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Jianhua Shi



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    MA14 - The Adequate MTarget Is Still the Issue (ID 140)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA14.05 - A Randomized Phase III Trial of Fruquintinib Versus Placebo in Patients with Advanced Non-Small Cell Lung Cancer (FALUCA) (Now Available) (ID 1490)

      15:45 - 17:15  |  Author(s): Jianhua Shi

      • Abstract
      • Presentation
      • Slides

      Background

      Fruquintinib, an orally active kinase inhibitor that selectively targets vascular endothelial growth factor (VEGF) receptor, demonstrated significant benefit in progression-free survival and disease control in a randomized Phase II study in patients with non-small-cell lung cancer (NSCLC) who had failed two lines of chemotherapy. This Phase III FALUCA trial is a randomized, double-blind, placebo-controlled, multicenter trial designed to confirm the efficacy in the same patient population (NCT02691299).

      Method

      From December 2015 to February 2018, 45 clinical centers across China participated in the trial. A total of 730 patients aged 18-75 with advanced NSCLC who had failed two lines of chemotherapy were screened and 527 who met the eligibility criteria were enrolled into the study. Patients were stratified based on epidermal growth factor receptor mutation status and prior use of VEGF inhibitor therapy, and were randomized in a 2:1 ratio to receive fruquintinib (n=354) or placebo (n=173) once daily in a 3 weeks on/1 week off 4-week cycle. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response. The final data cutoff was on September 21, 2018.

      Result

      Median OS was 8.94 months for fruquintinib and 10.38 months for placebo (hazard ratio, 1.02; 95% CI, 0.816 to 1.283; p=0.841). Median PFS was 3.68 months for fruquintinib comparing to 0.99 months for placebo, respectively (hazard ratio, 0.34; 95%CI, 0.279 to 0.425; p<0.001). The ORR and DCR were 13.8% and 66.7% for fruquintinib, compared with 0.6% and 24.9% for placebo (both p<0.001), respectively. The most frequent treatment-emergent adverse events with fruquintinib (≥grade 3) were hypertension (20.7%), hand-foot syndrome (11.0%), and proteinuria (1.4%). A sensitivity analysis revealed that median OS was significantly prolonged with fruquintinib compared with placebo in patients who received no subsequent systemic anti-tumor therapies (7.00 months versus 5.06 months ; hazard ratio, 0.64; 95%CI, 0.453 to 0.903; p=0.010).

      Conclusion

      The FALUCA trial failed to meet the primary end point of OS while confirming significant benefit in secondary end points including PFS, ORR and DCR. The safety profile of fruquintinib in this patient population was acceptable and consistent with that identified in the Phase II study. A post-hoc sensitivity analysis revealed that the anti-tumor therapies that patients received post disease progression probably contributed to the failure of this study on the primary end point.

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    OA02 - A New Vision of Targets and Strategies (ID 120)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      OA02.03 - The Third Generation EGFR Inhibitor (EGFR-TKI) HS-10296 in Advanced NSCLC Patients with Resistance to First Generation EGFR-TKI (Now Available) (ID 766)

      10:30 - 12:00  |  Author(s): Jianhua Shi

      • Abstract
      • Presentation
      • Slides

      Background

      HS-10296 is an oral, potent, high selective third generation EGFR tyrosine-kinase inhibitor (EGFR-TKI) for sensitizing mutations, and the EGFR Thr790Met (T790M) resistance mutation which has been demonstrated by phase I study. This phase II, open-label, multicenter single-arm study was designed to confirm the efficacy and safety of HS-10296 in a large population of non-small-cell lung cancer (NSCLC) patients with EGFR T790M mutation, who had progressed after first generation EGFR-TKI treatment.

      Method

      Patients aged at least 18 years with centrally confirmed EGFR T790M-positive mutations, locally advanced or metastatic (stage IIIB/IV) NSCLC after first generation EGFR-TKI treatment received HS-10296 110 mg orally once daily until disease progression, or intolerable toxicity, or patient withdrawal. Patients with asymptomatic, stable brain metastases not requiring steroids were allowed to enroll. The primary endpoint was the objective response rate (ORR) by independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1 every 6 weeks. Response endpoints (ORR and disease control rate [DCR]) were assessed in response analysis set. Secondary end points including progression-free survival (PFS), duration of response (DoR), depth of response (DepOR), overall survival (OS) and safety were evaluated in full analysis set. The final data cutoff was on Jan 5, 2019. The study is still ongoing.

      Result

      Totally, 244 patients (median age 60.8) entered study in 36 sites in mainland China (189 patients) and Taiwan (55 patients) between May 16, 2018 to Oct 23, 2018. 2 patients were excluded from the evaluable for response analysis set (n=242) due to absence of measurable disease at baseline by independent central review. At data cutoff, 182 (74.6%) patients remained on treatment. The median duration of follow-up was 4.7 months. 160 of 242 patients achieved confirmed partial responses by independent central review. The ORR was 66.1% (95% CI: 59.8-72.1). The DCR was 93.4% (95% CI: 89.5-96.2). The most common adverse reactions (≥ 10%) were blood creatine phosphokinase increased (43 [17.6%]), aspartate aminotransferase increased (29 [11.9%]), pruritus (28 [11.5%]), rash (28 [11.5%]) and alanine aminotransferase increased (26 [10.7%]). The most common all-causality grade 3 and 4 adverse events were blood creatine phosphokinase increased (14 [5.7%]) and hyponatraemia (4 [1.6%]). Serious adverse events were reported in 30 (12.3%) patients, of which 19 (7.8%) were investigator assessed as possibly treatment-related to HS-10296. Three deaths were due to adverse events; one was related to cardiopulmonary failure, other two events occurred after disease progression. There was no interstitial lung disease during study treatment.

      Conclusion

      HS-10296 has demonstrated good clinical benefit with minimal toxicity in patients with EGFR T790M-positive NSCLC patients who have progressed after first generation EGFR-TKI treatment. The Phase III study has already launched comparing HS-10296 with gefinitib in advanced NSCLC patients with EGFR sensitizing mutations. (The study was sponsored by Jiangsu Hansoh Pharmaceutical Co., Ltd.; ClinicalTrials.gov number, NCT02981108)

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    OA03 - Systemic Therapies for SCLC: Novel Targets and Patients' Selection (ID 121)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
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      OA03.02 - Effect of Anlotinib in Advanced Small Cell Lung Cancer Patients Previously Received Chemoradiotherapy: A Subgroup Analysis in ALTER 1202 Trial (Now Available) (ID 1698)

      13:30 - 15:00  |  Author(s): Jianhua Shi

      • Abstract
      • Presentation
      • Slides

      Background

      The ALTER 1202 trial showed significant improvement in progress-free survival and well tolerant with anlotinib in advanced small cell lung cancer (SCLC) patients received at least two lines chemotherapy. Here, we reported the effect of anlotinib in patients previously received chemoradiotherapy.

      Method

      The ALTER 1202 was a randomized, double-blind phase 2 trial conducted at 11 centers in China. Patients with advanced SCLC that received at least two previous lines of chemotherapy were enrolled and randomized in a 2:1 ratio to receive either anlotinib or placebo until tumor progression or unacceptable toxicity. The subgroup analysis assessed the effect of anlotinib in patients with previous concurrent, sequential and alternate chemoradiotherapy. The primary outcome was progressive-free survival (PFS). The secondary outcomes were overall survival (OS), objective response rate, disease control rate and safety. Data are reported as per the 30 June 2018, data cutoff date. This trial is registered with ClinicalTrials.gov, number NCT03059797.

      Result

      Between March 30, 2017 and June 8, 2018, a total of 120 patients who met all eligibility criteria were randomly assigned to the anlotinib group (82 patients) or placebo group (38 patients). And 46 patients in anlotinib group and 22 patients in placebo group previously received chemoradiotherapy. Among them, the median PFS was 5.49 months (95% confidence interval [CI], 2.83 to 6.47) with anlotinib versus 0.69 months (95% CI, 0.66 to 0.76) with placebo (hazard ratio [HR], 0.14; 95% CI, 0.07 to 0.28; P<0.0001). Meanwhile, anlotinib significantly prolonged OS compared with placebo (9.49 months [95% CI, 7.29 to 12.68] versus 2.56 months [95% CI, 0.49 to 5.22]; HR, 0.46 [95% CI, 0.22 to 0.98]; P=0.0388) in patients previously received chemoradiotherapy. The most common adverse events were hypertension (39.13%), weight loss (39.13%), hypertriglyceridemia (36.96%) and leukopenia (30.43%). While, the most common grade 3 or worse adverse events were hypertension (15.22%), hypertriglyceridemia (10.87%), γ-glutamyl-transferase increased (8.70%).

      Conclusion

      Anlotinib improved PFS and OS in advanced SCLC patients previously received chemoradiotherapy and was well tolerated.

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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): Jianhua Shi

      • 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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    P2.12 - Small Cell Lung Cancer/NET (ID 180)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.12-11 - Quality of Life in ALTER1202 Trial of Anlotinib as Third-or Further Line Therapy for Advanced Small Cell Lung Cancer (SCLC): A Post-Hoc Analysis (ID 1300)

      10:15 - 18:15  |  Author(s): Jianhua Shi

      • Abstract
      • Slides

      Background

      Anlotinib significantly improved progress-free survival of advanced small cell lung cancer (SCLC) patients in ALTER1202 trial. In this post-hoc analysis, we assessed the effect of anlotinib on health-related quality of life in ALTER1202 trial.

      Method

      In the randomised, phase 2, multicentre ALTER1202 trial, patients with advanced SCLC that received at least two previous lines of chemotherapy were enrolled from 11 centers in China. Eligible patients were randomly assign (2:1) to receive anlotinib or placebo. Health-related quality of life was assessed by EQ-5D scores. Patients filled out questionnaires at screening period and the end of each treatment cycle.

      Result

      Between March 30, 2017 and June 8, 2018, a total of 120 patients were enrolled. There were 119 patients with completed questionnaires at screening period, and 106 patients completed questionnaires at the end of the first treatment cycle (76 in anlotinib group, 30 in placebo group). EQ-5D scores had no significant difference between baseline and the end of the first treatment cycle in patients with anlotinib (0.85 versus 0.85, P=0.706). The median EQ-5D VASscores were 80.0 versus 85.0 in anlotinib and placebo group respectively (P=0.323) at screening period, and 90.0 versus 82.5 at the end of the first treatment cycle (P=0.273). The change of EQ-5D VAS scores from baseline to the end of the first treatment cycle was statistically significant (P=0.001) in patients with anlotinib compared to patients with placebo.

      Conclusion

      This post-hoc analysis showed that anlotinib maintained health-related quality of life in advanced SCLC patients.

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      P2.12-26 - The Impact of Anlotinib for Relapsed SCLC Patients with Brain Metastases: A Subgroup Analysis of ALTER 1202 (ID 489)

      10:15 - 18:15  |  Author(s): Jianhua Shi

      • Abstract
      • Slides

      Background

      ALTER1202 trial (NCT03059797), a multicentre, randomized, double-blind phase II study has demonstrated that anlotinib significantly prolonged progress-free survival (PFS) in relapsed SCLC patients as 3rdor further line treatment. Here, we performed a comparative analysis for patients with brain metastases in the placebo and anlotinib arms.

      Method

      Eligible either limited- or extensive-stage SCLC pts who failed ≥2 lines of chemotherapy (n=120) were randomized 2:1 to receive anlotinib or placebo (12 mg QD from day 1 to 14 of a 21-day cycle) till progression or intolerable toxicity. The primary endpoint was PFS. This subgroup analysis was based on patients with brain metastases at baseline.

      Result

      There are 30 pts with brain metastases in anlotinib and placebo groups (n=21 vs 9). Anlotinib significantly improved PFS (3.84 vs 0.76 months; HR = 0.15; 95% CI, 0.04–0.51; P = 0.0005) and OS (6.08 vs 2.56 months; HR = 0.26; 95% CI, 0.09–0.73; P = 0.0061) comparing to placebo in patients with brain metastases at baseline. In anlotinib group, loss of appetite (47.62%), loss of weight (42.86 %), leukopenia (38.10%) and hypertriglyceridemia (38.10%) were the most common adverse events (AEs); then, in placebo group were emesis (44.44%) and loss of appetite (33.33 %).

      Conclusion

      For patients with brain metastases in ALTER1202 trial, significant improvement in OS and PFS were found in anlotinib treated group with a manageable safety profile.

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