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Se-Hoon Lee
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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): Se-Hoon Lee
- 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.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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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 | Author(s): Se-Hoon Lee
- 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.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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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): Se-Hoon Lee
- 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.
6f8b794f3246b0c1e1780bb4d4d5dc53
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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 | Author(s): Se-Hoon Lee
- 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
6f8b794f3246b0c1e1780bb4d4d5dc53
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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): Se-Hoon Lee
- 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.
6f8b794f3246b0c1e1780bb4d4d5dc53
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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): Se-Hoon Lee
- 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
6f8b794f3246b0c1e1780bb4d4d5dc53
