Lord S et al. Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non-small cell lung carcinoma.A systematic review and meta-analysis. JAMA Oncol 2017
[2] Gettinger S, Chow LQ, Borghaei H et al. Nivolumab monotherapy for first-line treatment of advanced non-samll cell lung cancer. JCO, DOI: 10.1200/JCO.2016.66.9929.
[3] Hellman M et al. Efficacy of pembrolizumab in key subgroups of patients with advanced NSCLC. 16th World Conference on Lung Cancer, 2015.
[4] Leighl NB, Hellamn MD, Hui R, et al. KEYNOTE-001: 3-year overall survival for patients with advanced NSCLC treated with pembrolizumab. ASCO 2017.
[5] Carcereny E, Felip E, Reck M, et al. Updated efficacy results from the BIRCH study: First-line atezolizumab therapy in PD-L1 –selected patients with advanced NSCLC. World Conference on Lung Cancer 2017.
[6] Garassino MC, Cho B-C, Kim J-H, Mazières J, Vansteenkiste J, Lena H, et al. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Lancet Oncol 2018;19:521–36.
[7] Socinski M, Jotte RM, Capuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. NEJM DOI: 10.1056/NEJMoa176948.
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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: 12
- Now Available
- Moderators:Simon Ekman, Helena A Yu
- Coordinates: 9/08/2019, 15:15 - 16:45, Tokyo (1982)
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MA08.01 - Analysis of PD-L1 Expression on Circulating Stromal and Tumor Cells in Lung Cancer Patients Treated with Chemoradiation Therapy and Atezolizumab (Now Available) (ID 2965)
15:15 - 16:45 | Presenting Author(s): Steven H Lin | Author(s): Alexander Augustyn, Jianzhong He, Yawei Qiao, Zhongxing Liao, Ashvathi Raghavakaimal, Kirby Gardner, John Victor Heymach, Anne Tsao, Daniel Adams
- Abstract
- Presentation
Background
We have previously shown dynamic changes to PD-L1 expression during chemoradiotherapy (CRT) could be tracked by evaluating PD-L1 expression on circulating cells. How these changes relate to immunotherapy response is unknown. We prospectively monitored PD-L1 expression in 2 cell types found in circulation (Circulating tumor cells [CTCs] and Cancer Associated Macrophage-like Cells [CAMLs]) in locally advanced non-small cell lung cancer (LA-NSCLC) patients (pts) treated with atezolizumab and CRT.
Method
Samples were taken from a completed phase II DETERRED trial (NCT02525757) where atezolizumab was added for one year after completing CRT (N=10) or concurrently and after CRT (N=30). Samples from 39 pts from the study were available for analysis. Baseline blood sample (7.5 ml) were drawn prior to start of CRT (T0), and a second sample was drawn ~1 month after completing CRT (T1), and a 3rd sample was drawn ~2 months after completing CRT (T2). Blood was processed by CellSieve™ microfilters; stained for cytokeratin/PDL1/CD45 to identify CTCs and CAMLs. PD-L1 intensity was measured and grouped by 4 scores: 0-negative, 1-low, 2-medium, & 3-high. Tumor IHC for PD-L1 levels from core biopsies was done with Dako 22c3 and was compared to T0 samples. PD-L1 levels from tumor and in circulating cells were used to evaluate PFS and OS. Significance was assessed by log-rank testing.
Result
PD-L1 IHC was available for 85% of pts, and there was at least one cytokeratin positive cell (CTC or CAML) found in 100% of T0 samples. CTCs were found in 33% of T0, 24% of T1 & 43% T2. CAMLs were found in 92% of T0, 97% of T1, & 97% of T2 samples. No correlation was seen comparing tumor PD-L1 expression percentage and the T0 PD-L1 staining intensity on CTCs/CAMLs. Tumor PD-L1>1% was found in 58% and >50% in 24% of IHC samples, yet there was no correlation between tumor PD-L1 expression and PFS or OS. At T0, PD-L1 expression in CTCs/CAMLs was low (0-1) in 18 pts and high (2-3) in 15, but no relationship to PFS (HR=0.6, 95%CI 0.2-1.7, p=0.48) or OS (HR=1.7, 95%CI 0.5-6.4, p=0.66) was found. However, pts with high PD-L1 at T1 or T2, regardless of levels at T0, had a trend towards improved PFS (HR 2.5, 95%CI 0.7-8.6, p=0.13), and a significantly better OS (HR 14.2, 95%CI 2.4-81.8, p=0.003). Interestingly, of the 15 pts who had low PD-L1 at T0, 7 had induced PD-L1 expression at T1 or T2. All samples with induced PD-L1 expression had better PFS (HR 8.3, 95%CI 1.4-50.2, p=0.02) and OS (HR 8.7, 95%CI 1.2-64.0, p=0.03) compared to those who remained low.
Conclusion
While baseline tumor or circulating cellular PD-L1 expression was not correlated with clinical outcomes, sequential monitoring of high PD-L1 expression in CTCs/CAMLs after CRT appeared to be associated with better clinical outcomes in pts who received consolidation atezolizumab after CRT, particularly in pts who had induced expression at follow up during the consolidation phase. Dynamic tracking of PD-L1 may serve as a predictive biomarker for immunotherapy effectiveness in LA-NSCLC after CRT.
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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 | Presenting Author(s): Matteo Giaj Levra | Author(s): Justin Benet, Baktiar Hasan, Thierry Berghmans, Alessio Bruni, Anne Marie Clasina Dingemans, Niccolo' Giaj Levra, John G Edwards, Corinne Faivre-Finn, Nicolas Girard, Elisa Gobbini, Laurent Greillier, Lizza Hendriks, Sylvie Lantuejoul, Antonin Levy, Silvia Novello, Mary O'Brien, Martin Reck, Alessia Pochesci, Jessica Menis, Benjamin Besse
- 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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MA08.03 - Adjuvant Pembrolizumab in N2 Positive NSCLC Treated with Concurrent Chemoradiotherapy Followed by Surgery: Phase II, Prospective Study (Now Available) (ID 1744)
15:15 - 16:45 | Presenting Author(s): Sehhoon Park | Author(s): Hyun Ae Jung, Jong Ho Cho, Jong-Mu Sun, Hong Kwan Kim, Se-Hoon Lee, Yong Soo Choi, Jin Seok Ahn, Jhingook Kim, Keunchil Park, Jae Ill Zo, Young Mog Shim, Myung-Ju Ahn
- Abstract
- Presentation
Background
The standard treatment option for stage IIIA-N2 subgroup is still under discussion with controversies. We hypothesize that immune checkpoint inhibitor consolidation therapy could have an additional role in prolongation of the disease-free survival (DFS) for stage IIIA-N2 NSCLC treated with tri-modalities therapy.
Method
This is a phase 2 study evaluating the clinical efficacy of pembrolizumab treatment after CCRT with curative resection in stage IIIA-N2 NSCLC pts (NCT03053856). Pathologically confirmed pts were treated with five cycles of CCRT, weekly paclitaxel (50mg/m2) and cisplatin (25mg/m2) combined with radiotherapy (total of 44Gy over 22 fractions) followed by curative resection. Adjuvant Pembrolizumab (200mg fixed dose) is applied every three weeks up to 2 years or until disease recurrence. The primary objective is disease-free survival of more than 20 months. The first patient was recruited in October 2017, and the data for this abstract was locked at 20th of January, 2019.
Result
Total of 40 pts were screened, and 37 pts received treatment. Median age was 64 years (range 39-74), and twenty-three pts were male (62.2%). As a curative surgery, pts received lobectomy (n=34), bi-lobectomy (n=2), or pneumonectomy (n=1). Adenocarcinoma was predominant (n=27, 73.0%). After the neoadjuvant CCRT, down-staging were observed in nine pts (24.3%). The median follow-up duration was 10.6 months (range 3.1-17.2), and pts received a median of 11 cycles (range 1-22) of adjuvant pembrolizumab. DFS is not reached. Fourteen patients discontinued treatment due to disease progression (n=9), adverse events (n=4) and withdraw consent (n=1). There was a case of grade 4 pneumonitis and a case of grade 3 autoimmune hepatitis which lead to discontinuation of the treatment. Otherwise, grade 1-2 hypothyroidism (n=6), pneumonitis (n=5), skin rash (n=3) were observed. Patients with severe immune-related adverse event showed a significantly high percentage of Ki-67 + cells among CD8 T-cells in peripheral blood.
Conclusion
This study is the first study to demonstrate the feasibility of adjuvant pembrolizumab monotherapy in stage IIIA-N2 patients. Updated clinical outcome will be presented at the conference.
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MA08.04 - Discussant - MA08.01, MA08.02, MA08.03 (Now Available) (ID 3744)
15:15 - 16:45 | Presenting Author(s): Delvys Rodriguez-Abreu
- Abstract
- Presentation
Abstract not provided
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MA08.05 - A Multi-Center Analysis of Right vs Left-Sided Pneumonectomy Following Induction Therapy (Now Available) (ID 1178)
15:15 - 16:45 | Presenting Author(s): Chi-Fu Jeffrey Jeffrey Yang | Author(s): Nicholas R Mayne, Athar Battoo, Sai Yendamuri, Todd Demmy, Robert McKenna, Thomas A D’amico, Mark Berry
- Abstract
- Presentation
Background
Previous single-center studies of pneumonectomy following induction therapy for non-small-cell lung cancer (NSCLC) have found a significant perioperative risk associated with right-sided pneumonectomy. We examined the impact of laterality on long-term survival after induction therapy followed by pneumonectomy in a multi-institutional analysis.
Method
Perioperative and long-term outcomes of patients with NSCLC who underwent pneumonectomy following induction chemotherapy with or without radiation from 2000-2016 across 3 institutions were evaluated using multivariable logistic regression, Cox proportional hazards modeling and propensity score-matched analysis. Patients who underwent a completion pneumonectomy or who had M1 disease were excluded from the analysis.
Result
During the study period, 172 patients (right n = 78 [45%], left n = 94 [55%]) met inclusion criteria. Right-sided pneumonectomy was associated with a similar perioperative complication rate (38% [30/78] vs 27% [25/94], p=0.10), and 30-day (13% [10/78] vs 9% [8/94], p=0.36) and 90-day mortality (23% [18/78] vs 13% [12/94], p=0.08) when compared to left-sided pneumonectomy. In multivariable analysis, right-sided pneumonectomy was not found to be a predictor of higher perioperative complications (OR 0.85 [95% CI: 0.33-2.14], p=0.73) or 30-day (OR 2.06 [95% CI: 0.44-9.69], p=0.36) and 90-day mortality (OR 2.06 [95% CI: 0.54-7.88], p=0.29). Overall survival between right and left pneumonectomy was not significantly different in unadjusted (5-year survival 30% [95% CI: 19%-41%] vs 29% [95% CI: 20%-39%], log-rank p=0.77 [Figure]) or multivariable analysis (adjusted hazard ratio, 1.05 [95% CI: 0.63-1.76], p = 0.84). A propensity score-matched analysis of 108 patients balancing baseline characteristics—including pulmonary function, tumor size and stage—was also performed, and found no significant differences in perioperative complication rates (46% [25/54] vs 48% [26/54], p=0.85), 30-day (17% [9/54] vs 7% [4/54], p=0.14) and 90-day mortality (26% [14/54] vs 13% [7/54], p=0.09) between right versus left pneumonectomy, respectively. Overall survival was not significantly different between right- and left-sided pneumonectomy (5-year survival 33% [95% CI: 20%-47%] vs 28% [95% CI: 16%-41%], log-rank p=0.98).
Conclusion
In this multi-center analysis, right-sided pneumonectomy after induction therapy was not associated with significantly higher perioperative mortality rates or worse long-term survival when compared to a left-sided pneumonectomy.
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MA08.06 - Perioperative Outcomes of Lung Cancer Patients with Interstitial Pneumonia (Now Available) (ID 1372)
15:15 - 16:45 | Presenting Author(s): Aki Katarina Kobayashi | Author(s): Yu Okubo, Masaya Yotsukura, Yukihiro Yoshida, Kazuo Nakagawa, Noriko Motoi, Shun-ichi Watanabe
- Abstract
- Presentation
Background
Interstitial lung disease is mostly found in elderly male smokers who also have relatively high risks of developing lung cancer. For these patients, modality to treat malignancy is limited to prevent acute exacerbation of interstitial pneumonia. We analyzed the perioperative outcomes of this group of patients with both interstitial pneumonitis and resectable lung cancer with curative intent.
Method
We retrieved the characteristics and medical courses of consecutive patients who had undergone pulmonary resections from medical records. In this analysis, usual interstitial pneumonia (UIP) was characterized by the presence of basal predominant, subpleural reticular abnormalities with traction bronchiectasis and honeycomb cysts detected in bilateral lung field on chest computed tomography preoperatively. Pathological findings on surgical specimen were used confirmation of diagnosis. The incidence and outcomes of acute exacerbation within 30 days from operation were analysed.
Result
From 2015 to 2017, there were 1,477 patients who underwent pulmonary resection for primary lung cancer at our institute. Among them there were 81 (5.5%) patients diagnosed as UIP by specific findings on chest computed tomography. Of 81 patients evaluated, 68 (84.0 %) were men, the median age was 73 years (range, 55-88). For Eastern Cooperative Oncology Group (ECOG) performance status, all 81 patients were categorized in status 0. Seventy-four patients (91.4%) underwent lobectomy, 1 (1.2%) bi-lobectomy, 2 (2.5%) segmentectomy and 4 (4.9%) wide wedge resections for primary lung cancer. The mean duration of surgery was 129 mins (range, 54-316), and mean value for blood loss was 36.5 ml (range, 0-396). A complete resection (R0) was achieved in 79 cases (97.5%). Postoperative complications were observed in 19 patients (23.5%) including prolonged air leakage (n=4, 4.9%), late onset of air leakage (n=3, 3.7%), surgical site infection, chylothorax and cerebral infarction. Nine patients (11.1%) manifested acute exacerbation of interstitial pneumonia within 30 days after surgery. There were 3 post-operative deaths (3.7%) within 30 days after surgery. Two deaths (2.5%) were due to acute exacerbation of interstitial pneumonia and 1 (1.2%) case of SAH on 1POD.
Conclusion
Pulmonary resection for patients with interstitial lung disease led to 9 (11.1%) cases of acute exacerbation within 30 days from surgery. Mortality related to acute exacerbation was found only 2 cases (2.5%) at our hospital, which was tolerable postoperative outcome for pulmonary resection for lung cancer with curative intent.
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MA08.07 - The Concordance Between Patient Reported Outcomes and Clinician Reported Outcomes During Radiotherapy in Lung Cancer Patients (Now Available) (ID 2507)
15:15 - 16:45 | Presenting Author(s): Evalien Veldhuijzen | Author(s): Iris Walraven, Margriet Kwint, Laura Roose, José Belderbos, Tomas Janssen
- Abstract
- Presentation
Background
Capturing information on toxicity in (non-)small cell lung cancer patients receiving radiotherapy or chemoradiotherapy, is crucial for optimal symptom management. Patient Reported Outcomes (PROs) have the potential to improve toxicity detection by adding direct information from the patient perspective. The aim of this study is therefore to determine the predictive and additional value of PROs on prospectively scored clinician reported toxicity.
Method
An observational study was performed in lung cancer patients (n=111) treated with (chemo)radiation with curative intent. The EORTC QLQ-C30 and the EORTC LC-13 questionnaires were used to score PROs on a scale of 0-100 for a selection of commonly occurring toxicities (i.e. dysphagia, dyspnea, anorexia, fatigue, cough and nausea). Clinicians prospectively scored the maximum toxicity during, and at the end of treatment using the Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0. Receiver operating characteristic (ROC) curves were constructed to evaluate the performance (i.e. discrimination) of PROs on predicting clinician scored CTCAE toxicity (grade ≥2). Furthermore, cut-off points were determined from the ROC-curve on the basis of the best trade‐off values between sensitivity and specificity (0,5). Validity of the model was assessed with the ability to predict the number of grade ≥2 toxicities (calibration).
Result
Assessment of predictive performance in our cohort demonstrated a good fit for anorexia (AUC: 0,810 95% CI 0,699 to 0,921) and dysphagia (AUC: 0,828 95% CI 0,743 to 0,914) with sensitivity scores of 85,7%, 67,4% and specificity scores of 74,0% and 92,6% respectively. Both dyspnoea (AUC: 0,765 95% CI 0,60 to 0,910) and nausea (AUC: 0,745, 95% CI 0,548 to 0,942) showed a fair fit with sensitivity score of 74,1% for both toxicities and specificity of 69,1% and 68,3% respectively. A poor fit was found for cough (AUC: 0,667 95% CI 0,495-0,839) with a sensitivity of 55,6% and specificity of 30,4%. The model failed to discriminate for fatigue (AUC: 0,507 95% CI 0,368-0,645). Calibration showed that clinician based CTCAE toxicities substantially underestimated all PRO-based toxicities.
Conclusion
This study has identified that patient reported toxicities and clinician reported toxicities do not always concord. Only anorexia and dysphagia showed good agreement, while for the other toxicities, the agreement was only fair to poor. Furthermore, we showed that clinicians substancially underreport the existence of toxicities. This study adds to the growing body of evidence indicating the potential beneficial role of using PRO-based toxicity reporting in clinical cancer care for lung cancer.
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MA08.08 - Discussant - MA08.05, MA08.06, MA08.07 (Now Available) (ID 3745)
15:15 - 16:45 | Presenting Author(s): Norihiko Ikeda
- Abstract
- Presentation
Abstract not provided
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MA08.09 - Results of Trimodality Therapy for Patients with cN2 Lung Cancer Diagnosed by Video-Assisted Mediastinoscopic Lymphadenectomy (VAMLA) (Now Available) (ID 1295)
15:15 - 16:45 | Presenting Author(s): Sergi Call | Author(s): Carme Obiols, Ramon Rami-Porta, Silvia Catot, Miriam Nuñez, Marc Campayo, Francisco Perez Ochoa, Mireia Serra-Mitjans, Jose Belda-Sanchis
- Abstract
- Presentation
Background
After a properly performed transcervical lymphadenectomy, invasive restaging of the mediastinum is unnecessary because there is no material left for a new biopsy. Therefore, when video-assisted mediastinoscopic lymphadenectomy (VAMLA) is used at primary staging, the only parameters to select patients for lung resection after induction therapy are: the stability of the primary tumor and the absence of extrathoracic disease assessed by PET-CT. The aim of this study is to analyze the results of those patients with cN2 NSCLC diagnosed by VAMLA who underwent trimodality treatment in terms of feasibility and survival.
Method
Prospective observational single-center study of 250 patients (206 men; median age, 65.7; range, 42-86) with NSCLC cN0-1 (by PET-CT) who underwent VAMLA from 01-2010 to 12-2017. Patients with cN2 diagnosed by VAMLA who underwent trimodality treatment (cisplatin-based chemotherapy concomitant with radical radiotherapy [mean 54Gy, range 40-70Gy] plus lung resection) were analyzed. Follow-up was completed in March 2019. Median follow-up for surviving patients was 39.5 months (range, 8-108). Survival analysis was performed by the Kaplan-Meier method; the log-rank test was used for comparisons. Patients who died within 90 days after resection were excluded from survival analyses. A p-value of less than 0.05 was considered significant. The IBM SPSS Statistics for Mac, version 20.0 was used.
Result
The rate of unsuspected N2-3 disease in the whole series was 14.5% (35 patients). 28 patients out of 35 were considered for trimodality treatment. The results of restaging based on the PET-CT were: disease progression in 8 (28.5%) (mostly distant metastases), and stability of the primary tumor or partial response in 20 patients (71.5%). Of 20 patients without progression, 13 (46.5%) underwent lung resection; the remaining 7 were considered unfit for surgery. Three- and 5-year survival rates for those candidates for chemoradiotherapy (n=28) were: 91.7% and 80.2%, respectively, for patients in whom complete lung resection was achieved; 34.3% and 0%, respectively, for those considered unfit for surgery; and 19% and 0%, respectively, for those with progression after chemoradiotherapy (p < 0.0001)(Figure 1).
Conclusion
The use of VAMLA to select patients for trimodality treatment is feasible. Based on the results obtained (high rate of unsuspected cN2 diagnosed by VAMLA and prolonged survival of those patients in whom the trimodality treatment was accomplished), VAMLA should be included in the current staging algorithms, especially for those tumors with intermediate risk of N2 and normal mediastinum by PET-CT.
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MA08.10 - Early and Late Outcomes After Surgery for pT4 NSCLC Reclassified by AJCC 8<sup>th</sup> Edition Criteria (Now Available) (ID 2941)
15:15 - 16:45 | Presenting Author(s): Jack G Mouhanna | Author(s): Amit Katz, Pierre O Fiset, Roni F Rayes, Aya Siblini, Emma Lee, Andrew Seely, Christian Sirois, David Mulder, Jonathan Cools-Lartigue, Lorenzo E. Ferri, Jonathan D. Spicer
- Abstract
- Presentation
Background
Classically, T4 non-small cell lung cancers (NSCLC) are tumors of any size that have features of local extension often precluding surgical resection or necessitating complex extended pulmonary surgery. However, the new AJCC 8thedition includes tumors greater than 7cm regardless of adjacent organ extension. The early perioperative outcomes from T4 resections must be contextualized to the increasingly heterogeneous classification offered by the new staging system. Our goal was to examine perioperative and long-term outcomes from pT4 resections based on the AJCC 7thedition versus those of the expanded criteria of the 8thedition.
Method
This is a retrospective study of pT4 surgical resections at the Montreal General Hospital from 2011-2018. Data was analyzed using GraphPad Prism and SPSS.
Result
We identified 158 patients with pT4 tumors based on AJCC-8: 40 by AJCC-7 criteria (Group1) and 118 with tumors >7cm considered pT4 in AJCC-8 (Group2). Demographics and clinical characteristics are detailed in Table 1. The incidence of major complications (grade 3 or 4) was similar in both cohorts (17.5% in Group1 and 13.6% in Group2; p=0.37), with 3.8% in-hospital mortality (7.5% in Group1 and 2.5% in Group2; p=0.16). Overall survival was 76% at 1 year, 44% at 3 years and 34% at 5 years. Median overall survival was 27 months and was similar between Group1 and Group2 (25.8 and 27.4 months, respectively p=0.7). Nevertheless, Group2 had better peri-operative survival than Group1: 99% vs 92% 90-day mortality (p=0.02) and 95% vs 83% 6-month mortality (p<0.01). Finally, Kaplan-Meier curves adjusted for predictors of survival with Cox regression analysis show early mortality in Group 1 with equalization of the curves at 1 year (Figure 1).
Conclusion
While long-term oncological outcomes are similar for pT4 >7cm to those of AJCC-7 pT4 patients, differences in perioperative outcomes point to the heterogeneity of the new AJCC-8 classification with regards to surgical management.
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MA08.11 - SLCG SCAT Trial: Surgical Audit to Lymph Node Assessment Based on IASLC Recommendations (Now Available) (ID 2252)
15:15 - 16:45 | Presenting Author(s): Jose Ramon Jarabo Sarceda | Author(s): SERGIO Bolufer, Roberto Mongil, Pedro Lopez De Castro, RAMON Moreno, JUAN CARLOS PeÑalver, Raúl Embún, Joaquín Pac, Francisco Javier Algar, Pablo Gámez, Marcelo Jiménez, Gabriel Sales, Eva Pereira, Bartomeu Massuti, Mariano Provencio, Florentino Hernando-Trancho
- Abstract
- Presentation
Background
The Spanish Lung Cancer Group (SLCG) developed a multicenter trial in which completely resected pathological N positive NSCLC patients received different schemes of adjuvance based on level of tumoral BRCA expression (SCAT trial). We assess here surgical topics, with an in-depth analysis of quality of lymphadenectomy based on IASLC recommendations, evaluating their effect on survival.
Method
Phase-III SLCG-SCAT trial included patients with completely resected (R0) NSCLC with pathological hilar and/or ipsilateral mediastinal lymph node (LN) involvement. Patients from SLCG-SCAT trial in which complete pathologic report with information about mediastinal lymph node dissection was available (including number of lymph nodes assessed and involved by tumor in each hilar and mediastinal region), were included for our study. We also analyzed data about estimated overall survival (OS) and disease-free survival (DFS). All patients underwent surgical resection in high-volume departments of thoracic surgery.
Result
Lymph node assessment
From the whole series (451 patients), in 33.7%, 17.7% and 49.9% of cases, regions 7, 10 and 11 respectively were not assessed. No lymph nodes were biopsied from region 8, 9 and 12 in 80%, 61.9% and 91.1% of cases, respectively. Region 10 was that with the higher number of lymph nodes resected (medium 4.64). From them, 27.9% were involved by tumor. Median assessed mediastinal regions was 4. In 21.1% of patients, lymph nodes from only one or two regions were obtained. In most of the patients (91.8%), one or two N1 regions were assessed. From 272 patients with N1 (no N2) involvement, 15.4% had no N2 regions biopsied, 20.2% had one N2 region evaluated and only 39.7% had three or more N2 regions assessed. On the other hand, from 179 patients with positive N2, 8.9% had no N1 regions biopsied and 54.7% had one. From 409 patients with at least one N2 lymph node resected, 120 (29.3%) shown the highest region involved. Number of mediastinal regions assessed and affected, and number of lymph nodes resected and affected were significantly higher in patients with N1 plus N2 disease than those with isolated N1 or N2 involvement.
Survival
Median follow-up was 52.3 months. Five-year OS was 55.7% (CI95% 50.8%-60.3%). Differences were found on OS regarding type of lymph node involvement (N1, N2 or both) (p=0.002). Five-year OS was 61.7% (CI95%:55.4%-67.4%), 51.5% (CI95%:39.2%-62.4%) and 42.3% (CI95%:32.1-52.2%) for patients with N1, N2 and N1+N2 disease, respectively. No differences were found in survival regarding total number of N1 or N2 regions evaluated. Both number of regions involved and number of lymph nodes with tumor were significantly related to worse prognosis.
Conclusion
International recommendations for surgical lymph node assessment in NSCLC were not deemed for the design of the trial and were not followed in a high proportion of cases. Patterns of N1 and N2 involvement shown to impact prognosis. The design of trials assessing surgical series of patients undergoing complete resection requires the control of surgical procedures in order to avoid recruitment biases.
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MA08.12 - Discussant - MA08.09, MA08.010, MA08.11 (Now Available) (ID 3746)
15:15 - 16:45 | Presenting Author(s): Leah Backhus
- Abstract
- Presentation
Abstract not provided
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ES02 - Management of Oncogene Addicted Patients with Stage III NSCLC (ID 5)
- Event: WCLC 2019
- Type: Educational Session
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 1
- Now Available
- Moderators:Carlos Camps, Helena A Yu
- Coordinates: 9/08/2019, 10:30 - 12:00, Vancouver (2003)
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ES02.01 - Biomarker Testing in LA Disease (Now Available) (ID 3155)
10:30 - 12:00 | Presenting Author(s): Helena A Yu
- Abstract
- Presentation
Abstract
Routine biomarker testing in metastatic lung cancer has led to enormous improvements in outcomes for our patients with metastatic lung cancers. Oncogene testing has allowed us to identify the 50% of patients with metastatic lung cancer that are eligible for targeted therapies1. Consistently, targeted therapy for EGFR, ALK, ROS1, RET, BRAF have demonstrated superior progression-free survival compared to standard cytotoxic chemotherapy2. Identification of these genomic biomarkers has provided additional treatment options for our patients that are more effective and less toxic than standard treatments. In addition, serial biomarker testing allows us to also identify mechanisms of resistance to targeted therapy which can then inform subsequent treatment decisions. PDL1 testing is also routinely performed in the metastatic setting and assists us in identifying patients that may benefit from immunotherapy alone instead of first-line combination immunotherapy and chemotherapy treatment3. PDL1 testing allows us to predict likelihood of response to immunotherapy and selects patients that we can de-escalate treatment; patients with high PDL1 expression derive benefit from treatment with immunotherapy alone. Routine utilization of biomarker testing in metastatic lung cancer is easily the most importance advancement in this field to date.
Current recommendations
Biomarker testing for patients with locally advanced lung cancers is currently not recommended in the NCCN guidelines or any expert guidelines. This is likely because the current management for locally advanced lung cancers do not incorporate the use of biomarkers. Patients currently receive adjuvant durvalumab after concurrent chemoradiation for stage 3 disease irrespective of PDL1 status. Currently, adjuvant targeted therapies after definitive resection or radiation are not recommended in the NCCN or other cancer care guidelines.
Oncogene testing
The risk of recurrence for early stage lung cancers remain high. After surgical resection, adjuvant chemotherapy for high risk stage 1B, stage 3 and stage 4 and post-operative radiation for patients with mediastinal lymph node involvement are both recommended are they improve survival. Despite this, there is a large subset of patients that will have recurrent disease. Because of their demonstrated superiority over chemotherapy in the metastatic setting, there is great interest in assessing whether adjuvant targeted therapies would improve outcomes in the locally advanced disease setting. EGFR mutant lung cancer is the largest oncogene subset in which the bulk of previous studies have been done. However, all studies to date have been subsets of larger unselected patients (RADIANT study) or single arm studies (SELECT study). These smaller studies have shown a disease-free survival benefit but have been underpowered to demonstrate a survival benefit. There are several well-designed large studies ongoing that will definitively demonstrate whether adjuvant EGFR inhibitors improve overall survival. The ALCHEMIST study is a phase 3 randomized cooperative group study assessing erlotinib versus observation for patients with stage IB-IIIA resected lung cancers; accrual is ongoing. The ADAURA study is a randomized phase 3 study where patients with stage IB-IIIA resected lung cancers are randomized to osimertinib versus placebo for 3 years with a primary objective of DFS and a secondary objective of overall survival. These studies will help answer the question as to whether adjuvant targeted therapy should be utilized.
PDL1 testing
In stage 3 lung cancers, more than 60 percent of patients will ultimately die of their lung cancer4. Adjuvant durvalumab has improved outcomes with a clear improvement in overall survival but many patients still recur and ultimately die of their disease. An unplanned subset analysis of the PACIFIC study suggests that patients with PDL1 0% expression may not derive benefit from durvalumab. Further assessment will be needed to ascertain whether PDL1 expression can be used to select patients who would derive benefit from adjuvant durvalumab. Due to their efficacy in the metastatic setting, there are a significant number of studies looking at immunotherapy as both neoadjuvant and adjuvant treatment for locally advanced disease. Just as we utilize PDL1 as a biomarker that helps select appropriate therapies in the metastatic setting, I see similar use of PDL1 in the future in the locally advanced setting.
Future directions
As personalized medicine infiltrates our care of patients with lung cancers, we will need biomarker results for patients with locally advanced lung cancer to better tailor and personalize their care. In particular, if the EGFR TKI studies demonstrate improved overall survival with adjuvant EGFR TKI, we will certainly need to incorporate biomarker testing as standard of care for locally advanced disease. In addition, because a significant portion of patients recur, already having molecular test results available which were done on their surgical sample, makes their care later more stream-lined. We also need to assess whether PDL1 is a useful biomarker to select patients for immunotherapy in the adjuvant setting. Results from ongoing clinical trials will provide definitive answers.
Works cited:1. Jordan, E.J., et al. Prospective Comprehensive Molecular Characterization of Lung Adenocarcinomas for Efficient Patient Matching to Approved and Emerging Therapies. Cancer discovery 7, 596-609 (2017).
2. Sequist, L.V., et al. Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2013).
3. Reck, M., et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. The New England journal of medicine 375, 1823-1833 (2016).
4. Pisters, K.M., et al. Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline. Journal of clinical oncology 25, 5506-5518 (2007).Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MA21 - Non EGFR/MET Targeted Therapies (ID 153)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:Benjamin Besse, Michael Thomas
- Coordinates: 9/10/2019, 14:30 - 16:00, Vienna (2016)
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MA21.06 - Preliminary Phase 1 Results of U3-1402 — A Novel HER3-Targeted Antibody–Drug Conjugate—in EGFR TKI-Resistant, EGFR-Mutant NSCLC (Now Available) (ID 1720)
14:30 - 16:00 | Presenting Author(s): Helena A Yu
- Abstract
- Presentation
Background
Treatment options are limited for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) resistant to EGFR tyrosine kinase inhibitors (TKIs), in particular osimertinib. Overall, 57%–83% of NSCLC tumors express human epidermal growth factor receptor 3 (HER3). Because signaling through HER3 is not an established mechanism of resistance to EGFR TKIs, treatment with an anti-HER3 antibody–drug conjugate (ADC) presents an approach to targeting diverse resistance mechanisms in EGFR-mutant NSCLC. U3-1402 is a HER3-targeted ADC with a fully humanized antibody, novel cleavable peptide-based linker, and topoisomerase I inhibitor payload. Here, we present the safety/tolerability and antitumor activity data from the dose-escalation phase of an ongoing, multicenter, phase 1 study (NCT03260491).
Method
Patients had locally advanced or metastatic EGFR TKI-resistant, EGFR-mutant NSCLC. Patients with stable brain metastases were eligible. Dose escalation was based on dose-limiting toxicities (DLTs) guided by a Bayesian logistic regression model. U3-1402 was administered every 3 weeks via intravenous infusion. Pretreatment tumor tissue was required for retrospective HER3 immunohistochemistry analysis. Next-generation sequencing analysis was performed on available tumor tissue. Primary objectives included safety, tolerability, and identification of the recommended dose for expansion (RDE).
Result
As of May 2019, 30 patients were enrolled across 4 doses (3.2 [n=4], 4.8 [n=9], 5.6 [n=12], and 6.4 [n=5] mg/kg). Thirteen patients (43%) have discontinued (progressive disease [n=9], clinical progression [n=1], consent withdrawal [n=2], adverse event [AE; n=1]). All 30 patients received prior EGFR TKIs, of which 28 (93%) received prior osimertinib, and 15 (50%) prior chemotherapy. Activating EGFR mutations were reported in all patients (Ex19del: 57%; L858R: 40%; L861Q: 3%). All 25 evaluable tumors demonstrated HER3 expression (median HER3 membrane H-score, 183 [range, 56–290]). History of central nervous system (CNS) metastases was reported in 15 patients (50%). Treatment-emergent AEs were reported in 29 patients (97%; 13 patients [43%] reported grade 3/4). Two DLTs (grade 3 febrile neutropenia and grade 4 platelet count decrease) were reported in 1 patient (5.6 mg/kg) and 3 DLTs (all grade 4 platelet count decrease) in 3 patients (6.4 mg/kg). Of patients with a history of CNS metastases, 9 have progressed (2 with CNS progression; 3 with both CNS and non-CNS progression). One patient without a history of CNS metastasis progressed with new CNS disease. Of 26 efficacy-evaluable patients, 6 had confirmed partial responses (2 each at 4.8, 5.6, and 6.4 mg/kg), including 2 patients with an EGFR C797S mutation. Median best percentage change in sum of diameters (SoD) was −25.7% (range, −82.6% to 13.3%), including decreases in SoD in patients with CDK4 amplification (–25.7% and –17.8%), HER2 amplification (–28.6%), and both CCNE1 amplification and PIK3CA mutation (–28.8%).
Conclusion
U3-1402 demonstrated tolerable safety and antitumor activity in this ongoing study. Antitumor activity of U3-1402 was seen in cancers with EGFR-mediated and other resistance mechanisms. These findings support the hypothesis that targeting HER3 with U3-1402 may provide clinical benefit to patients with EGFR-mutant NSCLC with diverse mechanisms of resistance. RDE evaluation is ongoing.
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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
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-89 - A Multicenter Phase 1/2a Trial of CLN-081 in NSCLC with EGFR Exon 20 Insertion Mutations (ID 488)
09:45 - 18:00 | Author(s): Helena A Yu
- Abstract
Background
First and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are largely ineffective against EGFR exon 20 insertion mutations (ins20) and, while several novel agents targeting EGFR ins20 are in development (poziotinib, TAK-788), preliminary reports suggest that EGFR-related adverse events are common and may limit long-term efficacy (Heymach, WCLC 2018, Neal WCLC 2018). Targeted therapies which are safe and effective in patients with EGFR ins20 are needed. CLN-081 (also known as TAS-6417) is a novel, orally available EGFR TKI that selectively inhibits ins20 mutant EGFRs (Mol Cancer Ther 2018; 17:1648). In a cell-based assay using genetically engineered cell lines, CLN-081 potently inhibited intracellular phosphorylation of a wide spectrum of ins20 mutant EGFRs. The selectivity for mutant over wild type EGFR (WT/mut ratio) ranged from 4 to 134-fold depending on the specific mutation, representing an unprecedented level of mutant specificity.
Method
This is an adaptive phase 1/2a trial evaluating CLN-081 as monotherapy in advanced non-small cell lung cancer (NSCLC) harboring EGFR ins20. Dose escalation will proceed initially according to an accelerated titration (AT) design, converting to a rolling six (R6) design based upon pre-specified safety criteria. Cohort expansion in Phase 1 can occur at one or more doses where responses are observed in R6 cohorts. Transition from Phase 1 into Phase 2a is based upon a Simon-Two Stage design. The starting dose will be 60mg. Once daily and twice daily dosing will be explored. Approximately 90 patients will be enrolled. Eligible patients will have advanced, exon 20 insertion mutation positive NSCLC, and at least one prior platinum containing treatment regimen. EGFR ins20 will be identified based on local testing (tissue or plasma). Patients who have discontinued a previous EGFR TKI due to progressive disease will be allowed in AT dose escalation cohorts but will be excluded from R6, and the Phase 1 and 2a expansion cohorts. The primary objectives in Phase 1 are to demonstrate safety and determine the maximum tolerated dose. Secondary Phase 1 objectives include evaluation of PK and preliminary efficacy. The primary objectives in Phase 2a are to define the recommended phase 2 dose and evaluate the overall response rate. The secondary Phase 2a objectives include additional measures of response and confirmation of CLN-081’s safety profile.
Result
Section not applicable
Conclusion
Section not applicable
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-06 - Tissue-Based Molecular and Histologic Landscape of Acquired Resistance to Osimertinib in Patients with EGFR-Mutant Lung Cancers (ID 1392)
09:45 - 18:00 | Author(s): Helena A Yu
- Abstract
Background
Even though osimertinib (osi) is now the initial treatment for patients with EGFR-mutant lung cancers, our knowledge about mechanisms of resistance (MOR) is largely derived from patients who received osi after acquiring EGFR T790M on treatment with another EGFR inhibitor. Other studies of osi resistance have mainly reported genotyping of plasma which suboptimally detects lineage plasticity, copy number changes, and chromosomal rearrangements.
Method
To identify MOR to osi and characterize clinical, molecular and histologic factors associated with duration of response, we identified patients with EGFR-mutant lung cancers who had targeted next-generation sequencing (MSK-IMPACT) performed on tumor tissue obtained before treatment and after developing resistance to osi received as either first-line or later line EGFR-TKI.
Result
From January 2016 to March 2019, we collected paired pre-treatment and resistance specimens from 53 patients (1st line osi: 21. Osi after prior TKI: 32). MOR are summarized in the table. Histologic transformation was identified in 18% of 1st line cases and 17% of all cases. When osi was given as initial treatment, with median follow up of 18 months, early emerging MOR rarely included on-target resistance mechanisms (acquired EGFR G724S in 1/21). Other acquired alterations representing potential resistance mechanisms not listed in the table included CCNE1 and MYC amplifications, and mutations in MTOR A1098S and MET H1094Y.
ConclusionFirst line (n = 21)
Osi after prior TKI
(n = 32)
All
(n = 53)
Squamous transformation
3
3
6
Neuroendocrine transformation
1
2
3
On target mutation (EGFR C797X or other)
1
9
10
Loss of EGFR T790M only
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8
8
Fusions (ALK, RET, BRAF)
0
3
3
Amplifications (HER2, MET, EGFR)
2
3
4
Off target mutations (KRAS, BRAF, HER2)
1
2
3
In this analysis of MOR identified on NGS from tumor tissue, we found a spectrum of resistance mechanisms to osi. By evaluating tissue rather than plasma we provide data on histologic transformation (including squamous cell transformation). Subsequent studies are needed to assess patients with a longer time on initial osi as early progressors may have different MOR, with off-target MOR emerging earlier and on-target resistance mutations later.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-22 - ORCHARD: A Phase II Platform Study in Patients with Advanced NSCLC Who Have Progressed on First-Line Osimertinib Therapy (ID 1303)
10:15 - 18:15 | Presenting Author(s): Helena A Yu
- Abstract
Background
Osimertinib is a third-generation, central nervous system (CNS)-active, irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitising mutations (EGFRm) and EGFR T790M. First-line osimertinib has demonstrated superiority in progression-free survival (PFS) compared with first-generation EGFR-TKIs in patients with EGFRm advanced NSCLC (Soria et al, NEJM 2018). The most common resistance mechanisms to first-line osimertinib identified from plasma samples are MET amplification (15%) and EGFR C797S (7%) (Ramalingam et al, Ann Oncol 2018). Further clinical studies are needed to better understand resistance mechanisms and evaluate post-progression targeted treatment options.
Method
ORCHARD is an open-label, multicentre, biomarker-directed, Phase II platform study evaluating the optimal treatment for individual patients with EGFRm NSCLC depending on their underlying resistance mechanism to first-line osimertinib.
Adult patients with EGFRm locally advanced/metastatic NSCLC and radiological progression on first-line osimertinib monotherapy will be eligible.
Treatment assignment will be based on molecular characterisation of the tumour at progression from a mandatory tissue biopsy.
ORCHARD will comprise of three groups assigned by tumour molecular profile (Figure). An adaptive design allows addition of new treatments based on emerging findings. Tumour assessments (RECIST 1.1) will be performed every 6 weeks for the first 24 weeks and every 9 weeks thereafter until progression. An interim analysis of each cohort will be performed when ≈16 patients have reached the second on-treatment RECIST assessment. Based on preliminary signals, the cohort may be stopped or expanded to 30–40 patients for further evaluation.
The primary outcome is investigator-assessed objective response rate; secondary outcomes include PFS, duration of response, overall survival, and pharmacokinetics of each treatment module, evaluated independently. Exploratory outcomes include tumour and plasma biomarker and resistance analyses, and correlation between biomarker profiles and treatment effect. Safety data will also be reported.
Result
Section not applicable
Conclusion
Section not applicable
