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Xiaorong Dong
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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
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JCSE01.10 - A Ph3 Study of Niraparib as Maintenance Therapy in 1L Platinum Responsive Extensive Disease Small Cell Lung Cancer Patients (ID 11679)
10:25 - 10:35 | Author(s): Xiaorong Dong
- Abstract
- Presentation
Background
Small cell lung cancer (SCLC) accounts for 15% of lung cancer, characterized by early dissemination and rapid development of chemo-resistant disease after platinum response (60-80%). Less than 2% of extensive disease SCLC (ED-SCLC) patients survive 5 years. The bi-allelic loss or inactivation of TP53 and RB1 is common in SCLC, the poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA damage repair enzyme, is highly expressed in SCLC, and SCLC is sensitive to platinum based chemotherapy, suggesting that the defect in DNA damage repair pathways plays an important role in SCLC. ZL2306/ Niraparib is a highly selective PARP-1/2 inhibitor which was exclusively licensed for development in China by Zai Laboratory from TESARO. In SCLC PDX model, niraparib demonstrated anti-tumor activities as monotherapy. In addition, niraparib demonstrated promising tumor growth inhibition in maintenance post platinum treatment in platinum sensitive SCLC PDX models. Clinically, in phase III NOVA study, niraparib demonstrated clear clinical benefit as maintenance treatment by significantly extending progression free survival in all platinum-sensitive recurrent ovarian cancer patients regardless gBRCA or HRD status which led to the approval by FDA and EMA in ovarian cancer. It is suggested that niraparib maintenance therapy could provide potential clinical benefit in platinum responsive SCLC. ZL-2306-005 is a randomized double-blind multi-center phase 3 study to evaluate the efficacy and safety of niraparib versus placebo as maintenance therapy in ED-SCLC patients who have had responses to platinum based chemotherapy.Approximately 590 Chinese patients with histologically or cytologically confirmed ED-SCLC who have achieved either complete response or partial response to their platinum based chemotherapy to their newly diagnosed disease will be randomized (2:1) to 2 groups, receiving either ZL-2306 or placebo in ZL-2306-005 study. Patients need to complete 4 cycles of etoposide + cisplatin/ carboplatin. All patients will be stratified by gender, LDH level and history of prophylactic cranial irradiation. ZL-2306 will be started with 300mg PO QD for patients with a baseline body weight ≥77 kg and a baseline platelet count ≥150,000/μL, or 200 mg PO QD for patients with a baseline body weight <77 kg or a baseline platelet count <150,000/μL based on RADAR analysis in NOVA study. Patients will remain on treatment until disease progression or intolerable toxicity. The co-primary endpoints are PFS assessed by independent central radiologic review and OS; the secondary endpoints are PFS assessed by investigator, CFI, QoL, safety and tolerability.Section not applicable
Section not applicable
a9ded1e5ce5d75814730bb4caaf49419Only 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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MA27 - Novel Drugs and PDX Models (ID 931)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 13:30 - 15:00, Room 206 BD
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MA27.02 - Hypofractionated Radiotherapy Normalizes Tumor Vasculature in Non-Small Cell Lung Cancer Xenografts Through p-STAT3/HIF-1 Alpha Pathway (ID 14322)
13:35 - 13:40 | Presenting Author(s): Xiaorong Dong
- Abstract
- Presentation
Background
Our study aimed to investigate specific biological effect of hypofractionated radiotherapy (HFRT) on tumor angiogenesis, when compared with conventional radiotherapy (CRT).
a9ded1e5ce5d75814730bb4caaf49419 Method
Firstly, models of nude mice as well as dorsal skinfold window chamber (DSWC) bearing H460 and HCC827 (NSCLC cell lines) were established. Tumors suffered irradiation with doses of 0 Gy (control group), 22 Gy delivered into 11 fractions (CRT group) or 12 Gy delivered into 1 fraction (HFRT group). After irradiation, xenograft volumes were recorded every other day. At different time points after irradiation, the vasculature of DSMC was visualized by FITC-Dextran; α-SMA and CD34 immune-histochemical staining was employed to detect the micro-vessel density (MVD) and coverage rates of pericyte on tumor vessels; pimonidazole hydrochloride was used to detect hypoxia; western blotting and RT-PCR were used to detect the expression levels of p-STAT3, HIF-1α, SDF-1 and VEGFA. Then, S3I-201, the STAT3 inhibitor, was used to further verify the mechanism of the effect of HFRT on vascular normalization.
4c3880bb027f159e801041b1021e88e8 Result
Compared to CRT groups, the growth suppression effect of HFRT on tumor tissue was enhanced, accompanied by stronger effect on decrease in MVD, vascular normalization and improvement of tumor hypoxia. RT-PCR and western blotting exhibited that HFRT promoted the vascular normalization by activating STAT3/ HIF-1α signaling pathway.
8eea62084ca7e541d918e823422bd82e Conclusion
Compared to CRT, the pathway of p-STAT3/HIF-1α and its downstream angiogenic factors (VEGFA and SDF-1) might play important roles in forming of a window-period of vascular normalization in NSCLC, which contributed to the specific biological effect of HFRT on tumor vasculature.
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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P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-105 - Lung Cancer Patients with Concurrent EGFR and MET Mutations: A Retrospective Analysis of 29 Cases (ID 12864)
16:45 - 18:00 | Author(s): Xiaorong Dong
- Abstract
Background
It has been reported that about 5%-20% of EGFR-TKIs resistant NSCLC patients harbors MET amplification or activating mutations. However, the extent that MET abnormal activation contributes to EGFR-TKIs resistance remains widely unknown. Here, we describe the clinical and genetic characteristics of 29 lung cancer patients harboring concurrent EGFR and MET mutations.
a9ded1e5ce5d75814730bb4caaf49419 Method
Genetic mutations were reviewed in 6000 lung cancer patients who underwent genetic testing at our institute from 2016 to 2018. Mutation profiles were analyzed using hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations of at least 59 genes (range 59 – 1021 genes).
4c3880bb027f159e801041b1021e88e8 Result
The selected patients included 24 lung adenocarcinoma patients, 1 squamous cell lung cancer patient and 3 lung cancer patients with unspecified pathology. Both MET amplification and activating mutations were included for analysis. MET amplification was detected in 90% (27/30) of samples, while activating mutations was present in 13.3% (4/30) of samples, including H1112Y, D1228N, D1246Y and D1246H. 14% (4/29) of patients had not received EGFR-TKIs treatment before genetic testing, which were considered as primary resistance. 79% (23/29) of patients were treated with EGFR-TKIs. Surprisingly, 60% (18/30) of cases had other functional mutations which may also affect the effectiveness of EGFR-TKIs, such as EGFR T790M mutation (3 cases), rare EGFR mutations (I744M, R108K and C769S, 3 cases), EGFR amplification (7 cases), CDK4 amplification (2 cases), loss-of-function mutations of CDKN2A (2 cases) and so on. One patient had two samples tested. He was resistant to gefitinib and osimertinib, and EGFR L858R mutation and MET amplification were detected in the first sample. Later, he was treated with combined gefitinib and crizotinib and reached PR at the 2nd month. However, his disease finally progressed probably due to an additional MET mutation (D1246Y) that caused resistance to crizotinib.
8eea62084ca7e541d918e823422bd82e Conclusion
MET amplification and activating mutations may lead to primary and acquired resistance of EGFR-TKIs. Moreover, additional potentially resistant mechanisms were detected in most cases. Therefore, it is apparently requisite to provide a comprehensive genetic testing to lung cancer patients.
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P1.01-27 - Influence of EGFR-TKIs Treatment Lines and PFS on the Emergence of T790M Mutation (ID 13584)
16:45 - 18:00 | Presenting Author(s): Xiaorong Dong
- Abstract
Background
For sensitizing EGFR mutation positive lung cancer patients, EGFR-TKIs can be used as the first-line or second-line (after chemotherapy) therapy according to NCCN guideline. However, whether different lines of EGFR-TKIs therapy or different PFS would affect the emergence of T790M, the leading cause of resistance to first and second generation of EGFR-TKIs was unknown.
a9ded1e5ce5d75814730bb4caaf49419 Method
We retrospectively analyzed 142 advance NSCLC patients with 93 patients received 1st-line EGFR-TKIs, and 49 patients received 2nd-line EGFR-TKIs after chemotherapy. EGFR sensitizing mutation and T790M mutation was detected simultaneously by hybridization capture-based NGS panel sequencing with tumor biopsy , ctDNA or pleural effusion samples.
4c3880bb027f159e801041b1021e88e8 Result
For the patients received 1st-line EGFR-TKIs, 47 carried L858R mutation and 46 carried EX19del mutation; while patients received 2nd-line EGFR-TKIs, 24 carried L858R mutation and 25 carried EX19del mutation. When those patients progressed on TKIs, T790M emerged in 25 of the 47 (53.19%) L858R carriers, and 23 of the 46 (50.00%) EX19del carriers with 1st-line EGFR-TKIs (p=0.76). However, only 6 of the 24 (25.00%) L858R carriers yet 16 of the 25 (64.00%) EX19del carriers with 2nd-line EGFR-TKIs had T790M detected (p=0.006). The incidence of T790M was significant lower in L858R carrier treated with 2nd-line compared with 1st-line EGFR-TKIs (25.00% vs 53.19%, p=0.023), however, there was no difference for EX19del carrier (50.00% vs 64.00%, p=0.26). To further analyzed whether different PFS affected the appearance of T790M, we divided patients into 3 groups as PFS≥13 months (n=48), PFS≤8 months (n=60) and the between (n=34). The incidence of T790M was significantly lower in the PFS≤8 months group compared with the PFS≥13 months (31.67% vs 62.5%, p=0.001). The difference was also significant if only counting the L858R carriers (18.52% vs 59.26%, p=0.002), but not significant in the EX19del carriers (42.42% vs 66.67%, p=0.082).
8eea62084ca7e541d918e823422bd82e Conclusion
1st-line or 2nd-line EGFR-TKIs generally did not significantly alter the emergence of T790M. But for the L858R mutation carriers, the incidence of T790M is significantly decreased if treated as a 2nd-line EGFR-TKIs therapy. In addition, patients with longer PFS were associated with higher incidence of T790M mutation.
6f8b794f3246b0c1e1780bb4d4d5dc53
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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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P1.12-04 - A Ph3 Study of Niraparib as Maintenance Therapy in 1L Platinum Responsive Extensive Disease Small Cell Lung Cancer Patients (ID 12119)
16:45 - 18:00 | Author(s): Xiaorong Dong
- Abstract
Background
Small cell lung cancer (SCLC) accounts for 15% of lung cancer, characterized by early dissemination and rapid development of chemo-resistant disease after platinum response (60-80%). Less than 2% of extensive disease SCLC (ED-SCLC) patients survive 5 years. The bi-allelic loss or inactivation of TP53 and RB1 is common in SCLC, the poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA damage repair enzyme, is highly expressed in SCLC, and SCLC is sensitive to platinum based chemotherapy, suggesting that the defect in DNA damage repair pathways plays an important role in SCLC. ZL2306/ Niraparib is a highly selective PARP-1/2 inhibitor which was exclusively licensed for development in China by Zai Laboratory from TESARO. In SCLC PDX model, niraparib demonstrated anti-tumor activities as monotherapy. In addition, niraparib demonstrated promising tumor growth inhibition in maintenance post platinum treatment in platinum sensitive SCLC PDX models. Clinically, in phase III NOVA study, niraparib demonstrated clear clinical benefit as maintenance treatment by significantly extending progression free survival in all platinum-sensitive recurrent ovarian cancer patients regardless gBRCA or HRD status which led to the approval by FDA and EMA in ovarian cancer. It is suggested that niraparib maintenance therapy could provide potential clinical benefit in platinum responsive SCLC. ZL-2306-005 is a randomized double-blind multi-center phase 3 study to evaluate the efficacy and safety of niraparib versus placebo as maintenance therapy in ED-SCLC patients who have had responses to platinum based chemotherapy.
a9ded1e5ce5d75814730bb4caaf49419 Method
Approximately 590 Chinese patients with histologically or cytologically confirmed ED-SCLC who have achieved either complete response or partial response to their platinum based chemotherapy to their newly diagnosed disease will be randomized (2:1) to 2 groups, receiving either ZL-2306 or placebo in ZL-2306-005 study. Patients need to complete 4 cycles of etoposide + cisplatin/ carboplatin. All patients will be stratified by gender, LDH level and history of prophylactic cranial irradiation. ZL-2306 will be started with 300mg PO QD for patients with a baseline body weight ≥77 kg and a baseline platelet count ≥150,000/μL, or 200 mg PO QD for patients with a baseline body weight <77 kg or a baseline platelet count <150,000/μL based on RADAR analysis in NOVA study. Patients will remain on treatment until disease progression or intolerable toxicity. The co-primary endpoints are PFS assessed by independent central radiologic review and OS; the secondary endpoints are PFS assessed by investigator, CFI, QoL, safety and tolerability.
4c3880bb027f159e801041b1021e88e8 Result
Section not applicable
8eea62084ca7e541d918e823422bd82e Conclusion
Section not applicable
6f8b794f3246b0c1e1780bb4d4d5dc53
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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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P1.13-08 - Distribution, Differences in Clinical Characteristics and Resistance Mechanism of ALK Variants in Chinese Lung Cancer Patients. (ID 13678)
16:45 - 18:00 | Author(s): Xiaorong Dong
- Abstract
Background
ALK rearrangements are established targetable drivers in NSCLC. Recent reports indicate differential progression-free survival to ALK inhibitors according to specific EML4-ALK variant.
a9ded1e5ce5d75814730bb4caaf49419 Method
A total of 172 unique Chinese lung cancer patients with tumors harboring ALK rearrangements (ALK+) were enrolled in the study from 2016 to 2018. ALK+ were detected by Ventana, FISH, or next-generation sequencing based ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations across at least 59 genes (59-1021). Tissue biopsy was the first choice for NGS mutation profiling, and ctDNA or pleural effusion testing was used as an alternative.
4c3880bb027f159e801041b1021e88e8 Result
Of these 172 cases, the median diagnosis age was 50 (range 24-78), 58% were female, 90% was NSCLC. Of the 147 ALK+ cases detected by NGS, we identified 65 (44%) EML4-ALK v1 (E13; A20), 18 (12%) EML4-ALK v2 (E20; A20), 43 (29%) EML4-ALK v3 (E6; A20), 13 (9%) other EML4-ALK, and 8 (5%) non-EML4-ALK rearrangements. 2 new fusion genes were found in non EML4-ALK rearrangements (SRBD1-ALK (EX20; EX20) and CLIP4-ALK (EX9; EX20)), and the CLIP4-ALK patient’s tissue was also ALK positive by Ventana. V1 found a higher proportion of pleural effusion at baseline than non-v1 (12% v.s.5%). Mutation profiling by NGS were performed after disease progression in 55 patients treated with crizotinib. mPFS was 8.1 months, no significant difference existed between v1 and v3 (P=0.69). But the presence of known ALK resistance mechanisms was significantly higher in v3 as compared to non-v3 (67% v.s. 27%, P=0.038).
8eea62084ca7e541d918e823422bd82e Conclusion
Next generation sequencing allows for detection of the specific ALK fusion partner and variants, increases the understanding of the biology of ALK+ NSCLC, and may have value to foretell potential mechanisms of resistance.
6f8b794f3246b0c1e1780bb4d4d5dc53
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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: 2
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.01-107 - Analysis of Mutation Detection by ctDNA on the Basis of Metastatic Sites in Lung Adenocarcinoma Patients (ID 13635)
16:45 - 18:00 | Author(s): Xiaorong Dong
- Abstract
Background
Circulating tumor DNA (ctDNA) testing represents a powerful tool to detect gene alterations in patients. However, differences in mutation detected by ctDNA related to metastatic sites in lung cancer have not been addressed before and remain to be explored.
a9ded1e5ce5d75814730bb4caaf49419 Method
We reviewed 317 ctDNA samples from 310 lung adenocarcinoma patients with definite metastasis at our institute. Somatic mutation profiles were analyzed using hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations of 1021 genes.
4c3880bb027f159e801041b1021e88e8 Result
Patients were divided into two groups according to metastatic sites. Any case with metastasis to the bone, liver or adrenal gland falls into the major organ metastasis group, while any case with metastasis to the lung, pleura or lymph node belongs to the local metastasis group. No genetic alteration was detected in 14 (11.5%) of 122 samples in the major organ group and 35 (17.9%) of 195 in the local group. And distant metastasis is associated with more mutations on average detected by ctDNA (5.26 for the major organ group vs 3.72 for the local group; p=0.0039). As for genes involved, the most common mutated ones are EGFR and TP53 for both groups, with an overall mutation rate being 40.6% and 33.2% respectively. And just as average gene alterations mentioned above, the mutation rates of EGFR and TP53 are much higher in the major organ group (49.6% vs 35.2% for EGFR; 43.6% vs 26.9% for TP53). Besides, mutations of NF1, MLL3, KRAS and KEAP1 are more frequent in the major organ group while mutation rate of PIK3CA is slightly higher in the local group (Table).
8eea62084ca7e541d918e823422bd82e ConclusionTable. Some mutated genes detected by ctDNA
major organ metastasis (117)
local metastasis (193)
EGFR
58 (49.6%)
68 (35.2%)
TP53
51 (43.6%)
52 (26.9%)
KRAS
9 (7.7%)
7 (3.6%)
MLL3
9 (7.7%)
6 (3.1%)
NF1
9 (7.7%)
3 (1.6%)
ERBB2
5 (4.3%)
6 (3.1%)
PIK3CA
3 (2.6%)
7 (3.6%)
KEAP1
7 (6.0%)
3 (1.6%)
More gene alterations were detected by sequencing of ctDNA in patients of lung adenocarcinoma with major organ metastasis compared to those with only local metastasis.
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P2.01-126 - MicroRNA-330-3p Modulates Tumor Vascular Normalization After Hypofractionated Radiotherapy by Targeting p-STAT3/ HIF-1 Alpha Pathway (ID 14339)
16:45 - 18:00 | Presenting Author(s): Xiaorong Dong
- Abstract
Background
Our study aimed to explore the effect of microRNA-330-3p (miR-330-3p) on radiosensitivity of NSCLC on HFRT both in vivo and in vitro.
a9ded1e5ce5d75814730bb4caaf49419 Method
The miR-330-3p over-expressed H460 (H460-OE) and HCC827 (HCC827-OE) cell lines were established using lentivirus vector expressed miR-330-3p. Tumor-bearing nude mice and the dorsal skinfold window chamber (DSWC) models (divided into H460-OE, HCC827-OE, H460 and HCC827 groups) were established and received 0-Gy (control group) or 12-Gy (HFRT group) radiation respectively. At different time points after irradiation, the vasculature of DSMC was visualized by FITC-Dextran; co-immunofluorescence of α-SMA/CD34 staining was employed to detect the coverage rate of pericyte cells on tumor vessels; pimonidazole hydrochloride (PIM) was used to detect the hypoxia; Western blotting and RT-PCR were used to detect the expression levels of p-STAT3/HIF-1α/VEGFA signal pathway and downstream factors CXCL12/CXCR4. In vitro, after radiation, the colony formation assay was used to detect the radiosensitivity. The rate of apoptosis cells were detected by flow cytometry. Moreover, STAT3 inhibitor, S3I-201, was used to further verify the mechanism of miR-330-3p regulating HIF-1α and its downstream factor by Western blotting.
4c3880bb027f159e801041b1021e88e8 Result
The curve of relative volume-time displayed that the radiosensitivity of miR-330-3p over-expressed xenografts decreased as compared to H460 and HCC827 xenografts. HFRT-induced decrease of MVD and hypoxia, increase of pericyte coverage on tumor vasculars in H460 and HCC827 xenografs were inhibited in H460-OE and HCC827-OE xenografts (P <0.05). Colony formation assay showed that the radiosensitivities in miR-330-3p over-expressed groups decreased and the flow cytometry assay showed that after HFRT, apoptosis rate was higher in H460-OE than H460 cell lines. Western blotting and RT-PCR displayed that, both on the 7th and 14th day after HFRT, the levels of p-STAT3, HIF-1α, VEGFA and CXCL12/CXCR4 in miR-330-3p over-expressed xenografts were higher than that in HCC827 and H460 xenografts (P <0.05). The in vitro studies showed that 2-28 hours after HFRT, the expression levels of p-STAT3, HIF-1α and VEGFA in H460-OE cells was up-regulated as compared to H460 cells (P<0.05). After adding S3I-201, the levels of p-STAT3/HIF-1α could not be inhibited in H460-OE, but could be inhibited in the H460 group (P<0.05). Also compared to the HCC827 cells after HFRT, the levels of p-STAT3 in HCC827-OE group could not inhibited by S3I-201 (P<0.05).
8eea62084ca7e541d918e823422bd82e Conclusion
miR-330-3p may decrease the HFRT-radiosensitivity of NSCLC via upregulating the p-STAT3/HIF-1α pathway and its downstream factors, VEGFA and CXCL12/CXCR4, therefore inhibiting vascular normalization effect of HFRT.
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