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Yuankai Shi
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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: 4
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-06 - Plinabulin, a Novel Immuno-Oncology Agent Mitigates Docetaxel Chemotherapy -Induced-Neutropenia and -Thrombocytopenia in NSCLC Patients. (ID 13016)
16:45 - 18:00 | Author(s): Yuankai Shi
- Abstract
Background
Plinabulin (Plin) is a novel non-GCSF small molecule with anti-cancer activity, in development for prevention of Chemotherapy (Chemo)-Induced-Neutropenia (CIN) and under evaluation with induced by Docetaxel (Doc), Adriamycin, Cyclophosphamide, Irinotecan, Gemcitabine, Carboplatin, Abraxane). Plin is administered as a single IV infusion per cycle, and on the same day of Chemo, 30 minutes after Chemo. In contrast to G-CSF, Plin has anti-cancer, immune-enhancing activity due to dendritic cell activation and related T-cell proliferation, and Plin does not cause bone pain. Our randomized phase (Ph) 2 study 101 (NCT00630110) in lung cancer (NSCLC) with Docetaxel (Doc) 75 mg/M2 +/- Plin established the baseline for Grade 4 neutropenia without Plin. We recently completed the Ph2 portion of the Ph2/3 Study 105 (NCT03102606), comparing Plin with Pegfilgrastim (Peg) for Doc CIN prevention in NSCLC. The 20 mg/m2 Plin dose was equally effective as Peg for CIN, and this dose will be taken into Ph3. The CIN nadir was earlier with Peg, and occurrence of bone pain was higher with Peg vs Plin (33% vs 11%, resp), suggesting a different mechanism of action (MoA). To further understand Plin’s MoA, we analyzed hematology results with Plin and Peg treated subjects.
a9ded1e5ce5d75814730bb4caaf49419 Method
Ph2 Study 105: NSCLC Pts were randomized to Doc 75 mg/ m2 day (D)1, and either Peg 6 mg D2 (n=14), or Plin at 5 (n=14),10 (n=13), 20 (n=14) mg/ m2 D1 (30 minutes after Doc). Blood for central hematology analysis was collected through Cycle 1. Grade (Gr) 4 neutropenia data without Plin (that is Plin 0 mg/ m2) data was taken from study 101.
4c3880bb027f159e801041b1021e88e8 Result
Docetaxel-induced Gr 4 Neutropenia was 14%, 23%, 14%, 33% when Doc was combined with Plin at a dose of 20, 10, 5, 0 mg/ m2 . At the highest Plin dose of 20 mg/ m2, Gr 4 Neutropenia frequency (14% for Plin or Peg) and Duration of Grade 4/Severe Neutropenia (DSN; 0.5 days for Plin or Peg) were similar for Plin and Peg, however Gr 4 thrombocytopenia frequency was 50% with Peg and 36% with Plin. All Grade thrombocytopenia was significantly higher (p=0.036) with Peg vs Plin.
8eea62084ca7e541d918e823422bd82e Conclusion
Plin appears to be equally effective as Peg against Doc CIN, however Plin, but not Peg, reduced Doc-induced thrombocytopenia. This is further indication of a difference in MoA for Plin vs Peg.
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P1.01-107 - The Impact of Anlotinib on Quality of Life in Patients with Advance NSCLC: Post-Hoc Analysis of a Phase III Randomized Control Trial (ALTER0303) (ID 12249)
16:45 - 18:00 | Author(s): Yuankai Shi
- Abstract
Background
Anlotinib is a novel multi-target tyrosine Kinase inhibitor that inhibits VEGFR2/3, FGFR1-4, PDGFD α/β, c-Kit and Ret. In the phase Ⅲ ALTER-0303 trial (Clinical Trial Registry ID: NCT 02388919), anlotinib significantly improved overall survival versus placebo in advanced non-small-cell lung cancer (NSCLC) patients who had received at least two previous chemotherapy and epidermal growth factor receptor /anaplastic lymphoma kinase targeted therapy regimens. This study assessed quality of life (QoL) in these patients.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients were randomized (2:1) to anlotinib or placebo up to progression or intolerable toxicity. The QoL were assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the associated EORTC Quality of Life Lung Cancer Specific Module (QLQ-LC13) at baseline, end of cycle 1, end of every two cycles, and at the final visit. The analyses were conducted in the first 6 cycles. Differences in scores of 10 points or more between two arms or from baseline were considered clinically meaningful.
4c3880bb027f159e801041b1021e88e8 Result
A total of 437 patients were assigned to anlotinib (n=294) and placebo (n=143). The completion rates of the QoL questionnaires were from 69.9 % to 97.0%. Mean scores of QLQ-C30 and QLQ-LC13 subscales were similar in the anlotinib and placebo arms at baseline. Compared to placebo, anlotinib improved role functioning (at cycle 2), social functioning (at cycle 4), dyspnea (at cycle 2, 4), insomnia (at cycle 6), constipation (at cycle 2) and financial problems (at cycle 2). Only sore mouth or tongue symptom was worse in the anlotinib arm (at cycle 2, 4, 6) than in the placebo arm.
8eea62084ca7e541d918e823422bd82e Conclusion
Anlotinib improved quality of life versus placebo in advanced NSCLC patients who had received at least two previous chemotherapies. The QoL analyses provided evidence that anlotinib should be a choice for the third-line treatment or beyond in advanced NSCLC.
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P1.01-108 - Management of Anlotinib-Related Adverse Events: Data From ALTER 0303 (ID 12054)
16:45 - 18:00 | Author(s): Yuankai Shi
- Abstract
Background
Anlotinib is an oral tyrosine kinase inhibitor targeting VEGFR, FGFR, PDGFR and c-kit. In the phase Ⅲ ALTER-0303 trial (Clinical Trial Registry ID: NCT 02388919), anlotinib significantly improved overall survival versus placebo in advanced non-small-cell lung cancer (NSCLC) patients who had received at least two previous chemotherapy and epidermal growth factor receptor /anaplastic lymphoma kinase targeted therapy regimens. This study summarized adverse event management in this trial.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients were randomized (2:1) to anlotinib or placebo up to progression or intolerable toxicity. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 4.0) and managed by investigators. Adverse events and key strategies for preventing and managing the most common adverse events were described. Proportions were compared using the χ2 test or Fisher’s exact test, as appropriate. Two-sided values of P <0.05 were considered statistically significant. Analyses were calculated by SAS 9.4.
4c3880bb027f159e801041b1021e88e8 Result
Between February 2015, and August 2016, a total of 437 patients were randomized to anlotinib group (n=294) and placebo group (n=143). The most common anlotinb related adverse events were hypertension (64.6%), fatigue (46.3%), TSH elevation (44.6%), hand-foot syndrome (HFS) (43.2%), hypertriglyceridemia (38.8%), anorexia (38.4%). The most common anlotinib related grade ≥3 adverse events were hypertension (13.3%), HFS (3.7%), and hypertriglyceridemia (2.4%). The median onset time of hypertension, HFS, and hypertriglyceridemia were 6 days, 30 days, and 22 days respectively.
To monitor blood pressure, every patient had an electronic manometer. One hundred and eight (36.7%) patients received dihydropyridine calcium channel blockers, 79 (26.9%) patients received converting enzyme inhibitors of angiotensin /angiotensin receptor blockers, 57 (19.4%) patients received diuretics, 35 (11.9%) patients received beta-blockers. Only 3 (1.0%) patients need dose modification due to hypertension.
Prophylactic measures of HFS were recommended. Frequent emollients should be used on hands and feet to maintain skin hydration, manicure or pedicure to control calluses, protect pressure points and tender areas of feet with insole cushions, shock-absorbing soles, comfortable shoes. Seven (2.3%) patients required dose reduction due to hand-foot skin syndrome. Eleven (3.7%) patients received cortisone cream for topical therapy.
Twenty-four patients received fibrates to reduce plasma triglyceride level. Two (0.7%) patients required dose reduction due to hypertriglyceridemia.
8eea62084ca7e541d918e823422bd82e Conclusion
Anlotinb-related adverse events could be controlled by prophylactic measures, and early intervention.
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P1.01-37 - BPI-9016M, a Novel c-Met Inhibitor, in Pretreated Advanced Solid Tumor: Results from a First-In-Human, Phase 1, Dose-Escalation Study (ID 12317)
16:45 - 18:00 | Author(s): Yuankai Shi
- Abstract
Background
BPI-9016M (Betta Pharmaceuticals Co, Ltd, Hangzhou, China) is a potent targeted therapy that inhibits MET and Axl. This first-in-human study is to assess the safety, tolerability, and pharmacokinetics (PK) of BPI-9016M in patients with advanced solid tumor, and to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for the phase Ib/II study.
a9ded1e5ce5d75814730bb4caaf49419 Method
Eligible patients were enrolled into sequential dose-escalating cohorts from 100 mg to 1000 mg given orally once per day continually following the conventional 3+3 design. The primary endpoint was safety and tolerability. MTD was defined as the highest dose level resulting in <1 of 3 dose limiting toxicities (DLTs). Blood levels of BPI-9016M were evaluated after single and multiple administration (NCT02478866).
4c3880bb027f159e801041b1021e88e8 Result
Twenty patients were enrolled and treated in 6 of 7 predefined dose cohorts (100 mg n=4, 200 mg n=3, 300 mg n=3, 450 mg n=4, 600 mg n=3, 800 mg n=3), dose escalation stopped at 800 mg due to saturation. All had stage IV non-small cell lung cancer (NSCLC) progressed on previous systemic therapy (including previous EGFR TKI in 16 patients). BPI-9016M was well-tolerated in all dose cohorts without DLT. The incidence of overall and grade 3/4 TRAEs was 85% and 45%, respectively. Common TRAEs included elevated ALT (45%), constipation (30%), elevated bilirubin (25%), and oral paresthesia (25%). Tumor response was seen in 1 patients in the 800 mg dose cohort. Systemic exposure to BPI-9016M (maximum plasma concentration and AUC) increased with increasing dose. Mean time to maximum plasma concentration and half-life were 2 to 5.33 hours and 8.09 to 22.3 hours, respectively. Two metabolites (M1, M2-2) were detected.
8eea62084ca7e541d918e823422bd82e Conclusion
BPI-9016M was well tolerated in patients with advanced solid tumor. A phase Ib study is ongoing to investigate the safety and activity of BPI-9016M in patients with c-Met-dysregulated advanced NSCLC (NCT02929290).
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P1.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 944)
- 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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P1.12-03 - A Prospective Study of Apatinib in Advanced Small Cell Lung Cancer Patients Failed from Two or More Lines of Chemotherapy (ID 13140)
16:45 - 18:00 | Author(s): Yuankai Shi
- Abstract
Background
Small lung cancer (SCLC), a highly malignant neoplastic, chemoresponsive disease. For SCLC patients who with worsening status after second-line treatment, there is currently no affirmative and widely accepted chemotherapy regimen. Apatinib is a novel oral multi-target small-molecule TKI mainly targeting the intracellular ATP-binding domain of VEGFR-2, which has a significant effect of anti-angiogenesis to suppress the growth of tumors. This study evaluated the efficacy and safety of Apatinib in SCLC patients who failed from second- or further-line chemotherapy.
a9ded1e5ce5d75814730bb4caaf49419 Method
Data was collected from the files of patients treated with Apatinib 500mg qd who diagnosed with advanced SCLC and failed from second or more lines of chemotherapy. Efficacy assessed after one cycles (4 weeks), then every two cycles (8 weeks) once again. The primary endpoint was PFS and the tumor response was determined according to the RECIST 1.1. PFS were graphed by Kaplan-Meier curves of progression-free survival. AEs were also evaluated and toxicity grade was determined based on CTCAE 4.0.
4c3880bb027f159e801041b1021e88e8 Result
22 patients were enrolled from November 10, 2016 to April 18, 2018, the number of patients that can be evaluated is 19. One patients obtained partial response, and 15 obtained stable disease, representing a DCR of 84.11%. Median PFS was 140 days (95% confidence interval [CI] 94.84–185.16). Although only one patient showed PR, all the patients’ target lesions were reduced. A total of 46 AEs were reported during the trial, grade 3-4 AEs were hypertension (9.09%), leukopenia (4.55%) and proteinuria (4.55%) which most could be relieved by dose reduction.
8eea62084ca7e541d918e823422bd82e Conclusion
In conclusion, Apatinib has a certain therapeutic effect in patients with advanced SCLC (third- or further-line). To further investigate the role of Apatinib in advanced SCLC patients, large sample and additional clinical trials are needed.
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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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P1.13-18 - Exploring the Resistance Mechanism of Osimertinib and Monitoring the Treatment Response Using Plasma ctDNA in Chinese NSCLC Patients (ID 13297)
16:45 - 18:00 | Presenting Author(s): Yuankai Shi
- Abstract
Background
Osimertinib (AZD9291; Tagrisso) is a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) known to be effective for patients harboring the EGFR-T790M variant, which is accounts for more than half of the acquired resistance mechanisms to the first generation EGFR-TKIs. However, limited osimertinib resistance-mechanism was reported. Study on potential osimertinib-resistance mechanisms in advanced NSCLC is necessary.
a9ded1e5ce5d75814730bb4caaf49419 Method
This study enrolled eight T790M-positive (tissue validated) patients, treated with osimertinib after first generation EGFR-TKI (Erlotinib, Gefitinib, Icotinib) resistance and progressed rapidly. Serial plasma samples were collected until disease progressed. Plasma DNA was extracted and sequenced by target-capture deep sequencing of 1021 previously annotated genes related to solid tumors. Clonal EGFR T790M mutation was defined if mutation was in the cluster with the highest mean variated allele frequency with PyClone, and otherwise subclonal EGFR T790M mutation. Molecular tumor burden index (mTBI) was calculated with the mean variant allele frequency of mutations in trunk clonal population.
4c3880bb027f159e801041b1021e88e8 Result
The median progression-free survival (PFS) of these eight rapidly-progressed patients was 3.82 months [95% CI 2.05-5.01] .Targeted capture sequencing of pretreatment ctDNA showed all of the eight patients (100%) were EGFR-positive (Exon19del [n=6] and L858R [n=2]), and seven patients (88%) harbored EGFR T790M mutation, except for the only one patient (P006) who showed an extremely low level of ctDNA. During the Osimertinib treatment, five patients (63%) had osimertinib resistance-related mutations: EGFR C797S (in cis position), G724S, KRAS G12D, PIK3CA E542K, EGFR amplification, and ERBB2 amplification. Among them, two patients had more than one resistance mechanisms: patient P034 had EGFR G724S, KRAS G12D and EGFR amplification, simultaneously; patient P013 had amplification in both EGFR and ERBB2. Other potential resistance mechanisms were identified including EGFR T751I and K754E mutations in P002 and ERBB2 S603 in P013. Notably, the only one patient (P004) who had not been detected to have any known osimertinib resistance mechanism but progressed in 3 months, was demonstrated to harbor a subclonal EGFR T790M mutation by analysis of ctDNA clonal structure. Serial ctDNA monitoring showed mTBI increased when disease progressed in 88% (7/8) patients, except P006, whose mutation were negative at second (stable disease) and third (progressed disease) therapeutic evaluations due to the extremely low level of ctDNA.
8eea62084ca7e541d918e823422bd82e Conclusion
This study presented comprehensive the resistance mechanism of osimertinib progressed rapidly in ctDNA including multiple mechanisms co-occurred in same patient. Serial monitoring of plasma ctDNA may be a promising approach to explore resistance mechanism and monitored the treatment response of third generation EGFR-TKI.
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P2.17 - Treatment of Locoregional Disease - NSCLC (Not CME Accredited Session) (ID 966)
- 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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P2.17-13 - Genome-Wide Copy Number Alterations Profiling Predict Efficacy of Resected Stage II-IIIA Lung Adenocarcinoma (ID 13314)
16:45 - 18:00 | Author(s): Yuankai Shi
- Abstract
Background
The efficacy of platinum-based adjuvant chemotherapy(PBAC) varies for stage II-IIIA resected lung adenocarcinoma(RLUAD) patients, which necessitates the discovery of new potentially prognostic biomarkers. As a major source of genomic variations driving tumor evolution, somatic copy number alterations(CNAs) screening may identify predictive biomarkers.
a9ded1e5ce5d75814730bb4caaf49419 Method
The patterns of CNAs were analyzed by Oncoscan MIP array on formalin fixed paraffin embedded(FFPE) tumor specimens collected from 163 consecutive stage II-IIIA RLUAD patients, 145 out of which received PBAC.
4c3880bb027f159e801041b1021e88e8 Result
Among the 163 patients, 91(55.8%) relapsed within three years after surgery. The most frequent aberrations identified were 1q, 5p, 5q, 7p, 8q, 14p, 16p, 17q, 20q for copy number gains and 8p, 9p, 13p, 16q , 18q for losses. GISTIC2 analysis generated 45 amplification peaks and 40 deletion peaks, including some significantly mutated genes TERT, EGFR, MYC, CCND1, CDK4, MDM2, ERBB2, NKX2-1, CCNE1, CDKN2A, most of which were consistent with TCGA database. It was found that amplifications of 12p12.1（CMAS, GOLT1B, GYS2, LDHB, RECQL, ETNK1, IAPP, PYROXD1, KRAS）and KDM5A were associated with worse prognosis in our cohort(table), and validated in 506 LUADs from TCGA. 163 patients could be well classified into 4 groups with significantly different clinical outcomes based on thresholded copy number at reoccurring alteration peaks from GISTIC2 analysis. Among the 145 received PBAC patients, focal amplification of ERBB2 and deletion of 4q34.3 were found to be specific in relapsed patients compared with unrelapsed patients,This result was validated in an independent 183 cases corhort in Imielinski et al, indicating these two CNAs may contribute to RLUAD recurrence.
8eea62084ca7e541d918e823422bd82e ConclusionAmplifications of 12p12.1 and KDM5A associated with overall survival
Characteristics
Univariate analysis
(Amp vs Non-Amp)
Multivariate analysis
(Amp vs Non-Amp)
Genes
Location
HR (95% CI)
p
HR (95% CI)
p
CMAS
12p12.1
1.99 (1.22~3.23)
0.006
2.80 (1.60~4.88)
<0.001
GOLT1B,GYS2,LDHB,RECQL
12p12.1
1.87 (1.14~3.07)
0.014
2.48 (1.41~4.37)
0.002
ETNK1
12p12.1
1.79 (1.10~2.93)
0.020
2.26 (1.60~3.94)
0.004
IAPP,PYROXD1
12p12.1
1.78 (1.07~2.94)
0.025
2.30 (1.30~4.07)
0.004
KRAS
12p12.1
1.74 (1.06~2.84)
0.027
2.14 (1.24~3.71)
0.006
KDM5A
12p13.33
1.67 (1.02~2.74)
0.043
1.88 (1.08~3.26)
0.026
This study suggests that CNAs may be a potential prognostic classifier in RLAUD patients, amplifications of 12p12.1 and KDM5A might be prognostic biomarkers for RLUAD , and amplification of ERBB2 and deletion of 4q34.3 predicted early relapse after PBAC. These novel findings may provide implication for better clinical decision making.
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