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Keunchil Park
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MA08 - Clinical Trials in Brain Metastases (ID 906)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 15:15 - 16:45, Room 203 BD
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MA08.07 - Real World Data of Osimertinib in Patients with Central Nervous System (CNS) Metastasis in ASTRIS Korean Subset. (ID 13581)
15:50 - 15:55 | Author(s): Keunchil Park
- Abstract
- Presentation
Background
More than 40% of non-small cell lung cancer (NSCLC) patients develop CNS metastasis in their lifetime. Osimertinib is a third-generation EGFR-TKI which selectively inhibits both EGFR-sensitizing and EGFR T790M resistance mutations. Clinical studies have shown superior efficacy of osimertinib in CNS compared to platinum chemotherapy. Treatment efficacy in patients with or without CNS metastasis were observed within the second interim analysis of ASTRIS (NCT02474355). Data cut-off (DCO) was 20 October 2017.
a9ded1e5ce5d75814730bb4caaf49419 Method
In ASTRIS, advanced NSCLC patients with a locally confirmed T790M mutation, WHO performance status 0-2, prior EGFR-TKI therapy were enrolled. Patients with stable CNS metastases were allowed. The primary endpoint was overall survival (OS); other endpoints included investigator-assessed response rate (RR), progression-free survival (PFS), time to treatment discontinuation (TTD) and safety. These endpoints were also analyzed according to presence of CNS metastasis.
4c3880bb027f159e801041b1021e88e8 Result
A total of 466 patients received at least one dose of osimertinib 80mg from 31 Korean sites. CNS metastasis was evaluated in 310 patients and was present in 211 (68.1%) patients (CNS-met); 181 brain only, 1 leptomeningeal only, 29 both. 99 (31.9%) patients did not have CNS metastasis (CNS-no), and 155 patients were not evaluated (CNS-ne). At DCO, 236 patients (50.6%) were ongoing and median duration of exposure was 11.2 (0–19) months. In patients evaluable for response, defined as at least one dose of osimertinib and one response assessment, RR was 71.0% (320/451; 95% CI, 66.5–75.1): Patients with (N=211), without (N=99), and not-evaluated CNS metastasis (N=155) had RR of 68% (134/197; 95% CI, 61.0-74.5), 79.6% (78/98; 95% CI, 70.3-87.1), and 69.7% (108/155; 95% CI, 61.8-76.8), respectively. Median PFS was 12.4 months (95% CI, 11.1-13.6 months); 10.8 months (95% CI, 9.5-11.5) in CNS-met,11.0 months (95% CI, 9.2-14.5) in CNS-no, and 15.1 months (95% CI, 13.6-18.2) in CNS-ne. Median TTD was 16.5 months (95% CI, 14.1-NC); 11.2 months (95% CI, 9.4-14.8) in CNS-met, 14.7 months (95% CI, 12.2-NC) in CNS-no, and NC (95% CI, 15.5-NC) in CNS-ne. OS was not reached (data maturity: 19.7%). Serious adverse event (AE) regardless of causality were reported in 116 patients (24.9%) and AEs leading to death in 13 patients (2.8%). ILD/pneumonitis-like events were reported in 8 patients (1.7%), and QTc prolongation in 7 patients (1.5%).
8eea62084ca7e541d918e823422bd82e Conclusion
In ASTRIS Korean subset, patients with or without CNS metastasis had comparable efficacy outcome. This data continues to support osimertinib’s clinical benefit on EGFRm T790M NSCLC patients with CNS metastasis.
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MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
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MA26.10 - CNS Activity of Ramucirumab in Combination with Osimertinib in Patients with Advanced T790M-Positive EGFR-Mutant NSCLC (ID 12295)
14:35 - 14:40 | Author(s): Keunchil Park
- Abstract
- Presentation
Background
Many patients with NSCLC develop central nervous system (CNS) metastasis. Osimertinib, a novel third-generation EGFR tyrosine kinase inhibitor (TKI), has previously demonstrated CNS and systemic efficacy in patients with EGFR-mutant NSCLC. Combination of an EGFR TKI with a VEGF/VEGFR2-directed monoclonal antibodies (mAb) have shown promising results in EGFR-mutant NSCLC. Ramucirumab, human IgG1 VEGFR2 mAb, was used in combination with osimertinib. Planned exploratory and CNS response analyses aim to examine the safety/efficacy of ramucirumab+osimertinib in patients with CNS metastasis.
a9ded1e5ce5d75814730bb4caaf49419 Method
In this ongoing, open-label, multicenter Phase 1 study (NCT02789345), patients with T790M-positive EGFR-mutant (Ex19del or L858R) NSCLC who had relapsed after first-line EGFR TKI therapy were enrolled. Patients with asymptomatic and stable CNS metastasis (with/without prior radiotherapy) were eligible. Primary objective of the study was to assess safety and tolerability of ramucirumab+osimertinib. Secondary endpoints include objective response rate (ORR) and disease control rate (DCR). Exploratory endpoints relevant to CNS include CNS ORR and CNS DCR.
4c3880bb027f159e801041b1021e88e8 Result
Patients (N=25) were 45-80 years (median 64) with ECOG-PS 0 (n=3) or 1 (n=22) and 10 patients had CNS metastasis at enrollment while 15 never had CNS metastasis. Patients with CNS metastasis could have had prior radiotherapy (n=7) or no radiotherapy (n=3) to the CNS. Median follow-up time was 7.23 months. Fifteen patients remained on study treatment (five with CNS metastasis, ten without). TEAEs of interest (CNS metastasis, no CNS metastasis), such as headache (4/10, 5/15), vomiting (3/10, 4/15), and nausea (2/10, 4/15), were observed with comparable rates in patients with or without CNS metastasis. One patient developed TEAE of cerebral hemorrhage (Grade 1), related to CNS metastasis, but unrelated to study treatment, according to the investigator. Another patient with CNS metastasis developed Grade 5 TRAE of subdural hemorrhage, unrelated to CNS metastasis, ~7 weeks after the last dose of ramucirumab. Only one patient with CNS metastasis had measurable CNS lesions (tumor shrinkage of 24% [SD] as best response). The other nine patients with CNS metastasis had non-measurable CNS lesions, one of whom had a CNS complete response; his systemic best response was SD. The rest of patients had CNS non-CR/non-PD. To date, one patient (1/25) developed CNS progression (due to new CNS lesion); her CNS best response was SD.
8eea62084ca7e541d918e823422bd82e Conclusion
Ramucirumab+osimertinib showed potential antitumor activity in the CNS. Patients with CNS metastasis, with/without prior radiotherapy, appeared to tolerate this combination similarly to patients without CNS metastasis.
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OA05 - Clinical Trials in IO (ID 899)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 13:30 - 15:00, Room 106
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OA05.05 - Avelumab vs Docetaxel for Previously Treated Advanced NSCLC: Primary Analysis of the Phase 3 JAVELIN Lung 200 Trial (ID 12930)
14:15 - 14:25 | Author(s): Keunchil Park
- Abstract
- Presentation
Background
Avelumab is a human anti–PD-L1 IgG1 monoclonal antibody that is an approved treatment for metastatic Merkel cell carcinoma (various regions) and platinum-treated advanced urothelial carcinoma (US). We report findings from a global, open-label, phase 3 trial of avelumab vs docetaxel in patients with advanced NSCLC after platinum failure (NCT02395172).
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with stage IIIB/IV or recurrent NSCLC with disease progression after platinum doublet therapy were randomized 1:1 to avelumab 10 mg/kg Q2W or docetaxel 75 mg/m2 Q3W, stratified by PD-L1 status (PD-L1+/PD-L1−) and histology (squamous/nonsquamous). The primary endpoint was overall survival (OS) in the PD-L1+ population (expression on ≥1% of tumor cells, assessed using the PD-L1 IHC 73-10 assay).
4c3880bb027f159e801041b1021e88e8 Result
Between April 2015 and February 2017, 792 patients were randomized to receive avelumab or docetaxel, including 264 and 265 with PD-L1+ tumors, respectively; 0.8% vs 7.5% did not receive study treatment. Median follow-up in the avelumab and docetaxel arms was 18.9 and 17.8 months; 15.5% vs 1.5% remained on treatment at data cutoff (November 22, 2017). In the avelumab and docetaxel arms, 39.8% vs 47.5% received subsequent anticancer therapy after discontinuation, including checkpoint inhibitors in 5.7% vs 26.4%, respectively. In the PD-L1+ population, median OS in the avelumab and docetaxel arms was 11.4 vs 10.3 months (hazard ratio [HR], 0.90 [96% CI, 0.72-1.12]; P=0.1627, 1-sided). Pre-planned exploratory analyses based on higher PD-L1 cutoffs showed increased OS with avelumab vs docetaxel, including PD-L1-high (≥80% cutoff, 29% of patients; 17.1 vs 9.3 months; HR, 0.59 [95% CI, 0.42-0.83]; P=.0022, 2-sided) and PD-L1-medium/high (≥50% cutoff, 40% of patients; 13.6 vs 9.2 months; HR, 0.67 [95% CI, 0.51-0.89]; P=0.0052, 2-sided) subgroups. In the PD-L1+ population (≥1% cutoff), ORR was 18.9% vs 11.7% (odds ratio, 1.76 [95% CI, 1.08-2.86]; P=0.0105, 1-sided); median duration of response was not reached with avelumab (95% CI, 9.9-not estimable [NE]) vs 6.9 months with docetaxel (95% CI, 3.5-NE). Overall rates of treatment-related adverse events (AEs) were lower with avelumab than docetaxel, including all grades (63.9% vs 85.8%) and grade ≥3 (9.9% vs 49.3%). Immune-related AEs occurred in 16.5% of avelumab-treated patients (grade ≥3 in 2.8%).
8eea62084ca7e541d918e823422bd82e Conclusion
Avelumab showed increasing clinical activity in patients who had platinum-treated NSCLC with higher tumor PD-L1 expression; however, the trial did not meet its primary objective of improving OS vs docetaxel in PD-L1+ tumors (≥1% cutoff). OS findings may have been confounded by subsequent checkpoint inhibitor therapy in the docetaxel arm.
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OA10 - Right Patient, Right Target & Right Drug - Novel Treatments and Research Partnerships (ID 910)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 9/25/2018, 10:30 - 12:00, Room 106
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OA10.05 - An Open-Label, Multicenter, Phase II Single Arm Trial of Osimertinib in NSCLC Patients with Uncommon EGFR Mutation(KCSG-LU15-09) (ID 14365)
11:15 - 11:25 | Author(s): Keunchil Park
- Abstract
- Presentation
Background
Approximately 10% of EGFR mutants harbor uncommon mutations, which represent a heterogeneous group of rare molecular alterations within exons 18-21 and the sensitivity to EGFR TKIs is variable. Osimertinib is a potent irreversible inhibitor of both sensitizing EGFR mutation and T790M. In preclinical data, osimertinib was found to be active against most uncommon EGFR mutants, apart from the exon 20 insertion variant. Here we present the efficacy and safety of osimertinib in patients with uncommon EGFR mutation positive NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with histologically confirmed metastatic or recurrent NSCLC with activating EGFR mutation other than exon 19 deletion, L858R, T790M and insertion in exon 20 were eligible. Patients received 80mg of osimertinib orally, once daily until progression or unacceptable toxicity. Response was assessed every 8 weeks by investigator. The trial was registered with ClinicalTrials.gov, number NCT03424759.
4c3880bb027f159e801041b1021e88e8 Result
Between Mar 2016 and Oct 2017, 35 patients were enrolled. Median age was 59, 63% male, 43% never smoker, 97% adenocarcinoma. 63% of patients were treated as first-line therapy. The mutations identified were G719A/C/D/S/X (19, 54.3%) followed by L861Q (9, 25.7%), S7681 (8, 22.9%), and others (3, 8.6%). The overall response rate was 50.0% (95% CI 32.8-67.2) and DCR was 88.9% (95% CI 78.1-99.7). Seven patients (77.8%) with L861Q mutation achieved partial response; 10/19 (52.6%) with G719A/C/D/S/X mutation; 3/8 (37.5%) with S768I mutation. At data cutoff (Apr, 2018), the median PFS was 8.2 months (95% CI 1.9- 14.4) and median duration of response was 9.8 months (95% CI 7.6-12.0). The most common adverse events were rash (n=11, 31.4%), anorexia (n=8, 22.9%), and diarrhea (n=7, 20.0%). Grade 3 or 4 AEs were reported in 8 of 35 patients (23%), but all of AEs were manageable.
8eea62084ca7e541d918e823422bd82e Conclusion
Osimertinib showed highly active in NSCLC patients harboring uncommon EGFR mutation with manageable safety profile, consistent with previous reports. Further analysis will be provided.
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OA10.06 - A First-in-Human Phase 1 Trial of the EGFR-cMET Bispecific Antibody JNJ-61186372 in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 13006)
11:25 - 11:35 | Presenting Author(s): Keunchil Park
- Abstract
- Presentation
Background
JNJ-61186372 (JNJ-372) is a bispecific antibody targeting both EGFR and cMET. In preclinical studies, JNJ-372 demonstrated efficacy in EGFR and cMET driven tumor xenograft models (including EGFR T790M and MET-amplified/HGF secretion), consistent with inhibition of ligand binding, receptor degradation, and ADCC activity. The goal of Part 1 of this study (reported here) was to assess the safety, pharmacokinetics (PK), and preliminary efficacy of JNJ-372 and to identify the recommended phase 2 dose(s) to be explored in Part 2.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with previously treated, advanced NSCLC were enrolled at two sites and treated with escalating doses of JNJ-372 administered IV weekly for the first 4-week cycle, then biweekly for each subsequent cycle. PK sampling was taken at multiple time points within cycle 1 and 2. Disease assessments were performed every 8 weeks. Tumors were characterized at baseline through next-generation sequencing of circulating tumor DNA (Guardant 360).
4c3880bb027f159e801041b1021e88e8 Result
25 patients were treated with JNJ-372 during dose escalation: 140mg (n=3), 350mg (n=3), 700mg (n=9), 1050mg (n=7), 1400mg (n=3). Median age was 63y, 48% were male, 100% were Asian, 84%/12%/4% had adenocarcinoma/squamous/other histology, and median prior therapies was 4. No dose-limiting toxicities were observed at any dose level tested. The most frequent treatment-emergent AEs were infusion-related reactions (76%), rash/acneiform dermatitis (40%), dyspnea (24%), paronychia (24%), pruritus (20%), fatigue (20%), and nausea (20%); incidence of peripheral edema (cMET-related toxicity) was 12%. Infusion-related reactions were grade ≤2 severity, observed primarily with the first dose. The worst severity of rash/acneiform dermatitis was grade 2 (16%). One treatment-related AE of grade ≥3 severity was reported (neutropenia grade 3, possibly related). JNJ-372 demonstrated linear PK at dose levels 350 mg and above with non-linear PK at lower concentrations, suggesting target-mediated drug disposition. Doses ≥700mg resulted in average steady-state concentrations at or above the preclinically established therapeutic target level. Preliminary evidence of efficacy (maximum change from baseline in sum of target lesion diameters) was observed in a patient with squamous cell carcinoma (-20%), a patient with wtEGFR adenocarcinoma (-20%), and 4 patients with EGFR-mutant adenocarcinoma (≥-30%).
8eea62084ca7e541d918e823422bd82e Conclusion
JNJ-372 is a novel EGFR-cMET bispecific antibody. The manageable safety profile and preliminary evidence of clinical activity support active accrual of patients with previously treated EGFR-mutant NSCLC. The first recommended dose of 1050mg is being evaluated in Part 2.
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OA12 - Novel Therapies in MET, RET and BRAF (ID 921)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 15:15 - 16:45, Room 106
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OA12.07 - Clinical Activity of LOXO-292, a Highly Selective RET Inhibitor, in Patients with RET Fusion+ Non-Small Cell Lung Cancer (ID 13922)
16:20 - 16:30 | Author(s): Keunchil Park
- Abstract
- Presentation
Background
RET kinase gene fusions are actionable drivers that occur in ~2% of non-small cell lung cancers (NSCLC). However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET fusion+ NSCLC patients has been limited. LOXO-292 is a highly selective RET inhibitor, with preclinical activity against diverse RET fusions, potential acquired resistance mutations, and against brain metastases.
a9ded1e5ce5d75814730bb4caaf49419 Method
LIBRETTO-001 is a multicenter global phase 1/2 study (26 sites, 9 countries) enrolling patients w/ advanced solid tumors (NCT03157128) including RET fusion+ NSCLC. Patients are dosed orally in 28-day cycles with dose escalation following a 3+3 design. The primary endpoint is MTD/recommended dose determination. Secondary endpoints include safety, overall response rate (ORR, RECIST 1.1) and duration of response (DoR). Initial data were presented at the ASCO 2018 Annual Meeting.
4c3880bb027f159e801041b1021e88e8 Result
As of 02-April 18, 82 solid tumor patients (including 38 RET fusion+ NSCLC) were treated at 8 doses (20 mg QD-240 mg BID). The MTD was not reached. AEs (≥10% of patients) were fatigue (20%), diarrhea (16%), constipation (15%), dry mouth (12%), nausea (12%), and dyspnea (11%); most were grade 1-2. 2 TEAEs ≥ grade 3 were attributed to LOXO-292 (Gr3 tumor lysis syndrome, Gr3 increased ALT). Of the 38 RET fusion+ NSCLC pts, 30 had at least 1 post-baseline assessment or discontinued LOXO-292 prior to such assessment. 26 of 30 patients (87%) had >20% radiographic tumor reduction (range: -21 to -72%). The ORR was 77% (23/30, 3 responses pending confirmation) with a confirmed ORR of 74% (20/27, excluding 3 patients with unconfirmed responses). The response rate was similar regardless of prior MKI treatment (12/15 MKI-naïve, 11/15 MKI pretreated). Responses occurred independent of upstream fusion partner when known (13/16 KIF5B vs 9/11 other) and included patients w/ baseline brain metastases. Most patients remained on treatment (33/38), including all responders. The median DoR was not reached (longest response was the first responder: >10+ months). Rapid plasma clearance of RET variants was observed, with complete clearance by day 15 in 10 of 17 (59%) NSCLC patients with assessable baseline and day 15 ctDNA.
8eea62084ca7e541d918e823422bd82e Conclusion
LOXO-292 was well-tolerated and had marked antitumor activity in RET-fusion+ NSCLC patients, including those w/ resistance to prior MKIs and brain metastases. Phase 2 cohorts are now open globally (160 mg BID). Updated safety and efficacy data as of 19 Jul 2018 will be presented.
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P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 3
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-11 - Named Patient Use Program for Afatinib in Advanced NSCLC with Progression on Prior Therapy: Experience from Asian Centers (ID 12968)
16:45 - 18:00 | Presenting Author(s): Keunchil Park
- Abstract
Background
A global named patient use (NPU) program for afatinib in patients with advanced/metastatic NSCLC who had progressed during prior therapy was conducted between May 2010 and January 2016 (Cappuzzo F et al, Future Oncol 2018). Here we describe treatment outcomes for patients at Asian centers.
a9ded1e5ce5d75814730bb4caaf49419 Method
Eligible patients had progressed after clinical benefit on prior erlotinib/gefitinib and/or had an activating EGFR/HER2 mutation, had exhausted all other treatments, and were ineligible for afatinib trials. Patients received afatinib (starting dose:30-50 mg/day). Dose modifications were allowed as tolerated. Time to treatment failure (TTF) was calculated from treatment initiation to discontinuation. Adverse event (AE) reporting was mandatory.
4c3880bb027f159e801041b1021e88e8 Result
Data were collected from 2242 NSCLC patients across 10 Asian countries. Patients were heavily pretreated, 62% received ≥2 prior chemotherapy lines, and for most, afatinib was 4th-line therapy; almost all had received erlotinib/gefitinib (Table 1). 97% of patients with known tumor status were EGFR mutation-positive (m+). Median TTF was 7.6 months overall, and 7.2 months in patients with EGFR m+ tumors (Table 1). TTF was >12 months in patients with EGFR exon20 insertions and Her2 mutations. ORR was numerically higher in patients with exon20 insertions and G719X/L861Q/S761I mutations than other subgroups (Table 1). Disease control rate was 78% overall. The most frequently reported AEs were rash and diarrhea; no new/unexpected safety signals were identified.
Table 1. Named patient use (NPU) program for afatinib in advanced/metastatic NSCLC: results from Asian centers Total number of patients 2242 Age; years, median 61 Female/male; % 60/40 Any prior treatment; n (%) 2223/2242 (99.2) Prior erlotinib and/or gefitinib; n (%) 2202/2223 (99.1) Prior erlotinib only; n (%) 866/2202 (39) Prior gefitinib only; n (%) 927/2202 (42) Prior lines of chemotherapy ≥3, 32%; ≥2, 62%; 1, 23%; 0, 15% Prior lines of systemic therapy ≥4, 37%; ≥3, 65%; 2, 21%; 1, 14%; 0, 0% EGFR m+; n (%) 1240/1281 (97) Specified EGFR mutation; n (%) 1101/1240 (89) TTF; months* n ORR, % n All patients with data available 7.6 1550 24.4 431 EGFR m+ 7.2 834 27.7 267 EGFR mutation specified 6.5 740 - - Common mutations (Del19 or L858R) 6.4 692 27.4 230 Uncommon mutations (all) 8.0 84 30.3 33 T790M 6.0 34 21.1 19 G719X, L861Q, or S761I 7.8 28 42.9 7 Exon 20 insertion 18.0 25 42.9 7 Her2 m+ 12.2 12 14.2 7 p.A775 G776insYVMA 12.4 7 25.0 4 *median
m+ve, mutation-positive; ORR, objective response rate;
TTF, time to treatment failure
8eea62084ca7e541d918e823422bd82e Conclusion
This analysis from Asian countries in the afatinib NPU program revealed clinically meaningful TTF/ORR in this heavily pre-treated and refractory advanced NSCLC patient population, including activity in common and uncommon EGFR mutations. TTF was numerically longer in patients with uncommon mutations (particularly EGFR exon20 insertions) and HER2 mutations than in those with common EGFR mutations. The safety profile of afatinib was consistent with non-Asian centers.
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P1.01-21 - Safety of Durvalumab Retreatment in Advanced NSCLC Patients Who Progressed Following Initial Disease Control In ATLANTIC (ID 12386)
16:45 - 18:00 | Author(s): Keunchil Park
- Abstract
Background
In ATLANTIC, patients who completed a year of durvalumab (anti-PD-L1) treatment but later progressed off therapy were eligible for retreatment. We evaluated safety in these patients compared with the overall study population.
a9ded1e5ce5d75814730bb4caaf49419 Method
ATLANTIC (NCT02087423) was a Phase 2, open-label, single-arm trial in patients with Stage IIIB–IV NSCLC who had received ≥2 prior systemic treatment regimens, including one platinum-based. The study included three independent cohorts. In C1 (EGFR+/ALK+) and C2 (EGFR−/ALK−), enrollment was enriched for patients with ≥25% of tumor cells (TC) expressing PD-L1, while patients in C3 (EGFR−/ALK−) only had PD-L1 TC ≥90%. Patients received durvalumab 10 mg/kg q2w for ≤12 months. Patients who achieved and maintained disease control but then progressed after completing the initial 12-month treatment period were offered retreatment for a maximum of 12 months of further treatment. Safety and tolerability was a secondary outcome.
4c3880bb027f159e801041b1021e88e8 Result
As of November 7, 2017, of 442 patients in the ATLANTIC full analysis set, 102 (23.1%) had completed 12 months of initial treatment and 95 (21.5%) had disease control at the end of initial treatment. A total of 40 patients started retreatment. The median actual duration of exposure to durvalumab was 16.0 weeks (range 1–62; 40.1% of patients on treatment for ≥24 weeks) during initial treatment and 18.1 weeks (range 2–52; 37.5% of patients on retreatment for ≥24 weeks) during retreatment. The table shows safety during initial treatment and retreatment.
8eea62084ca7e541d918e823422bd82e ConclusionInitial treatment (n=444)
Retreatment phase (n=40)
Cohort,* n (%)
C1 (EGFR+/ALK+)
111 (25.0)
7 (17.5)
C2 (EGFR−/ALK−)
265 (59.7)
26 (65.0)
C3 (EGFR−/ALK−; TC ≥90%)
68 (15.3)
7 (17.5)
Any TRAE, n (%)
256 (57.7)
19 (47.5)
Grade ≥3 TRAEs
42 (9.5)
6 (15.0)
TRAEs leading to death
0
2 (5.0)†
Serious TRAEs
28 (6.3)
4 (10.0)
TRAEs leading to discontinuation
10 (2.3)
4 (10.0)
Safety analysis set. *A more detailed analysis of exposure and safety by cohort will be presented. †Causes of death were: pneumonitis and respiratory failure; cardiac arrest. TRAE=treatment-related adverse event.
A large proportion of patients (37.5%) maintained retreatment for ≥24 weeks, suggesting that patients who originally completed 12 months of treatment can tolerate sustained retreatment. The tolerability profile of durvalumab upon retreatment was similar to that seen during initial treatment, although there were two treatment-related deaths during the retreatment phase. Retreatment with anti-PD-L1 may be feasible for selected patients with NSCLC who demonstrate original benefit and progress off therapy.
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P1.01-81 - Phase 3 Study of Pemetrexed-Platinum with or without Pembrolizumab for TKI-Resistant/EGFR-Mutated Advanced NSCLC: KEYNOTE-789 (ID 14192)
16:45 - 18:00 | Author(s): Keunchil Park
- Abstract
Background
In the phase 3 KEYNOTE-189 study, pembrolizumab plus pemetrexed-platinum improved OS and PFS over chemotherapy plus placebo in first-line, metastatic NSCLC without targetable EGFR mutations (Gandhi et al. NEJM 2018). The phase 3 KEYNOTE-789 (ClinicalTrials.gov, NCT03515837) study evaluates pemetrexed-platinum combined with pembrolizumab vs placebo in EGFR-TKI–resistant, EGFR-mutated, metastatic nonsquamous NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
Eligibility for this multicenter, randomized, double-blind, placebo-controlled study requires age ≥18 years; EGFR-TKI–resistant EGFR-mutated (exon 19 deletion or L858R mutation), histologically/cytologically confirmed stage IV, nonsquamous NSCLC; measurable disease per RECIST version 1.1; ECOG PS 0/1; and archival/newly obtained pretreatment tumor sample to evaluate PD-L1 expression. If progression on prior EGFR-TKI occurred with first- or second-generation TKIs (eg, erlotinib, afatinib, gefitinib) and T790M mutation is present, patients must have had subsequent progression on osimertinib; patients with progression on first-line osimertinib are eligible regardless of EGFR T790M mutation status. Patients are randomized 1:1 to pembrolizumab 200 mg or placebo, each in combination with pemetrexed 500 mg/m2 plus platinum chemotherapy (carboplatin AUC 5 or cisplatin 75 mg/m2; investigator’s choice) Q3W for 4 cycles. Patients continue allocated treatment (pembrolizumab or placebo) plus pemetrexed for up to 35 cycles, followed by pemetrexed maintenance therapy until documented disease progression or intolerable toxicity. Randomization is stratified by PD-L1 tumor proportion score ≥50% vs <50%, prior osimertinib vs no prior osimertinib, and geographic region of East Asia vs non-East Asia. Tumor response is assessed radiographically at baseline, week-6, then every 9 weeks through week-54 and every 12 weeks thereafter, per RECIST version 1.1 by blinded, independent central review. Treatment decisions are based on iRECIST criteria by investigator review. PFS and OS are dual primary endpoints, which will be tested with one-sided alphas of 0.001 and 0.02, respectively. Secondary endpoints are ORR; duration of response; change from baseline global health status and quality-of-life scores on the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-Core 30; time to true deterioration in composite endpoint of cough, chest pain, or dyspnea on EORTC QLQ-Lung Cancer Module 13; and safety and tolerability. Severity of AEs will be graded per NCI CTCAE version 4.0. Approximately 480 patients will be enrolled beginning June 1, 2018.
4c3880bb027f159e801041b1021e88e8 Result
Section not applicable
8eea62084ca7e541d918e823422bd82e Conclusion
Section not applicable
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P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.04-03 - Suppressive Immune Cell Profiling in Patients with Non-Small Cell Lung Cancer. (ID 12878)
16:45 - 18:00 | Author(s): Keunchil Park
- Abstract
Background
The factors in tumor microenvironment hinder T cell activities against tumor cells. The major immunosuppressive cells in tumor sites are myeloid derived suppressor cell (MDSC), tumor associated macrophage (TAM), and regulatory T (Treg) cell, and the effector molecules released by those immunosuppressive cells also regulate T cell activities. Therefore, in this study we examined the pattern of immunosuppressive cells in patients with non-small cell lung cancer depending on their stages and we compared those immunosuppressive cells in healthy donor blood PBMC as well. Then, we tested T cell activities to verify whether suppressive immune cell populations can influence T cell activity.
a9ded1e5ce5d75814730bb4caaf49419 Method
Granulocytic-MDSC, Monocytic-MDSC, TAM, and Treg population from patients’ PBMC (n=59) and healthy donors’ PBMC (n=20) were analyzed by FACS Verse with appropriate antibodies. For suppressive assay, isolated T cells were activated with anti-CD3 and anti-CD28 for an hour and then MDSC was co-cultured with T cells for a week followed by Ki-67 level analysis by FACS Verse. T cell activity and suppression were tested by FACS analysis with identified cell surface markers.
4c3880bb027f159e801041b1021e88e8 Result
G-MDSC (p-value=0.0023) and M-MDSC (p-value=0.0032) population were higher in advanced non-small cell lung cancer patients (stage III&IV) compared with stage I&II patients or healthy donor. G-MDSC isolated from patient’s blood was co-cultured with activated T cells from the same patient. After one week, T cell activity was dramatically inhibited compared with T cell alone (p < 0.001, E:T = 5:1, 10:1) confirming suppressive activity of MDSC against T cells. TAM population was increased as disease progressed (p<0.001), and Treg also slightly increased (p-value=0.0373) in stage III&IV. Activated T cells were higher in stage III&IV, but suppressed T cells were also higher in stage III&IV compared with stage I&II.
8eea62084ca7e541d918e823422bd82e Conclusion
G-MDSC and M-MDSC population increased as disease progressed and G-MDSC effectively suppressed T cell activities. TAM population increased in advanced non-small cell lung cancer patients, and Treg population also slightly increased in stage III&IV. Both activated and suppressed T cells were higher in stage III&IV compared with stage I&II.
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P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.13-36 - Randomized Phase 2 Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer (ID 13960)
16:45 - 18:00 | Author(s): Keunchil Park
- Abstract
Background
Seribantumab (MM-121) is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 (HER3/ErbB3), to block heregulin (HRG/NRG)-mediated ErbB3 signaling and induce receptor downregulation. This open-label, randomized Phase 1/2 study evaluated safety and efficacy of seribantumab in combination with erlotinib in advanced NSCLC. Here, we report the activity of seribantumab in combination with erlotinib, versus erlotinib alone, in patients with EGFR wild-type tumors and describe the potential predictive power of HRG.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with EGFR wild-type NSCLC were assigned randomly to receive seribantumab plus erlotinib or erlotinib alone. Patients underwent pre-treatment core needle biopsy, and archived tumor samples were collected to support pre-specified biomarker analyses.
4c3880bb027f159e801041b1021e88e8 Result
One hundred twenty-nine patients received seribantumab/erlotinib (n=85) or erlotinib alone (n=44). Median estimated PFS in the unselected ITT population was 8.1 and 7.7 weeks in the experimental and control arm, respectively (HR=0.822; 95% CI, 0.37 to 1.828; P=0.63). In patients whose tumors had detectable HRG mRNA expression, treatment benefit was observed in the seribantumab/erlotinib combination (HR=0.35; 95% CI, 0.16 to 0.76; P=0.008). In contrast, in patients whose tumors were HRG negative, the HR was 2.15 (95% CI, 0.97 to 4.76; P = 0.059).
8eea62084ca7e541d918e823422bd82e Conclusion
The addition of seribantumab to erlotinib did not result in improved PFS in unselected patients. However, pre-defined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial is validating this finding in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216).
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P1.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 948)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.16-04 - Outcomes of Patients < 70 or ≥70 Years of Age in PACIFIC (ID 13012)
16:45 - 18:00 | Author(s): Keunchil Park
- Abstract
Background
In the Phase 3 PACIFIC study of durvalumab versus placebo in patients with stage III, unresectable NSCLC without progression after concurrent chemoradiotherapy (cCRT), the co-primary endpoint PFS was significantly longer with durvalumab (stratified HR 0.52, 95% CI, 0.42–0.65; P<0.0001). In a prespecified analysis, PFS benefit with durvalumab was observed regardless of a 65-year age cutoff. However, median age at NSCLC diagnosis is 70 (CA Cancer J Clin, 2014). We therefore performed subgroup analyses to explore outcomes using a 70-year age cutoff.
a9ded1e5ce5d75814730bb4caaf49419 Method
PACIFIC (NCT02125461) was a Phase 3, randomized, double-blind, all-comers study of patients with WHO PS 0/1 who did not progress following ≥2 cycles of platinum-based cCRT. Patients were stratified by age, sex, and smoking history and randomized (2:1) 1–42 days after cCRT to receive durvalumab 10 mg/kg IV Q2W or placebo up to 12 months. Co-primary endpoints were PFS (BICR, RECIST v1.1) and OS (not available). Secondary endpoints included ORR, time to death/distant metastasis (TTDM), and safety. Between-treatment endpoint comparisons were performed for patients <70 and ≥70 years.
4c3880bb027f159e801041b1021e88e8 Result
As of Feb 13, 2017, 713 patients were randomized; 78% and 22% were <70 and ≥70 years, respectively. Baseline patient and tumor characteristics were generally well balanced across subgroups. However, patients ≥70 were more likely to be male, have PS 1, and, within the placebo arm, to be Asian. Older patients more commonly received carboplatin-based CT than younger patients. Durvalumab demonstrated PFS benefit compared with placebo, regardless if patients were <70 years (median 16.9 vs 5.6 months, HR=0.53, 95% CI: 0.42–0.67) or ≥70 years (median 12.3 vs 6.1 months, HR=0.62, 95% CI: 0.41–0.95). Durvalumab improved TTDM (<70 years: HR=0.53, 95% CI: 0.39–0.71; ≥70 years: HR=0.66, 95% CI: 0.39–1.13) and ORR (<70 years: 27.6% vs 15.4%; ≥70 years: 31.9% vs 17.6%) regardless of age. Younger patients on durvalumab received treatment longer (median total duration 45.5 vs 36.0 weeks). Regardless of treatment, older patients discontinued more due to AEs (durvalumab: 22.0% vs 13.7%; placebo: 16.1% vs 7.8%) and had more grade 5 AEs (durvalumab: 10.9% vs 2.7%; placebo: 9.1% vs. 4.5%). Among patients receiving durvalumab, older patients experienced more all-cause SAEs (42.6% vs 24.9%) and grade 3/4 AEs (41.6% vs 29.4%) but fewer AESIs (56.4% vs 67.9%) than younger patients.
8eea62084ca7e541d918e823422bd82e Conclusion
Patients achieved clinical benefit with durvalumab regardless of age. Increased AEs/SAEs observed in older patients across treatments may reflect age/cCRT related morbidity.
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P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 3
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.01-33 - Open-Label, Biomarker-Directed Platform Study in NSCLC Patients Who Progressed on an Anti-PD-(L)1 Containing Therapy (HUDSON) (ID 13743)
16:45 - 18:00 | Author(s): Keunchil Park
- Abstract
Background
Immune checkpoint inhibitor (ICI)-containing regimens have significantly improved survival outcomes in first- and second-line NSCLC. However, the majority of patients do not respond or have non-durable responses to anti-programmed cell death-1/programmed cell death-ligand 1 (anti-PD-1/PD-L1) containing therapy (primary resistance) or progress during anti-PD-1/PD-L1 containing therapy (acquired resistance). HUDSON addresses the urgent need to identify treatments and understand ICI resistance for this emerging ICI-resistant population.
a9ded1e5ce5d75814730bb4caaf49419 Method
HUDSON is a multi-centre, international multi-arm umbrella study that will 1) evaluate therapies to reverse ICI resistance and 2) define mechanisms of ICI resistance in NSCLC patients who have progressed following standard-of-care platinum and ICI-based therapies. HUDSON is a platform study that consists of two groups; a biomarker matched and a biomarker non-matched group. Within the biomarker matched group, different cohorts will test 1) homologous recombination repair (HRR) defects and 2) LKB1 aberration for response to durvalumab and olaparib (PARP inhibitor), 3) ATM deficiency for response to durvalumab and AZD6738 (ATR inhibitor) and 4) RICTOR amplification for response to durvalumab and vistusertib (mTORC1/2 inhibitor). In the biomarker non-matched group, cohorts will test durvalumab in combination with either i) olaparib, ii) AZD9150 (STAT3 inhibitor) or iii) AZD6738, in patients with primary and acquired resistance to a prior ICI. Allocation to a cohort is informed by the tumour molecular profile according to a pre-specified assignment algorithm. New cohorts will be added as new translational hypotheses are established. Translational research will be performed on serial peripheral blood samples (including ctDNA) and tumour biopsies. HUDSON enrols ICI-resistant patients in a signal searching manner. Biomarker matched and non-matched groups will be opened simultaneously, and all eligible patients can be allocated a treatment option irrespective of their tumour profile. Enrolment is ongoing, clinical trial information: NCT03334617.
4c3880bb027f159e801041b1021e88e8 Result
Section not applicable
8eea62084ca7e541d918e823422bd82e Conclusion
Section not applicable
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P2.01-57 - Prognostic Implication of Clinical, Imaging, and Pathologic Parameters in N2(+) Stage IIIA Lung Cancer Patients (ID 13564)
16:45 - 18:00 | Author(s): Keunchil Park
- Abstract
Background
As a comprehensive study of large scale and long-term clinical outcomes from a single institution, we are trying to analyze any predictive or prognostic factors for survival outcomes in N2(+) NSCLC patients. The purpose of this study is to investigate the efficacy of clinical, imaging (CT and PET-CT), and pathologic parameters, as a prognostic factor in N2(+) NSCLC patients undergoing tri-modality therapy.
a9ded1e5ce5d75814730bb4caaf49419 Method
We retrospectively reviewed 160 patients with N2(+) NSCLC patients between January 2008 and June 2014. All patients underwent preoperative concurrent chemoradiotherapy (CCRT) (44-45 Gy in 22-25 fractions concurrent with weekly DP chemotherapy) and surgery. Clinical, imaging (CT and PET-CT), and pathologic parameters were analyzed with respects to outcomes.
4c3880bb027f159e801041b1021e88e8 Result
Overall pathologic down-staging and pathologic complete response following preoperative CCRT were achieved in 66 (41.3%) and 13 patients (8.1%), respectively. The median follow-up durations of all patients was 43 months (2~106 months). The 5-year rates of disease-free survival (DFS) and overall survival (OS) were 33.3% and 53.0%, respectively. Pathologic N down-staging (HR 2.604; 95% CI 1.418-4.779; p value=0.002) was a significant factor for DFS. Histopathology (HR 0.475; 95% CI 0.242-0.930; p =0.030), GTV of nodal lesion(s) on pre-RT CT (HR 1.066; 95% CI 1.029-1.104; p <0.001), type of surgery (HR 2.985; 95% CI 1.114-7.997; p =0.030), and proportion of viable tumor on cross-section area (HR 0.986; 95% CI 0.973-0.999; p =0.034) were significant factors for OS. Neither tumor volume reduction rate (TVRR) nor SUVmax was significant for DFS or OS.
8eea62084ca7e541d918e823422bd82e Conclusion
In patients with N2(+) NSCLC undergoing tri-modality therapy, we proved that none of the imaging parameters correlated with prognosis, except pretreatment nodal volume. We confirmed that patients with adenocarcinoma showed prominently improved survival and pathologic N down-staging was a most important pathologic parameter as a prognosticator.
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P2.01-74 - Docetaxel-Related Febrile Neutropenia (FN) And Patient Reported Symptoms/ QOL (PROs) in East Asian (EA) and Non-EA Patients (ID 11871)
16:45 - 18:00 | Author(s): Keunchil Park
- Abstract
Background
A post hoc analysis of JVCG, a Japanese phase 2 trial suggested that the QOL (quality of life) deteriorated more rapidly in patients with docetaxel-related FN than in patients without FN. A post hoc analysis of REVEL, a global phase 3 trial, was performed to explore the association between FN and PROs in East Asian (EA) (Korea, Taiwan) and Non-EA patients.
a9ded1e5ce5d75814730bb4caaf49419 Method
Lung Cancer Symptom Scale (LCSS) and EQ-5D-3L were assessed at baseline, every cycle, at discontinuation and 30-day follow up. The summary statistics of LCSS total score and EQ-5D Visual Analog Scale (VAS) score were calculated. Time to deterioration (TtD) was defined as the time from randomization to the first 15-mm increase from baseline for the LCSS and first 15% decrease for the EQ-5D VAS and analysed with the Kaplan-Meier method and Cox proportional hazard model by treatment-emergent FN status regardless of assigned treatment. Also the changes in LCSS total score and EQ-5D VAS score from baseline to the treatment completion were summarized.
4c3880bb027f159e801041b1021e88e8 Result
1253 patients randomized to receive RAM+DOC (EA: n=43 and Non-EA: 585) or PLA+DOC (n=46 and 579). FN occurred in 21.3% of EA and 12.3% of Non-EA patients. Patient compliance with the LCSS and EQ-5D were 84.2% and 84.4%, respectively in EA and 82.7% and 83.2% in Non-EA patients. For EA patients, HRs (95% CI) for TtD were 0.572 (0.250, 1.313) in LCSS total and 0.792 (0.350, 1.790) in EQ-5D VAS, indicating longer TtD in PROs for patients without FN. For Non-EA patients, HRs (95% CI) for TtD were 0.994 (0.728, 1.357) in LCSS total and 1.023 (0.787, 1.330) in EQ-5D VAS and there seemed to be no difference in TtD between patients with and without FN. At treatment completion, the unadjusted mean change from baseline of LCSS total was numerically lower in EA patients without FN: 12.97 (with FN) vs 5.94 (without FN) (p=0.1748) and significantly lower in Non-EA patients without FN: 10.50 (with FN) vs 5.55 (without FN) (p=0.0147), demonstrating a greater PROs deterioration in patients with FN.
8eea62084ca7e541d918e823422bd82e Conclusion
PROs of EA patients with FN deteriorated more rapidly than in those without FN in contrast with non-EA patients. This finding was consistent with a result in the Japanese phase 2 JVCG trial. Also Non-EA patients without FN maintained their PROs significantly better than patients with FN upon treatment completion. This trend was also shown in EA patients. Prevention of docetaxel-related FN may contribute to maintaining QOL.
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P2.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 961)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.12-05 - SUKSES (Small Cell Lung Cancer Umbrella Korea Studies): A Phase II Biomarker-Driven Umbrella Study in Relapsed or Refractory SCLC (ID 12673)
16:45 - 18:00 | Presenting Author(s): Keunchil Park
- Abstract
Background
Although initial platinum-based treatment demonstrated high response rate (RR) in extensive stage SCLC, limited options are available for subsequent systemic therapy. Recent studies with comprehensive genomic profiling identified cell cycle-related gene alteration, such as TP53 and RB1 inactivation, and RICTOR amp as a major characteristic of SCLC. Based on this observation, we designed umbrella clinical trial based on the hypothesis that controlling cell cycle checkpoint, DNA damage repair mechanism, and mTOR pathway with small molecules and monoclonal antibodies targeting these pathways might be an effective approach for the later line SCLC treatment.
a9ded1e5ce5d75814730bb4caaf49419 Method
SUKSES trial (NCT02688894) is a phase 2 study with seven treatment arms. Four arms for the biomarker-positive population. Arm A (AKT1 mt); Arm B (BRCA1 or BRCA2 mt, ATM deficiency, MRE11A mt or other HR pathway gene mt); Arm C (MYC family protein amplification or CDKN2A mt either of which combined with TP53 mt); Arm D (RICTOR amp). Three arms for the biomarker-negative population. Arm-N1, N2, and N3.
Pathologically confirmed SCLC patients are eligible for the molecular screening. For study participation, patients must have at least one measurable lesion after progression from first-line platinum-based therapy. Patients are enrolled in either second or third line based on their initial treatment response. Following treatment is applied after allocation: Arm-A (AZD5363); arm-B (Olaparib); arm-C (AZD1775); arm-D (AZD2014); arm-N1 (AZD1775); arm-N2 (Olaparib and AZD6738); arm-N3 (AZD2811). Primary endpoint for this study is objective RR. Duration of treatment, disease control rate at eight weeks, progression-free survival, exploratory biomarker will be evaluated as secondary endpoint.
As of May 2018, 157 patients have been screened for the molecular profiling. Arm A was closed due to low discovery rate of AKT1 mutation. Of the planned 28 patients for each biomarker positive arm, 9 for arm B, 7 for arm C and 4 for arm D have enrolled. For the negative-biomarker arms, 24 out of 45 patients are recruited for arm N1 and 9 patients for Arm N3. Arm N2 is under review by Institutional Review Board.
4c3880bb027f159e801041b1021e88e8 Result
Section not applicable
8eea62084ca7e541d918e823422bd82e Conclusion
Section not applicable
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P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.01-18 - Comparison of PD-L1 Immunohistochemical Assays and Clinical Response to Anti PD-1 Checkpoint Inhibitors in Patients with Lung Cancer (ID 14296)
12:00 - 13:30 | Author(s): Keunchil Park
- Abstract
Background
The anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors, nivolumab and pembrolizumab, are currently approved for the treatment of patients with NSCLC. The PD-L1 expression represents the most validated predictive marker of response to PD-1 inhibitors. However, there are several different immunohistochemical assays to assess the PD-L1 expression using different antibodies, platforms, and cutoff values. We compared the PD-L1 expression evaluated by IHC 22C3 PharmDx with that observed by Ventana SP263 and analyzed correlation with response to anti PD-1 inhibitors.
a9ded1e5ce5d75814730bb4caaf49419 Method
We retrospectively analyzed 109 patients with lung cancer to be treated with anti PD-1 inhibitors who have PD-L1 expression levels obtained with both the 22C3 and SP263 assays. We reviewed medical records to obtain information about the patient’s clinical characteristics, response evaluation and survival data. The relationship between PD-L1 expression levels evaluated by the 22C3 and SP263 assays was calculated using the concordance correlation coefficient, Pearson’s precision analysis.
4c3880bb027f159e801041b1021e88e8 Result
Most patients were male (70%), smoker (65%), ECOG PS 1 (73%), and histologically adenocarcinoma (55%) or squamous cell carcinoma (29%). 30% of patients had EGFR mutations. Patients were treated with pembrolizumab (n=41, 38%), or nivolumab (n=67, 61%). The median cycle of anti PD-1 checkpoint inhibitor was three (range, 1-25). There was moderate analytical correlation between 22C3 and SP263 PD-L1 levels. At the clinically relevant cutoffs ( < 10% vs. ≥10%; and <1% vs. 1-49% vs. ≥50%), the concordance correlation coefficient between 22C3 and SP263 were 0.68 (95%CI: 0.59-0.77) and 0.66 (95%CI: 0.51-0.81), respectively. The overall response rate (ORR) was 25.0% for all patients. The ORR was comparable regardless of the cutoff levels of PD-L1 expression by SP263 assays (ORR 39.6%, 41.7%, and 47.4% respectively for PD-L1 expression by 1%, 10%, 50% cutoff levels). But, the correlation between ORR and PD-L1 expression by 22C3 assays was not statistically significant. At 1% cutoff value, progression free survival was longer in patients with high vs. low tumor PD-L1 expression (2.8 months vs. 1.2 months, HR 0.63, 95%CI: 0.41-0.97, p=0.03) by the 22C3 and (3.1 months vs. 1.3 months, HR 0.61, 95% CI:0.40-0.93, p=0.02) by the SP263, respectively.
8eea62084ca7e541d918e823422bd82e Conclusion
We showed a moderate correlation between PD-L1 expression data obtained with the 22C3 and SP263 assays. These two assays could be used interchangeably and might be helpful for decision with anti PD-1 checkpoint inhibitors. Further analysis will be updated.
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P3.04 - Immunooncology (Not CME Accredited Session) (ID 970)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.04-23 - Phase 1b/2 Study to Evaluate Novel Combinations With Oleclumab (MEDI9447) in Previously Treated Advanced EGFRm NSCLC (ID 12300)
12:00 - 13:30 | Author(s): Keunchil Park
- Abstract
Background
Patients with mutant EGFR (EGFRm) non–small cell lung cancer (NSCLC) have a limited chance of benefiting from treatment with programmed death-1 inhibitors. EGFR activation leads to overexpression of CD73 and may provide a mechanism of immune evasion. CD73 overexpression has also led to worse outcomes in multiple tumor types, including NSCLC. Recent studies demonstrated that an orthogonal therapeutic approach to cancer, such as combining tyrosine kinase inhibitors (TKIs) with immunotherapy, may result in synergistic clinical activity. Oleclumab is a human monoclonal antibody (mAb) that selectively binds to CD73 and inhibits the enzymatic production of adenosine. Adenosine exerts its immunosuppressive effects on various immune cells via the adenosine 2A receptor (A2AR). AZD4635 is a potent, selective A2AR antagonist that inhibits this signaling pathway. Osimertinib is a potent and selective inhibitor of EGFRm, including the T790M resistance mutation. We hypothesize that novel combinations of targeted and immunotherapeutic agents targeting the adenosine pathway will be well tolerated and lead to increased antitumor activity in subjects with EGFRm NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
This is a multi-arm, open-label, multicenter, phase 1b/2 study (NCT03381274) consisting of 2 parts. In Part 1, the safety and tolerability of oleclumab in combination with either osimertinib (Arm A) or AZD4635 (Arm B) will be evaluated, and a recommended phase 2 dose for each combination will be identified. In Part 2, the safety, tolerability, and preliminary antitumor activity will be evaluated. In both parts, patients will be allocated to treatment arms based upon their EGFRm status and their prior therapy. For Part 2, the primary objective of antitumor activity will be assessed by objective response according to RECIST v1.1. Key secondary objectives include additional evaluation of clinical activity, the pharmacokinetic profiles of oleclumab, osimertinib, and AZD4635, and the evaluation of oleclumab immunogenicity. Additional treatment arms may be added as the study progresses. The study is open for enrollment and recruitment is ongoing, with a planned enrollment of up to approximately 98 patients.
4c3880bb027f159e801041b1021e88e8 Result
Section not applicable
8eea62084ca7e541d918e823422bd82e Conclusion
Section not applicable
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P3.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 982)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.16-41 - Postoperative Pembrolizumab for the Patients with Pathologic Stage I Adenocarcinoma with Solid or Micropapillary Pattern (ID 14418)
12:00 - 13:30 | Author(s): Keunchil Park
- Abstract
Background
Prognosis of surgically resected stage I adenocarcinoma was relatively fair with up to 75% of 5 year disease free survival rate. However, in some cases, in spite of the very small-sized tumor, recurrence as systemic metastasis is found. Solid or micropapillary subtype adenocarcinoma are reported as poor prognostic subtypes, additional treatment after surgical resection for those subgroup was required to improve survival. We reported that incidence of PD-L1 strong positivity is significantly higher in solid-predominant subtype of adenocarcinoma, PD-L1 inhibitor can be more effective adjuvant treatment modality in those subtype.
a9ded1e5ce5d75814730bb4caaf49419 Method
Design: Open-label, single arm, single center, phase 2 trial. (NCT03254004)
Eligibility: The subject must have primary lung adenocarcinoma with stage I and less than 4 centimeter, whose tumor should be solid-predominant or micropapillary (>5%) by postsurgical pathological examination.
Objective: The primary objective of this study is to assess the improvement of disease-free survival rate by adjuvant therapy with pembrolizumab for solid or micropapillary adenocarcinoma with pathologic stage I and tumor size less than 4 cm. The secondary objective is to assess the safety profile of adjuvant pembrolizumab in adjuvant setting.
Treatment: Pembrolizumab 20mg IV infusion every 3 weeks for 12 months until disease progression or prohibitive toxicity. The treatment should be started within 8 weeks after surgery.
Statistics: The hypothesis is that adjuvant pembrolizumab will improve 3-year disease-free survival from 65% to 80% in pathologic stage Ia lung adenocarcinoma patients with solid/micropapillary subtypes. Assuming that the subject enrollment period is 1.5 years, follow-up of last registered subject period is 4 years, and the disease free survival period follows the exponential distribution, a significance level 5% (one side) and 63 peoples are required 85% at the power of test. At this time, assuming that the dropout rate is 10%, it is necessary to register 70 subjects
Assessment : Chest CT (covering up to both adrenals) will be done every 3 months till 1 year since the study treatment, and then every 4 months afterward till 2 years and thereafter every 6 months till 3 years. Brain MRI and bone scan will be done at 1 year and 2 years since the study treatment. This study is an investigator-initiated trial with support from MSD.
4c3880bb027f159e801041b1021e88e8 Result
Section not applicable
8eea62084ca7e541d918e823422bd82e Conclusion
Section not applicable
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PC07 - The Future of Cytotoxic Chemotherapy in Advanced NSCLC (ID 846)
- Event: WCLC 2018
- Type: Pro-Con Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 13:30 - 15:00, Room 202 BD
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PC07.02 - Debate 2: Chemotherapy Will Become a Thing of the Past in the Management of Advanced NSCLC - Against (ID 11630)
14:30 - 14:50 | Presenting Author(s): Keunchil Park
- Abstract
- Presentation
Abstract not provided
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