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Lin Wu
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FP14 - Targeted Therapy - Clinically Focused (ID 252)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP14.11 - Icotinib versus Chemotherapy as Adjuvant Treatment for Stage II–IIIA EGFR-Mutant NSCLC (EVIDENCE): A Randomized, Open-Label, Phase 3 Study (ID 3605)
00:00 - 00:00 | Author(s): Lin Wu
- Abstract
Introduction
Recent studies have shown significant benefits of EGFR tyrosine kinase inhibitors in the adjuvant setting for patients with EGFR-mutant stage IB–IIIA resected NSCLC. This study aimed to compare the efficacy and safety of icotinib with standard chemotherapy in adjuvant setting in patients with EGFR mutant stage II-IIIA NSCLC.
Methods
In this randomized, open-label, phase 3 study, eligible patients aged 18-70 years who had completely resected (R0), stage II-IIIA EGFR-mutant NSCLC (in-frame deletion in exon 19 or Leu858Arg point mutation in exon 21) were randomly assigned, in a 1:1 ratio, to receive either adjuvant icotinib (125 mg thrice daily administered orally for 2 years) or four-cycle chemotherapy (cisplatin plus vinorelbine, or cisplatin plus pemetrexed for non-squamous carcinoma). Patients were stratified by clinical stage (II vs IIIA), EGFR mutation type (exon 19 vs 21), and resection methods (lobectomy vs pneumonectomy). The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety.
Results
A total of 365 patients were screened, and 322 patients (161 for each arm) were enrolled from 29 centers across China between June 2015 and July 2019. Thirty-nine patients had major protocol violations and were excluded, leaving 283 patients in full analysis set (151 in icotinib arm and 132 in chemotherapy arm, respectively). 53% and 47% of patients had an EGFR mutation of 19 Del and 21 L858R, respectively. At the data cutoff (March 31, 2020) for the pre-specified interim analysis, 98 out of 196 (50%) events were recorded with a median follow-up of 24.9 months (95% CI, 22.1 to 28.8). In full analysis population, the median DFS (mDFS) was 47.0 months (95% CI, 36.44 to not reached) in the icotinib group and 22.1 months (95% CI, 16.8 to 30.4) in the chemotherapy group (stratified hazard ratio=0.36; 95% CI, 0.24 to 0.55; P < 0.0001). Analyses of DFS based on stratification criteria and vital demographic and prognostic factors showed consistent benefits of icotinib treatment across subgroups. The 3-year DFS was 63.9% in the icotinib group and 32.5% in the chemotherapy group. It is immature to perform OS analysis with14 (9.3%) patients in the icotinib group and 14 (10.6%) patients in the chemotherapy group died, respectively. Adverse events of grade 3 or 4 were observed in 10.9% of the patients in the icotinib group and 61.2% in the chemotherapy group. Treatment-related serious adverse events occurred in 2 (1.3%) patients in the icotinib group and 19 (13.7%) patients in the chemotherapy group. No interstitial pneumonia or treatment-related death was observed in each group.
Conclusion
Adjuvant icotinib significantly improved DFS in patients with EGFR mutant stage II-IIIA NSCLC compared with standard chemotherapy and demonstrated a better tolerability profile. Icotinib can provide a new treatment option for stage II-IIIA NSCLC patients with activating EGFR mutation.
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JICC01 - Joint IASLC-CAALC-CSCO Session: The Truth and Myth of Oral Anti-VEGFR Inhibitors for Advance NSCLC (ID 276)
- Event: WCLC 2020
- Type: Workshop
- Track: N.A.
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 07:00 - 09:00, Scientific Program Auditorium
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JICC01.11 - Icotinib versus Chemotherapy as Adjuvant Treatment for Stage II–IIIA EGFR-Mutant NSCLC (EVIDENCE): A Randomized, Open-Label, Phase 3 Study (ID 4275)
07:00 - 09:00 | Author(s): Lin Wu
- Abstract
- Presentation
Introduction
Recent studies have shown significant benefits of EGFR tyrosine kinase inhibitors in the adjuvant setting for patients with EGFR-mutant stage IB–IIIA resected NSCLC. This study aimed to compare the efficacy and safety of icotinib with standard chemotherapy in adjuvant setting in patients with EGFR mutant stage II-IIIA NSCLC. Methods
In this randomized, open-label, phase 3 study, eligible patients aged 18-70 years who had completely resected (R0), stage II-IIIA EGFR-mutant NSCLC (in-frame deletion in exon 19 or Leu858Arg point mutation in exon 21) were randomly assigned, in a 1:1 ratio, to receive either adjuvant icotinib (125 mg thrice daily administered orally for 2 years) or four-cycle chemotherapy (cisplatin plus vinorelbine, or cisplatin plus pemetrexed for non-squamous carcinoma). Patients were stratified by clinical stage (II vs IIIA), EGFR mutation type (exon 19 vs 21), and resection methods (lobectomy vs pneumonectomy). The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety. Results
A total of 365 patients were screened, and 322 patients (161 for each arm) were enrolled from 29 centers across China between June 2015 and July 2019. Thirty-nine patients had major protocol violations and were excluded, leaving 283 patients in full analysis set (151 in icotinib arm and 132 in chemotherapy arm, respectively). 53% and 47% of patients had an EGFR mutation of 19 Del and 21 L858R, respectively. At the data cutoff (March 31, 2020) for the pre-specified interim analysis, 98 out of 196 (50%) events were recorded with a median follow-up of 24.9 months (95% CI, 22.1 to 28.8). In full analysis population, the median DFS (mDFS) was 47.0 months (95% CI, 36.44 to not reached) in the icotinib group and 22.1 months (95% CI, 16.8 to 30.4) in the chemotherapy group (stratified hazard ratio=0.36; 95% CI, 0.24 to 0.55; P < 0.0001). Analyses of DFS based on stratification criteria and vital demographic and prognostic factors showed consistent benefits of icotinib treatment across subgroups. The 3-year DFS was 63.9% in the icotinib group and 32.5% in the chemotherapy group. It is immature to perform OS analysis with14 (9.3%) patients in the icotinib group and 14 (10.6%) patients in the chemotherapy group died, respectively. Adverse events of grade 3 or 4 were observed in 10.9% of the patients in the icotinib group and 61.2% in the chemotherapy group. Treatment-related serious adverse events occurred in 2 (1.3%) patients in the icotinib group and 19 (13.7%) patients in the chemotherapy group. No interstitial pneumonia or treatment-related death was observed in each group. Conclusion
Adjuvant icotinib significantly improved DFS in patients with EGFR mutant stage II-IIIA NSCLC compared with standard chemotherapy and demonstrated a better tolerability profile. Icotinib can provide a new treatment option for stage II-IIIA NSCLC patients with activating EGFR mutation.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.
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P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 4
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P76.24 - A Randomized Phase 2 Trial of Anlotinib Plus Docetaxel vs Docetaxel as 2nd-Line Therapy for EGFR-Negative NSCLC (ALTER-L018) (ID 1351)
00:00 - 00:00 | Presenting Author(s): Lin Wu
- Abstract
Introduction
Anlotinib is an oral multi-target angiogenesis TKI targeting the VEGFR, FGFR, PDGFR and c-Kit. Phase III trial: ALTER0303 showed that compared with placebo, anlotinib improved both progression-free survival (PFS) and overall survival (OS) in refractory advanced non-small cell lung cancer (NSCLC) as third-line treatment. The combination of docetaxel and ramucirumab/nintedanib has demonstrated antitumor activity in the second-line therapy of NSCLC. We performed ALTER-L018 to assessed the efficacy and safety of anlotinib plus docetaxel as second-line treatment in EGFR-negative refractory advanced NSCLC .
Methods
ALTER-L018 is a randomized, controlled comparative, open-label, multicenter, phase II trial, which was conducted at 10 sites in China. Eligible EGFR-negative NSCLC patients who has been assesed progression on first-line platinum-base chemotherapy, were randomly assigned (in a 1:1 ratio) to receive anlotinib plus docetaxel (A+D) or docetaxel (D). Anlotinib was given at 12mg Qd from day 1 to 14 in a 21-day cycle, and docetaxel was given at 75mg/m2 Q3W. The efficacy was evaluated every 6-weeks(2 cycles) through treatment. Primary end points was PFS, secondary endpoints were OS, objective response rate (ORR), disease control rate (DCR), and safety. This trial is registered with ClinicalTrial.gov, NCT03624309, and is ongoing.
Results
Between Jan 14, 2019, and Aug 2, 2020, 58 patients (pts.) were enrolled and 6 pts. were excluded from the safety and efficacy analysis set(n=52) due to inclusion violations(demographics are shown in table 1). At data cutoff( Aug 15, 2020), 52 pts. were available for efficacy analysis. The median PFS were 5.18 months(95%Cl: 1.23-9.14) versus 1.74 months(95%Cl: 0.71-2.77) in A+D and D arms, respectively(HR: 0.41; 95%Cl:0.20-0.85, p=0.01). The median OS didn’t achieve. For tumor response, 44 pts. were evaluable: the ORR were 33.33% versus 7.69% (p=0.048) and DCR were 72.22% versus 56.52%(p=0.62) in A+D and D arms, respectively. The adverse events that possibly or definitely related to therapy occurred in 14 ( 61%) of pts. experienced total of 28 grade 1-2 adverse events in A+D arms, and in 10 (34%) of pts. experienced total of 20 grade 1-2 adverse events in D arms. The most common grade≥3 TRAE were leukopenia(2, 9%), neutropenia(1, 4%) and myelosuppression(2, 9%) in A+D arm, and leukopenia(4, 14%), neutropenia(2,7%) and myelosuppression(2, 7%) in D arm.
Conclusion
Second-line anlotinib plus docetaxel showed clinical benefit in EGFR-negative NSCLC patients in terms of PFS, ORR and DCR. The overall safety profile in ALTER-L018 was similar between two arms, with comparable frequencies of grade 3 or 4 adverse events.
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P76.48 - A CT-Based Radiomic Feature Predicts EGFR Mutation and Response to Targeted Therapy in NSCLC (ID 2211)
00:00 - 00:00 | Presenting Author(s): Lin Wu
- Abstract
Introduction
Biomarkers that predict response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is critical in NSCLC. EGFR mutation is a common and common use biomarker, but it is still constrained by tumor or liquid biopsy and tumor heterogeneity. Medical imaging-based biomarkers are research hotspots in certain anticancer therapy. Since computer tomography (CT) imaging is less costly and much easier for clinical application, several radiomics bio-markers have been proposed in lung cancer. The aim of this study is to identify radiomic signatures that distinguish the EGFR mutational status and explore feature related biomarkers associated with response in lung adenocarcinoma patients treated with first-line EGFR TKI.
Methods
CT imaging before treatment from 692 Lung adenocarcinoma patients with certain EGFR mutational status at Hunan Cancer Hospital were analyzed retrospectively. The features were quantified by radiomic features and enrolled into the support vector machine (SVM) classifier to build a radiomic model for predicting EGFR status. The performance was evaluated by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. We included top-ranked features to evaluate the relationship between survival and CT features using COX regression survival analysis.
Results
In this cohort, 355 patients were EGFR mutant while 337 patients was EGFR wild type. Two hundred and twenty-five EGFR-mutant patients suffered disease progression after first-line EGFR TKI therapy. The 13 features were input to the SVM classifier to build a radiomic model trained on the training cohort with 514 patients. The predictive performance was evaluated on an independent validation cohort and achieved an AUC of 74.13%. We found that higher value of skewness feature (HR=1.722,95%CI:1.261–2.352,P=0.001) and higher 10percentile feature (HR=1.466, 95% CI: 1.085-1.981, P=0.013) before treatment were significantly correlated with shorter PFS.
Conclusion
The radiomics signature based on CT imaging features in addition with clinical variables can be used to predict EGFR mutational status of lung adenocarcinomas. Skewness and 10percentile features may help the stratification of progression of advanced lung adenocarcinoma patients treated EGFR targeted therapy.
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P76.63 - Dacomitinib Induces a Drastic Response in Metastatic Brain Lesions of Patients with EGFR-mutant Non-small-cell Lung Cancer: A Brief Report (ID 3280)
00:00 - 00:00 | Presenting Author(s): Lin Wu
- Abstract
Introduction
Dacomitinib is a potent, irreversible and pan-HER tyrosine kinase inhibitor (TKI) of EGFR-mutant NSCLC lacking evidence about its activity on brain metastasis. In this retrospective realworld cohort, we evaluated the intracranial efficacy and tolerability of dacomitinib in treatment-naïve NSCLC patients with EGFR-mutation and brain metastases.
Methods
Between July, 2019 and July, 2020, patients diagnosed of EGFR mutatant stage IV NSCLC with brain metastasis from Hunan Cancer hospital were reviewed. Paitents treated with Dacomitinib were enrolled. Objective response rate (ORR) and depth of response in brain metastasis was assessed with RECIST 1.1 criteria or RANO-LM.
Results
Brain radiographic review of patients.
Response assesment of patients
In total, 59 EGFR-mutant NSCLC patients were prescribed first-line Dacomitinib and 14 had brain metastasis before treatment. In 14 patietns, starting dose of 45 mg once daily was given to 5 patients while the remaining 9 patients received 30 mg until progression of disease or unbearable toxity. In this cohort, 7 (50%) were male. Eight patients harbored EGFR 19del, 5 with L858R and one patient had EGFR G719A and I706T. All patients received at least one radiographic review. At the data cut-off, the median follow up duration was 5 months. The ORR was 92.9% (13/14) and the DCR was 100% according to RECIST 1.1 criteria. A measurable response of intracranial metastases was observed in 12 of the 14 patients (85.7%), including 12 of 13 (92.3%) with brain parenchymal metastasis, but the one patient with meningeal metastasis did not respond well (RANO-LM criteria). All patients (100%) had grade 1-2 adverse effects, but none discontinued treatment or required a dosage adjustment.
Conclusion
This real-world cohort study with 14 patients has shown for the first time that dacomitinib have potent efficacy for CNS metastasis in both L858R and 19del EGFR-positive patients with NSCLC. More data are required to confirm its advantages and optimize its clinical application.
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P76.65 - CNS Efficacy of AST2818 in Patients with T790M-Positive Advanced NSCLC: Data from a Phase I-II Dose-Expansion Study (ID 3286)
00:00 - 00:00 | Author(s): Lin Wu
- Abstract
Introduction
Furmonertinib (AST2818, former name: alflutinib) is a new third-generation EGFR-tyrosine kinase inhibitor that selectively inhibits EGFR-sensitizing and EGFR T790M mutation. We have reported promising clinical activity and well-characterized tolerability of AST2818 in EGFR T790M-positive locally advanced or metastatic non-small-cell lung cancer (NSCLC) patients including its preliminary efficacy in patients with central nervous system (CNS) metastases (Shi Y et al JTO 2020;15(6):1015-1026). Herein, we report the result of recent subgroup analysis from phase I-II dose-expansion study (NCT03127449) where the CNS efficacy of different AST2818 doses was evaluated.
Methods
Patients aged ≥18 years with centrally confirmed EGFR T790M-positive locally advanced or metastatic NSCLC received AST2818 ranging from 40-240 mg doses once daily until disease progression. Patients with asymptomatic, stable CNS metastases not requiring steroids for at least 4 weeks before the first dose of AST2818 were enrolled. A subgroup analysis was conducted in patients with ≥1 measurable CNS lesion (per RECIST 1.1) at baseline brain imaging (CNS evaluable-for-response set, cEFR) and patients with ≥1 measurable and/or non-measurable CNS lesion at baseline brain imaging (CNS full analysis set, cFAS) by blinded independent central review (BICR). CNS efficacy was evaluated in terms of CNS objective response rate (ORR), CNS disease control rate (DCR), CNS progression-free survival (PFS), and CNS duration of response (DoR) (assessed by BICR).
Results
At data cutoff (29 January 2020), 116 patients were enrolled, of which 45 patients (38.8%) were included in cFAS and 23 patients (19.8%) were included in cEFR. Confirmed CNS ORR was 65.2% (15/23) while CNS DCR was 91.3% (21/23) in cEFR. The CNS ORR in the 40-, 80-, 160-, and 240-mg groups was 0 (no response of 1), 60% (3/5 partial response [PR]), 84.6% (1/13 complete response [CR] and 10/13 PR), and 25% (1/4 PR), respectively. In the cFAS, median CNS PFS was not reached (95% confidence interval [CI], 8.3 months to not reached), while median CNS PFS in 40-, 80-, 160-, and 240-mg groups were 2.8, 9.7, 19.3 months, and not reached, respectively. Median CNS DoR (19% maturity) in cFAS was not reached (range, 2.8 months to not reached). At 12 months, 50%, 81.8%, and 100% of patients were estimated to remain in response in 80-, 160-, and 240-mg groups, respectively.
Conclusion
AST2818 demonstrated clinically meaningful efficacy against CNS metastases. 160 mg provided relevant benefit with a high CNS ORR and PFS. Further studies are required to confirm these findings.
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P79 - Immunotherapy (Phase II/III Trials) - Immunotherapy Plus Chemotherapy (ID 256)
- Event: WCLC 2020
- Type: Posters
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P79.08 - Sintilimab ± IBI305 Plus Chemotherapy for Patients With EGFR-Mutant Non-Squamous NSCLC Failed to EGFR-TKI Treatment (ID 1304)
00:00 - 00:00 | Author(s): Lin Wu
- Abstract
Introduction
The standard treatment for advanced non-squamous non-small cell lung cancer (nsqNSCLC) patients with EGFR-mutation is osimertinib or other recommended tyrosine kinase inhibitors (TKIs). For those who failed to TKI treatment, the choice of systemic treatment is limited, including platinum-based chemotherapy, and new therapy regimens are needed to improve the efficacy. T-cell mediated cancer cell killing of anti-PD-1 antibody may be enhanced through reversal of vascular endothelial growth factor (VEGF)-mediated immunosuppression. Sintilimab is a humanized, monoclonal antibody that blocks the interaction between PD-1 and its ligands. IBI305 is a biosimilar candidate for bevacizumab which is a monoclonal antibody against VEGF. ORIENT-31 study is a randomized, double-blind, multi-center, phase 3 study to compare the efficacy and safety of sintilimab with or without IBI305 plus pemetrexed and cisplatin versus placebo plus pemetrexed and cisplatin. (NCT03802240).
Methods
Patients, who have failed to epidermal growth factor receptor (EGFR)-TKI treatment, with histologically/cytologically confirmed Stage IIIB-IV nsqNSCLC with EGFR mutations will be enrolled in this two-stage study. The total planned sample size is 600, with 480 patients in the common enrollment stage and 120 patients in the extension enrollment stage. In the common enrollment stage, 480 patients will be enrolled and randomized (1:1:1) into Group A (sintilimab + IBI305 + pemetrexed + cisplatin), Group B (sintilimab + placebo 2 + pemetrexed + cisplatin) and Group C (placebo 1 + placebo 2 + pemetrexed + cisplatin). In the extension enrollment stage, 120 patients will be enrolled and randomized (1:1) into Group A and Group B. Stratification factors include gender (male or female) and brain metastasis (with or without). Sintilimab 200 mg with or without IBI305 15 mg/kg will be administrated every 3 weeks (Q3W) until disease progression, unacceptable toxicity or voluntary patient withdrawal for up to 24 months. The pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 will be administrated Q3W for up to 4 cycles. The primary efficacy endpoint is progression-free survival per RECIST V 1.1 by Independent Radiographic Review Committee. The secondary efficacy endpoints include overall survival, objective response rate, disease control rate, time to response and duration of response per RECIST V1.1. By March 9, 2020, 112 patients have been enrolled in this study.
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P86 - Targeted Therapy - Clinically Focused - New Target (ID 263)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P86.14 - Next-Generation Sequencing Guided the Gene Mutations Associated with mTOR-Inhibitors in Chinese Lung Cancer Patients (ID 1780)
00:00 - 00:00 | Presenting Author(s): Lin Wu
- Abstract
Introduction
mTOR-inhibitors, especially everolimus, are being studied for use in multiple cancers. Clinical trials in mTOR-inhibitors and lung cancers are in full swing. PIK3CA, AKT1, PTEN, STK11, mTOR, TSC1 and TSC2 mutations are reported clinically variable responses to mTOR-inhibitors, but rare comprehensive studies about genetic changes of these genes. Previous studies indicated that mTOR pathway mutations used as driver mutations co-existing with EGFR aberrations to jointly promote tumor progression and result in EGFR-TKI resistance. Co-targeting EGFR and mTOR pathways could reverse EGFR-TKI resistance in this situation. However, the main actionable mTOR pathway mutations that co-exist with TKI-sensitive classical EGFR mutations are unknown. Uncovering them may find the mutation target of drug resistance and effective countermeasures.
Methods
We performed a retrospective analysis of 14,429 Chinese lung cancer patients who underwent genetic testing using next generation sequencing targeting the whole exons of up-mentioned seven genes which may benefit from mTOR-inhibitor.
Results
First, the genomic landscape of the potential target genes of mTOR-inhibitors were comprehensively analyzed. The mutation ratio of PIK3CA, AKT1 and PTEN were relatively higher than that in TCGA data. Whereas the mutation ratio of STK11, mTOR, TSC1 and TSC2 were relatively lower. Details were showed in Table 1. The top three recurrent mutations were STK11 H154Q (2.14% of all patients), PIK3CA E545K (1.25%) and AKT1 I186M (0.35%). Excepting PIK3CA E545K known as a hotspot mutation, little is known about the functions of STK11 H154Q and AKT1 I186M. Loss of function mutations in tumor suppressor genes, such as PTEN and STK11, may promote tumor progression. In our data, loss of function mutations were found in almost all (98.67%) of PTEN-mutant patients, while only in 31.55% of STK11-mutant patients, suggesting PTEN mutations may play a more central role in lung cancer biology and in response to mTOR-inhibitor. Next, the co-mutation properties of these mTOR-pathway had the co-existing mutations. 2.0% of patients had actionable co-mutations and mainly in EGFR L858R and PIK3CA E545K (22 patients), E542K (18 patients) or H1047R (16 patients). These mutations combo may be responsible for promoting tumor progress and limiting the efficacy of EGFR-TKIs. A combination therapy of EGFR-TKI and mTOR inhibitors may be attempted in these patients.
ConclusionTable 1. The mutation ratio of the genes that clinically variable responses to mTOR-inhibitors
Genes
14,429 patients
TCGA data
PIK3CA
8.52%
7.1%
AKT1
1.64%
0.6%
PTEN
4.5%
4.0%
STK11
8.21%
10.5%
mTOR
1.55%
3.6%
TSC1
1.23%
1.4%
TSC2
0.96%
2.4%
We systematically revealed the mutation feature of the genes that clinically variable responses to mTOR-inhibitors. 2.0% patients with the co-mutations of TKI-sensitive classical EGFR mutations and actionable mTOR pathways gene maybe benefit from mTOR-inhibitors added treatment.
