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Yun Fan



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    JCSE01 - Joint IASLC-CSCO-CAALC Session (ID 63)

    • Event: WCLC 2019
    • Type: Joint IASLC-CSCO-CAALC Session
    • Track:
    • Presentations: 1
    • Now Available
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      JCSE01.09 - A Phase II Umbrella Study of Camrelizumab in Different PD-L1 Expression Cohorts in Pre-Treated Advanced/Metastatic Non-Small Cell Lung Cancer (Now Available) (ID 3423)

      07:00 - 11:15  |  Author(s): Yun Fan

      • Abstract
      • Presentation
      • Slides

      Abstract
      Background
      The role of PD-L1 expression in 2nd line and beyond non-small cell lung cancer (NSCLC) remains controversial. Camrelizumab (SHR-1210) is a potent anti-PD-1 monoclonal antibody and has shown promising activity in NSCLC in Phase I studies. We report results from the SHR-1210-201 study (NCT03085069), a phase II umbrella study of camrelizumab monotherapy in different PD-L1 expression cohorts in Chinese patients with previously treated advanced or metastatic NSCLC.

      Methods
      Patients who progressed during or following platinum-based doublet chemotherapy were enrolled and assigned to one of 4 cohorts based on PD-L1 expression. Patients with EGFR or ALK genomic alterations were eligible provided they had disease progression with at least one approved tyrosine kinase inhibitor and with ≥50% PD-L1 expression in tumor. All enrolled patients received camrelizumab at 200 mg IV Q2W until loss of clinical benefit. The primary endpoint was objective response rate (ORR), other endpoints included progression-free survival (PFS) and overall survival (OS).

      Results
      As of Aug 1st 2018, of all the 259 patients who underwent screen, 229 cases could be pathologically evaluated. PD-L1 expression were 47.6% (109/229) in PD-L1 < 1%, 27.1% (62/229) in PD-L1 1-<25%, 8.7% (20/229) in 25-<50% and 16.6% (38/229) in 50%. A total of 63.8% (146/229) patients were enrolled. 89.0% of patients had stage IV NSCLC and 54.8% had non-squamous tumor histology. ORR was 18.5% (95%CI: 12.6%–25.8%) in ITT population. Subgroup analysis showed increased PD-L1 expression was associated with better response rate (Table 1). No response was observed in patients with EGFR mutation. The responders had durable response (median: 15.1 months; 95%CI: 5.5–not reached). Median PFS was 3.2 months (95%CI: 2.0–3.4) and median OS was 19.4 months (95%CI: 11.6–not reached) (Table 1). Treatment-related adverse events (AEs) occurred in 87.7% of patients (all Grade); 20.5% had ≥G3 related AE; and 15.8% had related SAE. 21.2% of AEs led to dose interruption and 7.5% led to treatment discontinuation.

      Table 1 - Efficacy data in subgroups
      Population No of pts ORR, % (95%CI)

      PFS (month),

      median (95%CI)

      1YOS, % (95%CI)

      OS (month),

      median (95%CI)

      PD-L1<1% 74

      12.2% (5.7%, 21.8%)

      2.1 (1.9, 3.2) 47.1% (33.8%, 59.2%) 11.6 (7.8, NR)
      PD-L1 ≥1% and < 25% 31 19.4% (7.5%, 37.5%) 3.1 (1.8, 4.9) 76.7% (57.2%, 88.2%) NR (NR, NR)
      PD-L1 ≥25% and < 50% 11 45.5% (16.7%, 76.6%) 6.0 (1.9, NR) 81.8% (44.7%, 95.1%) NR (2.9, NR)
      PD-L1 ≥50% (without EGFR mutation) 25 28.0% (12.1%, 49.4%) 7.6 (3.3, 11.4) 55.2% (32.3%, 73.2%) NR (8.6, NR)
      PD-L1 ≥50% (with EGFR mutation) 5 0 1.7 (1.2, NR) 40.0% (5.2%, 75.3%) 10.3 (1.2, NR)
      ITT 146 18.5% (12.6%, 25.8%) 3.2 (2.0, 3.4) 56.6% (47.3%, 64.9%) 19.4 (11.6, NR)

      Abbreviation: NR, Not Reached.

      Conclusion
      In Chinese patients with previously treated advanced/metastatic NSCLC, camrelizumab demonstrated improved ORR, PFS, and OS compared with historical data of the 2nd line chemotherapy. The efficacy in patients with PD-L1 <1% is similar as the 2nd line mono-chemotherapy, while patients with higher PD-L1 expression derived greater benefit from camrelizumab, the ORR, PFS and OS in patients with PD-L1 ≥25% was comparable to the 1st line doublet chemotherapy in advanced NSCLC. Camrelizumab was well tolerated. This phase 2 data warrant further clinical studies of camrelizumab in NSCLC.

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    MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 2
    • Now Available
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      MA11.02 - KEYNOTE-042 China Study: First-Line Pembrolizumab vs Chemotherapy in Chinese Patients with Advanced NSCLC with PD-L1 TPS ≥1% (Now Available) (ID 1772)

      14:00 - 15:30  |  Author(s): Yun Fan

      • Abstract
      • Presentation
      • Slides

      Background

      In the global, open-label KEYNOTE-042 study (NCT02220894), pembrolizumab significantly improved OS vs chemotherapy in PD-L1–positive locally advanced/metastatic NSCLC without targetable EGFR/ALK aberrations (HRs: TPS ≥50%, 0.69; ≥20%, 0.77; and ≥1%, 0.81). We present the very first results for Chinese patients enrolled in the KEYNOTE-042 global and China extension (NCT03850444) studies.

      Method

      The global and extension studies were designed identically. Patients were randomized 1:1 (stratified by ECOG PS 0/1, squamous/nonsquamous histology, and TPS ≥50%/1‒49%) to up to 35 cycles of pembrolizumab 200 mg Q3W or up to 6 cycles of paclitaxel/pemetrexed + carboplatin with optional pemetrexed maintenance (nonsquamous only). Primary endpoints were OS in patients with PD-L1 TPS ≥50%, ≥20%, and ≥1%. No alpha was allocated to the China extension analysis. Overall, ~350 patients from China will be enrolled including 140 patients with TPS ≥50%, to determine the OS effect of pembrolizumab and consistency across outcomes in Chinese patients.

      Result

      As of September 4, 2018, 262 Chinese patients with PD-L1–positive (TPS ≥1%) NSCLC were enrolled (global, n=92; China extension, n=170) and randomized to pembrolizumab (n=128) or chemotherapy (n=134). 146 patients (55.7%) had PD-L1 TPS ≥50%; 204 (77.9%) had PD-L1 TPS ≥20%. After median (range) follow-up of 11.3 (0.1‒23.2) months, 32 patients (25.0%) were still receiving pembrolizumab and 6 (4.8%) were receiving pemetrexed maintenance. Pembrolizumab improved OS vs chemotherapy in patients with PD-L1 TPS ≥50%, ≥20%, and ≥1% (Table). Among patients who received ≥1 dose of pembrolizumab (n=128) or chemotherapy (n=125), grade 3–5 drug-related AEs occurred in 17% vs 68%, respectively.

      Overall Survival

      n

      Median (95% CI), mo

      HR (95% CI)

      PD-L1 TPS ≥50%

      Pembrolizumab

      72

      20.0 (15.5–NR)

      0.62 (0.38–1.00)

      Chemotherapy

      74

      14.0 (10.0–17.9)

      PD-L1 TPS ≥20%

      Pembrolizumab

      101

      20.0 (17.4–NR)

      0.62 (0.41–0.95)

      Chemotherapy

      103

      13.7 (10.1–17.9)

      PD-L1 TPS ≥1%

      Pembrolizumab

      128

      20.0 (17.4–NR)

      0.65 (0.45–0.94)

      Chemotherapy

      134

      13.7 (10.1–17.9)

      PD-L1 TPS 1–49%a

      Pembrolizumab

      56

      19.9 (11.9–NR)

      0.69 (0.40–1.20)

      Chemotherapy

      60

      10.7 (8.3–20.9)

      NR, not reached. aExploratory analysis.

      Conclusion

      Pembrolizumab monotherapy improved OS with a favorable safety profile vs platinum-based chemotherapy as first-line therapy in Chinese patients with locally advanced/metastatic NSCLC without sensitizing EGFR/ALK aberrations and a PD-L1 TPS ≥1%. Findings are consistent with the global study primary endpoints, supporting first-line use of pembrolizumab for PD-L1–expressing advanced/metastatic NSCLC in China.

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      MA11.06 - A PII Study of Toripalimab, a PD-1 mAb, in Combination with Chemotherapy in EGFR+ Advanced NSCLC Patients Failed to Prior EGFR TKI Therapies (Now Available) (ID 1160)

      14:00 - 15:30  |  Author(s): Yun Fan

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR TKI is the standard 1st line therapy for the patients (pts) with advanced NSCLC harboring EGFR mutations. While PD-1 checkpoint blockade has become an integral component of disease management for EGFR wild type NSCLC pts at various settings, platinum-based chemotherapy is still the standard of care for EGFR mutated NSCLC pts who progress after EGFR targeting therapy. Early attempts to combine EGFR TKI with checkpoint blockade had resulted in exacerbated immune related toxicity in the lung. Here we aimed to prospectively evaluate toripalimab, a humanized PD-1 mAb approved for 2nd line treatment of melanoma, in combination with chemotherapy to treat EGFR mutated NSCLC pts after failure of EGFR targeting therapy.

      Method

      This is a phase II, multicenter, open-label, single-arm study for pts with EGFR activating mutations who have failed prior EGFR-TKI therapies without T790M mutation or failed osimertinib treatment. Pts were treated with 240mg or 360mg fixed dose toripalimab once every 3 weeks in combination with carboplatin and pemetrexed for up to 6 cycles, followed by toripalimab plus pemetrexed maintenance therapy until disease progression or intolerable toxicity. Primary endpoint was objective response rate (ORR) at week 12 as assessed by investigator per RECIST v1.1 once every 6 weeks. Secondary endpoints were safety, ORR, DOR, DCR, TTR, PFS, OS, PK and immunogenicity.

      Result

      f14_2_1_3_pub.png

      Forty pts were enrolled from Apr 25, 2018 to March 22, 2019 with 52.5% female pts and a median age of 57.5. 57.5% pts harbored EGFR exon19 deletion while 42.5% pts had exon21 L858R mutation. Only 1 pt had T790M mutation who progressed after osimertinib treatment. In ITT population, 13 confirmed partial response (PR) and 22 stable disease (SD) were observed at week 12 for a 32.5% ORR. As of Jul 25 2019, among 40 pts, 20 confirmed PR and 15 SD were observed for a 50% ORR (95% CI, 33.8% to 66.2%) and an 87.5% DCR (95% CI, 73.2% to 95.8%). Median progression free survival (PFS) was 7.0 months, and median duration of response (DOR) was 7.0 months. Treatment emergent adverse events (TEAE) occurred in 39 (97.5%) of the pts, grade 3 or higher events occurred in 25 (62.5%) of pts including two deaths. Most common AE included leukopenia, neutropenia, thrombocytopenia, anemia, nausea, and loss of appetite. Treatment discontinuation due to AE occurred in 4 (10%) of the pts.

      Conclusion

      Anti-PD-1 mAb, toripalimab in combination with carboplatin and pemetrexed has shown a promising anti-tumor efficacy with a tolerable safety profile for advanced NSCLC patients with EGFR mutated who progressed after EGFR TKI therapies. Pts will be continuously monitored for safety and efficacy readouts (DOR, PFS and OS). A phase III registration study will be initiated in May 2019.

      (Clinical trial information: NCT03513666)

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    OA04 - Immuno Combinations and the Role of TMB (ID 126)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      OA04.03 - A Randomized Phase 3 Study of Camrelizumab plus Chemotherapy as 1<sup>st</sup> Line Therapy for Advanced/Metastatic Non-Squamous Non-Small Cell Lung Cancer (Now Available) (ID 1682)

      15:15 - 16:45  |  Author(s): Yun Fan

      • Abstract
      • Presentation
      • Slides

      Background

      Platinum-based chemotherapy remains 1st line therapy for advanced non-small cell lung cancer (NSCLC) without oncogenic drivers in China. Camrelizumab (SHR-1210, a potent anti‒PD-1 monoclonal antibody) has shown promising activity in multiple malignancies. Here, we report interim analysis results on efficacy and safety of camrelizumab plus carboplatin/pemetrexed as 1st line treatment in Chinese advanced/metastatic non-squamous NSCLC patients with negative oncogenic drivers.

      Method

      In this open-label, randomized, multicenter phase 3 study (SHR-1210-303), patients with advanced/metastatic, non-squamous NSCLC with negative EGFR or ALK were stratified by sex and smoking history (≥ 400/year versus ˂ 400/year) and were randomly assigned (1:1) to receive 4 to 6 cycles of carboplatin (AUC=5) plus pemetrexed (500 mg/m2) with or without camrelizumab (200 mg), followed by pemetrexed with or without camrelizumab as maintenance therapy up to disease progression or intolerable toxicity. Treatment was given every 3 weeks. Crossover to camrelizumab monotherapy was permitted for patients in the chemotherapy arm who had confirmed disease progression. The primary endpoint was PFS per blinded independent central review according to RECIST v1.1. Secondary endpoints included ORR, DCR, DoR and OS. Data of subgroup analysis will be reported. Clinical Trials.gov number: NCT03134872.

      Result

      Between May 12, 2017 and Jun 6, 2018, 419 patients were randomized, among whom 205 received camrelizumab plus chemotherapy and 207 received chemotherapy treatment. After a median follow-up of 11.9 months, median PFS was 11.3 months (95% CI 9.5‒not reached) in camrelizumab plus chemotherapy arm and 8.3 months (95% CI 6.0‒9.7) in chemotherapy arm (HR 0.61 [95% CI 0.46‒0.80], p=0.0002). ORR, DCR, DoR and OS with camrelizumab plus chemotherapy were superior to chemotherapy (Table 1). Grade 3/4 adverse events occurred in 66.8% of patients in camrelizumab plus chemotherapy arm and 51.2% of patients in chemotherapy arm. There were 5 treatment-related deaths in camrelizumab plus chemotherapy arm and 4 in chemotherapy arm.

      Table 1. Responses per blinded independent central review and overall survival in the total study population

      Camrelizumab plus chemotherapy

      (n=205)

      Chemotherapy alone

      (n=207)
      p-value
      Objective response rate 60.0% (53.0‒66.8) 39.1% (32.4‒46.1) p<0.0001
      Disease control rate 87.3% (82.0‒91.6) 74.4% (67.9‒80.2) p=0.0009
      Duration of response (months) 17.6 (11.6‒NR) 9.9 (8.5‒13.8) p=0.0356
      Overall survival (months) NR (17.1‒NR) 20.9 (14.2‒NR) p=0.0272
      Data are shown in % (95% CI) or median (95% CI). NR: not reached.

      Conclusion

      First-line camrelizumab plus chemotherapy shows substantial clinical benefit in patients with advanced/metastatic non-squamous NSCLC with negative EGFR or ALK in terms of PFS, ORR, and OS and acceptable safety profiles. The combination should become novel standard 1st line therapy for this population.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 3
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-100 - Effect of Osimertinib in Non-Small Cell Lung Cancer Patients with Brain Metastases After Progression Following Front-Line EGFR-TKI Therapy (Now Available) (ID 2985)

      09:45 - 18:00  |  Presenting Author(s): Yun Fan

      • Abstract
      • Slides

      Background

      Osimertinib has been adopted as the standard of care for T790M-mediated acquired epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance. In this study, we aim to investigate the effect of osimertinib in advanced NSCLC with brain metastases after the failure of first-line therapy.

      Method

      We retrospectively studied 43 NSCLC patients with BM received osimertinib after progression following front-line EGFR-TKI therapy from January 2013 to December 2016 at our institution. Overall survival (OS) was measured from the date of brain metastases.

      Result

      Among the 43 patients, 25(58.1%) received EGFR-TKIs as first-line therapy, 15(34.9%) were treated with EGFR-TKIs therapy after the progression of chemotherapy, and there’re also 3(7.0%) received the combination of EGFR-TKIs and chemotherapy as first-line therapy. 16(37.2%) were EGFR T790M positive, 4(9.3%) were EGFR T790M negative and 23(53.5%) were unknown T790M status. 34(79.1%) patients had received local radiation therapies (RT). The median overall survival (OS), and the median intracranial progression free survival (iPFS) was 32.0 months, 14 months, respectively. Patients with EGFR T790M mutation had the median OS of 24.7 months, these without T790M mutation had the median OS of 17.0 months, and the patients with unknown status of T790M showed the longest OS of 34.4months, although it did not reach statistical significance (P =0.727). There was also no difference in iPFS among the T790M-positive group, T790M-negetive group and the unknown status group (5.0 vs. 7.0 vs. 18.0 months, P=0.195). Similar results in OS were found among the first line TKIs group, chemotherapy followed by EGFR-TKI therapy group and the combination of TKIs and chemotherapy group (P=0.491). Three patients had leptomeningeal metastasis (LM), showed to have a worse iPFS of 12 months compared to 14 months of these without LM (P=0.991).

      Conclusion

      Osimertinib had a good efficacy in patients with brain metastasis of advanced non–small-cell lung cancer in whom disease had progressed following front-line EGFR-TKIs.

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      P1.01-18 - Integrated Genomic and DNA Methylation Analyses of Non-Small Cell Lung Cancer Patients with Brain Metastases (ID 1570)

      09:45 - 18:00  |  Presenting Author(s): Yun Fan

      • Abstract

      Background

      Brain metastases (BM), with a dismal prognosis, are a common and lethal complication of non-small cell lung cancer. Approximately, 10% patients present with BM at their initial diagnosis. Although, surgery and/or radiation therapy remain to be the mainstay treatment, targeted therapies are finding increasing application in treating BM. However, due to the very limited accessibility of brain lesions, its genomic and epigenomic landscape remain elusive.

      Method

      Capture-based targeted sequencing for somatic mutation profiling was performed on 27 treatment-naïve advanced NSCLC patients with paired lung primary and BM lesions using a pane consisting of 520 cancer related genes. DNA methylation analyses was performed on same samples using a DNA methylation panel consisting of 100,000 CpG sites.

      Result

      Collectively, we identified 370 (291 SNVs+Indels, 78 CNVs and 1 rearrangement) and 574 (245 SNVs+Indels, 327 CNVs and 2 rearrangements) mutations from lung primary lesions and BM, respectively. Among them, 242 mutations were shared; 128 were lung primary-specific and 332 were BM-specific. Among the BM specific mutations, a majority of them (82%, 272/332) were copy number variations (CNVs). Only 16% of CNVs were shared by lung lesions and BM. The concordance for SNVs and indels were much higher-54% between the two sources of tissues. Furthermore, we observed a much higher concordance rate (79%) in TP53 and classic lung cancer driver genes than other genes (p<0.001), indicating that they might be stem mutations. Next, we performed pathway analysis of genes that were only mutated in BM and revealed an enrichment of genes participating in PI3K-AKT and focal adhesion pathways. We also compared tumor mutation burden (TMB) between them and revealed comparable TMB (p=0.1). Our DNA methylation analysis revealed distinct methylation patterns with 268 blocks that are significantly differentially methylated between primary lung lesions and BM. Among them, 211 blocks were hypermethylated in BM and the remaining 57 blocks were hypermethylated in lung lesions. These blocks were enrichment in genes participating in cell adhesion, Rap1 signaling and calcium signaling pathways.

      Conclusion

      We revealed diverse somatic mutation and DNA methylation profiles between lung primary lesions and BM. BM had significantly more unique CNVs. A great concordance was observed for classic lung cancer driver genes and TP53. Our study provided a comprehensive view of genomic and DNA methylation profiling for lung primary lesions and BM, paving the avenue for the development of targeted therapies for treating BM.

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      P1.01-61 - A Phase II Umbrella Study of Camrelizumab in Different PD-L1 Expression Cohorts in Pre-Treated Advanced/Metastatic Non-Small Cell Lung Cancer (ID 1633)

      09:45 - 18:00  |  Author(s): Yun Fan

      • Abstract

      Background

      The role of PD-L1 expression in 2nd line and beyond non-small cell lung cancer (NSCLC) remains controversial. Camrelizumab (SHR-1210) is a potent anti-PD-1 monoclonal antibody and has shown promising activity in NSCLC in Phase I studies. We report results from the SHR-1210-201 study (NCT03085069), a phase II umbrella study of camrelizumab monotherapy in different PD-L1 expression cohorts in Chinese patients with previously treated advanced or metastatic NSCLC.

      Method

      Patients who progressed during or following platinum-based doublet chemotherapy were enrolled and assigned to one of 4 cohorts based on PD-L1 expression. Patients with EGFR or ALK genomic alterations were eligible provided they had disease progression with at least one approved tyrosine kinase inhibitor and with ≥50% PD-L1 expression in tumor. All enrolled patients received camrelizumab at 200 mg IV Q2W until loss of clinical benefit. The primary endpoint was objective response rate (ORR), other endpoints included progression-free survival (PFS) and overall survival (OS).

      Result

      As of Aug 1st 2018, of all the 259 patients who underwent screen, 229 cases could be pathologically evaluated. PD-L1 expression were 47.6% (109/229) in PD-L1 < 1%, 27.1% (62/229) in PD-L1 1-<25%, 8.7% (20/229) in 25-<50% and 16.6% (38/229) in 50%. A total of 63.8% (146/229) patients were enrolled. 89.0% of patients had stage IV NSCLC and 54.8% had non-squamous tumor histology. ORR was 18.5% (95%CI: 12.6%–25.8%) in ITT population. Subgroup analysis showed increased PD-L1 expression was associated with better response rate (Table 1). No response was observed in patients with EGFR mutation. The responders had durable response (median: 15.1 months; 95%CI: 5.5–not reached). Median PFS was 3.2 months (95%CI: 2.0–3.4) and median OS was 19.4 months (95%CI: 11.6–not reached) (Table 1). Treatment-related adverse events (AEs) occurred in 87.7% of patients (all Grade); 20.5% had ≥G3 related AE; and 15.8% had related SAE. 21.2% of AEs led to dose interruption and 7.5% led to treatment discontinuation.

      Table 1 - Efficacy data in subgroups
      Population No of pts ORR, % (95%CI)

      PFS (month),

      median (95%CI)

      1YOS, % (95%CI)

      OS (month),

      median (95%CI)

      PD-L1<1% 74

      12.2% (5.7%, 21.8%)

      2.1 (1.9, 3.2) 47.1% (33.8%, 59.2%) 11.6 (7.8, NR)
      PD-L1 ≥1% and < 25% 31 19.4% (7.5%, 37.5%) 3.1 (1.8, 4.9) 76.7% (57.2%, 88.2%) NR (NR, NR)
      PD-L1 ≥25% and < 50% 11 45.5% (16.7%, 76.6%) 6.0 (1.9, NR) 81.8% (44.7%, 95.1%) NR (2.9, NR)
      PD-L1 ≥50% (without EGFR mutation) 25 28.0% (12.1%, 49.4%) 7.6 (3.3, 11.4) 55.2% (32.3%, 73.2%) NR (8.6, NR)
      PD-L1 ≥50% (with EGFR mutation) 5 0 1.7 (1.2, NR) 40.0% (5.2%, 75.3%) 10.3 (1.2, NR)
      ITT 146 18.5% (12.6%, 25.8%) 3.2 (2.0, 3.4) 56.6% (47.3%, 64.9%) 19.4 (11.6, NR)

      Abbreviation: NR, Not Reached.

      Conclusion

      In Chinese patients with previously treated advanced/metastatic NSCLC, camrelizumab demonstrated improved ORR, PFS, and OS compared with historical data of the 2nd line chemotherapy. The efficacy in patients with PD-L1 <1% is similar as the 2nd line mono-chemotherapy, while patients with higher PD-L1 expression derived greater benefit from camrelizumab, the ORR, PFS and OS in patients with PD-L1 ≥25% was comparable to the 1st line doublet chemotherapy in advanced NSCLC. Camrelizumab was well tolerated. This phase 2 data warrant further clinical studies of camrelizumab in NSCLC.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-17 - Genomic Evolution During TKI Treatment in Non-Small Cell Lung Cancer Patients With or Without Acquired T790M Mutation (ID 2988)

      09:45 - 18:00  |  Author(s): Yun Fan

      • Abstract

      Background

      EGFR-mutant non-small-cell lung cancer (NSCLC) patients inevitably develop drug resistance when treated with EGFR tyrosine kinase inhibitors (TKIs). Clonal and clinical analyses of genetic alterations at baseline and progressive disease (PD), as well as differences between acquired T790M and T790M-negative patients in drug-resistant mechanisms, have not been systematically studied.

      Method

      We performed targeted sequencing of pre-treatment and PD tumor samples from 54 EGFR-mutant NSCLC patients. Ten additional patients were sequenced using whole exome sequencing to infer the clonal evolution patterns.

      Result

      We observed new co-occurring alterations and pathways limiting EGFR-inhibitor response, including 9p34.3/19p13.3 (NOTCH1/STK11) co-deletion and TGF-beta pathway alterations. Besides acquired T790M mutation, chromosomal instability (CIN) related genes including AURKA and TP53 alterations were the most frequently acquired events. CIN significantly increased with TKI treatment in T790M-negative patients. Transcriptional regulators including HNF1A, ATRX and NKX2-1 acquired alterations were enriched in T790M-positive patients, and diverse oncogenic pathway alterations were more common in T790M-negative patients. T790M-positive patients had improved PFS compared to T790M-negative patients. We further identified subgroups within T790M-positive or T790M-negative patients with distinct PFS. Clonal evolution analysis indicated progression of T790M-positive patients depends on competition between T790M and non-T790M resistant subclones.

      Conclusion

      Our study is the first attempt to identify co-occurring copy number events to stratify patients resistant to TKI treatment. Besides acquired T790M mutation, chromosomal instability (CIN) related genes were identified as the most frequently acquired events. Clonal evolution analysis indicated indicate that higher competitive advantage of T790M was associated with improved PFS.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-71 - Comprehensive Analysis of EGFR T790M-Mutant Abundance of Different Technologies and Its Effect on Efficacy of Osimertinib in Advanced NSCLC (Now Available) (ID 2573)

      10:15 - 18:15  |  Presenting Author(s): Yun Fan

      • Abstract
      • Slides

      Background

      Osimertinib has been adopted as the standard of care for T790M-mediated acquired epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance. And detecting EGFR T790M mutation can be challenging in routine care, low abundance of the mutation and difficulty for re-biopsy in patients with advanced disease. We aim to compare droplet digital PCR (ddPCR) and next generation sequencing (NGS) in T790M mutation testing, and analyze whether the abundance of T790M mutation is associated with the efficacy of osimertinib in advanced Non–small cell lung cancer (NSCLC).

      Method

      We retrospectively studied 132 T790M-positive advanced NSCLC patients who have received osimertinib after acquired TKI resistance from April 2017 to August 2018 at our institution. Treatment response was evaluated and survival data were collected and analyzed.

      Result

      Among the 132 patients, 18(13.6%) had adopted amplifcation refractory mutation system (ARMS), 58(43.9%) adopted ddPCR, 43(32.6%) used NGS in T790M testing, and the detection methods of 13(9.9%) patients were unknown. Data of T790M-mutatnt abundance were obtained in 64 patients, 57 of whom were tested by ddPCR in plasma and the other 7 by NGS. The median progression free survival (PFS) was 15 months, median OS was not reached, objective response rate (ORR) was 88%. We found that ARMS, ddPCR, NGS have no difference in T790M testing (p=0.114). Among the 57 ddPCR testing patients with the abundance of T790M, there was no difference in PFS of T790M abundance in the cutoff value of 0.5 (p=0.303).

      Conclusion

      Our results suggest that ARMS, ddPCR and NGS are all useful and reliable methods in EGFR T790M mutation detection. And the association between the abundance of T790M mutation using ddPCR in plasma and the efficacy of osimertinib seemed not strong and remained to be explored.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-94 - PD-L1 Expression in Uncommon EGFR-Mutant Non-Small Cell Lung Cancer and Its Response to Immunotherapy (Now Available) (ID 300)

      10:15 - 18:15  |  Presenting Author(s): Yun Fan

      • Abstract
      • Slides

      Background

      The efficacy of immunotherapy treating EGFR-positive non-small cell lung cancer (NSCLC) patients has been proved to be limited. However, a series of mutant-patients could be benefit from PD-1 blockade. Therefore, this study evaluated the immune microenvironment in NSCLC with uncommon EGFR mutation, and explored the prospect of immunotherapy in this cohort.

      Method

      We retrospectively evaluated the expression of PD-L1, CD4 and CD8 in NSCLC patients who harbored uncommon EGFR mutation at Zhejiang Cancer Hospital between April 2016 and September 2017. The association with clinical factors and outcomes were also explored, as well as the effectiveness of immunotherapy in uncommon mutation-positive cases.

      Result

      图片 1.png

      Among the 600 NSCLC patients with EGFR mutation, we retrospectively collected 49 (8.2%) cases bearing uncommon mutation. In total, 49.0% (24/49) of NSCLC patients showed a strong PD-L1 expression in tumor cells, which was significantly higher than common sensitive (19del and L858R) or negative EGFR mutation (49.0% vs 12.1% vs 26.3%, respectively, P<0.05). Furthermore, positive PD-L1 expression was associated with a significantly shortened OS when compared with the negative PD-L1 expression (20.0 vs 44.3 months, P=0.006). And PD-L1 positivity was predominantly observed among patients with high CD8 expression rather than low cases (72.0% vs 25.0%, P=0.001). Notably, we found PD-L1 and CD8 dual-positive cases demonstrated the worst prognosis (OS: 19.3[dual-positive] vs 31.1[single-positive] vs 44.3[dual-negative] months, P=0.023). Additionally, this approach revealed PD-L1 and CD8 positivity were not associated with the response to EGFR-TKIs, playing no role in the de novo resistance of EGFR-TKIs among the uncommon mutated patients. Finally, one patient harboring EGFR G719A mutation with PD-L1 and CD8 dual positivity experienced a favorable response to anti-PD-1 therapy.

      Conclusion

      This study revealed the expression of PD-L1, CD4 and CD8 in uncommon EGFR-mutated NSCLC patients. The findings indicated the reshaping of an inflamed immune phenotype characterized by PD-L1 and CD8 dual positivity and suggest potential therapeutic sensitivity to PD-1 blockade.

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