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Benjamin Besse
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MA21 - Non EGFR/MET Targeted Therapies (ID 153)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Targeted Therapy
- Presentations: 12
- Now Available
- Moderators:Benjamin Besse, Michael Thomas
- Coordinates: 9/10/2019, 14:30 - 16:00, Vienna (2016)
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MA21.01 - Generation and Characterization of Novel Preclinical Disease Models of NSCLC with NRG1 Rearrangements to Improve Therapy (Now Available) (ID 2811)
14:30 - 16:00 | Presenting Author(s): Eric Gladstone | Author(s): Morana Vojnic, Michael Offin, Lukas Delasos, Allan J. W. Lui, Evan Siau, Hirko Sato, Ryma Benayed, Renate Kurth, Marissa Mattar, Inna Khodos, Elisa De Stanchina, Robert Daly, Alison Schram, Alexander Drilon, Marc Ladanyi, Romel Somwar
- Abstract
- Presentation
Background
Chimeric proteins encoded by NRG1 rearrangements retain the EGF-like domain of NRG1, a HER3 ligand that triggers HER3-HER2 heterodimerization and drives tumor growth. Activating NRG1 fusions have been identified in a variety of cancers including lung, pancreatic, breast, head and neck, etc, and previous work by our group has shown that anti-HER3 antibody (GSK2849330) therapy was effective at inducing a durable response in a NSCLC patient with a CD74/NRG1-fusion. It is possible that targeting both HER2 and HER3 would be more effective than targeting HER3 alone given that HER3-HER2 dimerization is necessary for tumorigenesis induced by NRG1 rearrangements. However, this has not been explored extensively due to a paucity of well-characterized preclinical models of NRG1-driven NSCLC. We aimed to establish patient-derived xenograft (PDX) and cell line models with NRG1-rearrangements to evaluate signaling networks and the role of novel therapies for this recently identified oncogene.
Method
Approximately 30,000 tumor samples were evaluated for the presence of NRG1-fusions by targeted DNA and RNA sequencing (using the MSK-IMPACT and MSK-Fusion panels, respectively). Fresh tumor samples were collected and implanted into immune-compromised mice to generate PDX models and/or used to generate cell lines. Separately, NRG1-fusions were genomically engineered using CRISPR-Cas9 systems or by lentiviral transduction of cDNAs into immortalized human bronchiolar epithelial (HBEC) cells. RT-PCR and Sanger sequencing were used to verify NRG1-fusion mRNA expression, whereas western blot analysis examined fusion protein expression and phosphorylation. Subsequently, cell viability following inhibition of HER2, HER3 and downstream signaling pathways was assessed.
Result
NRG1 fusions were identified in 24 patients (9 NSCLC); and we successfully generated two PDX models with corresponding cell lines from two NSCLC surgical specimens (2/2). One model harbors a CD74/NRG1 fusion whereas the second harbors a SLC3A2/NRG1-fusion. Using CRISPR-Cas9 mediated gene editing, we are introducing NRG1 fusions that were identified in NCSLC (CD74/NRG1, SLC3A2/NRG1, VAMP2/NRG1) into HBEC cells, and have generated a stable cell line with VAMP2/NRG1 fusion to date. In addition, we established a CD74/NRG1-positive model in HBEC cells using lentiviral transduction. Treatment of NRG1-fusion positive cells with small molecule inhibitors of HER2 (afatinib, neratinib, sapitinib) or trastuzumab inhibited growth, induced caspase 3/7 activity and blocked activation of PI3K and ERK signaling. Neratinib was more potent than other small anti-HER2 molecules. The PI3K inhibitor pictilisib inhibited growth of NRG1 fusion-positive cells as a single agent with little effect on non-tumor control cells.
Conclusion
We generated novel NSCLC PDX and cell line models with verified NRG1 chromosomal rearrangements. In vitro studies show that targeting HER2 and PI3K effectively inhibits growth and induces apoptosis. Studies exploring the efficacy of additional agents targeting HER2, HER3 and PI3K alone or in combination using in vivo models are ongoing and results will be presented.
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MA21.02 - Genomic Origin and EGFR-TKI Efficacy of Pulmonary Adenosquamous Carcinoma (Now Available) (ID 578)
14:30 - 16:00 | Presenting Author(s): Gen Lin | Author(s): Chao Li, Pansong Li, Wenzhang Fang, Haipeng Xu, Yuhua Gong, Zhengfei Zhu, Yi Hu, Wenhua Liang, Qian Chu, Wen-Zhao Zhong, Lin Wu, Huijuan Wang, Zhijie Wang, Ziming Li, Jie Lin, Yan-Fang Guan, Xuefeng Xia, Xin Yi, Qian Miao, Biao Wu, Kang Jiang, Xiaobin Zheng, Weifeng Zhu, Xinlong Zheng, Huang Peisha, Xiao Wenjin, Dan Hu, Longfeng Zhang, Xirong Fan, Tony Mok, Cheng Huang
- Abstract
- Presentation
Background
Lung adenosquamous carcinoma (ASC) is a heterogeneous disease that comprises of both adenocarcinoma (AC) and squamous cell carcinoma (SCC) components. Their genomic profile, evolutionary origin, and clinical management remain controversial. Objective of this study is to define the genomic origin of this heterogeneous tumor by independent genomic analyses of the AC and SCC components.
Method
Surgical ASCs were collected. AC component and SCC component were obtained separately by microdissection, and Lymph node (LN) metastases were gathered. Targeted sequence was performed for the two components using a 1021-gene panel, independently. Evolutionary relationship of the two components was analyzed. The independent cohorts of adenocarcinoma (n=170) and squamous cell carcinomas (n=62) were used for comparison. EGFR and concomitant mutations with response to EGFR-TKI were analyzed. Retrospective 517 ASCs underwent EGFR detections were collected from 11 centers. Objective response rate (ORR), disease control rate (DCR) and progression free survival (PFS) were analyzed in EGFR-positive patients received EGFR-TKIs.
Result
28 ASCs were collected. NGS was performed on AC component and SCC component samples, respectively. The most frequent alterations in 28 ASCs were EGFR mutation (79%), TP53 mutation (68%), MAP3K1 mutation (14%), EGFR amplification (32%), and MDM2 amplification (18%). 27 patients had trunk variations in the both components suggesting the monoclonal origin of ASCs. The prevalence of trunk mutations was correlated to those of AC, indicating that ASC might originate from AC. Only one patient did not carry any trunk variations between AC and SCC components, which were clearly and geographically distinguishable under the microscope. 22 had AC component or/and SCC component specific variations suggesting the common event of branch evolution. The 23 LNs of 13 patients mainly contained AC and ASC components (AC, SCC, and ASC: 11, 1, and 11, respectively), and each of the LNs carried the trunk mutations of the primary ASC. Like pure AC, the alterations of L858R and Exon 19 Dels of EGFR were common in the 28 ASCs. Unfortunately, these patients have not been treated with TKIs. Further, of 517 retrospective ASCs from 11 centers, 51.8% were EGFR-positive. For the 129 EGFR-positive ASCs who had received TKIs, the ORR and DCR were 56.6% and 89.1%, respectively. The median PFS was 10.1 months (95% CI: 9.0-11.2).
Conclusion
The AC and SCC components share a monoclonal origin, and a majority have branching evolution. ASC may represent a subtype of adenocarcinoma with EGFR mutation being the most common genomic anomaly and sharing similar efficacy to EGFR-TKIs.
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MA21.03 - The International Association for the Study of Lung Cancer (IASLC) Global Survey on Molecular Testing in Lung Cancer (Now Available) (ID 1198)
14:30 - 16:00 | Presenting Author(s): Matthew P Smeltzer | Author(s): Murry W Wynes, Meghan Taylor, Kristin Richeimer, Kelsey Wood, Kristen Howell, Mercedes Liliana Dalurzo, Enriqueta Felip, Keith Kerr, Edward Kim, Sylvie Lantuejoul, Clarissa Mathias, Pieter E. Postmus, Charles Powell, Suresh S Ramalingam, Ross Soo, Masahiro Tsuboi, Ignacio Wistuba, Marileila Varella-Garcia, Giorgio Vittorio Scagliotti, Fred R. Hirsch
- Abstract
- Presentation
Background
Evidence-based standards for molecular testing of lung cancer have been established, but the global frequency and practice of testing are not well understood. The IASLC conducted an international survey to evaluate current practice and barriers to molecular testing.
Method
Distributed to IASLC members and other healthcare professionals, content included: 7-question introduction, 32 questions for those requesting tests/treating patients, 45 questions on performing/interpreting assays, and 24 questions on tissue acquisition. All respondents were asked to provide 3-5 barriers to implementing/offering molecular testing.
Respondents’ countries were grouped by geography or developing/developed using IASLC and World Bank criteria. Surveys were available in 7 languages. Regional comparisons used the Chi-squared test or ANOVA; free-text was analyzed with Nvivo.
Result
We obtained 2,537 responses from 102 countries. Respondents were 45% Medical Oncologists, 12% Pulmonologists, 12% Thoracic Surgeons, 9% Pathologists, and 22% scientists or other. 56% of responses were from developing countries, 44% developed. Regions included: 52% Asia, 19% Europe, 11% Latin America, 11% US/Canada, 7% Other.
1683 (66%) chose the requesting/treating track (50% government, 42% academic, 8% other). 61% reported most patients in their country do not receive molecular testing, with the lowest rates in Latin America/Other (p<0.0001). 39% were not satisfied with the conditions of molecular testing in their country. Indications for requesting testing included: adenocarcinoma (89%), never-smoker (61%), female (57%), and young (54%) (variable by region, p<0.0001). 99% ordered EGFR, 95% ALK, 84% PDL1, 79% ROS1, all other tests <50%. 56% typically received results within 10 days. Only 67% were aware of CAP/IASLC/AMP guidelines, least frequently in Asia/Other (p=0.041). 37% have trouble understanding molecular testing result reports, most of whom cited a need for more technical and scientific knowledge. 75% had multidisciplinary tumor boards, but 23% met <1/month.
The 316 (12%) testing track respondents were from laboratories that were 49% academic, 35% government, and 16% private/other. 94% of laboratories offered EGFR, 83% ALK, 69% KRAS, 68% BRAF, 64% ROS1, 56% HER2, and others <50%; 68% tested for PDL1. 57% offered Multiplex assays, less frequently in Latin America/Asia (p=0.0294). 69% tested blood-derived DNA, less frequently in US/Canada/Other (0.0013). 23% of respondents reported >10% of cases are rejected due to inadequate samples; however, 47% stated there is no policy or strategy to improve the quality of the tissue samples in their country. 52% reported patients/physicians are not satisfied with the state of molecular testing in their country. Respondents performing/interpreting assays (334, 14%) were typically informed of biopsy results (91%), and notified when the sample was inadequate (84%).
The most frequent barrier to molecular testing in every region was cost, followed by quality/standards, turnaround-time, access, and awareness. After cost, time was the most common barrier in developed countries, while it was quality in developing countries. The second largest barrier was quality in Asia, access in Europe/Latin America/Other, and turn-around time in US/Canada.
Conclusion
These preliminary analyses show molecular testing usage varies across the globe. Barriers vary by region, and one-third of respondents were unaware of evidence-based guidelines. Global and regional strategies should be developed to address barriers.
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MA21.04 - Discussant - MA21.01, MA21.02, MA21.03 (Now Available) (ID 3806)
14:30 - 16:00 | Presenting Author(s): Michael Duruisseaux
- Abstract
- Presentation
Abstract not provided
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MA21.05 - Phase II Trial of the Combination of Alectinib with Bevacizumab in ALK-Positive Nonsquamous Non-Small Cell Lung Cancer (Now Available) (ID 1306)
14:30 - 16:00 | Presenting Author(s): Satoshi Watanabe | Author(s): Naoya Matsumoto, Jun Koshio, Akane Ishida, Tomohiro Tanaka, Tetsuya Abe, Daisuke Ishikawa, Satoshi Shoji, Koichiro Nozaki, Kosuke Ichikawa, Rie Kondo, Aya Otsubo, Ami Aoki, Tomosue Kajiwara, KENICHI Koyama, Satoru Miura, Hirohisa Yoshizawa, Toshiaki Kikuchi
- Abstract
- Presentation
Background
Alectinib is a 2nd generation highly selective anaplastic lymphoma kinase (ALK) inhibitor. Although alectinib has improved progression-free survival (PFS) in patients with ALK-positive Non-Small Cell Lung Cancer (NSCLC), there are limited treatment options after progression of alectinib. Recent evidences have described promising results of the combination of bevacizumab with EGFR-TKIs, cytotoxic chemotherapies and immune-checkpoint inhibitors. We report the results from a phase II study of the combination of alectinib with bevacizumab in ALK-positive Nonsquamous NSCLC patients who were treated with alectinib and showed disease progression (UMIN 000017828).
Method
Patients with ALK+ Nonsquamous NSCLC who had progressed after alectinib treatment were enrolled. Primary objective of this study was PFS and safety. Secondary endpoints included overall survival, objective response rate and disease control rate.
Result
Twelve patients received alectinib (600 mg/day) with bevacizumab (15 mg/kg, Q3W). Nine patients were treated with crizotinib and alectinib, and 2 patients were treated with crizotinib, alectinib and ceritinib before enrollment to this study. The median PFS was 3.1 months (95% CI 1.2-16.1) and the median survival time was 32 months (95% CI 8.3-NE). The median treatment cycle was 5 (range, 1-37) and 3 patients received alectinib with bevacizumab more than 20 cycles. The objective response rate and disease control rate were 8% and 67%, respectively. The most common treatment related adverse events were decreased appetite (42%), proteinuria (42%), hypertension (33%), anemia (33%) and fatigue (33%). Treatment related adverse events of grade > 3 were anemia (8%), proteinuria (8%), diarrhea (8%) and hypokalemia (8%). No severe adverse events were observed.
Conclusion
This is the first study to investigate the combination of alectinib and bevacizumab. This combination had clinical efficacy and was well tolerated.
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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 | Author(s): Melissa Johnson, Conor E Steuer, Michele Vigliotti, Shuquan Chen, Yasuki Kamai, Channing Yu, Pasi A Jänne
- 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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MA21.07 - Circulating Tumor DNA Analysis Depicts Potential Mechanisms of Resistance to BRAF-Targeted Therapies in BRAF+ Non-Small Cell Lung Cancer (Now Available) (ID 1365)
14:30 - 16:00 | Presenting Author(s): Sandra Ortiz-Cuaran | Author(s): Laura Mezquita, Aurélie Swalduz, Mihaela Aldea, Julien Mazieres, CECILE Jovelet, Washington René Chumbi Flores, LUDOVIC Lacroix, Yohan Loriot, Luc Friboulet, Virginie Westeel, Maud Ngocamus, Anne Pradines, Claire Tissot, Christelle Clement Duchene, Christine Raynaud, Xavier Quantin, Radj Gervais, Etienne Brain, Isabelle Monnet, Etienne Giroux Leprieur, Virginie Avrillon, Céline Mahier-Aït Oukhatar, Natalie Hoog-Labouret, Frank De Kievit, Karen Howarth, Jean-Francois Guichou, Clive Morris, Emma Green, Maurice Perol, Benjamin Besse, Jean-Yves Blay, Pierre Saintigny, David Planchard
- Abstract
- Presentation
Background
Oncogenic BRAF-V600 mutations are observed in 1-2% of non-small cell lung cancer (NSCLC). Targeted therapies including vemurafenib (V), dabrafenib (D) or combination of dabrafenib plus trametinib (D+T) are associated with favorable outcomes in these patients (pts). The mechanisms of resistance to BRAF-targeted therapies (BRAF-TT) in NSCLC are largely unknown.
Method
We performed genomic profiling of serial circulating-tumor DNA (ctDNA) in a cohort of 79 metastatic BRAF-mutant NSCLC pts (96% V600E, 4% non-V600). BRAFmutational status was ascertained based on local testing. Plasma samples were collected, from 2014-2018 in 27 Hospitals, from pts treated with V (n=34), D (n=2) or D+T (n=23). We collected 41 plasma samples at baseline to BRAF-TT, 40 at progressive disease (PD) and ~200 samples during treatment follow-up, concomitant to routine radiological evaluation. Inivata InVisionSeq™ assay was used to detect the presence of SNVs, indels and CNAs in 36-cancer related genes.
Result
At baseline, 72,5% of BRAF mutations (V600E and non-V600E) were detected in plasma. BRAF-V600E detection in plasma was associated with the presence of liver metastasis, versus BRAF-V600E-negative cases (22% vs. 7%, respectively). Co-occurring molecular alterations at baseline, besides BRAF-V600E, were observed in 18/26 (70%) cases: FGFR2 (1pt), PIK3CA (2pts), ERBB2 (1pt), CTNNB1 (2pts) and IDH1 (2pts). FGFR2, PIK3CA or CTNNB1 alterations were associated with PD as the best response to the subsequent BRAF-TT. TP53 and STK11 mutations were observed in 54% (14/26) and 8% (2/26) of pts, respectively. Complete clearance of BRAF-V600E in plasma at baseline was observed at the first CT-scan evaluation in 42% (3/7) and 82% (9/11) pts treated with V or D+T, respectively. These pts were in complete or partial response, suggesting that monitoring BRAF-V600E levels in plasma on treatment may be a clinically useful marker of tumor response. At PD, a consistent rebound in BRAF-V600E plasma levels was observed in 60% (24/40) pts. Resistance to V was associated with alterations in the MAPK pathway: 1pt (KRAS), 1pt (GNA11), 1pt (NRAS and GNAS) and 1pt (MAP2K1 and NFE2L2). Activating PI3KCA mutations were observed in 4 pts who progressed in <6 months on V treatment. ctDNA analyses at PD under D+T revealed that, similar to what we observed in patients who progressed on V, alterations in KRAS, NRAS, PIK3CA and CTNNB1 are associated with D+T resistance. Prediction of the impact of these alterations, at the protein level, was assessed using in silico structure modeling and will be presented.
Conclusion
ctDNA monitoring might be an informative tool for assessing disease response and resistance in NSCLC pts treated with BRAF-TT. MAPK reactivation remains an important resistance mechanism to BRAFi-monotherapy or to BRAFi and MEKi combination therapy.
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MA21.08 - Discussant - MA21.05, MA21.06, MA21.07 (Now Available) (ID 3807)
14:30 - 16:00 | Presenting Author(s): Toyoaki Hida
- Abstract
- Presentation
Abstract not provided
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MA21.09 - Tyrosine Kinase Inhibitors' Plasma Concentration and Oncogene-Addicted Advanced Non-Small Lung Cancer (aNSCLC) Resistance (Now Available) (ID 830)
14:30 - 16:00 | Presenting Author(s): Arthur Geraud | Author(s): Laura Mezquita, Edouard Auclin, David Combarel, JULIA Delahousse, CHARLES Naltet, CECILE Jovelet, pernelle Lavaud, Anas Gazzah, LUDOVIC Lacroix, Jordi Remon, CAROLINE Caramella, David Planchard, OLIVIER Mir, ANGELO Paci, Benjamin Besse
- Abstract
- Presentation
Background
The development of TKIs against driver molecular alteration has changed treatment paradigm in aNSCLC patients (pts). All tumors eventually progress and a resistance mechanism is identified in only a fraction of pts. Plasma concentration of TKI can decrease after chronic exposition but limited data are available. Our hypothesis is that an insufficient plasma exposure could contribute to tumor progression (PD).
Method
We assessed the plasma concentration of TKI in pts with aNSCLC harboring ALK rearrangement, EGFR or BRAF V600E mutation. We defined chronic exposure as a treatment administered > 3 months. Patients’ characteristics and co-medications were collected. Residual plasma concentrations were measured using Ultra Performance Liquid Chromatography coupled with tandem mass spectrometry validated methods. We compared results to currently recommended therapeutic targets and correlated exposure levels to treatment benefit.
Result
Between Apr. 2014 and Feb. 2019, 51 samples were prospectively collected (gefitinib n=11, osimertinib n=10, erlotinib n=13, crizotinib n=7, dabrafenib + trametinib n=5) in 41 pts. Median time of exposure was 20.3 months (range 2.18 - 67.813). Low plasma concentration was observed in 31 (61%) samples. Out of 14 samples collected in pts with ongoing benefit, 10 (71%) had low plasma exposure. Smoking status was associated with low plasma TKI concentration (P=0.01) whatever the TKI used. A total of 37 samples were collected at PD, 21 (57%) had low plasma exposure. The median time to treatment failure (TTF) in the ‘low exposure group' (n=31) was 14.9 months (95% CI 12.48 – 33.2) vs. 24.6 months (95% CI 8.65 -not reached (NR) in the ‘normal exposure group’ (P=0.55). No significant impact of protons pump inhibitors on TTF was found (p=0.12), including with gefitinib and erlotinib (p=0.76; n=24). In case of isolated brain PD (n=4), 3 pts (75%) had low plasma exposure. TKI dose was reduced in 14 pts because of toxicity, median TTF was 17.0 months (95% CI 10.4-NR) vs. 20.1 months (95% CI 10.4-59.8, P=0.45 in pts treated with standard dose. In the EGFR mutated aNSCLC population at PD (n=19), T790M resistance mutation was more frequent in the ‘normal exposure group’ (37.5%, n= 3/8,) than in the ‘low exposure group’ (9.1%, n=1/11), OR=0.13 95%CI (0.01-1.29), p=0.08.
Conclusion
TKI is underdose in the majority of aNSCLC patients at PD. Low TKI concentration were more frequent in pts without tumor resitance mechanism. Altogether, it suggests that low TKI exposure might contribute to PD.
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MA21.10 - Phase II Study of 160mg of Osimertinib in EGFR T790M Positive NSCLC with Brain or Leptomeningeal Metastases Who Progressed on Prior EGFR TKI (Now Available) (ID 1705)
14:30 - 16:00 | Presenting Author(s): Myung-Ju Ahn | Author(s): Sehhoon Park, Sunyoung Hong, JuYoun Park, MI RA Park, Hyun Ae Jung, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park
- Abstract
- Presentation
Background
EGFR tyrosine kinase inhibitor (TKI) has successfully improved clinical outcome in non-small cell lung cancer (NSCLC) with activating EGFR mutation. However, up to 40% of TKI treated patients present with disease progression in the central nerve system (CNS) either as brain metastases (BM) or leptomeningeal metastases (LM). Osimertinib is a 3rd generation EGFR TKI effective in T790M mutant NSCLC and characterized by high blood-brain barrier penetration. In this phase II, multicenter prospective single-arm two cohort study, the clinical efficacy of 160mg of osimertinib in T790M mutant BM or LM patients progressed on prior EGFR TKI was evaluated. (NCT0325712)
Method
BM only patients were included in the BM cohort (n=40). Patients with cerebrospinal cytology confirmed LM with or without BM were included in the LM cohort (n=40). 3rd generation TKI, including 80mg of osimertinib, was exposed to 18 patients in BM and 16 patients in LM cohort. T790M need to be identified from either tissue, plasma or cerebrospinal fluid. The primary endpoint was overall response rate (ORR) (H1=30%) for BM cohort and overall survival (OS) (H1=5months) for LM cohort, respectively.
Result
Median follow-up duration was 7.9 months for BM and 8.3 months for LM cohort. In BM cohort, median progression-free survival (PFS) was 7.3 months (95% confidential interval [CI] 3.6-13.7), and median OS was not reached (NR). Intracranial ORR and disease control rate (DCR) was 40.0% and 77.5%. Extracranial ORR and DCR was 30.0% and 67.5%. In LM cohort, median PFS was 8.9 months (95%CI 5.6-NR) and median OS was 13.2 months (95%CI 8.0-NR). When response of leptomeningeal lesion is separately evaluated, CR rate was 25.0% (n=10) and non-CR/non-PR rate was 65.0% (n=26). Extracranial ORR and DCR was 22.5% and 85.0%. Intracranial median PFS was not reached in both BM and LM cohort. Grade 3 adverse event (AE) was observed in 7 BM and 11 LM patients. Four patients required dose reduction due to AE. Among the patients who previously received 3rd generation TKI, 33.3% (6 out of 18) in BM cohort and 81.2% (13 out of 16) in LM cohort showed an intracranial DCR to 160mg of osimertinib. Extended survival analyses and exploratory outcomes will be presented at the conference.
Conclusion
In this study, 160mg of osimertinib demonstrated promising ORR and survival benefit with tolerable safety profile in EGFR T790M positive NSCLC patients with CNS metastasis who progressed on prior EGFR TKI.
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MA21.11 - A Multicenter Phase II Study of Low-Dose Erlotinib in Frail Patients with EGFR Mutation-Positive, Non-Small Cell Lung Cancer: TORG1425 (Now Available) (ID 633)
14:30 - 16:00 | Presenting Author(s): Sakiko Otani | Author(s): Kazuhiko Yamada, Shingo Miyamoto, Koichi Azuma, Hidenobu Ishii, Akihiro Bessho, Shinobu Hosokawa, Hideo Kunitoh, Kazuhito Miyazaki, Hiroshi Tanaka, Satoru Miura, Hiromi Aono, Yoshiro Nakahara, Kei Kusaka, Yukio Hosomi, Akinobu Hamada, Hiroaki Okamoto
- Abstract
- Presentation
Background
We conducted a multicenter phase II trial evaluating the efficacy of low-dose erlotinib (ERL) in frail patients with EGFR-mt non-small cell lung cancer (NSCLC). The primary endpoint was met, with the objective response rate (ORR) of 60%. Here we present the final overall survival (OS) results. Furthermore, we investigated the effect of ABCB1 genetic polymorphisms on the ERL plasma concentration pharmacokinetics (PK) and pharmacodynamics (PD).
Method
Chemotherapy-naïve NSCLC patients with EGFR mt who had frailty were enrolled and received ERL 50 mg/d. Patient’s frailty was defined as follows: (Group 1) 20 to 74 years of age with Eastern Cooperative Oncology Group performance status (PS) ≥2 or Charlson Comorbidity Index (CCI) ≥6 points; (Group 2) 75 to 80 years of age with PS ≥1 or CCI ≥6 points; (Group 3) ≥81 years of age with any PS and CCI. ABCB1 gene polymorphism analysis were using the i-densyTM genetic testing platform, and blood samples for the ABCB1 genetic testing were collected prior to treatment. Steady-state trough plasma ERL concentration was measured with a high-performance liquid chromatograph-tandem mass spectrometry at 15 days (±7 days) after initiating ERL administration.
Result
From December 2014 and April 2017, 80 patients were enrolled: males/females 26/54; median age 80 (range 49-90); Group 1/2/3 15/28/37; Ad/Sq/Others 76/1/3. EGFR mt types were: exon 19/21 42/38. All 80 patients were included in efficacy and safety analysis. Median progression-free survival and OS were 9.3 (95%CI: 7.2-11.4), 26.1 (95%CI: 21.9-30.4) months respectively. The trough of ERL could be measured in 48 patients, and 45 of these patients were analyzed for ABCB1 genetic polymorphism. The ORR for the 48 patients was 62.5%, and their median trough of ERL was 685 ng/ml (range 153-1950) , which surpassed the reported “effective” level (500ng/ml). Nine (60%) of 15 the patients who failed to achieve the level responded. Genetic polymorphisms were not correlated with ERL PK, nor were they associated with efficacy and adverse events.
Conclusion
This is the first prospective study evaluating low-dose ERL for frail patients with EGFR mt NSCLC. This treatment was safe and effective, and the ABCB1 genetic polymorphisms did not affect ERL PK/PD. Clinical trial information: UMIN 000015949.
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MA21.12 - Discussant - MA21.09, MA21.10, MA21.11 (Now Available) (ID 3808)
14:30 - 16:00 | Presenting Author(s): Hong-Xu Liu
- Abstract
- Presentation
Abstract not provided
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Author of
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IBS04 - Hyperprogressive Disease (Ticketed Session) (ID 35)
- Event: WCLC 2019
- Type: Interactive Breakfast Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 07:00 - 08:00, Amsterdam (2011)
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IBS04.02 - Clinical Characteristics (Now Available) (ID 3326)
07:00 - 08:00 | Presenting Author(s): Benjamin Besse
- Abstract
- Presentation
Abstract not provided
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MA05 - Update on Clinical Trials and Treatments (ID 123)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:Seiki Hasegawa, Enrico Ruffini, Angel Artal
- Coordinates: 9/08/2019, 13:30 - 15:00, Melbourne (1991)
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MA05.11 - Safety and Efficacy of Nintedanib in Combination with Pembrolizumab in Patients with Refractory/Relapsing Malignant Pleural Mesothelioma (Now Available) (ID 2170)
13:30 - 15:00 | Author(s): Benjamin Besse
- Abstract
- Presentation
Background
Malignant pleural mesothelioma (MPM) is an aggressive disease with no standard of care after progression to first line pemetrexed and platinum-based chemotherapy. Combinations between anti-angiogenic agents and immunotherapy are being developed as angiogenesis and immunosuppression influence each other leading to a more powerful anti-tumor response. Both Nintedanib and Pembrolizumab have been investigated as single agents or in different treatment combinations in MPM patients with interesting activity.
Method
The PEMBIB trial is a multi-centric open-label non-randomized basket phase 1 trial evaluating the combination of nintedanib with pembrolizumab in multiple tumor types. The safety and activity of the dose escalation part of the study were reported at AACR & ASCO meetings in 2018 with an established DLT defined as grade 3 alanine and/or aspartate aminotransferase elevation (ALT/AST). The recommended phase 2 dose is set at 150 mg BID of nintedanib with 200 mg flat dose of pembrolizumab. We would like to report the safety and activity of one of the expansion cohorts of patients with relapsing/refractory MPM which has now been completed. Eligible MPM patients were 18 years or older with an ECOG performance status of 0 or 1, histologically proven MPM that relapsed after at least one line of pemetrexed and platinum-based combination, specific anti-angiogenic eligibility criteria such as no radiographic evidence of cavitary/necrotic or tumors with local invasion of major blood vessels.
Updated results on the safety profile and efficacy of this anti-angiogenic and anti-PD-1 combination therapy including overall response rate as per RECIST, irRC and mRECIST criteria, disease control rate will be presented at the meeting.
Result
The first patient from the MPM cohort was enrolled in July 2017 and the last one in April 2019. Thirty-one eligible MPM patients have been evaluable at the data cut off onJuly 2019, one of them had been enrolled since the dose-escalation part at dose level of 200mg. The age at inclusion was 68 (ranging from 38 to 85), 68% of the patients having an ECOG of 1 and 58% of the histological type was epithelioid. The most frequent adverse events (grades 1, 2 and 3) related to any of the combination drugs were liver enzymes increase, fatigue, decreased appetite, nausea, diarrhea and hypothyroidism. There were two cases of myocarditis, one of grade 3 (pembrolizumab related) and one of grade 5(pembrolizumab and nintedanib related). At the time of the data analysis the efficacy data shows six partial responses (overall response rate of 21%) and seventeen stable disease (disease control rate at 61%.).
Conclusion
The combination of Nintedanib with Pembrolizumab shows promising activity in relapsed MPM patients .The toxicity profile appear consistent with previous reports of anti-angiogenic agents and immunotherapy combination.
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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: 2
- Now Available
- Moderators:David R Spigel, Roberto Ferrara
- Coordinates: 9/08/2019, 13:30 - 15:00, Vancouver (2003)
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MA07.01 - Circulating Immature Neutrophils, Tumor-Associated Neutrophils and dNLR for Identification of Fast Progressors to Immunotherapy in NSCLC (Now Available) (ID 1618)
13:30 - 15:00 | Author(s): Benjamin Besse
- Abstract
- Presentation
Background
Neutrophils are active regulators of the antitumor immune response, with pro- and antitumor- properties, but generally are associated with progression (PD) and poor outcomes. We reported that pretreatment dNLR ((neutrophils/[leucocytes-neutrophils]; high>3) correlated with immune checkpoint inhibitor (ICI) outcomes in advanced (a) NSCLC pts. Although neutrophil population is heterogeneous, the immature neutrophils (i.e. CD15+CD244-CD16low, among others) seem to be a key subpopulation linked to PD. Tumor-associated neutrophils (TAN) can be also modulator on the microenvironment. We aimed to assess the role of pretreatment circulating immature-neutrophils and tissue-TAN, combined with dNLR, on ICI outcomes in aNSCLC pts.
Method
aNSCLC pts treated with ICI at our institution between 11/2012 and 08/2018 were eligible. Pretreatment immunophenotyping of monocytes, monocytic MDSC (mMDSC) and granulocytes (CD15, CD11b, CD33, CD244, CD16, CD14, CD32, CD64, HLA-DR) was prospectively performed by flow cytometry in fresh whole blood in 58 pts; we defined immature-neutrophils as CD15+CD244-CD16low. TAN in the stroma were assessed using H&E staining from archival specimen, available from 80 pts. dNLR was retrospectively collected; available from 343 pts. Correlation between baseline circulating neutrophils phenotype, TAN and dNLR was evaluated as well as their impact on outcomes: progression-free survival (PFS), overall (OS), including death before 12 weeks (12wk-death) (fast-PD)
Result
366 pts included; 320 (90%) smokers, median age 63; 280 (77%) nonsquamous, 117 (64%) ≥1%PDL1 and 183 missing. Median PFS (mPFS) was 1.93 months (m) [95%CI, 1.8-2.3] and mOS 8.8m [6.5-11.6]. Overall, 12wk-death rate was 31% [25.9-35.6].
Pretreatment high-dNLR (143/343; 42%) was correlated with poor PFS (P=0.002), OS P=0.0003) and a 12wk-death rate of 43% [34.5-50.9]. Pretreatment high immature-neutrophils (30/58; 53%), defined by logrank maximization method (>0.22%), were also associated with poor PFS (P=0.04), OS (P=0.0007) and a 12wk-death rate of 48.7% [26.7-64.1]. TAN (9/80; 11%) were not correlated with outcomes. There was not a correlation between immature-neutrophils, tissue-TAN and dNLR.
When evaluating pretreatment immature-neutrophils and dNLR together, we identified a fast-PD phenotype (high immature-neutrophils/high-dNLR, 10/58; 17%), with a mOS of 1.3m [0.73- not reached (NR)] and 12wk-death rate of 60% [14.5-81.3] compared to a responder-phenotype (low immature-neutrophils/low-dNLR, 12/58; 21%), associated with good outcomes: mOS NR [18.23-NR] (P=0.002).
Conclusion
Pretreatment high circulating immature-neutrophils (CD15+CD244-CD16low) correlate with early failure to ICI and fast-PD phenotype. The combination of circulating immature-neutrophils and dNLR could improve the identification of this population. The impact of immature-neutrophils on ICI should be more deeply explored.
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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): Benjamin Besse
- 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): 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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MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:Frank Griesinger, Lecia Sequist
- Coordinates: 9/09/2019, 14:00 - 15:30, Hilton Head (1978)
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MA11.11 - STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (Now Available) (ID 2898)
14:00 - 15:30 | Author(s): Benjamin Besse
- Abstract
- Presentation
Background
Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread use of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we present updated data on the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy from a large retrospective multi-institution international study.
Method
620 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 21 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 468 pts treated with first-line CPP (or >1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 152 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP.
Result
Among 468 CPP-treated pts, STK11/LKB1 genomic alterations (N=118) were associated with significantly shorter PFS (mPFS 5.0m vs 6.8m, HR 1.45, 95% CI 1.11 to 1.91; P=0.007) and shorter OS (mOS 10.6m vs 16.7m, HR 1.46, 95% CI 1.04 to 2.07; P=0.031) compared with STK11/LKB1-wt tumors (N=350). The likelihood of disease progression as BOR to CPP differed significantly between the two groups (29.5% vs 17%, P= 0.006). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N=435) (mPFS 5.0m vs 6.9m, HR 1.48, 95% CI 1.12-1.95, P=0.006 and mOS 10.6m vs 16.7m, HR 1.45, 95% CI 1.02-2.05, P=0.036). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not result in significant improvement of PFS (mPFS 5.0m vs 3.9m, HR 0.82, 95% CI 0.63 to 1.07, P=0.14) or OS (mOS 10.6m vs 9.1m, HR 0.93, 95% CI 0.67 to 1.30, P=0.69) compared to CP alone.
Conclusion
In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.
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MA21 - Non EGFR/MET Targeted Therapies (ID 153)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Targeted Therapy
- Presentations: 2
- Now Available
- Moderators:Benjamin Besse, Michael Thomas
- Coordinates: 9/10/2019, 14:30 - 16:00, Vienna (2016)
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MA21.07 - Circulating Tumor DNA Analysis Depicts Potential Mechanisms of Resistance to BRAF-Targeted Therapies in BRAF+ Non-Small Cell Lung Cancer (Now Available) (ID 1365)
14:30 - 16:00 | Author(s): Benjamin Besse
- Abstract
- Presentation
Background
Oncogenic BRAF-V600 mutations are observed in 1-2% of non-small cell lung cancer (NSCLC). Targeted therapies including vemurafenib (V), dabrafenib (D) or combination of dabrafenib plus trametinib (D+T) are associated with favorable outcomes in these patients (pts). The mechanisms of resistance to BRAF-targeted therapies (BRAF-TT) in NSCLC are largely unknown.
Method
We performed genomic profiling of serial circulating-tumor DNA (ctDNA) in a cohort of 79 metastatic BRAF-mutant NSCLC pts (96% V600E, 4% non-V600). BRAFmutational status was ascertained based on local testing. Plasma samples were collected, from 2014-2018 in 27 Hospitals, from pts treated with V (n=34), D (n=2) or D+T (n=23). We collected 41 plasma samples at baseline to BRAF-TT, 40 at progressive disease (PD) and ~200 samples during treatment follow-up, concomitant to routine radiological evaluation. Inivata InVisionSeq™ assay was used to detect the presence of SNVs, indels and CNAs in 36-cancer related genes.
Result
At baseline, 72,5% of BRAF mutations (V600E and non-V600E) were detected in plasma. BRAF-V600E detection in plasma was associated with the presence of liver metastasis, versus BRAF-V600E-negative cases (22% vs. 7%, respectively). Co-occurring molecular alterations at baseline, besides BRAF-V600E, were observed in 18/26 (70%) cases: FGFR2 (1pt), PIK3CA (2pts), ERBB2 (1pt), CTNNB1 (2pts) and IDH1 (2pts). FGFR2, PIK3CA or CTNNB1 alterations were associated with PD as the best response to the subsequent BRAF-TT. TP53 and STK11 mutations were observed in 54% (14/26) and 8% (2/26) of pts, respectively. Complete clearance of BRAF-V600E in plasma at baseline was observed at the first CT-scan evaluation in 42% (3/7) and 82% (9/11) pts treated with V or D+T, respectively. These pts were in complete or partial response, suggesting that monitoring BRAF-V600E levels in plasma on treatment may be a clinically useful marker of tumor response. At PD, a consistent rebound in BRAF-V600E plasma levels was observed in 60% (24/40) pts. Resistance to V was associated with alterations in the MAPK pathway: 1pt (KRAS), 1pt (GNA11), 1pt (NRAS and GNAS) and 1pt (MAP2K1 and NFE2L2). Activating PI3KCA mutations were observed in 4 pts who progressed in <6 months on V treatment. ctDNA analyses at PD under D+T revealed that, similar to what we observed in patients who progressed on V, alterations in KRAS, NRAS, PIK3CA and CTNNB1 are associated with D+T resistance. Prediction of the impact of these alterations, at the protein level, was assessed using in silico structure modeling and will be presented.
Conclusion
ctDNA monitoring might be an informative tool for assessing disease response and resistance in NSCLC pts treated with BRAF-TT. MAPK reactivation remains an important resistance mechanism to BRAFi-monotherapy or to BRAFi and MEKi combination therapy.
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MA21.09 - Tyrosine Kinase Inhibitors' Plasma Concentration and Oncogene-Addicted Advanced Non-Small Lung Cancer (aNSCLC) Resistance (Now Available) (ID 830)
14:30 - 16:00 | Author(s): Benjamin Besse
- Abstract
- Presentation
Background
The development of TKIs against driver molecular alteration has changed treatment paradigm in aNSCLC patients (pts). All tumors eventually progress and a resistance mechanism is identified in only a fraction of pts. Plasma concentration of TKI can decrease after chronic exposition but limited data are available. Our hypothesis is that an insufficient plasma exposure could contribute to tumor progression (PD).
Method
We assessed the plasma concentration of TKI in pts with aNSCLC harboring ALK rearrangement, EGFR or BRAF V600E mutation. We defined chronic exposure as a treatment administered > 3 months. Patients’ characteristics and co-medications were collected. Residual plasma concentrations were measured using Ultra Performance Liquid Chromatography coupled with tandem mass spectrometry validated methods. We compared results to currently recommended therapeutic targets and correlated exposure levels to treatment benefit.
Result
Between Apr. 2014 and Feb. 2019, 51 samples were prospectively collected (gefitinib n=11, osimertinib n=10, erlotinib n=13, crizotinib n=7, dabrafenib + trametinib n=5) in 41 pts. Median time of exposure was 20.3 months (range 2.18 - 67.813). Low plasma concentration was observed in 31 (61%) samples. Out of 14 samples collected in pts with ongoing benefit, 10 (71%) had low plasma exposure. Smoking status was associated with low plasma TKI concentration (P=0.01) whatever the TKI used. A total of 37 samples were collected at PD, 21 (57%) had low plasma exposure. The median time to treatment failure (TTF) in the ‘low exposure group' (n=31) was 14.9 months (95% CI 12.48 – 33.2) vs. 24.6 months (95% CI 8.65 -not reached (NR) in the ‘normal exposure group’ (P=0.55). No significant impact of protons pump inhibitors on TTF was found (p=0.12), including with gefitinib and erlotinib (p=0.76; n=24). In case of isolated brain PD (n=4), 3 pts (75%) had low plasma exposure. TKI dose was reduced in 14 pts because of toxicity, median TTF was 17.0 months (95% CI 10.4-NR) vs. 20.1 months (95% CI 10.4-59.8, P=0.45 in pts treated with standard dose. In the EGFR mutated aNSCLC population at PD (n=19), T790M resistance mutation was more frequent in the ‘normal exposure group’ (37.5%, n= 3/8,) than in the ‘low exposure group’ (9.1%, n=1/11), OR=0.13 95%CI (0.01-1.29), p=0.08.
Conclusion
TKI is underdose in the majority of aNSCLC patients at PD. Low TKI concentration were more frequent in pts without tumor resitance mechanism. Altogether, it suggests that low TKI exposure might contribute to PD.
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MA25 - Precision Medicine in Advanced NSCLC (ID 352)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Sebastian Defranchi, Karen Kelly
- Coordinates: 9/10/2019, 14:30 - 16:00, Dublin (1997)
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MA25.03 - Tumor-Infiltrating Lymphocytes (TIL) and Outcomes with Immunotherapy (ICI) or Chemotherapy in Advanced NSCLC (aNSCLC) Patients (Now Available) (ID 1374)
14:30 - 16:00 | Author(s): Benjamin Besse
- Abstract
- Presentation
Background
Tumor infiltrating lymphocytes (TIL) morphologically assessed is prognostic in early stages in several tumors. We previously reported the correlation of TIL with immune checkpoint inhibitors (ICI) outcomes in 98 advanced (a) NSCLC patients treated with ICI. We aimed to assess the role of TIL in a larger cohort treated with ICI, and in patients exclusively treated with chemotherapy (CT).
Method
aNSCLC patients with treated with single-agent ICI, with H&E stained sample available, were included between 11/2012 and 02/2017 in 3 cancer centers (immuno-cohort). Patient’s characteristics, biological data were retrospectively collected. The CT-cohort was extracted from the prospective MSN study (NCT02105168), between 06/2009 and 10/2016, enrolling aNSCLC patients treated with platinum-based CT, and tissue available. TIL in the stroma was evaluated in archival samples. High-TIL was defined as ≥10% density. Multivariate Cox model was used to study its prognostic values on overall and progression-free survival (OS, PFS).
Result
A total of 221 patients were included in the immuno-cohort: 142 (64%) male, with median (m) age of 63, 182 (84%) smokers, 161 (77%) PS≤1, 162 (63%) adenocarcinoma; 125 (57%) received ICI as second-line. High-TIL was observed in 49/221 (28%), non-assessable in 46. High-TIL had independent impact on OS and PFS (HR 0.40; 95% CI 0.25-0.63, P<0.0001). The mPFS and OS were 3.1months (mo.) (2.5-4.9) and 11mo. (7.0-13.2) respectively. The high-TIL group had mPFS of 13mo. (5.0-NR) vs. 2.2mo. (1.7-3.0) in low-TIL group (P<0.0001). High-TIL group had mOS not reached (NR) (12.2-NR) vs. 8.4 mo. (5.0-11.6) in low-TIL (P=0.007). The CT-cohort (N=189) had high-TIL in 103/189 (54%). The mPFS and mOS were 5.7mo. (4.9-6.7) and 11.7mo. (9.3-13.0) respectively, with no association with TIL.
OS, Immuno-cohort (n=221) OS, Chemo-cohort (n=188) Hazard ratio (HR)
95% confidence interval (CI)P-value HR
95% CIP-value TIL
≥10% (high)0.46 (0.28-0.81) 0.006 1.03 (0.76-1.41) 0.84 Age
≥65 y0.86 (0.50-1.46) 0.57 0.99 (0.72-1.38) 0.99 Line of treatment*
≥ second line0.69 (0.44-1.09) 0.11 0.84 (0.60-1.16) 0.29 N# metastatic sites
>21.40 (0.88-2.20) 0.16 1.50 (1.07-2.12) 0.02 Performance status
≥22.75 (1.73-4.37) <0.0001 1.94 (1.23-3.04) 0.004 Histology
Squamous1.13 (0.70-1.81) 0.62 1.09 (0.65-1.83) 0.75 *Line of treatment: lines of immunotherapy for the Immuno-cohort; lines of chemotherapy for the Chemo-cohort.
Conclusion
High-TIL (≥10%) is a simple and accessible marker associated with better ICI outcomes, but not with CT. This suggests a potential predictive value that must be validated in larger prospectively studies.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 2
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-110 - Novel Regimens Versus Standard-of-Care in NSCLC: A Phase II, Randomized, Open-Label, Platform Trial Using a Master Protocol (Now Available) (ID 2288)
09:45 - 18:00 | Author(s): Benjamin Besse
- Abstract
Background
Although non-small cell lung carcinoma (NSCLC) is intrinsically resistant to immunotherapy agents, a subset of tumors are susceptible to T cell-mediated antitumor effects. Treatment regimens combining agents that target different processes within the cancer immunity cycle have the potential to enhance response in relapsed or refractory NSCLC. GSK3359609 is a humanized IgG4 antibody with potent agonist activity against Inducible T cell Costimulator (ICOS) and no or low depleting effect on antibody-dependent cell-mediated cytotoxicity.
Method
This is a randomized, phase II, open-label, platform trial utilizing a master protocol in patients with advanced NSCLC who have progressed on initial PD1/PDL1-based immunotherapy and platinum-based chemotherapy. The trial will consist of several sub-studies, with each sub-study comparing novel combinations vs. current standard-of-care (SOC). No treatment crossover is allowed. Additional sub-studies may be added over time following protocol amendments. In the first sub-study, patients are centrally randomized by internet to SOC (docetaxel) or novel ICOS drug combination (NIDC) (GSK3359609 + docetaxel) in a 1:2 ratio, stratified by squamous versus non-squamous NSCLC and line of PD1/PDL1; randomization to SOC is minimized thereafter. Primary endpoint is overall survival (OS). Secondary endpoints are survival rate at 12 and 18 months; tumor response according to RECIST 1.1 and iRECIST criteria; pharmacokinetic parameters of the novel immunotherapy; and safety. Exploratory endpoints include tumor and blood-based biomarker evaluations such as tumor mutational burden and gene expression. Interim analysis of OS will be done after approximately 45 deaths in both study groups, with ≥18 deaths in the combination immunotherapy group; final analysis will be done after 85 deaths (35 in combination immunotherapy group). The study will employ a Bayesian decision-making framework based on predictive probability of observing a significant improvement in OS in a future phase III trial. A sample size of ≤70 participants in each combination immunotherapy group and ≥35 participants in the SOC group will provide ≥81% power with a type 1 error of ≤2.3% for each pairwise comparison.
Sub-study 1 will compare the efficacy of GSK3359609 plus docetaxel versus docetaxel alone. At least 105 patients are expected to enroll. GSK3359609/docetaxel will be administered for ≤2 years or 35 visits, or until disease progression, death or unacceptable toxicity. Both drugs are given as an IV infusion (docetaxel 75mg/m2; GSK3359609 80 mg).
Result
Study enrollment has begun and the primary endpoint results of sub-study 1 are expected mid-2020.
Conclusion
The study will provide information on the efficacy of novel immunotherapies used in combination.
GlaxoSmithKline (NCT03739710).
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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): Benjamin Besse
- 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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P1.04 - Immuno-oncology (ID 164)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.04-31 - Immunosenescence Correlates with Poor Outcome from PD-(L)1 Blockade but Not Chemotherapy in Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 2268)
09:45 - 18:00 | Author(s): Benjamin Besse
- Abstract
Background
CD28, CD57 and KLRG1 on circulating T-lymphocytes have been identified as markers of immunosenescence. The characterization of a senescent immune phenotype (SIP) in advanced NSCLC (aNSCLC) and its impact on anti-PD(L)-1 (IO) or platinum-based chemotherapy (PCT) treatments are unknown.
Method
The percentage of circulating CD8+CD28-CD57+KLRG1+ T-lymphocytes (SIP) was assessed by flow cytometry on fresh blood from aNSCLC patients treated with IO or PCT. A SIP cut-off was identified by log-rank maximation method. Correlations with categorical or continuous variables were performed by logistic regression or t-test. Survival curves were estimated with Kaplan Meier and compared with log-rank.
Result
In the IO cohort, 43 patients were evaluated for SIP: 32% ≥ 65 years, 92% non-squamous, 51% with tumoral PD-L1 expression ≥1%, 93% chemotherapy pretreated. Disease control rate (DCR), median PFS and OS and FU were 57%, 4.6 (95% CI 0.5; 8.8) months, 13 (95% CI 2.8-23.2) months, and 14 (95% CI 8.8-19.8) months, respectively.
SIP median value was 15.4% (min 1.6%, max 57.7%). 32% of patients had >21.72% CD28-CD57+KLRG1+CD8+ lymphocytes (SIP+). SIP was not significantly associated with clinical characteristics. SIP changed according to IO response by T-sne algorithm (Figure 1A). Compared to SIP-, SIP+ patients had significantly lower DCR (81% vs 28%, p=0.002), PFS [7.3 (95% CI 4.1; 10.4) vs 1.7 (95% CI 1.2; 2.3), p=0.02] and OS [NR (95% CI 6.04; NR) vs 2.4 (95% CI 1.7; 3.1), p=0.01].
SIP was significantly associated with specific immune populations [higher peripheral activated (Ox40+ICOS+PD1+) T-regulatory (CD25highCD127low) cells, TEMRA (CCR7-CD45RA+) CD8+ and T-helper 1 (CXCR5-CXCR3+CCR4-CCR6-CCR10-) CD4+] (Figure 1B). The PCT cohort included 61 patients, 43% SIP+. No significant difference in DCR, PFS or OS were observed according to SIP.
Conclusion
Immunosenescence is observed in 32% of aNSCLC patients before IO and correlates with specific immune phenotypes. Immunosenescence predicts lower DCR, PFS and OS from IO but not from PCT.
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P1.10 - Prevention and Tobacco Control (ID 175)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Prevention and Tobacco Control
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.10-06 - Pathological Characterization of Radon-Induced Lung Cancer in Rats (ID 1616)
09:45 - 18:00 | Author(s): Benjamin Besse
- Abstract
Background
Radon is a radioactive gas, considered the leading cause of lung cancer in non-smokers. Although the risk of lung cancer is linear, there is no safe level and even low dose can be associated with risk. In humans, no specific pathological subtypes of lung cancer have been clearly associated with radon. In animals, the French Atomic Energy Commission (CEA) exposed to low dose of radon (25 working level month, WLM) a large cohort of rats in a radon-exposure chamber, showing lung cancer induced by low exposure (Chameaud J, Radiation Prot Dosimetry 1984). We aimed to describe pathological features of radon-induced tumors in rats from the CEA’s cohort.
Method
Retrospective assessment of archival samples available of the rats exposed to low-dose radon in the Laboratoire de Pathologie Pulmonaire Experimentale, COGEMA (France), between 1989 and 1992. Autopsy reports were also reviewed. The pathological assessment was performed for a thoracic oncology pathologist (JA) in H&E staining slides according to the current WHO histological classification.
Result
Samples from 117 rats were collected. Among 104 tumors, to date the analysis has been performed in 94. Forty tumors (43%) were classified as malignant, 28 (30%) as uncertain malignant potential (UMP) and 26 (28%) benign. In 2 rats (2%) synchronous malignant and non-malignant tumors were observed.
Among the malignant tumors, 23 (58%) were epithelial and 17 (42%) non-epithelial. Lung carcinoma was the most common primary epithelial tumor (n=10, 43%), followed by abdominal area tumors (n=5, 22%), and thyroid (n=3, 13%). In the UMP group, 7 (25%) were epithelial and 21 (75%) non-epithelial, with no lung tumors observed. In the benign group, most of them (n=24, 92%) were epithelial, with 4 cases with lung atypical adenomatous hyperplasia-like lesions; 2 synchronous with other malignant tumors (n=1 lymphoma, n=1 cutaneous squamous cell carcinoma).
A total of 26 tumors (27%) had thoracic involvement: 4 (15%) primary lung non-malignant lesions, 11 primary lung malignancies (42%) and 11 with metastases from other tumors (42%). As primary malignant lung tumors, we observed: 7 (64%) adenocarcinoma in situ, one papillary adenocarcinoma, one undifferentiated large cell carcinoma with bilateral metastases, one metastatic squamous carcinoma and one metastatic undifferentiated tumor, compatible with sarcoma
Conclusion
In this cohort of radon-induced tumors in rats, we observed different tumor types, from non-malignant lesions to aggressive malignancies, with predominance of epithelial tumors. Lung carcinoma was the most common primary tumor and adenocarcinoma the histological subtype more observed, with histological similarities with humans.
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P1.12 - Small Cell Lung Cancer/NET (ID 179)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.12-03 - Antitumor Activity of Single Agent Lurbinectedin in Patients with Relapsed SCLC Occurring ≥30 Days After Last Platinum Dose (ID 1710)
09:45 - 18:00 | Author(s): Benjamin Besse
- Abstract
Background
Lurbinectedin (L) inhibits activated transcription and induces DNA double-strand breaks, leading to apoptosis.
Method
This multicenter, single agent, phase II Basket trial treated a cohort of 105 SCLC patients (pts) with ECOG PS 0-2 who had received one prior chemotherapy line. L 3.2 mg/m2 was administered as a 1-hour i.v. infusion on Day 1 q3wk. Primary endpoint, confirmed overall response rate (ORR) by RECIST v.1.1 according to investigator assessment, was met (ORR=35.2%; 95% CI, 26.2-45.2%). A sub-analysis excluding the 21 pts with disease relapse < 30 days after last platinum dose is reported here.
Result
Median age of 84 evaluated pts was 60 years (range, 41-83), 58.3% were male, ECOG PS 0-1/2 in 96/4%, liver metastasis in 36.9%, history of CNS involvement in 4.8%, prior platinum in 100%, median chemotherapy-free interval (CTFI)=3.9 months (1.1-16.1); prior immunotherapy in 8.3%. A median of 5.5 cycles (range, 1-24) was administered.
ORR, % (95% CI) (confirmed responses) (n=84)
40.5 (29.9-51.7)*
CTFI≥90d (n=60)
45.0 (32.1-58.4)
CTFI 30-89d (n=24)
29.2 (12.6-51.1)
Disease Control Rate at 6 months, % (n=84)
48.8
Median duration of response (months) (95% CI) (n=34)
5.3 (3.5-6.4)
CTFI≥90d (n=27)
6.2 (3.5-7.3)
CTFI 30-89d (n=7)
4.1 (2.6-5.3)
Median overall survival (months) (95% CI) (n=84)**
10.9 (7.8-14.9)
CTFI≥90d (n=60)**
11.9 (9.7-16.2)
CTFI 30-89d (n=24)**
(4.1-7.6)
*4 of 7 pts who failed prior immunotherapy had confirmed response
**Preliminary data
L was well tolerated. Neutropenia was the most common adverse event (AE) (G3:21.5% and G4:25%), whereas febrile neutropenia was reported in 2.4%. Most common non-hematological AEs included fatigue (G3: 7.1%), nausea and vomiting (all G1-2: 32.1% and 16.7%) and transaminase increase (G3:7.2%). There was no death due to treatment related AE.
Conclusion
L is an active agent for second-line treatment of SCLC. The highest ORR (45.0%) was reported for pts with CTFI≥90d. Notable antitumor activity (ORR=29.2%) was also observed in pts with CTFI 30-89d, for whom no therapy is currently approved. Hence, L is a valuable therapeutic option for SCLC pts with disease relapse after first-line platinum-based therapy.
Updated trial results will be presented at the conference.
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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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P2.01-07 - Open-Label, Biomarker-Directed Platform Study in NSCLC Patients Who Progressed on an Anti-PD-(L)1-Containing Therapy (HUDSON) (ID 643)
10:15 - 18:15 | Author(s): Benjamin Besse
- Abstract
Background
Immune checkpoint inhibitor (ICI)-containing regimens have significantly improved survival outcomes in first- and second-line non-small cell lung cancer (NSCLC). However, few patients have-durable responses to anti-programmed cell death‑1/programmed cell death-ligand 1 (anti-PD-[L]1)-containing therapy (primary resistance) or other patients progress during anti-PD-(L)1-containing therapy (acquired resistance). HUDSON addresses the urgent need to identify new treatments and understand ICI resistance for patients who progressed after receiving anti-PD-(L)1-containing therapy.
Method
HUDSON is a multi-centre, international, multi-arm, platform study (NCT03334617), which will 1) evaluate therapies to reverse ICI resistance and 2) define mechanisms of ICI resistance in patients with NSCLC who have progressed following standard-of-care platinum- and ICI-based therapies. HUDSON consists of biomarker matched and non-matched groups (Figure). Allocation is guided by tumour molecular profile, using a pre-specified algorithm. Pre-existing local next generation sequence (NGS) data enables rapid patient allocation to biomarker-matched groups. Central molecular profiling comprises NGS and immunohistochemistry data. New groups will be added as new translational hypotheses emerge. Translational research will employ serial peripheral blood samples (including ctDNA) and tumour biopsies.
Figure. Study design and biomarker prevalence
Result
Enrolment is ongoing; as of 01 April 2019, patients have been dosed in each of the drug combinations currently open for recruitment. Analyses of tissue and blood samples collected for exploratory research are ongoing, including genomic, transcriptomic and chemistry biomarkers such as tumour mutation burden, human leukocyte antigen status, T-cell receptor repertoire, and peripheral immune activation signatures.
Conclusion
Specific differences between patients on individual HUDSON arms that inform anti-PD(L)1 resistance mechanisms, plus learnings from the implementation of this innovative and complex platform study will be presented.
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PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)
- Event: WCLC 2019
- Type: Plenary Session
- Track:
- Presentations: 1
- Now Available
- Moderators:Giorgio Vittorio Scagliotti, Ramon Rami-Porta
- Coordinates: 9/09/2019, 08:00 - 10:15, Barcelona (2005)
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PL02.08 - Registrational Results of LIBRETTO-001: A Phase 1/2 Trial of LOXO-292 in Patients with RET Fusion-Positive Lung Cancers (Now Available) (ID 964)
08:00 - 10:15 | Author(s): Benjamin Besse
- Abstract
- Presentation
Background
No targeted therapy is currently approved for patients with RET fusion-positive non-small cell lung cancer (NSCLC). LOXO-292 is a highly selective RET inhibitor with activity against diverse RET fusions, activating RET mutations and brain metastases. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion-positive NSCLC in August 2018.
Method
This global phase 1/2 study (87 sites, 16 countries) enrolled patients with advanced RET-altered solid tumors including RET fusion-positive NSCLC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. The phase 1 portion established the MTD/RP2D (160 mg BID). The phase 2 portion enrolled patients to one of six cohorts based on tumor type, RET alteration, and prior therapies. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, CNS ORR, CNS DoR, PFS, OS, safety and PK.
Result
As of 17-June 2019, 253 RET fusion-positive NSCLC patients were treated. The primary analysis set (PAS) for LOXO-292 registration, as defined with the US FDA, consists of the first 105 consecutively enrolled RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy; 58 patients (55%) also received prior anti PD-1/PD-L1 agents. The majority of PAS responders have been followed for ≥6 months from first response. Of the remaining 148 patients, 79 had previously been treated with platinum-based chemotherapy, 55 did not receive prior platinum-based chemotherapy and 14 did not have measurable disease at baseline.
Conclusion
Among PAS patients, the investigator-assessed ORR was 68% (95% CI 58-76%, n=71/105, 2 PRs pending confirmation). Responses did not differ by fusion partner or the type or number of prior therapies, including chemotherapy, anti PD-1/PD-L1 agents and multikinase inhibitors with anti-RET activity. The median DoR was 20.3 months (95% CI 13.8-24.0) with a median follow-up of 8 months; as evidenced by the wide confidence interval, this DoR estimate is not statistically stable due to a low number of events (16 of 69 confirmed responders). The intracranial ORR was 91% (n=10/11: 2 confirmed CRs, 8 confirmed PRs) for patients with measurable brain metastases at baseline.
The ORR in efficacy evaluable treatment naïve RET fusion-positive NSCLC patients was 85% (95% CI 69-95%, n=29/34, 7 PRs pending confirmation). In the safety data set of all 531 patients, 5 treatment-related AEs occurred in ≥15% of patients: dry mouth, diarrhea, hypertension, increased AST and increased ALT. Most AEs were grade 1-2. Only 9 of 531 (1.7%) patients discontinued LOXO-292 for treatment-related AEs.
LOXO-292 had marked antitumor activity in RET fusion-positive NSCLC patients and was well tolerated. These data will form the basis of an FDA NDA submission later this year.
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