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Keunchil Park
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PL 02 - Presidential Symposium including Top 3 Abstracts and James Cox Lectureship Award Presentation (ID 585)
- Event: WCLC 2017
- Type: Plenary Session
- Track: Early Stage NSCLC
- Presentations: 7
- Moderators:Hisao Asamura, Keunchil Park
- Coordinates: 10/17/2017, 08:15 - 09:45, Plenary Hall (Exhibit Hall D)
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PL 02.02 - Patient-Reported Outcomes with Durvalumab after Chemoradiation in Locally Advanced, Unresectable NSCLC: Data from PACIFIC (ID 10762)
08:20 - 08:30 | Presenting Author(s): R. Hui | Author(s): M. Özgüroğlu, D. Daniel, D.V. Baz, S. Murakami, T. Yokoi, A. Chiappori, K.H. Lee, M. De Wit, B. Chul Cho, J.E. Gray, A. Rydén, L. Viviers, L. Poole, P.A. Dennis, S.J. Antonia
- Abstract
- Presentation
Background:
Durvalumab, an engineered human IgG1 anti-PD-L1 mAb, demonstrated an improvement in PFS vs placebo and favorable benefit/risk profile in the Phase 3 PACIFIC study in locally advanced, unresectable NSCLC. Here we summarize patient-reported outcomes from PACIFIC.
Method:
In the randomized, double-blind, Phase 3 PACIFIC study (NCT02125461), patients who had previously received ≥2 cycles of platinum-based concurrent chemotherapy with definitive dose radiation without disease progression were randomized (2:1) to durvalumab 10 mg/kg i.v. q2w or placebo for up to 12 months. Secondary endpoints included evaluation of symptoms, function and global health status/QoL using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 v3 questionnaire and its lung cancer module, QLQ-LC13. Patients completed the questionnaires at baseline, Week 4, Week 8, q8w until Week 48, then q12w until disease progression. Changes from baseline for key symptoms were analyzed using a mixed model for repeated measures (MMRM). Time to deterioration (TTD) and odds of improvement were analyzed. Deterioration or improvement was defined as a change in score from baseline ≥10. Hazard ratios (HR) were calculated using a stratified log-rank test and odds ratios (OR) using logistic regression.
Result:
Compliance with completing the questionnaires was high in both durvalumab (n=476) and placebo (n=237) groups (>80% up to Week 48). There were no differences between groups at baseline in symptoms, function or global health status/QoL. MMRM analysis showed no statistically significant differences between treatment groups in adjusted mean changes from baseline (average over 12 months) in the prespecified symptoms of dyspnea, cough, chest pain, fatigue and appetite loss, and for global health status/QoL and physical functioning. Clinically relevant improvements from baseline were observed throughout the study in both durvalumab and placebo groups for dysphagia (mean [SD] change at Week 48, −14.2 [26.1] and −14.8 [25.3], respectively) and alopecia (−22.1 [33.0] and −21.4 [29.5]). There were no differences in median TTD between groups except ‘other pain’ (9.2 months with durvalumab vs 5.6 months with placebo [HR 0.72; 95%CI 0.58, 0.89]). The only difference in improvement rates between groups was for appetite loss (26.1% improvement rate with durvalumab vs 24.9% with placebo [OR 1.72; 95%CI 1.04, 2.85]). Other symptoms, function and health-related QoL remained stable throughout with no between-group differences in TTD or improvement rates.
Conclusion:
Durvalumab treatment did not worsen symptoms, function or health-related QoL. Clinically relevant improvement in alopecia and dysphagia with durvalumab and placebo was likely due to resolution of toxicities related to prior chemoradiation.
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PL 02.03 - Discussant - PL 02.02 (ID 10865)
08:30 - 08:40 | Presenting Author(s): Michael Boyer
- Abstract
- Presentation
Abstract not provided
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PL 02.04 - SCAT Ph III Trial: Adjuvant CT Based on BRCA1 Levels in NSCLC N+ Resected Patients. Final Survival Results a Spanish Lung Cancer Group Trial (ID 9523)
08:40 - 08:50 | Presenting Author(s): Bartomeu Massuti | Author(s): Manuel Cobo Dols, M. Rodriguez-Paniagua, I. Ballesteros, T. Morán, R. Arrabal, J.L. González-Larriba, I. Barneto, Y.W. Pun, J. De Castro, S. Ponce Aix, C. Baamonde, M.A. Muñoz, G. López-Vivanco, J.J. Rivas De Andrés, D. Isla, R. López, José Miguel Sánchez-Torres, J. Sánchez Paya, Rafael Rosell
- Abstract
- Presentation
Background:
Postop platinum-based CT is considered standard of care in resected NSCLC with lymph node involvement. BRCA1 and BRCA2 are important DNA repair factors primarily involved in the repair of double strand DNA breaks. BRCA-1 functions may act as a differential regulator of response to cisplatin (Cis) and antimicrotubule agents. BRCA1 defficiency enhances Cis resistance and loss of BRCA1 function is associated to sensitivity to DNA-damaging CT and may also be associated with resistance to spindle poisons.
Method:
SCAT randomized phase III multicenter trial tests individualized optimal CT based on expression of BRCA1. After surgery patients (p) with St II and Iii NCSLC were random 1:3 to control arm (3 cycles Cis-Docetaxel) or to experimental arm with treatment assigned according BRCA1 expression levels (low levels: Cis-Gemcitabine; intermediate levels: Cis-Doc; high levels: Docetaxel alone). Stratification factors: N1 vs N2; age < or > 65 y; non-Squamous vs Squamous (Sq) histology; lobectomy vs pneumonectomy). Planned PORT in N2. Primary end-point OS. Secondary end-points DFS, toxicity profile (CTCAE v 3.0) /compliance, recurrence pattern. Statistical hypothesis: 5y survival rate control group (45%) could be increase 20% in experimental arm.
Result:
From June/2007 to May/2013, a total of 591 p were screened and 500 of them were randomized in the study, 108 in control arm, 392 in experimental arm. In experimental arm 110 p received Cis-Gem, 127 Cis-Doc and 110 Doc alone. There were no significant differences between arm for known prognostic factors: Median age 64 y; 79% males, 21% females; 43% Sq, 49% Adenoca, 8% others; 57% former smokers, 32% current smokers, 11% never smokers; pneumonectomy 26%; N1 58%, N2 48%. Median tumor size 4.4 cm (0.8-15.5 cm). Median mRNA BRCA1 levels 15.78 (0.73-132). Mean BRCA1 levels 6.95 in Adenoca vs 20.29 in Sq (p<0.001). Compliance of CT was better in experimental arm with less dose-reductions and without differences according extent of surgery. CT compliance was lower in patients older 70 y. Median PFS: 38.7 m (control), 32.2 m Cis-Gem, 34.3 m Cis-Doc and 41 m Doc. At 5 years, event-free rate is 54% in control arm and 56% in experimental arm and median OS 73.3 m (control) vs 77.5 m (exp) (p=0.75). In experimental arm: Docetaxel alone 80.2 m, Cis-Doc 80.5 m and Cis-Gem 74 m.
Conclusion:
Higher survival than expected in patients with lymph node involvement. No significant difference in survival achieved with the experimental arm. In case of high levels BRCA CT treatment without cisplatin is not detrimental. (Eudract:2007-000067-15; NCTgov: 00478699)
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PL 02.05 - Discussant - PL 02.04 (ID 10869)
08:50 - 09:00 | Presenting Author(s): Joan Schiller
- Abstract
- Presentation
Abstract not provided
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PL 02.06 - The IASLC Lung Cancer Staging Project: Analysis of Resection Margin Status and Proposals for R Status Descriptors for Non-Small Cell Lung Cancer (ID 10325)
09:00 - 09:10 | Presenting Author(s): John G Edwards | Author(s): K. Chansky, L. Shemanski, Paul Emile Van Schil, Hisao Asamura, Ramon Rami-Porta
- Abstract
- Presentation
Background:
The residual tumor (R) classification describes the tumor status after treatment. It reflects the effectiveness of treatment, has prognostic impact and may affect further treatment. We analyzed existing and potential R status criteria, including the proposed IASLC definition for “uncertain” resection margin status (2005), from data collected for the IASLC Lung Cancer Staging Project.
Method:
This analysis is based on 14,712 patients undergoing NCSLC surgery, for whom full R status and survival data were available. R status criteria and the following data were evaluated: number of N2 stations explored; lobe-specific systematic lymph node dissection (SLND); extra-capsular extension (ECE); status of the highest station; bronchial carcinoma in situ (cis) at bronchial resection margin (BRM); pleural lavage cytology (PLC). Revised categories of R0, R(un), R1 and R2 were designated and tested for survival impact.
Result:
There were 14,293 R0, 263 R1 and 156 R2 cases, with median survival not reached, 33 and 29 months (p<0.0001). R status correlated with T and N stages (p<0.0001). Greater or equal to 3 N2 stations were explored for 9,290 cases (63%) and lobe-specific SLND in 6,619 (45%), with positive associations for increasing pN2 stage (p<0.0001). ECE was recorded in 61 (20%) of 304 N+ cases evaluated. The highest station was positive in 942 (6.4%) cases. PLC was positive in 59 (3.6%) of 1,646 cases and there was BRM cis in 13 cases. After reassignment according to the IASLC proposed definition, there were 6,103 R0 cases, 8,203 R(un), 250 R1 and 156 R2. Figure 1
Conclusion:
These data confirm the proposed criteria for Uncertain R status, R(un), with a prognosis stratifying between R0 and R1. Further detailed prospective data collection is required to characterize fully the prognostic impact of these criteria. Detailed evaluation of R status is of particular importance in the design and analyses of clinical trials of adjuvant therapies.
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PL 02.07 - Discussant - PL 02.06 (ID 10870)
09:10 - 09:20 | Presenting Author(s): Kemp Kernstine
- Abstract
- Presentation
Abstract not provided
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PL 02.08 - James Cox Lectureship Award Presentation (ID 10868)
09:20 - 09:45 | Presenting Author(s): James D. Cox
- Abstract
- Presentation
Abstract not provided
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PL 03 - Immunology in Lung Cancer Update 2017 (ID 584)
- Event: WCLC 2017
- Type: Plenary Session
- Track: Immunology and Immunotherapy
- Presentations: 4
- Moderators:David P Carbone, Keunchil Park
- Coordinates: 10/18/2017, 08:15 - 09:45, Plenary Hall (Exhibit Hall D)
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PL 03.01 - Serendipities of Acquired Immunity (ID 7834)
08:15 - 08:45 | Presenting Author(s): Tasuku Honjo
- Abstract
- Presentation
Abstract:
Summary of the Lecture “Serendipities of acquired immunity” In 1992, we started working on PD-1 and found that this acts as a brake in the immune system. Then, in 2002, we discovered that PD-1 inhibition could be effective in treating cancer in animal models. After 22 years of study, this idea has borne fruit in a new, breakthrough immunotherapy that is being hailed as a 'penicillin moment' in cancer treatment. I believe that, just as a number of antibiotics developed in the wake of the discovery of penicillin now protect humans against threats of infectious diseases, this discovery will play a leading role in advancement of cancer immunotherapy so that in the future the fear of dying from cancer will cease to exist. Through evolution, vertebrate animals have developed immunity against infection by microorganisms. In the process, they incidentally acquired a sophisticated system for diversifying genomic information by combining gene fragments. It was doubly fortunate that the success in cancer treatment via PD-1 inhibition brought the realization that immunity, a “weapon” against infectious diseases, could also serve as a “shield” against cancer. It has been said that, whereas humankind’s greatest enemies in the 20th century were infectious diseases, cancer is the major foe in the 21st century. It is a pleasant surprise to discover that the acquired immunity system holds the keys to overcoming both of these difficult medical challenges.
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PL 03.02 - Biomarkers in Immunooncology Therapy (ID 7835)
08:45 - 09:05 | Presenting Author(s): Naiyer Rizvi
- Abstract
- Presentation
Abstract not provided
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PL 03.03 - Blueprint 2: PD-L1 Immunohistochemistry Comparability Study in Real-Life, Clinical Samples (ID 7836)
09:05 - 09:25 | Presenting Author(s): Ming Sound Tsao | Author(s): Keith M Kerr, Yasushi Yatabe, Fred R. Hirsch
- Abstract
- Presentation
Abstract:
PD-L1 immunohistochemistry (IHC) has been established as companion or complementary diagnostic assays, each having been developed as a predictive biomarker for specific anti-PD-1/PD-L1 immunotherapies.[1] The Blueprint phase 1 was conducted as a feasibility study to assess the staining (analytical) comparability of four PD-L1 IHC assays (22C3, 28-8, SP142, and SP263) that were developed for their respective immune checkpoint inhibitor therapies.[2] Without correlation with treatment outcome, the study also assessed the putative diagnostic performance of these assays through comparisons of PD-L1 status classification above and below selected expression cutoffs associated with the clinical use of various assays. Serial sections from paraffin blocks of 39 resected non-small cell lung cancers (NSCLC) were stained using assays that were used in the clinical trials, and three experts in interpreting the four respective assays independently assessed the percentages of tumor and immune cells staining positive at any intensity. The results demonstrated that three PD-L1 assays (28-8, 22C3, SP263) showed comparable analytical performance for assessment of PD-L1 expression on tumor cells, while the SP-142 PD-L1 assay appeared to stain less tumor cells compared to the other assays.[2] In contrast, all assays stained tumor infiltrating immune cells, but with poor concordance between assays. The phase 1 study had several limitations: (1) samples were obtained from a commercial source and did not necessarily reflect the real-world samples tested clinically, and (2) the number of pathologists involved in the scoring was small. In addition, a fifth PD-L1 assay (73-10) has since been developed as a potential biomarker for avelumab (EMD Serono/Merck KGaA/Pfizer). The goals of Blueprint phase 2 are: (1) to validate the assay comparability results obtained in Blueprint phase 1 study using real world clinical lung cancer samples and all five clinically used PD-L1 assays (28-8, 22C3, SP142, SP263, and 73-10), (2) to assess the comparability and heterogeneity of PD-L1 assay results in surgical tumor resection, core needle and FNA samples prepared from same tumor, and (3) to assess the concordance of PD-L1 scoring by pathologists from around the world using standard light microscopy vs. digital images accessed by a web-based system. In blueprint phase 2A, 18 participating pathologists, with respective institutional research ethics board approval, contributed unstained serial sections from altogether 81 lung cancer cases that came through routine clinical practice. These included 40 adenocarcinomas, 25 squamous cell carcinomas, 5 poorly differentiated non-small cell carcinoma and 11 small cell carcinomas. The cases included resected tumor (n=20), core/bronchial biopsies (n=20), tumor positive lymph node biopsy/resection (n=20) and cytology cell block (n=21) samples. In blueprint phase 2B, 9 pathologists prepared from 30 freshly resected NSCLC specimens, paraffin blocks of matched resection, core needle and fine needle aspiration samples. Each slide set of 81 cases from phase 2A were stained with the FDA-cleared (28-8, 22C3, SP142) or clinical trial (SP263 and 73-10) PD-L1 assays, in a CLIA-approved immunohistochemistry laboratory. The slides were scored by 24 experienced pulmonary pathologists (IASLC Pathology committee Blueprint phase 2 members),[4] all having received group training on scoring the PD-L1 IHC on tumor and immune cells. PD-L1 stained tumor cells were scored as continuous number (0% to 100%), and placed into 1 of 7 categories (<1%, 1-4%, 5-9%, 10-24%, 25-49%, 50-79%, 80-100%). These categories represent cut-offs that have been used in various immune checkpoint inhibitor trials. All assays were also scored for immune cell PD-L1 staining based on the scoring system developed for the SP-142 assay. As only one set of glass slides is available for each assay, each pathologist was randomly assigned to conduct the scoring using microscope (2 glass assays) or by web-based digital images (3 digital assays). The inter-assay concordance of PD-L1 staining on tumor cells and tumor infiltrating immune cells will be assessed using the mean scores from all pathologists. The large sample size scores should provide more reliable data on their analytical comparability. Inter-pathologist concordance results should provide evidence on reliability of scoring with different cut-points. Importantly, the above concordance results across different sample types should also provide insights on potential variability and feasibility in PD-L1 scoring across different sample types, especially cytology samples. This may then allow for a broad implementation strategy on PD-L1 testing in clinical practice. The results of phase 2A will be presented at the meeting.IASLC Pathology Committee Blueprint phase 2 members: Mary-Beth Beasley, Alain Borczuk, Johan Botling, Lukas Bubendorf, Gang Chen, Lucian Chirieac, Teh-Ying Chou, Jin-Haeng Chung, Sanja Dacic, Fred R. Hirsch, Keith M. Kerr, Mari Mino-Kenudson, Sylvie Lantuejoul, Andre Moreira, Andrew Nicholson, Masayuki Noguchi, Guiseppe Pelosi, Claudia Poleri, Prudence Russell, Jennifer Sauter, Erik Thunnissen, William D. Travis, Ming S. Tsao, Ignacio Wistuba, Murry Wynes, Yasushi Yatabe, Hui Yu. References: IASLC ATLAS of PD-L1 Immunohistochemistry Testing in Lung Cancer. M.S.Tsao, K.M. Kerr, Y. Yatabe, S. Dacic, F.R. Hirsch (Editors), International Association for Study of Lung Cancer (IASLC) Press, 2017 Hirsch FR, McElhinny A, Stanforth D, et al. PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the "Blueprint PD-L1 IHC Assay Comparison Project". J Thorac Oncol. 2017 Feb;12(2):208-222. Feng Z, Schlichting M, Helwig C, et al. Comparative study of two PD-L1 expression assays in patients with non-small cell lung cancer (NSCLC). J Clin Oncol 35, 2017 (suppl; abstr e20581)
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PL 03.04 - Current Status and Future of Immunotherapy in Lung Cancer (ID 7837)
09:25 - 09:45 | Presenting Author(s): Martin Reck
- Abstract
- Presentation
Abstract:
The therapeutic approach to overcome Tumor-induced suppression of specific T-cell activation by using specific antibodies, which are interacting with regulating pathways, the immune check-points has substantially changed treatment of patients with advanced NSCLC. In particular the development of antibodies inhibiting cytotoxic T-lymphocyte-associated antigen 4 (anti CTL4), programmed death receptor 1 (anti PD-1) or programmed death receptor ligand 1 (anti PDL-1) have shown efficacy in NSCLC. In five randomized trials anti PD-1/anti PD-L1 antibodies have shown significant improvement in overall survival (OS) compared to chemotherapy and an improved safety profile. Efficacy was correlated to PD-L1 expression on tumor cells. However confirmed activity has also been documented in patients with PD-L1 negative tumors. Besides harmonization of different existing tests for assessment of PD-L1 expression identification of novel markers like tumor mutational burden (TMB) might help to identify best benefitting patients. In selected patients with high PD-L1 expression on tumor cells (TPS =/> 50%) monotherapy with the anti PD1 antibody pembrolizumab has demonstrated superiority in response, progression free survival and OS compared to platinum based chemotherapy in first-line treatment. Current randomized trials evaluate the activity of combinations of chemotherapy with checkpoint inhibitors or of immunotherapy combinations compared to chemotherapy and will provide important information about the next steps in the development of immunotherapy in lung cancer. For the future the development of novel immunotherapeutic agents either as monotherapy or in combination with checkpoint inhibitors as well as the understanding of resistance mechanisms and strategies to overcome resistance will be of paramount importance.
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Author of
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MA 03 - Chemotherapy (ID 651)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Jin-Hyoung Kang, W. Su
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 502
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MA 03.06 - Effect of 2L Ramucirumab after Rapid Time to Progression on 1L Therapy: Subgroup Analysis of REVEL in Advanced NSCLC (ID 7947)
11:35 - 11:40 | Author(s): Keunchil Park
- Abstract
- Presentation
Background:
In REVEL, ramucirumab+docetaxel in the second-line (2L) treatment of patients with advanced NSCLC led to improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), independent of histology. This exploratory, post-hoc analysis focuses on patients who progressed rapidly on first-line (1L), and who traditionally have a poor prognosis in the 2L setting. In REVEL, treatment benefit was observed in patients with progressive disease as their best overall response to 1L and in patients who were on 1L for only a short time (Reck M, ASCO 2017, Abstr 9079). Here, we report outcomes from patients who participated in REVEL according to their time to tumor progression (TTP) on 1L (ClinicalTrials.gov, NCT01168973).
Method:
Patients with advanced NSCLC of squamous or nonsquamous histology with disease progression during or after 1L platinum-based chemotherapy were randomized (1:1) to receive docetaxel 75 mg/m[2] and either ramucirumab 10 mg/kg or placebo on day 1 of a 21-day cycle. OS was the primary endpoint. Secondary endpoints included PFS, ORR, safety, and patient-reported quality-of-life (QoL). Response was assessed according to RECIST v1.1. QoL was assessed with the Lung Cancer Symptom Scale. TTP on 1L, defined as the time from start of 1L until progressive disease, was assessed for the REVEL intent-to-treat population.
Result:
Of 1253 patients in REVEL, 11% had TTP ≤9 weeks, 17% had TTP ≤12 weeks, and 28% had TTP ≤18 weeks on 1L therapy. Baseline characteristics of each subgroup generally were balanced between treatment arms. Efficacy, safety, and QoL outcomes by TTP are shown in the table.Outcomes in Patients From the REVEL Study by Time to Tumor Progression on First-Line Therapy
≤9 Weeks ≤12 Weeks ≤18 Weeks INTENT-TO-TREAT POPULATION Ramucirumab+Docetaxel N = 71 Placebo+Docetaxel N = 62 Ramucirumab+Docetaxel N = 111 Placebo+Docetaxel N = 98 Ramucirumab+Docetaxel N = 182 Placebo+Docetaxel N = 172 Median OS, months (95% Confidence Interval [CI]) 8.28 (5.19, 10.84) 4.83 (3.09, 6.90) 9.10 (6.70, 10.84) 5.78 (4.30, 7.49) 8.51 (6.97, 9.95) 5.95 (4.44, 6.97) Unstratified Hazard Ratio (HR) (95% CI) 0.69 (0.47, 1.01) 0.74 (0.54, 1.00) 0.80 (0.63, 1.01) 12-month survival rate, % (95% CI) 47 (35, 58) 32 (20, 44) 34 (25, 43) 23 (15, 32) 30 (23, 37) 24 (18, 31) 18-month survival rate, % (95% CI) 20 (11, 31) 12 (5, 24) 17 (10, 26) 13 (6, 22) 17 (11, 23) 13 (8, 20) Median PFS, months (95% CI) 3.01 (2.66, 4.07) 1.48 (1.41, 1.87) 3.61 (2.76, 4.21) 1.61 (1.45, 2.60) 3.22 (2.79, 4.14) 1.61 (1.48, 2.60) Unstratified HR (95% CI) 0.69 (0.48, 0.98) 0.73 (0.55, 0.97) 0.72 (0.58, 0.89) ORR (complete response [CR]+partial response [PR]), %, (95% CI) 18.3 (10.1,29.3) 3.2 (0.4, 11.2) 18.9 (12.1, 27.5) 9.2 (4.3, 16.7) 19.2 (13.8, 25.7) 10.5 (6.3, 16.0) Disease Control Rate (CR+PR+stable disease), % (95% CI) 50.7 (38.6, 62.8) 30.6 (19.6, 43.7) 49.5 (39.9, 59.2) 37.8 (28.2, 48.1) 50.5 (43.1, 58.0) 36.0 (28.9, 43.7) Average Symptom Burden Index, time to deterioration HR (95% CI) 0.60 (0.30, 1.22) 0.49 (0.27, 0.88) 0.74 (0.49, 1.12) Total Score Lung Cancer Symptom Scale, time to deterioration HR (95% CI) 0.89 (0.45, 1.78) 0.71 (0.41, 1.23) 0.90 (0.60, 1.36) SAFETY POPULATION Ramucirumab+Docetaxel N = 70 Placebo+Docetaxel N = 61 Ramucirumab+Docetaxel N = 109 Placebo+Docetaxel N = 97 Ramucirumab+Docetaxel N = 179 Placebo+Docetaxel N = 171 Any Treatment-Emergent Adverse Event (TEAE), n (%) 67 (95.7) 58 (95.1) 105 (96.3) 92 (94.8) 173 (96.6) 159 (93.0) Grade ≥3 50 (71.4) 46 (75.4) 80 (73.4) 69 (71.1) 134 (74.9) 113 (66.1) TEAE leading to discontinuation 4 (5.7) 2 (3.3) 5 (4.6) 3 (3.1) 13 (7.3) 6 (3.5) TEAE leading to dose adjustment 24 (34.3) 19 (31.1) 39 (35.8) 28 (28.9) 70 (39.1) 47 (27.5) TEAE leading to death 5 (7.1) 4 (6.6) 7 (6.4) 6 (6.2) 9 (5.0) 8 (4.7) TESAE 25 (35.7) 30 (49.2) 46 (42.2) 46 (47.4) 80 (44.7) 71 (41.5)
Conclusion:
Efficacy, toxicity, and QoL outcomes among ramucirumab+docetaxel patients who have aggressive disease with rapid TTP on 1L therapy appear consistent with the intent-to-treat population. The benefit/risk profile for these rapid progressors suggests that such patients may derive meaningful benefit from ramucirumab+docetaxel in the 2L setting.
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MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yoichi Nakanishi, P. Mitchell
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 303 + 304
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MA 05.09 - Pre-Existing Immunity Measured by Teff Gene Expression in Tumor Tissue is Associated with Atezolizumad Efficacy in NSCLC (ID 10759)
16:35 - 16:40 | Author(s): Keunchil Park
- Abstract
- Presentation
Background:
Association between T-effector (Teff) gene expression (GE), a marker of pre-existing immunity, and OS benefit with atezolizumab (anti–PD-L1) was demonstrated in the Phase II study POPLAR of atezolizumab vs docetaxel in 2L+ NSCLC. We analyzed Teff GE association with atezolizumab efficacy in a larger Phase III study, OAK.
Method:
Patients with 2L+ NSCLC were randomized to receive atezolizumab or docetaxel. Teff signature was defined by 3 genes (PD-L1, CXCL9, and IFNγ), and Teff GE was measured by averaging the normalized expression of each gene. Teff GE subgroups were defined by quartiles. PD-L1 expression was assessed using the SP142 IHC assay; the TC1/2/3 or IC1/2/3 subgroup had ≥ 1% PD-L1 expression on tumor cells (TC) or tumor-infiltrating immune cells (IC).
Result:
753 of 850 patients from the OAK primary analysis constituted the biomarker evaluable population (BEP) for Teff GE. Expression of the Teff signature was associated with PD-L1 expression by IHC (P = 7.3×10[−45]). Although no significant PFS benefit with atezolizumab vs docetaxel was observed in the BEP (HR, 0.94 [95% CI: 0.81, 1.10]) or the TC1/2/3 or IC1/2/3 subgroup (HR, 0.93 [95% CI: 0.76, 1.15]), a gradient of improved PFS benefit with atezolizumab was observed with increasing Teff GE. Significant PFS benefit occurred with ≥ median Teff GE cutoff (HR, 0.73 [95% CI: 0.58, 0.91]; Table). Teff GE also enriched for improved OS; however, a trend toward OS benefit was still observed in patients with low Teff GE (Table).Table. PFS and OS with atezolizumab vs docetaxel by PD-L1 IHC and Teff GE subgroups PFS, HR (95% CI) OS, HR (95% CI) OAK primary population (N = 850)[a] ITT[a] 0.95 (0.82, 1.10) 0.73 (0.62, 0.87) TC1/2/3 or IC1/2/3[a ](n = 463) 0.91 (0.74, 1.12) 0.74 (0.58, 0.93) TC2/3 or IC2/3[a] (n = 265) 0.76 (0.58, 0.99) 0.67 (0.49, 0.90) OAK BEP for Teff GE (N = 753) BEP 0.94 (0.81, 1.10) 0.71 (0.59, 0.85) TC1/2/3 or IC1/2/3 (n = 420) 0.93 (0.76, 1.15) 0.74 (0.58, 0.95) Teff GE subgroups ≥ 25% (n = 570) 0.91 (0.76, 1.09) 0.67 (0.54, 0.83) < 25% (n = 183) 1.11 (0.82, 1.49) 0.87 (0.63, 1.21) ≥ 50% (n = 379) 0.73 (0.58, 0.91) 0.59 (0.46, 0.76) < 50% (n = 374) 1.30 (1.05, 1.61) 0.87 (0.68, 1.11) ≥ 75% (n = 190) 0.66 (0.48, 0.91) 0.60 (0.42, 0.87) < 75% (n = 563) 1.10 (0.92, 1.31) 0.76 (0.62, 0.92) [a]Rittmeyer A. et al. Lancet, 2017;389:255-265. NCT02008227.
Conclusion:
This is the first demonstration of the association between markers of Teff biology and clinical outcomes with cancer immunotherapy in a randomized Phase III trial. Teff GE may reflect pre-existing immunity and be a more sensitive biomarker compared with PD-L1 IHC, identifying more patients (50% prevalence) likely to experience PFS benefit with atezolizumab.
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MA 10 - Immunotherapy I (ID 664)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:S. Wang, Robert Pirker
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 303 + 304
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MA 10.03 - 3-Year Survival and Duration of Response in Randomized Phase II Study of Atezolizumab vs Docetaxel in 2L/3L NSCLC (POPLAR) (ID 8703)
11:10 - 11:15 | Presenting Author(s): Keunchil Park
- Abstract
- Presentation
Background:
Atezolizumab (anti–PD-L1) has demonstrated OS benefit over docetaxel in a randomized Phase II study, POPLAR, in patients with advanced NSCLC. This benefit has been confirmed in the randomized Phase III study OAK (Rittmeyer, 2017). The 3-year survival analysis of the POPLAR study presented here describes the longest survival follow-up reported to date of an all-comer randomized PD-L1/PD-1 immunotherapy trial in 2L+ NSCLC.
Method:
Patients were randomized 1:1 to receive atezolizumab (1200 mg) or docetaxel (75 mg/m[2]) IV q3w. Tumors were prospectively evaluated for tumor cell (TC) or tumor-infiltrating immune cell (IC) PD-L1 expression using the VENTANA SP142 IHC assay. Landmark OS was estimated using the Kaplan-Meier method. Data cutoff, April 7, 2017; minimum follow-up, 3 years.
Result:
The 2-year and 3-year survival with atezolizumab vs docetaxel were 32.2% vs 16.6% and 18.7% vs 10.0%, respectively. The long-term OS benefit of atezolizumab vs docetaxel was observed across histology and PD-L1 expression subgroups (Table). While the TC3 or IC3 subgroup derived the greatest OS benefit, the TC0 and IC0 subgroup also had improved long-term OS with atezolizumab vs docetaxel. The ITT ORR was 15% in both atezolizumab and docetaxel arms, but the median duration of response was 3 times longer with atezolizumab (22.3 months [95% CI: 11.6, 31.1] vs 7.2 months [95% CI: 5.8, 12.2] with docetaxel). Seven of the 11 docetaxel-arm 3-year survivors received subsequent non-protocol therapy with anti–PD-L1/PD-1 agents. Atezolizumab had a favorable safety profile compared with docetaxel that was consistent with previous reports.
Conclusion:
Atezolizumab demonstrates superior 2-year and 3-year OS benefit compared with docetaxel, and this benefit is observed across histology and PD-L1 expression subgroups (including TC0 and IC0). Atezolizumab is well tolerated, and responses are highly durable. These results are consistent with long-term OS results from OAK, presented separately.Table. Landmark OS in the ITT, PD-L1 expression, and histology subgroups in POPLAR Population (n, atezolizumab vs docetaxel) 2-year OS rate, % 3-year OS rate, % Atezolizumab Docetaxel P value[a] Atezolizumab Docetaxel P value[a] ITT (144 vs 143) 32.2% 16.6% 0.0027 18.7% 10.0% 0.0419 PD-L1 Expression Subgroups TC3 or IC3 (24 vs 23) 41.7% 19.9% 0.1003 37.5% 14.9% 0.0724 TC2/3 or IC2/3 (50 vs 55) 36.1% 13.8% 0.0082 21.2% 9.9% 0.1166 TC1/2/3 or IC1/2/3 (93 vs 102) 36.0% 19.8% 0.0124 18.0% 11.0% 0.1759 TC0 and IC0 (51 vs 41) 25.0% 6.8% 0.0202 20.5% 6.8% 0.0693 Histology Subgroups Non-squamous (95 vs 95) 32.2% 21.1% 0.0960 23.3% 12.4% 0.0585 Squamous (49 vs 48) 32.7% 7.8% 0.0020 9.4% 5.2% 0.4603 [a ]For descriptive purpose only. TC3 or IC3 = PD-L1 ≥ 50% TC or 10% IC; TC2/3 or IC2/3 = PD-L1 ≥ 5% TC or IC; TC1/2/3 or IC1/2/3 = PD-L1 ≥ 1% on TC or IC; TC0 and IC0 = PD-L1 < 1% on TC and IC. NCT01903993.
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MA 12 - Circumventing EGFR Resistance (ID 665)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Wan Ling Tan, Nobuyuki Yamamoto
- Coordinates: 10/17/2017, 11:00 - 12:30, F205 + F206 (Annex Hall)
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MA 12.02 - Phase I/II Study of S49076, a MET/AXL/FGFR Inhibitor, Combined with Gefitinib in NSCLC Patients Progressing on EGFR TKI (ID 7974)
11:05 - 11:10 | Author(s): Keunchil Park
- Abstract
- Presentation
Background:
S49076 is a potent ATP-competitive TKI that targets MET, AXL and FGFR1/2/3 at clinically relevant doses. Preclinical data showed that combination of S49076 with 1[st] generation EGFR-TKI can overcome acquired resistance to EGFR inhibition in a NSCLC EGFR-mutated MET-amplified cell model. Here we report interim phase I data from NSCLC patients treated with S49076 in combination with gefitinib to overcome acquired non-EGFR-T790M-mediated resistance to EGFR TKI (1[st]/2[nd] generation).
Method:
This is a phase I dose-finding study of S49076 combination with a standard dose of gefitinib using a modified Bayesian Continual Reassessment Method with S49076 doses of 500 and 600mg. Both agents are administered orally once daily. The primary objective is to determine the safety profile of the combination and the recommended phase 2 dose (RP2D) based on safety assessments. Patients are selected according to tumor status; they carried an activating-EGFR mutation without secondary T790M mutation and with at least one of the following dysregulations: MET IHC3+, MET FISH 2+/3+, or AXL IHC 2+/3+.
Result:
In June 2017, molecular screening was performed in 48 EGFR/T790M-negative tumor samples to assess MET and AXL dysregulation. 17/48 met the molecular eligibility criteria: 12/17 with MET overexpression/amplification; 4/17 with both MET overexpression/amplification and AXL overexpression; and 1/17 with AXL overexpression. As regards S49076 dose levels, 4 patients were included at 500 mg and 4 at 600 mg. Five patients discontinued treatment: 4 disease progression and 1 consent withdrawal. The most frequent related AEs (≥2 patients) were asthenia (n=5), diarrhea, nausea and paronychia (n=4 each), ASAT/ALAT increase, anemia, and yellow skin (n=3 each), peripheral edema, stomatitis, blood creatinine increase, vomiting, hypoalbuminemia, and decreased appetite (n=2 each); most were grade 1-2. A DLT occurred in 1 patient at 600mg (grade 3 stomatitis). The other severe related AEs included grade 3 ALAT increase, asthenia, and neutrophil count decrease. Concomitant intake of gefitinib did not appear to modify the S49076 PK profile as compared to previous data. The best overall response rate were partial response (PR, 1/8), stable disease (SD, 6/8), and progressive disease (1/8), including 3 patients with PR/SD ≥6 months.
Conclusion:
According to preliminary data, the frequency of MET and AXL dysregulations is consistent with the literature. Combination of S49076 and gefitinib is well tolerated and safety data are consistent with the overall safety profile of each drug. The phase II part of this study will start once the RP2D is defined to evaluate the anti-tumour activity of the combination.
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OA 03 - Mediastinal and Esophageal Tumor: Insight and New Treatment (ID 654)
- Event: WCLC 2017
- Type: Oral
- Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:M. Chida, Jhingook Kim
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 311 + 312
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OA 03.04 - A Phase II Study of Pembrolizumab for Patients with Refractory or Relapsed Thymic Epithelial Tumor (ID 9689)
11:30 - 11:40 | Author(s): Keunchil Park
- Abstract
- Presentation
Background:
No standard treatment exists for patients with thymic epithelial tumor (TET) who progress after platinum-containing chemotherapy. We conducted a phase II study of pembrolizumab in patients with refractory or relapsed TET to evaluate the efficacy and safety.
Method:
Between March 2016 and June 2017, patients with histologically confirmed TET who progressed after at least one platinum-containing chemotherapy were eligible. Patients were excluded if they had an active autoimmune disease requiring systemic treatment within the past one year or documented history of clinically severe autoimmune disease. Patients received 200mg of pembrolizumab intravenously every 3 weeks until tumor progression or unacceptable toxicity. Response was assessed every 9 weeks by investigator. The trial was registered with ClinicalTrials.gov, number NCT02607631.
Result:
Thirty-three patients were enrolled, 26 with thymic carcinoma and 7 with thymoma. 19 (57.3%) patients received two or more prior lines of systemic chemotherapy. Median number of cycles was 8 (ranges, 1-22) and median follow-up was 11.8 months (ranges, 1.6-14.9 months). Of 33 patients, eight (24.2%) achieved partial responses, 17 (51.5%) stable disease, and 8 (24.2%) progressive disease as best response, resulting in overall response rate of 24.2% (7 confirmed PR). The median progression-free survival was 6.1 months for both of thymoma and thymic carcinoma. The most common adverse events of any grade include dyspnea (11 [33.3%] of 33 patients), chest wall pain (10 [30.3%]), anorexia (7 [21.2%]) and fatigue (7 [21.2%]). Treatment-related adverse events ≥ grade 3 associated with immune related adverse events (irAE) include hepatitis (4 [12.1%]), myocarditis (3 [9.1%]), myasthenia gravis (2 [6.1%]), thyroiditis (1 [3.0%]), ANCA-associated rapidly progressive glomerulonephritis (1 [3.0%]), colitis (1 [3.0%]), and subacute myoclonus (1 [3.0%]) except anemia (1 [3.0%]). Eight (24.2%) patients (5 thymoma, 3 thymic carcinoma) discontinued study treatment due to irAE, whereas irAEs were manageable with immediate administration of high dose corticosteroid and other immunosuppressive agents in most of patients (7 of 8 [87.5%]). In 18 (54.5%) patients who had tumor specimens available for correlative biomarker analysis, all of four patients achieved partial response had 50% or more proportion score of PD-L1 immunostaining and higher PD-L1 RNA expression compared with non-responders (p=0.0471).
Conclusion:
Pembrolizumab showed promising antitumor activity in patients with refractory or relapsed TET. Given the relatively high incidence of irAEs especially in thymoma, early detection and management of autoimmune toxicity is essential to ensure feasibility of pembrolizumab treatment in patients with TET.
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OA 05 - Next Generation TKI (ID 657)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:James Chih-Hsin Yang, Fiona Blackhall
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 301 + 302
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OA 05.03 - Clinical Activity of ASP8273 in Asian Non-Small Cell Lung Cancer Patients with EGFR Activating and T790M Mutations (ID 7889)
16:05 - 16:15 | Presenting Author(s): Keunchil Park
- Abstract
- Presentation
Background:
Epidermal growth factor receptor (EGFR) activating mutations confer sensitivity to tyrosine kinase inhibitor (TKI) treatment for non-small cell lung cancer (NSCLC) and occur in ~50% of East Asian patients with NSCLC. While initial TKI treatment can be effective, acquired resistance inevitably develops with a secondary mutation (T790M). ASP8273 is a highly specific, irreversible, once-daily, oral, EGFR TKI which inhibits both activating (eg, exon 19 deletions, L858R) and resistance (eg T790M) mutations.
Method:
This dose-escalation/dose-expansion study (NCT02192697) was conducted in two phases. In Phase 1, adult Japanese patients (≥20 yr) with NSCLC previously treated with ≥1 EGFR TKI were enrolled and received escalating ASP8273 doses (25–600mg) to assess safety/tolerability as well as to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). In phase 2, adult T790M-positive NSCLC patients in Japan, Korea, and Taiwan were enrolled to further define the ASP8273 safety/tolerability profile at RP2D and determine antitumor activity (assessed using RECIST v1.1). Antitumor activity in phase 2 was evaluated according to Simon’s 2-stage design (uninteresting response=0.3, desired response=0.5, α=0.05, β=0.1). If ≥9 of 24 ASP8273-treated patients achieved a desired response in the first stage, then 39 additional patients would be enrolled. If ≥ 25 of the 63 total patients achieved response, ASP8273 would be considered to have antitumor effects.
Result:
A total of 123 patients (n=47 phase 1; n=76 phase 2) were enrolled. In both phases, more women were enrolled. The median age was 65 years in phase 1 and 63 years in phase 2. Based on phase 1 findings, MTD and RP2D were 400mg and 300mg, respectively. As 27 of the 63 patients treated with ASP8273 300mg in the first and second stages combined achieved a clinical response (based on independent central review), ASP8273 was determined to have antitumor activity (ORR=42.9%; 95% CI: 30.5–56.0). The ORR at week 24 in all patients in the full analysis set was 42.1% (n=32/76; 95% CI: 30.9, 54.0). The median duration of PFS (central review) was 8.1 months (95%CI: 5.6,--). The most commonly reported treatment-emergent AEs (TEAE) in phase 2 were diarrhea (n=50/76), nausea (n=31/76), increased alanine aminotransferase (n=27/76), decreased appetite and vomiting (n=26/76 each), and hyponatremia (n=25/76). Drug-related TEAEs were reported in 93.4% (n=71/76) of patients, the most common of which was diarrhea (n=43/76).
Conclusion:
ASP8273 was generally well tolerated and demonstrated antitumor activity in Asian patients with both EGFR activating and T790M mutations.
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OA 05.07 - Efficacy and Updated Safety of Ceritinib (450 Mg or 600 Mg) with Low-Fat Meal vs 750 Mg Fasted in ALK+ Metastatic NSCLC (ID 9366)
16:50 - 17:00 | Author(s): Keunchil Park
- Abstract
- Presentation
Background:
Ceritinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of patients with ALK+ non-small cell lung cancer (NSCLC) who are treatment-naive or have progressed on crizotinib at the recommended dose of 750 mg/day under fasted state. Gastrointestinal (GI) adverse events (AEs), eg, diarrhea, nausea, vomiting, are common with ceritinib 750 mg/day under fasting conditions. ASCEND‑8 study, (NCT02299505) evaluated alternative methods of ceritinib administration, utilizing potential benefit of dosing ceritinib with food to reduce GI toxicity, while maintaining the pharmacokinetic exposure at lower doses. Based on the primary pharmacokinetics analysis previously presented (n=137; WCLC 2016), ceritinib 450 mg with food had similar exposure and a more favorable GI safety profile vs ceritinib 750 mg fasted in patients with ALK+ NSCLC.
Method:
This is a multicenter, randomized, 3-arm (450 mg or 600 mg ceritinib taken with low-fat meal vs 750 mg ceritinib taken in fasted state), open-label, phase 1 study (ASCEND-8). Patients were eligible if they had stage IIIB or IV ALK+ advanced NSCLC, were aged 18 years or older, who were either previously treated with chemotherapy and/or crizotinib or treatment naive. We plan to report the updated safety (n=228) and preliminary efficacy for treatment-naïve patients (ALK+ by immunohistochemistry [IHC]) who were randomized at least 18 weeks before the cutoff date (March 28, 2017; n=79). Updated analysis is planned to be made available by August 2017 and the following data will be included at the time of final abstract submission: patient disposition; patient demographics; disease characteristics and prior therapies; overall response rate and duration of response by blinded independent review committee (BIRC; key secondary endpoints) in treatment-naïve patients (ALK+ by IHC) randomized at least 18 weeks prior to the cut-off date; progression-free survival per BIRC in treatment-naïve patients (ALK+ by IHC) randomized at least 18 weeks prior to the cut-off date; updated safety results with detailed information on GI (diarrhea, nausea, vomiting) and liver (alanine transaminase/aspartate transaminase) toxicities.
Result:
LBA shell - not applicable
Conclusion:
LBA shell - not applicable
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OA 08 - Neuroendocrine Carcinoma: Translational (ID 667)
- Event: WCLC 2017
- Type: Oral
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:David S Ettinger, S. Zöchbauer-Müller
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 311 + 312
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OA 08.07 - Pazopanib Maintenance for Extensive Disease Small Cell Lung Cancer: a Randomized, Placebo-Controlled Phase II study (KCSG-LU12-07) (ID 8239)
12:05 - 12:15 | Author(s): Keunchil Park
- Abstract
- Presentation
Background:
We investigated whether pazopanib maintenance following first-line chemotherapy would improve survival in patients with extensive disease small-cell lung cancer (ED-SCLD).
Method:
This study is a randomized, placebo-controlled, phase II study that enrolled ED-SCLC patients who had not progressed after four cycles of etoposide plus platinum combination therapy. Eligible patients were randomly assigned (1:1 ratio) to either placebo or pazopanib 800 mg per day until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS).
Result:
Ninety-seven patients were enrolled and randomly assigned; 2 patients did not receive study drugs. In total, 95 patients received maintenance therapy (pazopanib, n = 48; placebo, n = 47) and were included into the analyses. Grade 3 toxicities for pazopanib maintenance included thrombocytopenia (10.4%, including 1 case with grade 4 toxicity), liver enzyme elevation (10.4%), fatigue (6.3%), and hypertension (6.3%). Median PFS was 3.7 months for pazopanib maintenance and 1.8 months for placebo (Hazard ratio [HR] 0.44, 95% CI: 0.29 – 0.69, p < 0.0001). Median PFS longer than 6 months were achieved by 9 patients (18.8%) in pazopanib arm and 2 (4.3%) in placebo. Median overall survival for the pazopanib and placebo arms were 10.6 months and 12.9 months, respectively (HR 1.14, 95% CI: 0.74 – 1.76, p = 0.54).
Conclusion:
Though this study met the primary endpoint of PFS, it failed to translate into improvement of overall survival with pazopanib maintenance. Given the unneglectable toxicity profiles, relevant biomarkers to select patients for benefit from pazopanib should be further investigated.
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OA 17 - Immunotherapy II (ID 683)
- Event: WCLC 2017
- Type: Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yuichiro Ohe, Anne Tsao
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 301 + 302
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OA 17.07 - Long-Term Survival in Atezolizumab-Treated Patients with 2L+ NSCLC from Ph III Randomized OAK Study (ID 8663)
15:35 - 15:45 | Author(s): Keunchil Park
- Abstract
- Presentation
Background:
Atezolizumab (anti–PD-L1) inhibits PD-L1 binding to PD-1 and B7.1, restoring anti-cancer immunity. OAK, a Phase III study of atezolizumab vs docetaxel demonstrated superior OS of atezolizumab. The characteristics of the long-term survivors (LTS) in the OAK primary population (n = 850) are evaluated and describe the largest cohort of cancer immunotherapy-treated NSCLC LTS yet reported.
Method:
Patients received IV q3w atezolizumab (1200 mg) until PD / loss of clinical benefit or docetaxel (75 mg/m[2]) until PD / unacceptable toxicity. No crossover was allowed. LTS were defined as patients with OS ≥ 24 months and non-LTS as those who died within 24 months of randomization. Patients with OS censored prior to 24 months were not included. Data cutoff, January 23, 2017.
Result:
A higher 2-year survival rate was observed for the atezolizumab-arm (31%) vs docetaxel-arm (21%). After a minimum follow-up of 26 months, there were 119 LTS vs 279 non-LTS in the atezolizumab-arm and 77 LTS vs 299 non-LTS in the docetaxel-arm. Characteristics of atezolizumab-arm LTS and non-LTS are shown (Table). Atezolizumab-arm LTS were enriched for non-squamous histology and high PD-L1–expressing tumors, but also included low/no PD-L1–expressing tumors (40.3%). Atezolizumab-arm LTS had higher ORR (39.5%) than non-LTS (5.0%) but included LTS subjects with PD. 52.9% atezolizumab-arm vs 71.4% docetaxel-arm LTS received anti-cancer non-protocol therapy (NPT) after discontinuation of protocol-defined therapy. 51.9% of docetaxel-arm LTS vs 12.7% non-LTS received non-protocol immunotherapy. Median treatment exposure in atezolizumab-arm LTS was 18.0 months. Atezolizumab-arm LTS had a comparable safety profile to all atezolizumab-treated population.
Conclusion:
Atezolizumab provides superior 2-year OS benefit vs docetaxel and is well tolerated. The majority of docetaxel-arm LTS received a checkpoint inhibitor as NPT. Atezolizumab LTS appeared to have favorable prognostic factors, including non-squamous histology, but notably were not limited to patients with RECIST v1.1 response or with PD-L1 expression.Table. Characteristics of Atezolizumab-Arm Long-Term Survivors (LTS) vs Non-Long Term Survivors (Non-LTS) Atezolizumab LTS (n = 119) n (%) Atezolizumab Non-LTS (n = 279) n (%) Sex Male 61 (51.3) 183 (65.6) Female 58 (48.7) 96 (34.4) Tobacco use history Never smoker 29 (24.4) 47 (16.8) Current/previous smoker 90 (75.6) 232 (83.2) Histology Non-squamous 101 (84.9) 195 (69.9) Squamous 18 (15.1) 84 (30.1) No. of prior therapies, 1 89 (74.8) 209 (74.9) ECOG performance status at baseline 0 60 (50.4) 89 (31.9) 1 59 (49.6) 190 (68.1) EGFR mutation status, positive 11 (9.2) 26 (9.3) PD-L1 IHC subgroup TC3 or IC3 28 (23.5) 39 (14.0) TC1/2/3 or IC1/2/3 71 (59.7) 156 (55.9) TC0 and IC0 48 (40.3) 119 (42.7) Best overall response Complete response 5 (4.2) 0 (0) Partial response 42 (35.3) 14 (5.0) Stable disease 47 (39.5) 97 (34.8) Progressive disease 25 (21.0) 142 (50.9) IC, tumor-infiltrating immune cell; TC, tumor cell. TC3 or IC3 = PD-L1 ≥ 50% TC or 10% IC; TC1/2/3 or IC1/2/3 = PD-L1 ≥ 1% on TC or IC; TC0 and IC0 = PD-L1 < 1% on TC and IC. NCT02008227.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-070 - BIW-8962, an Anti-GM2 Ganglioside Monoclonal Antibody, in Advanced/Recurrent Lung Cancer: A Phase I/II Study (ID 10421)
09:30 - 09:30 | Author(s): Keunchil Park
- Abstract
Background:
GM2 ganglioside is a tumor-associated antigen that is overexpressed in a high proportion of several malignancies, e.g. SCLC, NSCLC, mesothelioma, melanoma, neuroblastoma, multiple myeloma. BIW-8962 is a recombinant, humanized, non-fucosylated immunoglobulin G1 monoclonal antibody to GM2 ganglioside that shows pre-clinical activity towards lung cancer cell lines and in an animal model bearing SCLC xenografts. The aim of this study was to determine the safety and preliminary clinical efficacy of BIW-8962 administered as monotherapy in patients with previously treated lung cancer.
Method:
In phase I, patients (N=16) with advanced, recurrent lung cancer (8 each with SCLC and NSCLC) received increasing doses of BIW-8962 (1–10 mg/kg) intravenously every 3 weeks using a standard 3+3 design to determine the maximum tolerated dose (MTD). The highest dose (10 mg/kg) was administered to patients with advanced, recurrent SCLC (N=21) in phase II.
Result:
It was only possible to obtain pre-study biopsy samples for two patients, both of which showed cell surface GM2 overexpression of moderate intensity on immunohistochemistry testing. In phase I and II, all patients received the total planned dose. There were no dose-limiting toxicities in phase I and the MTD was not established. BIW-8982 10 mg/kg therefore used as the recommended phase II dose. The phase II study was prematurely terminated due to lack of efficacy. The objective response rate was 5.0% (95% CI, 0.1%–24.9%) in the efficacy evaluable population (N=20). Median overall survival was 304.0 days (95% CI, 70.0–406 days) and median progression free survival (PFS) was 43.0 days (95% CI, 38.0–43.0 days). One patient showed a durable partial response with PFS of 463 days and response duration of 382 days. There were a few patients with stable disease, which was generally not durable. No pattern of consistent toxicity was observed across the phases: there were no treatment-related adverse events (AEs) Grade ≥3, serious AEs, AEs leading to discontinuation of BIW-8962, or deaths. No unexpected trends or safety concerns were identified from laboratory parameter, vital sign, or electrocardiogram assessments. Anti-BIW-8962 antibodies were not detected in serum of any patient before or following treatment. Exploratory analysis of circulating tumor cells and other potentially predictive or pharmacodynamic markers did not reveal any results consistent with an effect from BIW-8962.
Conclusion:
This study was prematurely terminated due to lack of efficacy, for which the reason is unknown. Clinical development of BIW-8962 has been discontinued.
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P1.04 - Clinical Design, Statistics and Clinical Trials (ID 690)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.04-001 - Osimertinib with Ramucirumab or Necitumumab in Advanced T790M-positive EGFR-Mutant NSCLC: Preliminary Ph1 Study Results (ID 7940)
09:30 - 09:30 | Author(s): Keunchil Park
- Abstract
Background:
Combination studies of a first- or second-generation EGFR tyrosine kinase inhibitor (TKI) and either a VEGF or EGFR-targeting monoclonal antibody have recently shown promising clinical results in EGFR-mutant non-small cell lung cancer (NSCLC) patients. The preliminary safety results from the phase 1 study JVDL (NCT02789345), combining third-generation EGFR TKI osimertinib (Osi) with human IgG1 monoclonal antibodies ramucirumab (Ram) or necitumumab (Neci), are reported.
Method:
Eligible pts naïve to third-generation EGFR TKI therapy with advanced EGFR T790M-positive NSCLC who progressed after initial EGFR TKI therapy were enrolled. In the dose-finding portion, following a dose de-escalation 3+3 design, patients received daily oral Osi (80 mg) and either 10 mg/kg intravenous (IV) Ram on day 1 (D1) every two weeks (Q2W), or 800 mg (IV) Neci on D1 and D8 Q3W. Primary objective of the study is to assess the safety and tolerability of Ram or Neci combined with Osi, and secondary objectives include preliminary evaluation of efficacy.
Result:
As of data cutoff on 09-May-2017, 7 pts were treated in the completed dose-finding portion: 3 pts with Ram+Osi (Arm A) and 4 pts (1 non-evaluable and replaced) with Neci+Osi (Arm B). No DLTs were observed in either arm, and the initial dose level became the recommended dose for expansion cohort. After the DLT observation period was complete, the only Grade ≥3 (Gr≥3) treatment-related adverse event (TRAE) was dermatitis acneiform (Arm B), with one unrelated Gr≥3 treatment-emergent AE (TEAE) of increased lipase (Arm B) and one serious AE of Gr2 diverticulitis (unrelated to study treatment) (Arm A). Expansion cohort A of Ram+Osi is fully enrolled with 22 pts. Safety data were available for 18 out of 22 cohort A patients. Gr≥3 TEAEs were reported in 4 patients, including dyspnea (unrelated [n=1]), decreased appetite (unrelated [n=1]), and hypertension (related [n=2]). Three patients reported serious adverse events (none related to study treatment): Gr3 dyspnea and Gr2 pyrexia, Gr2 dyspnea, and Gr2 urinary tract infection. No death was reported in patients in the dose-finding portion, and one death unrelated to study treatment was reported in the expansion cohort.
Conclusion:
No DLTs were observed and no unexpected safety signals were seen to date. The recommended dose for expansion cohort was the initial dose level of 10 mg/kg ramucirumab IV Q2W with oral 80 mg osimertinib. Additional safety and efficacy observation for the combination of Ram+Osi is ongoing, and will be presented at the meeting.
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P1.08 - Locally Advanced NSCLC (ID 694)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.08-004 - Adjuvant Chemoradiotherapy vs. Chemotherapy for Completely Resected Unsuspected N2-Positive Non-Small Cell Lung Cancer (ID 8238)
09:30 - 09:30 | Author(s): Keunchil Park
- Abstract
Background:
We investigated whether concurrent chemoradiotherapy (CCRT) would increase survival in patients with completely resected unsuspected N2-positive non-small cell lung cancer (NSCLC), compared with adjuvant chemotherapy alone.
Method:
Eligible patients were randomly assigned (1:1 ratio) to either the CCRT arm or the chemotherapy arm. In the CCRT arm, patients received concurrent thoracic radiotherapy (50 Gy in 25 fractions) with five cycles of weekly paclitaxel (50 mg/m[2]) and cisplatin (25 mg/m[2]), followed by two additional cycles of paclitaxel (175 mg/m[2]) plus cisplatin (80 mg/m[2]) at three-week intervals. In the chemotherapy arm, patients received four cycles of adjuvant paclitaxel (175 mg/m[2]) and carboplatin (AUC 5.5) every three weeks. The primary endpoint was disease-free survival.
Result:
We enrolled and analyzed 101 patients. The median disease-free survival of the CCRT arm was 24.7 months, which was not significantly different from that of the chemotherapy arm (21.9 months; hazard ratio [HR] 0.94, 95% CI: 0.58–1.52, P = 0.40). There was no difference in overall survival (CCRT: 74.3 months, chemotherapy: 83.5 months, HR: 1.33, 95% CI: 0.71–2.49). Subgroup analysis showed chemotherapy alone increased overall survival in never-smokers and multi-station N2-positive patients. The pattern of disease recurrence was similar between the two arms.
Conclusion:
There was no survival benefit from adjuvant CCRT compared with platinum-based chemotherapy alone for completely resected unsuspected N2-positive NSCLC.
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P2.01 - Advanced NSCLC (ID 618)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:00 - 16:00, Exhibit Hall (Hall B + C)
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P2.01-064 - Co-Existing Mutations and Their Clinical Implications in Non-Small Cell Lung Cancer: Korean Lung Cancer Consortium (KLCC-13-01) (ID 8838)
09:00 - 09:00 | Author(s): Keunchil Park
- Abstract
Background:
Non-small cell lung cancer (NSCLC) is a common type of cancer with typically poor prognosis. As individual cancers exhibit unique mutation patterns, identifying and characterizing gene mutations in NSCLC might help predict patient outcomes and guide treatment. The aim of this study was to characterize the mutational landscape of NSCLC and identify biomarkers to predict patient outcome.
Method:
Archived DNA was extracted from formalin-fixed, paraffin-embedded, mostly small biopsy samples of 162 patients. Targeted sequencing of genomic alterations was conducted using Ion AmpliSeq Cancer Hotspot Panel v2.
Result:
The median age of patients was 64 years (range; 32-83 years) and the majority had stage IV NSCLC at the time of cancer diagnosis (90%). Among the 162 patients, 161 patients (99.4%) had novel or hotspot mutations (range: 1-16 mutated genes). Hotspot mutations were found in 20 genes. Three of the most frequently found hotspot mutations were in TP53 (82, 51.2%), EGFR (66, 40.8%), and STK11 (19, 11.7%). Given that 72.7% (48/66) of EGFR mutant patients were treated with EGFR TKIs, there was a significant difference in overall survival between EGFR mutant and EGFR wild-type patients. In EGFR wild-type subgroup analysis, TP53 status was associated with poor overall survival, while STK11 status was associated both poor progression-free survival and overall survival.
Conclusion:
These results suggest that targeted next-generation sequencing using small biopsy samples is feasible and allows for the detection of both common and rare mutations that have independent prognostic value.
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P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-025 - Increased Antitumor Response to Chemotherapy Administered after PD-1/PD-L1 Inhibitors in Patients with Non-Small Cell Lung Cancer (ID 8707)
09:30 - 09:30 | Author(s): Keunchil Park
- Abstract
Background:
The role of anti-PD-1/PD-L1 inhibitor monotheapy has been demonstrated for advanced non-small cell lung cancer (NSCLC). However, its benefits in terms of response and progression-free survival are limited to small proportion of patients. The successful treatment of advanced NSCLC requires a combination of various treatment modalities. Therefore, this study evaluated whether subsequent chemotherapy administered after immunotherapy (PD-1/PD-L1 inhibitors) (SCAI) would have enhanced antitumor response in patients with NSCLC.
Method:
This study included patients with available response data for their SCAI. We compared the objective response rates of SCIA with those of the last chemotherapy administered before immunotherapy (LCBI).
Result:
In total, 73 patients met the inclusion criteria and were included into the analyses. Among them, 10 patients received PD-1/PD-L1 inhibitors as first-line therapy, and therefore 63 had available response data for LCBI. The ORR of SCAI and LCBI were 53.4% and 34.9%, respectively (P = 0.03). Out of 73 SCAI, 24 were platinum-doublet chemotherapy and 49 were non-platinum monotherapy, and among 63 LCBI, 43 and 20 were platinum-doublet and non-platinum monotherapy, respectively. The ORR for platinum-doublet of SCAI and LCBI were 66.7% (16/24) and 39.5% (17/43), respectively (p = 0.03). The ORR for non-platinum of SCAI and LCBI were 46.9% (23/49) and 25.0% (5/20), respectively (p = 0.09). Figure 1
Conclusion:
The ORR for SCAI was significantly higher than that of LCBI. This data indicate anti-PD-1/PD-L1 inhibitors could make tumors more vulnerable to subsequent chemotherapy.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 7
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-005 - ASTRIS: A Real World Study of Osimertinib Treatment in Patients with EGFR T790M Positive Advanced NSCLC; Interim Analysis (ID 7884)
09:30 - 09:30 | Author(s): Keunchil Park
- Abstract
Background:
Osimertinib is a third-generation, CNS active EGFR-TKI that potently and selectively inhibits both EGFR-sensitizing and EGFR T790M resistance mutations in non-small cell lung cancer (NSCLC). We report interim clinical and molecular diagnostic testing results from a predefined interim analysis of the ongoing ASTRIS study (NCT02474355).
Method:
Patients (pts) received osimertinib 80 mg once daily. Eligible pts had advanced NSCLC that had progressed on prior EGFR-TKI therapy and with a T790M mutation determined by local validated molecular test, WHO performance status (PS) 0−2, acceptable organ and bone marrow function and no history of interstitial lung disease or QTc prolongation. Asymptomatic, stable CNS metastases were permitted. The primary efficacy outcome was overall survival; other outcomes included local test methods, specimen type, EGFR mutations identified, investigator-assessed response rate (RR), progression-free survival and time to treatment discontinuation. Safety data are also reported.
Result:
From 18 Sept 2015 to the planned 3 Nov 2016 data cut-off (DCO), 1217 pts received osimertinib 80 mg once-daily across 14 countries with a median age 64 yrs (27–92 yrs), 67% female, 61% White, 37% Asian, 87% WHO PS 0/1, 44% prior chemotherapy, 45% prior radiotherapy. All pts tested positive for T790M; T790M was reported alone in 185 pts (15%). The most common testing methods were PNA-Clamp 317 pts (27%), Qiagen therascreen 254 pts (22%), and Roche cobas 204 pts (17%). Exon 19 deletion was the most common co-occurring mutation with T790M (57%), followed by L858R (27%). Tissue or cytology specimens were used in 720 pts (59%), plasma in 433 pts (36%), and other specimens in 64 pts (5%). At DCO, the median duration of exposure was 3.8 months (<1–13.2 months) with a median follow-up time of 4.1 months (<1−14 months). In pts evaluable for response, the investigator-assessed RR was 64% (569/886; 95% CI 61, 67). Adverse events (AEs) leading to dose modification and treatment discontinuation were reported in 122 pts (10%) and 54 pts (4%), respectively. Serious AEs were reported in 165 pts (14%) and AEs leading to death in 28 pts (2%).
Conclusion:
ASTRIS is the largest reported global study of osimertinib in pts with T790M-positive NSCLC identified by a wide array of molecular testing methods and from various specimen types. Considering this breadth of T790M testing, the clinical activity of osimertinib is like that observed in the clinical trial program and no new safety signals were identified.
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P3.01-023 - First-line Afatinib for Non-Small Cell Lung Cancer in Real World Practice (ID 8947)
09:30 - 09:30 | Author(s): Keunchil Park
- Abstract
Background:
The efficacy of first-line afatinib was demonstrated for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) in large randomized trials, and it has been approved and reimbursed in South Korea since year 2014. This study evaluated clinical outcomes of afatinib in real world practice.
Method:
Patients treated with first-line afatinib for advanced EGFR-mutant NSCLC in Samsung Medical Center (Seoul, South Korea) from October 2014 to December 2016 were included into the analyses.
Result:
In total, 165 patients were analyzed. One hundred fourteen had deletion in exon 19, 37 L858R, and 14 patients had uncommon EGFR mutations including 4 de novo T790M. Median progression-free survival (PFS) was 19. 1 months (95% CI: 12.3- 25.9 months). There was difference in median PFS according to EGFR mutation type: deletion in exon 19 (19.1 months), L858R (15.8 months), de novo T790M (4.7 months), and uncommon EGFR excepting for T790M (not yet reached) (P = 0.01). Though 112 patients (67.8%) had to reduce afatinib dose from 40 mg per day into 30 mg or 20 mg per day due to adverse events, it did not impair its efficacy in terms of PFS (23.5 months in a reduction group vs. 12.4 months in no reduction group). Among 29 patients with evaluable follow-up brain MRI for non-irradiated brain metastatic lesions, significant response was documented in 22 cases (75.9%). Out of 20 patients who were biopsied again at disease progression (excluding one case with de novo T790M), T790M appeared in 7 the repeat-biopsied specimens (35.0%).
Conclusion:
In the real practice in South Korea, first-line afatinib showed comparable or better efficacy data compared with previous clinical trials.
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P3.01-026 - Analysis of Long-Term Response to First-Line Afatinib in the LUX-Lung 3, 6 and 7 Trials in Advanced EGFRm+ NSCLC (ID 9051)
09:30 - 09:30 | Author(s): Keunchil Park
- Abstract
Background:
In patients with advanced EGFR mutation-positive (EGFRm+) NSCLC, first-line afatinib significantly improved PFS and objective response rate (ORR) versus platinum-doublet chemotherapy in the phase III LUX-Lung (LL) 3 and LL6 studies, and PFS, time-to-treatment failure (TTF) and ORR versus gefitinib in the phase IIb LL7 study. Here, we present post-hoc analyses of efficacy, safety and patient-reported outcomes (PROs) in afatinib long-term responders (LTRs) in LL3/6/7.
Method:
Treatment-naïve patients with stage IIIb/IV EGFRm+ NSCLC who were randomized to 40mg/day afatinib in LL3/6/7 and remained on treatment for ≥3 years were defined as LTRs. In these patients, we assessed efficacy and safety outcomes, as well as PROs measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire and the EQ-5D™ health status self-assessment questionnaire; these included scores on the EORTC Global Health [GH]/QoL scale (0–100), EORTC Performance Functioning scale (PF; 0–100), EQ Visual Analogue Scale (VAS; 0–100) and EQ-5D UK utility scale (EQ UK utility; 0–1).
Result:
In LL3/6/7, there were 24/229 (10%)/ 23/239 (10%)/ 19/160 (12%) afatinib-treated LTRs; 6/9/14 remained on treatment at time of analysis. Baseline characteristics were similar to the overall study populations, except for the proportion of women (LL3/6 only [LTRs versus overall]: 92/78% vs 64/64%) and Del19+ patients (LL3/6/7: 63–79% vs 49–58%). In LL3/6/7, 4–11% of LTRs had brain metastases at enrolment. Median (range) duration of treatment in LL3/6/7 LTRs was 50 (41–73)/56 (37–68)/42 (37–50) months. Due to few deaths, median OS could not be estimated. Median follow-up for OS in LL3/6/7 was 64.6/57.0/42.1 months. ORR among LTRs in LL3/6/7 was 70.8% (complete response: 4.2%; n=1)/78.3% (13.0%; n=3)/89.5% (5.3%; n=1). The frequency of afatinib dose reductions due to treatment-related AEs, and the frequency/duration of subsequent treatments were similar to the overall LL3/6/7 populations. In afatinib-treated LTRs in LL3/6/7, PROs appeared stable between ~Week 24 to ~Week 160, with slight improvements after ~3 years afatinib treatment versus scores at the start of treatment.
Conclusion:
In LL3/6/7, 10%–12% of afatinib-treated patients were LTRs. Afatinib was well tolerated among these patients. Long-term treatment was independent of tolerability-guided dose adjustment or presence of brain metastases at time of enrolment, and had no detrimental impact on subsequent treatment. In afatinib-treated LTRs, PROs were not negatively affected by long-term treatment, and were slightly improved after ~3 years of treatment versus scores at treatment initiation.
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P3.01-029 - Transient Asymptomatic Pulmonary Opacities (TAPOs) during Osimertinib Treatment and Its Clinical Implication (ID 9117)
09:30 - 09:30 | Author(s): Keunchil Park
- Abstract
Background:
Osimertinib is an oral, potent, irreversible 3[rd] generation EGFR tyrosine kinase inhibitor(TKI) approved for the treatment of T790M positive non-small cell lung cancer (NSCLC) patients who failed 1[st] or 2[nd] generation EGFR TKIs. Interstitial lung disease (ILD) is a rare complication with osimertinib, accounting for 1-3%. Recently, relatively high incidence of transient asymptomatic pulmonary opacities (TAPOs) which are different from ILD has been described (Noonan et al, JTO 2016). However, its clinical implication has not been fully determined yet.
Method:
We retrospectively analyzed 75 EGFR mutant NSCLC patients treated with osimertinib at Samsung Medical Center. Serial CT findings were reviewed by radiologist (Dr. HY Lee) and TAPO was classified according to its radiologic pattern. We also analyzed the correlation of TAPO with clinical outcomes.
Result:
Among 74 patients, TAPO was found in 15 (20.3%). The median time to TAPOs development was 23.5 weeks (1 – 72 weeks) and the median duration of TAPOs was 6.0 weeks (5 – 24 weeks) during continued osimertinib treatment. The most common radiological patterns of TAPO include cryptogenic organizing pneumonia and/or simple eosinophilic pneumonia (SEP). There was no significant difference in patient characteristics between TAPO positive and negative group. The duration of exposure to osimertinib is longer in TAPO positive than negative group (25.2 months vs 14.0 months, p=0.016 ). The progression free survival (PFS) and overall survival (OS) was numerically longer in patients with TAPO positive than negative group (PFS : 15.0 m vs 12.5 m, p= 0.201/ OS : 37.0 m vs 24 m, p=0.155)
Conclusion:
TAPOs are frequently observed with osimertinib treatment and may be mistaken for isolated pulmonary progression or ILD. Given the lack of serious clinical deterioration, it is reasonable to continue osimertinib with regular CT scan follow-up. For further clinical validation of TAPOs, long-term and large studies are warranted.
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P3.01-050 - A Real World Treatment Study of Osimertinib: ASTRIS Study Korean Subgroup Analysis (ID 9678)
09:30 - 09:30 | Author(s): Keunchil Park
- Abstract
Background:
ASTRIS (NCT02474355) is an open-label, single-arm, multination, real world treatment study, investigating the safety and efficacy of osimertinib in patients with T790M-positive advanced non-small cell lung cancer (NSCLC), who have previously received EGFR-TKI. We report the first results of Korean subset from ASTRIS which is the largest real world treatment study of osimertinib to date.
Method:
Eligible patients had advanced NSCLC harbouring a T790M mutation determined by local validated molecular tests, received prior EGFR-TKI therapy, acceptable organ and bone marrow function and no history of interstitial lung disease (ILD) or QTc prolongation. Enrollment of patients with asymptomatic, stable CNS metastases were permitted. Patients received osimertinib 80 mg once daily. The primary efficacy outcome was overall survival; other outcomes included investigator-assessed response rate (RR), progression-free survival (PFS) and time to treatment discontinuation (TTD). Safety assessment was also conducted. Data cut-off (DCO) was 3 November 2016; results from 1,217 patients in the global study have been presented previously (ASCO 2017 Abstract 9036).
Result:
A total of 371 patients received at least one dose of osimertinib from 30 Korean sites (full analysis set); at DCO, 319 patients (81.4%) were ongoing and median follow-up time was of 3.1 (0–8) months. Baseline patients’ characteristics were median age 61.1 (27–85) years old, female 65.5%, PS 0/1 88%, prior chemotherapy 47%, prior radiotherapy 48%. Tissue was the most common specimen source to test T790M mutation as well as other EGFR mutations (287/371, 77.4%) and plasma was the next (39/371, 13.1%). Fifty two patients (13.3%) had discontinued treatment; median duration of exposure 3.3 (0–7) months, 30 pts (7.7%) had disease progression and 24 patients (6.5%) died. In patients evaluable for response, defined as at least one dose of osimertinib and one response assessment, the investigator-assessed RR was 72.1% (212/294; 95% CI 66.6 – 77.2). Due to limited follow-up period, OS, PFS, and TTD were immature to analyze. Adverse events (AEs) leading to dose modification and treatment discontinuation were reported in 26 patients (7%) and 14 patients (3.8%), respectively. Serious AEs were reported in 50 patients (13.5%) and AEs leading to death in 8 patients (2.2%). ILD/pneumonitis-like events were reported in 9 patients (2.4%), and QTc prolongation (>470ms) in 5 patients (1.3%).
Conclusion:
At DCO for the 1[st] interim analysis of ASTRIS, Korean subgroup results demonstrated similar clinical activities (RR) to that observed in the osimertinib clinical trial program with no new safety signals.
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P3.01-071 - Randomized Phase 1b/3 Study of Erlotinib + Ramucirumab in Untreated EGFR Mutation-Positive Stage IV NSCLC: Phase 1b Outcomes (ID 8468)
09:30 - 09:30 | Author(s): Keunchil Park
- Abstract
Background:
Despite the likelihood of an initial response to an EGFR TKI, NSCLC patients with an activating EGFR mutation eventually develop disease progression. Anti-angiogenic agents in combination with an EGFR TKI may provide additional benefit in EGFR-mutant NSCLC, but additional studies are needed to confirm the benefit.
Method:
This ongoing phase 1b/3 study (NCT02411448; RELAY) enrolled patients with previously untreated stage IV NSCLC, ECOG PS 0-1, and an activating EGFR mutation (exon 19 deletion or exon 21 L858R substitution). In part A (phase 1b), patients received ramucirumab (anti-VEGFR2 antibody) 10 mg/kg intravenously on day 1 of a 14-day cycle and oral erlotinib at 150 mg/day. Treatment continued until disease progression or unacceptable toxicity. The primary objective of part A was to assess safety and tolerability, in terms of dose-limiting toxicities (DLTs) during the first two cycles of therapy, and to determine the recommended dose for Part B (phase 3). Data cutoff was 31-May-2017.
Result:
Fourteen patients were enrolled and treated in part A. Two patients discontinued prior to completion of cycle 2, due to non-DLT adverse events of grade 2 interstitial pneumonia and grade 1 hemoptysis and were therefore not eligible for DLT assessment. Of the 12 DLT-evaluable patients (Japan, n=6; US/Europe, n=6), median age was 72 years (range 51-83), 83% were female, and 75% had ECOG PS of 1. Median duration of therapy was 64.3 weeks (interquartile range [IQR] 19.5-89.0) with ramucirumab and 68 weeks (IQR 44-95) with erlotinib. Treatment-emergent adverse events (TEAEs) occurred in all patients, most commonly rash (100%), diarrhea (92%), paronychia (67%), hypertension (58%), and dry skin (58%). Ten (83%) patients experienced grade 3 TEAEs (hypertension [n=4], rash [n=3], diarrhea [n=2], neutropenia, conjunctivitis, elevation of alanine aminotransferase [DLT; resolved within 4 days], and elevation of aspartate aminotransferase). No serious or grade 4-5 adverse events occurred. Median PFS was 17.1 months (95% CI 8.8-NR; 50% censored) and the PFS survival rate at 21-months was 46.9%. Five patients remain on study treatment.
Conclusion:
Ramucirumab plus erlotinib demonstrated encouraging clinical activity with no unexpected toxicities in Part A. Randomization into Part B began in January-2016, maintaining the dose of ramucirumab at 10 mg/kg Q2W with oral erlotinib at 150 mg/day.
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P3.01-082 - Surgical Rebiopsy in Advanced Non-Small Cell Lung Cancer Resistant to Previous Chemotherapy (ID 10505)
09:30 - 09:30 | Author(s): Keunchil Park
- Abstract
Background:
To optimize the personalized medicine for advanced non-small cell lung cancer (NSCLC), sufficient tumor tissue is mandatory to analyze molecular and genetic profile. The demand for repeat biopsy in NSCLC is increasing, it is more difficult to obtain specimen after initial treatment. The aim of this study was to evaluate the impact of surgical rebiopsy in advanced NSCLC.
Method:
From Jan 2014 to Mar 2017, 146 consecutive patients underwent surgical rebiopsy for NSCLC which was resistant to prior chemotherapy. Their medical record were reviewed retrospectively.
Result:
There were 60 male and 86 female patients with mean age of 57 years (range 30-83). Adenocarcinoma was most common histologic type (n=142, 93%). Among them, 107 patients represent EGFR mutation before chemotherapy, deletion in exon 19 (n=73) was most frequently observed. Before surgical rebiopsy, 121 patients (83%) were treated with EGFR-TKIs. The mean number of change in chemotherapy regimen was 2 (range 1-6) and 24% of patients underwent more than 3 different chemotherapy before rebiopsy. The median time between initial treatment and rebiopsy was 17.4 months (IQR 9-25). Surgical rebiopsy was possible in all cases. One hundred and seven patients (73%) underwent pleura biopsy, 22 underwent lung resection and 12 patients underwent both pleural and lung resection. Most procedure underwent video-assisted thoracic surgery (n=136, 93%), 10 patients required mini-thoracotomy. Median postoperative hospital stay was 4 days (IQR, 3-6) and the 30-day mortality was 2.7%. All specimens were confirmed as NSCLC and adequate for mutational and genetic analysis except 2 patients. One patient was failed to mutational analysis, other patients was failed to genetic sequencing due to low tumor volume. After surgery, 129 patients can resume chemotherapy. Of those, 85 patients were enrolled clinical trial or treated with new target agent. Thirty nine patients were treated with cytotoxic chemotherapy and 5 patients continued with prior target agent.
Conclusion:
Surgical rebiopsy can detect changes in cancer characteristics and may be used in therapeutic decision making in advanced NSCLC resistant to previous treatment.
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P3.03 - Chemotherapy/Targeted Therapy (ID 719)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.03-012 - The Relationship between Efficacy of Wee1 Inhibitor AZD1775 and Mutational Status of TP53 in KRAS-Mutant Non-Small Cell Lung Cancer (ID 8844)
09:30 - 09:30 | Author(s): Keunchil Park
- Abstract
Background:
KRAS is frequently mutated in non-small cell lung cancer (NSCLC). However, direct targeting of KRAS has proven to be challenging, and inhibition of KRAS effectors has resulted in limited clinical efficacy. Wee1 kinase is an important regulator of the G2 checkpoint and is overexpressed in various cancers. Inhibition of Wee1 exerts anticancer effects as a monotherapy or in combination with DNA-damaging agents when cancer cells harbor TP53 mutations. However, its role in KRAS-mutant NSCLC, especially as a single agent, has not been explored.
Method:
Here, we investigate the anticancer potential of Wee1 inhibitor AZD1775 as a monotherapy and uncover a possible cellular context underlying sensitivity to AZD1775. Eight KRAS-mutant NSCLC cell lines were treated with AZD1775 and cell viability, proliferation, and cell cycle were analyzed. Target modulation was assessed by Western blotting and immunohistochemistry.
Result:
Our data show that treatment with AZD1775 significantly inhibited cell survival, growth, and proliferation of TP53-mutant (TP53[MUT]) compared to TP53 wild-type (TP53[WT]) in KRAS-mutant (KRAS[MUT]) NSCLC cells. In KRAS[MUT]/TP53[MUT] cells, AZD1775 treatment led to DNA damage, a decrease of survival signaling, and cell death by apoptosis. Interestingly, cell death through apoptosis was found to be heavily dependent on specific cellular genetic context, rather than inhibition of Wee1 kinase activity alone. In addition, AZD1775 treatment was well tolerated and displayed single-agent efficacy in a mouse xenograft model.
Conclusion:
This study provides rationale for inhibiting Wee1 using AZD1775 as a potential anticancer therapy against the TP53[MUT] subgroup of KRAS[MUT] NSCLC.
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P3.08 - Locally Advanced Nsclc (ID 724)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.08-006 - Treatment Response and Survival Outcomes Are Associated with Histologic Type in Non-Small Cell Lung Cancer Treated with Trimodal Treatment (ID 9972)
09:30 - 09:30 | Author(s): Keunchil Park
- Abstract
Background:
Trimodal treatment incorporating neoadjuvant concurrent chemoradiotherapy (CCRT) and surgical resection is one of the treatment strategies for non-small cell lung cancer (NSCLC) patients with N2 disease. Although pathologic phenotypes as well as biological features might be different between adenocarcinoma (ADC) and squamous cell carcinoma (SqCC), histologic type has been rarely considered when selecting treatment strategy in patients with N2 disease. The aim of this study is to investigate if histologic type is associated with treatment response and survival outcomes in patients undergoing trimodal treatment for N2 disease.
Method:
A retrospective review of patients with N2 disease who underwent neoadjuvant CCRT followed by surgery at our institution was performed. Clinicopathologic features, response to CCRT, and survival outcomes were compared between ADC and SqCC.
Result:
From 2003 to 2013, 374 patients underwent curative-intent surgery after neoadjuvant CCRT for either ADC (n=233, 62.3%) or SqCC (n=141, 37.7%) with pathologically proven N2 disease. Sixty-nine patients (18.5%) had bulky and/or multi-stationed N2 diseases on pre-CCRT imaging tests. There were more male, more smokers, more advanced clinical T and N stages, and more bulky and/or multi-stationed N2 diseases in the SqCC group than in the ADC group. Conversely, the SqCC group had more radiologic responders, earlier pathologic T and N stages, more pathologic complete responders, and more frequent mediastinal downstaging than the ADC group. With a mean follow-up of 50.1 months, patients with SqCC showed significantly better 5-year recurrence-free survival than those with ADC (ADC, 22.8% vs. SqCC, 43%; p=0.001). However, there was no significant difference in the 5-year overall survival between the two groups (ADC, 57.5% vs. SqCC, 52.3%; p=0.366). This may be related to significantly better (p<0.001) post-recurrence survival in the ADC group (mean, 28 months) than in the SqCC group (mean, 14.5 months). In the ADC group, 164 patients developed recurrences and of those, 68 (41.5%) received targeted therapy. Patients who received targeted therapy for recurrences showed significant better 5-year overall survival than those who did not receive (61% vs. 45.6%, p=0.025).
Conclusion:
In this study, SqCC was associated with better treatment response and more favorable recurrence-free survival than ADC. Despite poor recurrence-free survival in ADC, its overall survival was improved by prolonged post-recurrence survival, which might be related to the use of targeted therapy for recurrence. Since treatment response and survival outcomes are different according to histologic type, individualized treatment strategy could be considered to improve outcomes of N2 disease.
