Virtual Library
Start Your Search
Bob T. Li
Author of
-
+
JCSE01 - Perspectives for Lung Cancer Early Detection (ID 779)
- Event: WCLC 2018
- Type: Joint IASLC/CSCO/CAALC Session
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:
- Coordinates: 9/23/2018, 07:30 - 11:15, Room 202 BD
-
+
JCSE01.13 - Discussant Poster Abstracts (ID 11682)
11:00 - 11:15 | Presenting Author(s): Bob T. Li
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
MA04 - Novel Approaches with IO (ID 900)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Immunooncology
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 13:30 - 15:00, Room 107
-
+
MA04.03 - Immunotherapy for Non-Small Cell Lung Cancers (NSCLC) with Oncogenic Driver Mutations: New Results from the Global IMMUNOTARGET Registry (ID 13187)
13:40 - 13:45 | Author(s): Bob T. Li
- Abstract
- Presentation
Background
Prospective data on immunotherapy for NSCLC with oncogenic driver mutations are limited. We recently reported first results from the global IMMUNOTARGET registry (Mazières, ASCO 2018). Here, we present new data for PD-L1 and mutation subgroups.
a9ded1e5ce5d75814730bb4caaf49419 Method
In 2017, we started an international retrospective registry study ("IMMUNOTARGET") for patients with advanced NSCLC, known driver mutations (KRAS, EGFR, ALK, ROS1, BRAF, HER2, MET and RET) and PD-L1 immune checkpoint inhibitor therapy. The registry is approved by University of Toulouse and Swissethics, and funded by University of Toulouse and Cantonal Hospital of Lucerne. Anonymized real-world data submitted to the coordinating center include: patient and tumor characteristics, mutation test methods and results, systemic therapy lines, immune related adverse events, best response by RECIST, survival, and tumor PD-L1 expression (optional). Statistical calculations including best response, median PFS and OS are done at University of Toulouse.
4c3880bb027f159e801041b1021e88e8 Result
In April 2018, the registry included 551 pts from Europe, USA, Israel and Australia. Patients were 50% male/female, 28% current smokers, median age 60 years (range 28-83), 85% had PS0/1. Most (73%) tumors were stage IV at diagnosis, almost all (96%) were adenocarcinomas. Molecular classification by dominant driver mutation: KRAS=271 (49%), EGFR=125 (23%), BRAF=43 (8%), MET=36 (7%), HER2=29 (5%), ALK=23 (4%), RET=16 (3%), ROS1=7 (1%), 1 (0.2%) not classified (ALK+RET+MET). Most pts received nivolumab (466) or pembrolizumab (48) and were treated with immunotherapy in second or third line (67%). The median number of cycles was 5 (range 1-68). Fifty (11%) pts had grade 3-5 toxicity. Median OS from start of immunotherapy was 13.3 months, median PFS was 2.8 months. Best response was PR/CR in: KRAS=26%, BRAF=24%, ROS1=17%, MET=16%, EGFR=12%, HER2=7%, RET=6%, ALK=0%. Percentage of PD-L1 positive cells was available for 177 pts: 0%=71 (40%), 1-49%=46 (26%), 50-100%=60 (34%). Median % of positive cells was highest for ROS1 (90%), BRAF (50%), MET (30%) and RET (26%) mutant tumors. PD-L1 positivity was predictive for improved PFS in KRAS and EGFR mutant tumors. PD-L1 status was known in 18 tumors with ALK, ROS1 or RET rearrangements: 5 had 0%, 4 had 1-49% and 9 had 50%-100%. No tumor remissions were observed in this subgroup. The registry remains open, updated results will be presented at the conference.
8eea62084ca7e541d918e823422bd82e Conclusion
Although response rates were lower than in KRAS mutant NSCLC, individual tumors with other driver mutations responded to immunotherapy. PD-L1 expression may not accurately predict clinical benefit from immunotherapy in some molecular subgroups, better markers are needed.
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.
-
+
OA02 - Novel Therapies in ROS1, HER2 and EGFR (ID 893)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 10:30 - 12:00, Room 105
-
+
OA02.07 - Updated Results of Phase 1 Study of DS-8201a in HER2-Expressing or –Mutated Advanced Non-Small-Cell Lung Cancer (ID 13325)
11:35 - 11:45 | Author(s): Bob T. Li
- Abstract
- Presentation
Background
DS-8201a is a HER2-targeting antibody-drug conjugate with a novel peptide-based cleavable linker, a topoisomerase I inhibitor payload, and a high drug-to-antibody ratio (7 to 8). In preclinical studies, DS-8201a showed broad antitumor activity, in a wide range of tumors. The ongoing phase 1 trial has a dose-escalation (part 1) and -expansion (part 2) and includes subjects with advanced breast cancer, gastric cancer, and other HER2-expressing/-mutated solid tumors. Here, we present updated results for subjects with HER2-expressing or -mutated non-small cell lung cancer (NSCLC).
a9ded1e5ce5d75814730bb4caaf49419 Method
Subjects with HER2-expressing (defined as IHC ≥1+ or amplified) or –mutated (detected by NGS or other platforms) NSCLC were eligible to enroll. HER2 expression and mutation were assessed using archival tissue. Adverse events (AEs), objective response rate (ORR), disease control rate (DCR: CR + PR + SD), and duration of response (DOR) were assessed.
4c3880bb027f159e801041b1021e88e8 Result
[Results will be updated for presentation at meeting] As of Apr 18, 2018, 12 subjects with HER2-expressing and/or -mutated NSCLC received ≥1 dose of DS-8201a at 6.4 mg/kg. Median age was 58.5 y with median of 3 prior regimens. At data cutoff, 8 of 12 (66.7%) subjects remain on treatment. HER2 IHC status was available for 7 subjects. Median duration of treatment was 3.66 months (range 0.69, 14.19). Eight of 10 (80.0%) subjects with ≥1 post-baseline scan (ps) experienced tumor shrinkage (100.0% of them at 1st ps at 6 weeks). Overall, confirmed ORR and DCR in the evaluable subjects was 5 of 8 (62.5%) and 6 of 8 (75.0%), respectively. Among subjects with HER2 IHC 2+ or IHC 3+ expression, 2 of 5 (40.0%) had a PR. Overall, median DOR was 11.5 months (range 0.03+, 11.53). Three of 12 (25.0%) subjects experienced a grade ≥3 AE. Common AEs included decreased appetite 66.7% (0.0% grade ≥3), nausea 58.3% (0.0% grade ≥3), alopecia 41.7% (0.0% grade ≥3), and fatigue 41.7% (0.0% grade ≥3). One fatal case of interstitial lung disease was reported in this subgroup.
8eea62084ca7e541d918e823422bd82e Conclusion
DS-8201a demonstrated promising antitumor activity in heavily pretreated NSCLC subjects.
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.
-
+
P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 4
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
-
+
P1.01-41 - A Phase 2 Study of DS-8201a in HER2-Overexpressing or -Mutated Advanced Non-Small-Cell Lung Cancer (ID 12939)
16:45 - 18:00 | Author(s): Bob T. Li
- Abstract
Background
Approximately 30% of non-small-cell lung cancers (NSCLC) are human epidermal growth factor receptor 2 (HER2)-overexpressing (immunohistochemistry [IHC] 2+ or 3+) and approximately 2% have HER2-activating mutations. Although HER2 is considered a potential target for NSCLC, no HER2-targeted therapies are approved for the treatment of NSCLC. DS-8201a is a novel HER2-targeted antibody-drug conjugate with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload (DXd) by a cleavable peptide-based linker, and with a high drug-to-antibody ratio of 7 to 8. In preliminary results from the ongoing phase 1, DS8201-A-J101 trial, DS-8201a (5.6 and 6.4 mg/kg) had a confirmed objective response rate (ORR) of 20.0% (1/5) in HER2-expressing NSCLC (Tsurutani et al, ESMO 2017). In addition to NSCLC, DS-8201a also showed substantial antitumor activity with a manageable safety profile in multiple other HER2-expressing tumors such as breast, gastric, and colorectal cancers.
a9ded1e5ce5d75814730bb4caaf49419 Method
This multicenter, open-label, 2-cohort, phase 2 study will assess the efficacy and safety of DS-8201a in subjects with HER2-overexpressing or -mutated unresectable and/or metastatic nonsquamous NSCLC that is relapsed/refractory to standard treatment or for which no standard treatment is available (NCT03505710). Overall, approximately 80 subjects will be enrolled; 40 subjects in each of 2 cohorts (cohort 1: HER2-overexpressing [IHC 3+ or IHC 2+]; cohort 2: HER2-mutated including exon 20 insertions and single-nucleotide variants in kinase, transmembrane, and extracellular domains [eg, L755S, V659E, S310F]). To be eligible for inclusion in cohort 1, HER2-overexpression must be assessed and confirmed by central testing based on archival samples. To be eligible for inclusion in cohort 2, any HER2-activating mutation must be documented based on archival tumor samples analyzed by Clinical Laboratory Improvement Amendment-certified laboratory or equivalent. All enrolled subjects will receive a 6.4 mg/kg dose of DS-8201a once every 3 weeks; study treatment will be continued until progressive disease or unacceptable toxicity. The primary endpoint is ORR based on RECIST version 1.1 (percentage of complete and partial response) by an independent radiologic facility. Secondary efficacy endpoints include progression-free survival, duration of response, disease control rate, and overall survival. Safety assessments include serious and treatment-emergent adverse events, physical examinations, vital signs, and clinical laboratory parameters. The study will enroll subjects in North America, Europe, and Japan. Recruitment began in May, 2018.
4c3880bb027f159e801041b1021e88e8 Result
Section not applicable
8eea62084ca7e541d918e823422bd82e Conclusion
Section not applicable
6f8b794f3246b0c1e1780bb4d4d5dc53 -
+
P1.01-74 - MET Exon 14-Altered Lung Cancers: Central Nervous System (CNS) Metastases and Patterns of CNS Progression on MET Inhibition. (ID 14263)
16:45 - 18:00 | Author(s): Bob T. Li
- Abstract
Background
MET exon 14 (METex14) alterations are targetable drivers found in 3-4% of lung cancers. The frequency of intracranial disease and patterns of central nervous system (CNS) progression on MET tyrosine kinase inhibitors (TKI) are not well characterized.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with advanced METex14-altered lung cancers identified by next-generation sequencing (MSK-IMPACT) between January 2014 and March 2018 were eligible for analysis. A retrospective review of clinical features, patterns of metastases, and CNS progression on MET-TKI was performed. The frequency of intracranial disease was compared to cohorts single-center of EGFR-mutant (n=200), ERBB2-mutant (n=98) and KRAS-mutant (n=200) lung cancers.
4c3880bb027f159e801041b1021e88e8 Result
82 patients with metastatic METex14-altered lung cancers were identified. The median age was 73; 56% (n=46) were female and 54% (n=44) were former smokers. The frequency of brain metastases at baseline was 11% (n=9/82). The lifetime frequency of intracranial metastases from diagnosis of metastatic disease was 34% (n=28/82). By comparison, the frequency of brain metastases was 47% (94/200, p=0.05) with EGFR-, 47% (46/98), p=0.09) with ERBB2-, and 32% (64/200, p=0.78) with KRAS-driven tumors. 6% (n=5/82) of patients developed leptomeningeal disease. The overall survival (OS) of patients who developed intracranial disease on therapy compared to those who did not develop intracranial disease was not significantly different (HR 0.66, 95% CI 0.30-1.43, p=0.29). 51 patients received crizotinib, 26 of whom developed progressive disease. The frequency of intracranial (alone), intracranial and extracranial, and extracranial (alone) progression was 8% (2/26), 19% (5/26), and 73% (19/26), respectively.
8eea62084ca7e541d918e823422bd82e Conclusion
A third of patients with METex14-altered lung cancers develop intracranial disease. This proportion is lower than that seen in EGFR- and ERBB2-mutant lung cancers and comparable to KRAS-mutant lung cancers. The frequency of CNS failure on crizotinib was lower than expected compared to historical rates in ALK-rearranged lung cancers.
6f8b794f3246b0c1e1780bb4d4d5dc53 -
+
P1.01-75 - Utility of cfDNA Testing for Acquired Resistance: The Memorial Sloan Kettering Experience with Plasma EGFR T790M Clinical Testing. (ID 12514)
16:45 - 18:00 | Author(s): Bob T. Li
- Abstract
Background
Liquid biopsy for circulating tumor DNA (ctDNA) has been increasingly adopted for the detection of oncogenic drivers and drug resistance mechanisms. Practice guidelines for liquid biopsy are lacking and biologic factors influencing ctDNA detection and shedding are poorly understood. We evaluated factors influencing ctDNA detection, using EGFR-T790M as a case-study, in patients with acquired resistance to first/second-generation EGFR tyrosine kinase inhibitors (EGFR-TKI).
a9ded1e5ce5d75814730bb4caaf49419 Method
This single-center study included metastatic sensitizing EGFR-mutant lung cancer patients (exon 19 deletions, L858R, G719) who underwent plasma EGFR-T790M testing after acquired resistance to erlotinib, gefitinib, or afatinib between January 2016 and August 2017. Plasma T790M was performed by digital PCR. Variant allele fraction (VAF) was calculated as mutant/(wildtype+mutant) allele. Concordance between plasma and tissue testing was examined if tissue analysis (MSK-IMPACT and/or targeted PCR) occurred within 90 days of blood draw. Turnaround time (TAT) was measured from date of blood draw and/or biopsy to result. ctDNA results were correlated with metastatic site and the number of organs involved.
4c3880bb027f159e801041b1021e88e8 Result
177 patients underwent plasma T790M testing; 65% female, 47% current/former smokers. Plasma T790M was positive in 32% (56/177) of patients, tissue testing was T790M-positive in 46% (45/97), and overall T790M-positivity by either platform was 49% (86/177). The median TAT was shorter for plasma T790M compared to tissue PCR (9 vs 15 days, p<0.0001), and led to osimertinib use in 84% (47/56) of positive patients. Concordance between plasma and tissue T790M was 80% (32/40). 15 patients with positive plasma had matched tissue, 87% (13/15) were concordant on tissue. 76% (19/25) of the patients that were T790M-negative on plasma also tested negative on tissue. Median plasma T790M-VAF was 0.98% (range 0.1–49.5%), lower than tissue T790M-VAF (12.8%, range 2.58–27.8, p<0.0001). Plasma T790M-VAF did not correlate with time on osimertinib (p=0.72). Plasma T790M status correlated with a higher number of metastatic sites (4 vs 3, p<0.0001). Plasma T790M detection by organ sites were: pleura (58% with metastases vs 34% without metastases, p=0.14), bone (80% vs 21%, p=0.0002), hepatic (61% vs 41%, p=0.28), nodal (61% vs 33%, p=0.07), adrenal (64% vs 44%, p=0.60), brain (71% vs 38%, p=0.08), and bone/hepatic concurrently (94% vs 98%, p=0.04).
8eea62084ca7e541d918e823422bd82e Conclusion
Using plasma T790M as an archetypal example, cfDNA testing showed concordance and a shorter turnaround compared to tissue testing. cfDNA was more likely to result positive in patients with more metastatic sites, or osseous and hepatic metastases possibly driven by increased ctDNA shedding.
6f8b794f3246b0c1e1780bb4d4d5dc53 -
+
P1.01-99 - Detecting HER2 Alterations by Next Generation Sequencing (NGS) in Patients with Advanced NSCLC from the United States and China (ID 11285)
16:45 - 18:00 | Author(s): Bob T. Li
- Abstract
Background
Advances in NGS have led to an increase in identifying specific actionable gene alterations across tumor types. We collected data on HER2 gene alterations detected by NGS from patients with advanced NSCLC and analyzed clinical characteristics and HER2 targeted treatments.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients diagnosed with advanced NSCLC and underwent NGS testing from Jun 2014 to Dec 2017 at Memorial Sloan-Kettering Cancer Center (MSK) and Guangdong General Hospital (GGH) were included. NGS platforms were MSK-IMPACTTM in MSK and GeneSeek or BurnStone in GGH. Descriptive statistics are used in data analysis.
4c3880bb027f159e801041b1021e88e8 Result
2200 patients from MSK and 490 patients from GGH underwent NGS testing. HER2 mutation and/or amplification were detected in 91/2200(4.1%) patients and 28/490(5.7%) patients from MSK and GGH respectively. Clinical characteristics were listed in Table1. 37.4%(34/91) and 21.4%(6/28) patients from MSK and GGH received HER2 targeted therapies. More patients were enrolled to HER2 inhibitors clinical trials in MSK(24.2%) than GGH(7.1%). The characteristics of HER2 alterations are summarized in Table2.
Table 1. Comparison of HER2 alterations in advanced NSCLC patients from U.S. and China
MSK
N (%)
GGH
N (%)
Total Patients
91
28
Age at Diagnosis (years)
<=60
34 (37.4%)
13 (46.4%)
>60
57 (62.6%)
15 (53.6%)
Sex
Male
37 (40.7%)
14 (50%)
Female
54 (59.3%)
14 (50%)
Smoking History
Former/Current Smoker
53 (58.2%)
7 (25%)
Non-Smoker
38 (41.8%)
21 (75%)
Histology
Adenocarcinoma
84 (92.3%)
25 (89.3%)
Squamous Cell Carcinoma
5 (5.5%)
0
Misc
2 (2.2%)
3 (10.7%)
HER2 status
Mutation
48 (52.7%)
16 (57.1%)
Amplification
32 (35.2%)
11 (39.3%)
Mutation + Amplification
11 (12.1%)
1 (3.6%)
HER2 targeted treatment
34 (37.4%)
6 (21.4%)
Enrolled to HER2 inhibitors clinical trials
22 (24.2%)
2 (7.1%)
8eea62084ca7e541d918e823422bd82e ConclusionTable 2. HER2 alteration in advanced NSCLC patients from U.S. and China combined
NGS Result
Mutation Only
N (%)
Amplification Only
N (%)
Mutation + Amplification
N (%)
Total Patients 64 43 12 Age at Diagnosis (years)
<=60
31 (48.4%)
20 (46.5%)
8 (66.7%)
>60
33 (51.6%)
23 (35.9%)
4 (33.3%)
Sex
Male
39 (60.9%)
19 (44.2%)
7 (58.3%)
Female
25 (39.1%)
24 (55.8%)
5 (41.7%)
Smoking History
Former/Current Smoker
31 (48.4%)
24 (55.8%)
5 (41.7%)
Non-Smoker
33 (51.6%)
19 (44.2%)
7 (58.3%)
Histology
Adenocarcinoma
58 (90.6%)
39 (90.7%)
12 (100%)
Squamous Cell Carcinoma
1 (1.6%)
4 (9.3%)
0
Misc
5 (7.5%)
0
0
HER2 targeted treatment
Yes
19 (29.7%)
14 (32.6%)
7 (58.3%)
No
45 (70.3%)
29 (67.4%)
5 (41.7%)
The incidence and clinical characteristics of HER2 alterations in advanced NSCLC were similar between two large cancer centers in the U.S. and China. These data support U.S.-China collaboration in clinical trials for patients with rare molecular subsets of NSCLC to accelerate new cancer drug development.
6f8b794f3246b0c1e1780bb4d4d5dc53
-
+
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
-
+
P1.13-43 - Molecular and Imaging Predictors of Response to Ado-Trastuzumab Emtansine in Patients with HER2 Mutant Lung Cancers: An Exploratory Phase 2 Trial (ID 14068)
16:45 - 18:00 | Presenting Author(s): Bob T. Li
- Abstract
Background
Ado-trastuzumab emtansine is a HER2 targeted antibody drug conjugate (ADC) that has demonstrated clinical activity in patients with HER2 mutant lung cancers, independent of HER2 protein expression. We hypothesize that the degree of HER2 homo- and/or heterodimerization may lead to preferential trastuzumab binding and internalization, and may serve as a predictor of response to HER2 ADC.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with metastatic HER2 mutant lung cancers were enrolled in a phase 2 trial of ado-trastuzumab emtansine, treated at 3.6mg/kg IV every 3 weeks. The primary endpoint was overall response rate (ORR) using RECIST v1.1. An expansion cohort included patients assessed using PERCIST, with pre-treatment 89Zr-trastuzumab PET/CT as correlative HER2-targeted imaging. HER2 mutation was identified by next generation sequencing (NGS), and tumors with adequate tissue were subsequently tested by fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), quantitative protein mass spectrometry, as well as quantitative HER2-HER3 heterodimerization by fluorescence lifetime imaging microscopy - Förster resonance energy transfer (FLIM-FRET).
4c3880bb027f159e801041b1021e88e8 Result
A total of 35 patients with HER2 mutant lung cancers were treated across 2 cohorts. ORR was 44% (8/18, 95% CI 22-69%) for RECIST cohort, and 46% (6/13, 95% CI 19-75%) for PERCIST cohort with 4 patients awaiting response assessment. Responders were seen across mutation subtypes (A775_G776insYVMA, G776delinsVC, V659E, S310F, L755P). Concurrent HER2 amplification was observed in 6 of 35 (17%) patients by either NGS or FISH. IHC ranged from 0 to 3+ and did not predict response. HER2 protein expression was low or absent in 15/18 cases tested by mass spectrometry. HER3 overexpression was seen in 7/18 cases tested and among them 5/6 evaluable patients had a partial response. FLIM-FRET efficiency was tested positive for HER2-HER3 heterodimer, which has been shown to be affected by the symmetrical heterodimer interface mutations (Claus et al, 2018), in 3 patients thus far and 1 of them had a partial response. Pre-treatment 89Zr-trastuzumab PET/CT showed increased uptake in 3/8 patients tested to date, and all 3 patients subsequently had partial metabolic response.
8eea62084ca7e541d918e823422bd82e Conclusion
This study confirmed the efficacy of ado-trastuzumab emtansine in patients with HER2 mutant lung cancers. HER2-containing dimers as indicated by HER3 overexpression or FLIM-FRET efficiency, and HER2-targeted imaging with 89Zr-trastuzumab PET/CT, may predict response to HER2 ADCs.
6f8b794f3246b0c1e1780bb4d4d5dc53
