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Ying Cheng
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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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JCSE01.22a - Tislelizumab Combined With Chemotherapy as First-Line Treatment in Chinese Patients With Advanced Lung Cancer (ID 14702)
11:15 - 11:15 | Author(s): Ying Cheng
- Abstract
Abstract not provided
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MA10 - Considerations in Immunotherapy / Real World (ID 911)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 10:30 - 12:00, Room 105
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MA10.08 - Choice of Taxane and Outcomes in the KEYNOTE-407 Study of Pembrolizumab Plus Chemotherapy for Metastatic Squamous NSCLC (ID 14698)
11:25 - 11:30 | Author(s): Ying Cheng
- Abstract
- Presentation
Background
In the randomized, double-blind, phase 3 KEYNOTE-407 study (NCT02775435), pembrolizumab plus chemotherapy with carboplatin and paclitaxel or nab-paclitaxel significantly prolonged OS (HR 0.64, 95% CI 0.49-0.85, P=0.0008) and PFS (HR 0.56, 95% CI 0.45-0.70, P<0.0001) compared with placebo plus chemotherapy in patients with previously untreated, metastatic squamous NSCLC. The benefit of pembrolizumab plus chemotherapy was observed irrespective of PD-L1 TPS. Pembrolizumab plus chemotherapy also had a manageable safety profile. We performed an exploratory analysis of outcomes by investigator’s choice of paclitaxel or nab-paclitaxel, which was a randomization stratification factor.
a9ded1e5ce5d75814730bb4caaf49419 Method
559 eligible patients were randomized 1:1 to pembrolizumab 200 mg or placebo Q3W for up to 35 cycles plus 4 cycles of carboplatin AUC 6 mg/mL/min Q3W and investigator’s choice of paclitaxel 200 mg/m2 Q3W or nab-paclitaxel 100 mg/m2 QW. Primary end points were OS and PFS; ORR and safety were secondary.
4c3880bb027f159e801041b1021e88e8 Result
Paclitaxel was the chosen taxane in 60% of patients. The addition of pembrolizumab to chemotherapy improved OS, PFS, and ORR regardless of choice of carboplatin and paclitaxel or carboplatin and nab-paclitaxel (Table). Incidence of grade 3-5 AEs in the pembrolizumab plus chemotherapy arm vs placebo plus chemotherapy arm was 63.9% vs 59.3% in paclitaxel recipients and 78.9% vs 81.4% in nab-paclitaxel recipients. AEs led to discontinuation of all treatment in 13.6% vs 8.4% of paclitaxel recipients and 12.8% vs 3.5% of nab-paclitaxel recipients and led to discontinuation of any treatment in 19.5% vs 13.2% and 29.4% vs 9.7%, respectively. Immune-mediated AEs occurred in 29.6% vs 9.6% of paclitaxel recipients and 27.5% vs 7.1% of nab-paclitaxel recipients.
8eea62084ca7e541d918e823422bd82e Conclusion
Adding pembrolizumab to chemotherapy with carboplatin and a taxane improved efficacy and was generally tolerable compared with chemotherapy alone as first-line therapy in patients with metastatic squamous NSCLC regardless of whether paclitaxel or nab-paclitaxel was the chosen taxane.
Carboplatin plus Paclitaxel Carboplatin plus Nab-Paclitaxel Pembrolizumab + Chemotherapy
N = 169
Placebo + Chemotherapy
N = 167
Pembrolizumab + Chemotherapy
N = 109
Placebo + Chemotherapy
N = 114
OS, median
(95% CI), mo
14.0 (12.6-16.6) 10.3 (8.2-14.8) NR (NE-NE) 12.6 (9.6-NE) HR (95% CI)a 0.67 (0.48-0.93) 0.59 (0.36-0.98) PFS, median
(95% CI), mo
6.4 (6.0-8.3) 4.4 (4.2-5.1) 6.5 (6.2-8.5) 5.9 (4.4-6.9) HR (95% CI)a 0.52 (0.40-0.68) 0.65 (0.45-0.94) ORR, % (95% CI) 57.4 (49.6-65.0) 37.7 (30.4-45.5) 58.7 (48.9-68.1) 39.5 (30.4-49.1) aBased on a Cox regression model with treatment as a covariate.
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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OA13 - Therapeutics and Radiation for Small Cell Lung Cancer (ID 927)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 10:30 - 12:00, Room 203 BD
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OA13.03 - Anlotinib as Third-Line or Further-Line Treatment in Relapsed SCLC: A Multicentre, Randomized, Double-Blind Phase 2 Trial (ID 12102)
10:50 - 11:00 | Presenting Author(s): Ying Cheng
- Abstract
- Presentation
Background
Treatment for patients with relapsed small cell lung cancer (SCLC) who failed ≥ 2 lines of chemotherapy have high unmet needs. Anlotinib is a novel TKI with highly selective inhibition effects on multi-targets, especially on VEGFR, c-Kit, PDGFR, FGFR. Here we report results of a phase 2 study of anlotinib for the third-line and further-line treatment of SCLC. (ALTER1202, NCT03059797).
a9ded1e5ce5d75814730bb4caaf49419 Method
Eligible either limited- or extensive-stage SCLC patients with disease progression after ≥ 2 lines of chemotherapy were randomized 2:1 to anlotinib or placebo (12 mg PO QD from day 1 to 14, every 3 weeks). The primary endpoint was PFS and secondary endpoints was OS, ORR, DCR, quality of life and safety.
4c3880bb027f159e801041b1021e88e8 Result
Between March 2017 and May 2018, 120 patients from 11 centers were randomized to either anlotinib arm (n=82) or placebo arm (n=38). Until the data cutoff date (30 Jun 2018), median PFS was 4.1 months (95%CI, 2.8 to 4.2 months) in anlotinib arm and 0.7 months (95% CI, 0.7 to 0.8 months) in placebo arm (HR, 0.19; 95% CI, 0.12 to 0.32, p<0.0001). OS data were not sufficiently mature for analysis. Although ORR was similar, considerable improvement in DCR was observed in anlotinib arm (71.6% vs 13.2%, p<0.0001). Treatment-related adverse events (TRAEs) occurred more frequently in anlotinib arm than that in placebo (87.7% and 74.4%). The most common TRAEs were hypertension, anorexia, fatigue, and hand-foot syndrome. Grade ≥3 TRAEs occurred in 29 (35.8%) of patients in anlotinib arm and 6 (15.4%) in placebo arm, respectively.
8eea62084ca7e541d918e823422bd82e Conclusion
ALTER 1202 study demonstrates anlotinib should be considered a treatment option for patients with relapsed SCLC who have experienced treatment failure with two lines of chemotherapy. The safety profile was consistent with the previous report and no newly adverse events were identified.
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: 4
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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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): Ying Cheng
- 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): Ying Cheng
- 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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P1.01-112 - Osimertinib vs Standard of Care (SoC) EGFR-TKI as First-Line Treatment in Chinese Patients With EGFRm Advanced NSCLC (ID 12211)
16:45 - 18:00 | Author(s): Ying Cheng
- Abstract
Background
Osimertinib is an irreversible, central nervous system (CNS) active EGFR-TKI, selective for both EGFRm and T790M resistance mutations. FLAURA (NCT02296125) is a PhIII, double-blind, randomized study assessing efficacy and safety of osimertinib vs SoC EGFR-TKI (erlotinib/gefitinib) in first-line patients with EGFRm advanced NSCLC. FLAURA results (556 patients, globally) are published. We present the China cohort results.
a9ded1e5ce5d75814730bb4caaf49419 Method
The cohort included self-identified Chinese patients, enrolled in China. Eligible patients: ≥18 years, Ex19del/L858R EGFRm advanced NSCLC, no prior EGFR-TKI/systemic anti-cancer therapy for advanced disease. Neurologically stable patients with CNS metastases were allowed, if definitive treatment/corticosteroids were completed ≥2 weeks before enrolment. Patients were randomized 1:1 to osimertinib 80 mg once daily (qd) orally or SoC EGFR-TKI (gefitinib 250 mg qd orally selected by all Chinese sites), stratified by mutation status (Ex19del/L858R). Primary endpoint: progression-free survival (PFS) by RECIST v1.1, per investigator. Data cutoff: 10/01/2018.
4c3880bb027f159e801041b1021e88e8 Result
Overall, 136 patients were randomized (osimertinib n=71; SoC n=65); 19 were also included in the global analysis. Baseline characteristics were balanced across arms (osimertinib/SoC): female 61/71%; smoking history 25/23%; WHO performance status 1 90/80%; Ex19del 51/51%, L858R 49/49%; CNS metastases 24/32%.
Efficacy endpoint Osimertinib
n=71SoC
n=65PFS events, total patients
(% maturity)40
(56%)51
(78%)PFS hazard ratio (HR)*
(95% CI)0.56 (0.37, 0.85); p=0.007 Median PFS, months
(95% CI)17.8
(13.6, 20.7)9.8
(8.3, 13.8)Objective response rate (ORR),
% (95% CI)83%
(72, 91)75%
(63, 85)Median duration of response (DoR), months
(95% CI)16.4
(12.3, NC)10.9
(8.3, 13.8)*A hazard ratio <1 favours osimertinib. PFS benefit was observed across all subgroups, irrespective of EGFR mutation status and including patients with/without CNS metastases at study entry. Median total treatment duration: osimertinib, 18.9 months; SoC, 13.6 months. No new safety signals were reported. Numerical increase in grade ≥3 AEs was reported in the osimertinib arm (49%) versus SoC arm (23%). Most grade ≥3 AEs in the osimertinib arm were investigator-reported laboratory and disease-related AEs; incidence of non-laboratory-related events was low. AEs leading to discontinuation: osimertinib, 13%; SoC, 6%. In the osimertinib arm, most AEs leading to discontinuation were fatal disease-related events.
8eea62084ca7e541d918e823422bd82e Conclusion
Osimertinib improved PFS vs SoC EGFR-TKI (HR: 0.56) as first-line treatment in Chinese patients with EGFRm advanced NSCLC, consistent with the global analysis.
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P1.01-98 - A Phase IIIb Trial of Afatinib in EGFRm+ NSCLC: Analyses of Outcomes in Patients with Brain Metastases or Dose Reductions (ID 12906)
16:45 - 18:00 | Author(s): Ying Cheng
- Abstract
Background
We previously reported interim results of a large (n=479) open-label, single-arm Phase IIIb study of afatinib in EGFR TKI-naïve patients with EGFRm+ NSCLC, in a setting similar to ‘real-world’ practice (Wu et al, WCLC, 2017). In this broad population of Asian patients, the tolerability profile of afatinib was predictable and manageable. Adverse events (AEs) were consistent with the LUX-Lung 3, 6 and 7 trials; 3.8% of patients discontinued due to drug-related AEs. Progression-free survival (PFS) and time to symptomatic progression (TTSP) was encouraging, in patients with both common and uncommon EGFR mutations. TTSP data suggested effective treatment beyond progression. Here, we assess the impact of baseline brain metastases and use of dose reductions on efficacy outcomes.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with locally advanced/metastatic EGFRm+ NSCLC were recruited in China, Hong Kong, India, Singapore and Taiwan. Afatinib 40mg/day was given until disease progression (investigator-assessed) or lack of tolerability. Treatment-related AEs could be managed by protocol-specified tolerability-guided dose adjustment.
4c3880bb027f159e801041b1021e88e8 Result
At data cut-off (13 Feb 2017), patient characteristics were as follows: median age, 59.0 years; female, 52.4%; EGFR mutations: Del19+/-L858R+/-uncommon, 86.0%; uncommon only, 14.0%; ECOG PS0, 19.8%; PS1, 78.1%. Prior chemotherapy lines: 0, 59.7%; 1, 30.1%; ≥2, 10.2%.
Overall, dose reductions from 40mg/day to 30mg/day occurred in 119 patients (25%). Incidences of the most frequently reported AEs before and after dose reduction were (any grade): diarrhea, 96/51%; rash/acne, 69/58%; stomatitis, 65/42%; (≥grade 3) diarrhea, 27/4%; rash/acne, 24/11%; stomatitis, 11/5%. A total of 96 patients had a dose reduction during the first six months; median PFS in this subgroup was 14.1 months (95% CI: 10.0–19.3) versus 11.33 (10.7–13.6) months in those who remained on the starting dose (n=383); HR=1.37 (1.01–1.85), p=0.041. Median TTSP was 17.7 (13.5–23.7) and 14.7 (12.7–17.0) months, respectively; HR=1.26 (0.92–1.72), p=0.15.
Among 92 patients (19.2%) with brain metastases at baseline, median PFS was 10.9 (8.3–14.3) months, versus 12.4 (10.8–13.9) months in those without metastases (n=387); HR=1.23 (0.91–1.65), p=0.18. Median TTSP was 14.8 (12.7–20.7) and 15.4 (12.9–18.0) months, respectively; HR=1.0 (0.71–1.40), p=1.0.
8eea62084ca7e541d918e823422bd82e Conclusion
These findings demonstrate that tolerability-guided dose adjustment of afatinib is an effective measure to reduce treatment-related AEs, while maintaining therapeutic efficacy. TTSP was similar between patients with and without brain metastasis. This is additional evidence for the efficacy of afatinib in patients with brain metastases.
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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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P1.04-36 - Tislelizumab Combined With Chemotherapy as First-Line Treatment in Chinese Patients With Advanced Lung Cancer (ID 12092)
16:45 - 18:00 | Author(s): Ying Cheng
- Abstract
Background
Immune checkpoint inhibitors have shown efficacy in patients with NSCLC as monotherapy and in combination with chemotherapy. Tislelizumab is a humanized IgG4 monoclonal antibody to PD‑1 specifically engineered to minimize FcϒR binding on macrophages, possibly minimizing negative interactions with other immune cells. In a phase 1 study, tislelizumab was generally well tolerated and showed antitumor activity; 200mg IV Q3W was established as the recommended dose.
a9ded1e5ce5d75814730bb4caaf49419 Method
This multi-arm phase 2 study, consisting of safety run-in and dose-extension phases, assessed tislelizumab in combination with platinum-based chemotherapy (by tumor histology) as a potential first-line treatment for Chinese patients with lung cancer. All patients received tislelizumab at 200mg Q3W in combination with 4–6 cycles of platinum-doublet until disease progression. Nonsquamous (nsq) NSCLC patients received pemetrexed + platinum Q3W for 4 cycles followed by pemetrexed maintenance, while squamous (sq) NSCLC patients received paclitaxel + platinum (A) or gemcitabine + platinum (B) Q3W, and small-cell lung cancer (SCLC) patients received etoposide + platinum Q3W. Tumor response (RECIST v1.1) and safety/tolerability were evaluated.
4c3880bb027f159e801041b1021e88e8 Result
As of 21 Feb 2018, 48 patients (median age, 62 years [range: 36–75], 71% male, 71% current/former smokers) received tislelizumab treatment (median, 3 cycles [range: 1–7]); 44 patients remain on the study. Across the four cohorts, confirmed and unconfirmed partial responses were observed in 13 and 9 patients, respectively (Table). The most frequent AEs were chemotherapy-related hematologic toxicities. The most commonly reported grade ≥3 treatment-related AEs were neutropenia (20.8%) and anemia (12.5%); the most common grade 3 immune-related AEs were pyrexia (6.3%) and rash (6.3%). One sq‑NSCLC patient experienced a fatal myocarditis/myositis following one cycle of paclitaxel/cisplatin; all other treatment-related AEs were managed/resolved by study-drug interruption (n=15) or discontinuation (n=4) and appropriate treatment.
8eea62084ca7e541d918e823422bd82e ConclusionBest Overall Response (Patients With ≥1 Post-Baseline Tumor Assessment)
nsq-NSCLC (n=9)
sq-NSCLC [A] (n=12 )
sq-NSCLC [B] (n=5 )
SCLC (n=8)
Total
(N=34)
PR
4 (44.4)
9 (75)
4 (80)
5 (62.5)
22 (64.7)
Confirmed PR
1 (11.1)
4 (33.3)
4 (80)
4 (50)
13 (38.2)
Unconfirmed PR
3 (33.3)
5 (41.7)
0 (0)
1 (12.5)
9 (26.5)
SD
3 (33.3)
2 (16.7)
1 (20)
2 (25)
8 (23.5)
PD
1 (11.1)
0 (0)
0 (0)
1 (12.5)
2 (5.9)
NE
1 (11.1)
1 (8.3)
0 (0)
0 (0)
2 (5.9)
Data presented as n (%).
Abbreviations: nsq-NSCLC, non-squamous non-small cell lung cancer; NE, not evaluable; PD, progressive disease; PR, partial response; SCLC, small cell lung cancer; SD, stable disease; sq-NSCLC, squamous non-small cell lung cancer.
Tislelizumab, in combination with platinum doublets, demonstrated preliminary antitumor activity and was generally well tolerated in patients with advanced lung cancer.
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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: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.01-101 - Dynamic Monitoring of Gene Alterations with ctDNA by NGS for EGFR Mutated Lung Adenocarcinoma Treated with Gefitinib in BENEFIT Study (CTONG 1405) (ID 14347)
16:45 - 18:00 | Author(s): Ying Cheng
- Abstract
Background
Blood-based cell-free tumor DNA (ctDNA) could be dynamically monitored to provide gene alterations during EGFR-TKI treatment, which might offer critical clue for prognosis and clinical treatment decision. Here we reported the dynamic gene alterations monitoring using next generation sequencing (NGS) in BENEFIT study to explore the mechanisms of different responses and resistances to EGFR-TKI in EGFR-sensitizing-mutated lung-adenocarcinoma (LADC) patients.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with systemic treatment-naïve, stage IV LADC and EGFR-sensitizing-mutation in ctDNA were enrolled to receive gefitinib. Blood samples were dynamically obtained at baseline, every 8 weeks and at disease progression (PD). The dynamic analysis of quantity of ctDNA, multiple driver genes and tumor suppressors were investigated with NGS (Nextseq500 sequencer, consisting of critical exons/introns of 168 genes), and were correlated with efficacy and resistance.
4c3880bb027f159e801041b1021e88e8 Result
Totally 181 LADC patients with EGFR-sensitizing-mutation (exon-19-deletion and exon-21-L858R-point-mutation) provided sufficient blood samples for NGS analysis at baseline, of which 143 patients obtained at least four timepoints of dynamic blood sample collection until PD (baseline, 8 weeks, 8 weeks before PD and PD). At baseline, 180 of patients (99.4%) were confirmed as EGFR-sensitizing-mutation with NGS (92 EGFR-19-deletion and 88 EGFR-L858R-point-mutation) including 44 (24.3%) EGFR-amplification, 116 (64%) TP53-mutation, or other known oncogenic drivers including MET (N=5, 2.8%), ERBB2 (N=7,3.9%), KRAS (N=6, 3.3%), BRAF (N=2, 1.2%), RET (N=1, 0.6%), ROS1 (N=1, 0.6%), or EGFR-T790M (N=4, 2.2%), which was correlated with poor efficacy compared with those with only EGFR-sensitizing-mutation (PFS 4.7 months [m] vs. 13.2m , p=0.002). Additionally, tumor suppressor genes exhibiting cumulative effect to poor prognosis: PFS for 164 patients with TP53&RB1&PTEN-mutation≤1 was 11.1m, while for 16 patients with TP53&RB1&PTEN-mutation＞1，PFS was 4.7 m, p<0.0001. To cut-off date, 117 patients had PD, among them, 63 (54%) patients acquired EGFR-T790M-mutation presented as dominant resistance mechanism besides MET-amplification/ERBB2-amplification/ERBB2-S310F (N=16, 14%), RET fusion/splice (N=2, 1.7%), ROS1-C2336F-mutation (N=1, 0.9%), RB1-nonsense-mutation (N=2, 1.7%), TP53-Y205S-mutation (N=1, 0.9%) and TP53-Y205S-mutation accompanied with FGFR1-amplification (N=1, 0.9%). The remaining resistance mechanisms (31%) were unknown. Patients with only T790M-mutation had a significantly longer PFS (11.5m) compared with patients obtaining other acquired resistant mechanisms (3.0m). Interestingly, seventy-five (53.2%) patients had molecular progression before radiographic progression, and the median time difference was 8.7 weeks.
8eea62084ca7e541d918e823422bd82e Conclusion
Dynamic alterations of multi-drivers and suppressors together with EGFR-sensitizing-mutation and T790M-mutation could separate LADC into different subgroups with distinguished molecular features, which may play a vital role during EGFR-TKI treatment for resistance-predicting, and initial/subsequent treatment decision-making.
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