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Makoto Nishio



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    OA05 - Clinical Trials in IO (ID 899)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 106
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      OA05.06 - CheckMate 227: Patient-Reported Outcomes of First-Line Nivolumab + Ipilimumab in High Tumor Mutational Burden Advanced NSCLC (ID 13450)

      14:25 - 14:35  |  Author(s): Makoto Nishio

      • Abstract
      • Presentation
      • Slides

      Background

      The randomized, open-label, multipart phase 3 study CheckMate 227 (NCT02477826) demonstrated a significant progression-free survival benefit (co-primary endpoint) with first-line nivolumab+ipilimumab versus histology-based, platinum-doublet chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and high tumor mutational burden (TMB; ≥10 mutations/Mb). Patient-reported outcomes (PROs) for this population within CheckMate 227 are presented.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible chemotherapy-naïve patients had stage IV or recurrent NSCLC, ECOG performance status 0−1, and no known sensitizing EGFR/ALK alterations. PROs were assessed as an exploratory endpoint; this analysis included patients with high TMB randomized to nivolumab+ipilimumab or chemotherapy; specific outcomes included proportion of patients with disease-related symptom deterioration by 12 weeks and time to deterioration in symptoms (by Lung Cancer Symptom Scale [LCSS] Average Symptom Burden Index [ASBI]), and assessment of quality of life and overall health status (by EuroQoL-5 Dimension [EQ-5D] utility index [UI] and visual analog scale [VAS]). PROs were evaluated each cycle (Q2W, nivolumab+ipilimumab; Q3W, chemotherapy) for the first 6 months, every 6 weeks thereafter during treatment, and at follow-up visits 1/2. EQ-5D was also assessed during survival follow-up.

      4c3880bb027f159e801041b1021e88e8 Result

      PRO completion rates were ~90% at baseline and >80% for nearly all on-treatment assessments. Among patients with high TMB, fewer patients in the nivolumab+ipilimumab (n=139) versus chemotherapy (n=160) groups reported symptom deterioration by week 12, irrespective of whether they were still on therapy or had discontinued (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% CI: 2.4–22.5]). Time to first deterioration (TTD) using common assessment time points (on/off treatment) was delayed with nivolumab+ipilimumab versus chemotherapy for the LCSS ASBI (hazard ratio [HR]: 0.40; 95% CI: 0.26–0.63) and 3-Item Global Index (3-IGI; HR: 0.56; 95% CI: 0.38–0.82). The estimated benefit in TTD generally favored nivolumab+ipilimumab for individual symptoms in the ASBI and each item in the 3-IGI (HRs: 0.48–0.74), except for hemoptysis (HR: 1.20), which exhibited very low burden; an advantage for nivolumab+ipilimumab was also seen in the EQ-5D VAS (HR: 0.62; 95% CI: 0.42–0.92) and UI (HR: 0.50; 95% CI: 0.34–0.73). Mean changes from baseline with nivolumab+ipilimumab showed early and clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; for patients treated with chemotherapy, symptoms and quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following completion of chemotherapy (EQ-5D VAS).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Nivolumab+ipilimumab demonstrated early and sustained improvements in health-related quality of life versus chemotherapy in patients with advanced NSCLC and high TMB.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA05.07 - IMpower132: PFS and Safety Results with 1L Atezolizumab + Carboplatin/Cisplatin + Pemetrexed in Stage IV Non-Squamous NSCLC (ID 12389)

      14:35 - 14:45  |  Author(s): Makoto Nishio

      • Abstract
      • Presentation
      • Slides

      Background

      In addition to the combination of atezolizumab (anti–PD-L1)+platinum+taxane±bevacizumab, non-squamous NSCLC patients may derive benefit from adding atezolizumab to platinum+pemetrexed. The randomized Phase III IMpower132 study (NCT02657434) evaluated first-line pemetrexed+carboplatin or cisplatin±atezolizumab in patients with stage IV non-squamous NSCLC without EGFR or ALK driver mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients were randomized 1:1 to receive 4 or 6 cycles of carboplatin AUC 6 mg/mL/min or cisplatin 75 mg/m2 + pemetrexed 500 mg/m2 Q3W alone (arm PP) or in combination with atezolizumab 1200 mg Q3W (arm APP), followed by pemetrexed (arm PP) or atezolizumab + pemetrexed (arm APP) maintenance. Atezolizumab could be continued beyond disease progression per protocol guidelines. PFS and OS were co-primary endpoints. Efficacy by PD-L1 expression was an exploratory endpoint. Here, we present investigator-assessed PFS per RECIST v1.1 (final analysis), OS (interim analysis) and safety data.

      4c3880bb027f159e801041b1021e88e8 Result

      292 pts were enrolled in arm APP and 286 pts in arm PP. 43% and 40% in arms APP and PP, respectively, had ECOG PS 0. At the data cutoff (22 May 2018), median follow-up was 14.8 mo overall. PFS analysis showed a statistically significant improvement between arm APP vs PP (median PFS 7.6 vs 5.2 mo; HR=0.596; 95% CI: 0.494, 0.719; P<0.0001). Interim analysis showed a numerical but non-statistically significant OS improvement (Table). Efficacy results were consistent across all key clinical subgroups. Grade 3-4 TRAEs occurred in 53.6% of patients (APP) vs 39.1% (PP). 7.2% of patients (APP) vs 5.1% (PP) had a Grade 5 AE, 3.8% (APP) vs 2.6% (PP) were treatment related. 48.5% of patients (APP) vs 38.0% (PP) experienced AEs of special interest specific to atezolizumab.

      8eea62084ca7e541d918e823422bd82e Conclusion

      IMpower132 met its co-primary endpoint of investigator-assessed PFS in the ITT. Interim OS data (not fully mature) showed numerical improvement. Atezolizumab+pemetrexed+carboplatin or cisplatin was well tolerated, and no new safety signals were identified.

      Table. IMpower132 Efficacy Analyses

      APP Arm
      (atezolizumab+pemetrexed+ carboplatin or cisplatin)
      PP Arm
      (pemetrexed+carboplatin or cisplatin)
      ITT n=292 n=286
      Median PFS (95% CI), mo 7.6 (6.6, 8.5) 5.2 (4.3, 5.6)
      HRa (95% CI; P value) 0.596 (0.494, 0.719; P < 0.0001)
      12-Month PFS (95% CI), % 33.7% (28.2, 39.2) 17.0% (12.6, 21.4)
      Median OS (95% CI), mo 18.1 (13.0, NE) 13.6 (11.4, 15.5)
      HRa (95% CI; P value) 0.813 (0.644, 1.025; P = 0.0797)
      12-Month OS (95% CI), % 59.6% (53.9, 65.3) 55.4% (49.5, 61.2)
      ORR (confirmed, inv-assessed), % 46.9% 32.2%
      DOR (95% CI), mo 10.1 (7.2, 13.3) 7.2 (5.7, 9.0)
      PD-L1–highb n=25 n=20
      Median PFS (95% CI), mo 10.8 (7.9, NE) 6.5 (2.4, 10.6)
      HR (95% CI; P value) 0.464 (0.224, 0.960; P = 0.0339)
      PD-L1–lowb n=63 n=73
      Median PFS (95% CI), mo 6.2 (4.4, 8.4) 5.7 (4.2, 7.9)
      HR (95% CI; P value) 0.804 (0.556, 1.163; P = 0.2462)
      PD-L1–negativeb n=88 n=75
      Median PFS (95% CI), mo 8.5 (6.1, 11.2) 4.9 (4.2, 5.8)
      HR (95% CI; P value) 0.448 (0.313, 0.642; P < 0.0001)

      DOR, duration of response; HR, hazard ratio; inv, investigator; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

      a Stratified. b Baseline tissue available in 60% of patients. PD-L1high (TC3/IC3): patients with PD-L1 expression in ≥50% of tumor cells or ≥10% of tumor-infiltrating immune cells; PD-L1low (TC12/IC12): patients with PD-L1 expression in ≥1% and <50% of tumor cells or ≥1% and <10% of tumor-infiltrating immune cells; and PD-L1negative (TC0/IC0): patients with PD-L1 expression in <1% of tumor cells and <1% of tumor-infiltrating immune cells.

      NCT02657434

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.11 - Screening and Early Detection (Not CME Accredited Session) (ID 943)

    • 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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      P1.11-07 - Utility of the Maximum CT Value in Predicting Invasiveness of Pure GGNs (ID 12197)

      16:45 - 18:00  |  Author(s): Makoto Nishio

      • Abstract
      • Slides

      Background

      In the current TNM classification of lung cancer, the pulmonary lesions presenting pure ground-glass nodules (GGNs) without solid component are classified as cTis tumor. However, some of them are pathologically diagnosed as invasive adenocarcinomas. This study aimed to predict the histological invasiveness using the computed tomography (CT) value in pure GGN lesions.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      138 patients underwent resection of pure GGNs between 2011 and 2016. The maximum diameter and CT value were measured using a computer graphics support system. We selected the axial section which showed the densest component of each GGN. The CT value was measured separately in several areas excluding portions of apparent vessels and bronchi manually. We analyzed the correlation between the CT value of pure GGNs and the histological diagnosis, such as atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (Ad).

      4c3880bb027f159e801041b1021e88e8 Result

      The number of the patients with AAH, AIS, MIA and Ad was 6, 81, 45 and 6, respectively. 37% of the pure GGN lesions contained histologically invasive component and 4% of them were diagnosed as Ad. One tumor of Ad had lymphatic invasion, while there was no case with vascular invasion. 37 lobectomies, 38 segmentectomies and 63 wedge resections were performed and there was no recurrence. In comparison between the preinvasive lesions (AAH and AIS) and the invasive lesions (MIA and Ad), the latter was significantly correlated with the higher age of the patients (60 ± 9 years vs 67 ± 7 years), the larger total size (12 ± 5 mm vs 16 ± 5 mm), the higher maximum CT value (-388 ± 125 HU vs -208 ± 129 HU) and the presence of pleural indentation (odds ratio, 2.8).

      When the cut-off point of the maximum CT value in predicting histological invasiveness was set at -300 HU using the ROC curve analysis, the sensitivity, specificity, positive predictive value and negative predictive value were 80%, 77%, 67% and 87%, respectively. The 100% of Ad and the 78% of MIA were correctly estimated.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Invasive adenocarcinoma and MIA accounted for 4% and 33% of the pure GGN lesions, respectively. The maximum CT value was correlated with the pathological diagnosis. It may be useful as a predictor of histological invasiveness. The threshold at -300 HU can be the basis of the computer-aided automatic diagnosis.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.14 - Thymoma/Other Thoracic Malignancies (Not CME Accredited Session) (ID 946)

    • 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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      P1.14-03 - Phase II Trial of Amrubicin and Cisplatin Chemotherapy for Invasive Thymoma: WJOG5509L (ID 11706)

      16:45 - 18:00  |  Author(s): Makoto Nishio

      • Abstract

      Background

      Background: Platinum and anthracycline combination chemotherapy has been considered as the standard treatment for invasive thymoma for a long time. The clinical activity of amrubicin (AMR)—an anthracycline agent—has been previously reported in the treatment of small cell lung cancer (SCLC). The aim of this study was to evaluate the efficacy and safety of the combination of AMR and cisplatin (CDDP) in patients with advanced or recurrent invasive thymoma.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Methods: Patients were eligible for inclusion in the study if they met the following criteria: were chemo-naive; not amenable to curative surgery or radiotherapy; and presented with histologically confirmed invasive thymoma in each site. The patients received AMR (35 mg/m2, on days 1–3) and CDDP (60 mg/m2, on day 1) every 3 weeks, for up to 4 cycles. The primary endpoint was the objective response rate (ORR) assessed by an independent review, and the secondary endpoints were overall survival (OS) and toxicity profile of the patients. Based on the SWOG 2-stage design, the planned sample size of 40 patients was determined to reject the ORR of 60% under the expectation of 80% with a power of 0.85 and a type I error of 0.05. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000003933.

      4c3880bb027f159e801041b1021e88e8 Result

      Results: From August 2010 to November 2014, a total of 26 patients were enrolled at 14 institutions in Japan. During the planned interim analysis in April 2014, the ORR of the 20 patients who had been enrolled so far, was assessed via independent review and found to be 55.6% (11/20), resulting in the early termination of this study because of its futility. In the final assessment, the ORR was 54.2% (95% confidence interval, 32.8–74.4) and the disease control rate was 95.8%. The OS did not reach the median value. The major grade 3 or 4 toxicities noted were neutropenia (96.2%), anemia (26.9%), anorexia (11.5%) and febrile neutropenia (26.9%), albeit these were transient and manageable. There was one treatment-related death.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Conclusions: The combination of AMR with CDDP had minimal activity on invasive thymoma. Thus, we do not recommend further study of this regimen.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 948)

    • 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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      P1.16-21 - Phase I / II Study of Carboplatin, Nab-Paclitaxel, and Concurrent Radiotherapy for Patients with Locally Advanced NSCLC (ID 12112)

      16:45 - 18:00  |  Author(s): Makoto Nishio

      • Abstract

      Background

      We performed an open-label, multicenter phase I/II study (UMIN ID 000012719) to prospectively evaluate the efficacy and safety of the combination of nab-paclitaxel plus carboplatin (nab-P/C) with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In the phase I study (standard 3+3 design), escalating doses of weekly nab-paclitaxel were given along with weekly carboplatin area under the plasma concentration time curve (AUC) 2 and concurrent radiotherapy 60 Gy in 30 fractions, followed by 2 cycles of nab-paclitaxel (100 mg/m2 on Days 1, 8 and 15) plus carboplatin (AUC 6 on Day 1). In the phase II study, nab-P/C at recommend dose (RD) was administered.

      4c3880bb027f159e801041b1021e88e8 Result

      In the Phase I study, 11 patients were enrolled with 9 evaluable for dose limiting toxicity (DLT). At level 1 (nab-paclitaxel 40mg/m2), none of 3 patients experienced DLT. At level 2 (nab-paclitaxel 50mg/ m2), 1 of 6 patients experienced DLT: grade 3 leukopenia requiring a second consecutive skip in the administration of weekly nab-P/C. Level 2 was defined as the RD. A total of 56 patients including 6 patients who received at dose of RD, were evaluable for the efficacy and safety. Of the 56 patients for safety analysis, common toxicities in the concurrent phase included grade 3/4 leukopenia (60.7 %), neutropenia (26.8 %), anemia (7.1 %), anorexia (7.1 %), esophagitis (5.4 %) and febrile neutropenia (1.8 %). In one patient, grade 3 pneumonitis was observed. There were no treatment-related deaths. The objective response rate was 76.8 % (95% confidence interval (CI), 64.2 to 85.9 %). The median progression-free survival was 11.8 months (60% CI, 10.6 to 16.2 months, 95% CI, 8.2 to 20.8 months), and the median overall survival was not reached.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This is the first study to demonstrate encouraging feasibility and activity for concurrent chemoradiation with nab-paclitaxel 50 mg/m2 and CBDCA AUC 2 in patients with locally advanced NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.16-43 - Analyses of Long-Term Outcomes and Prognostic Factors in Surgically Resected ALK-Rearranged Lung Adenocarcinoma (ID 12721)

      16:45 - 18:00  |  Author(s): Makoto Nishio

      • Abstract
      • Slides

      Background

      Anaplastic lymphoma kinase (ALK)-rearrangement (ALK+) in lung cancer has made an epoch in the molecular classification. Specific inhibitors of the kinase activity of ALK have been developed as therapeutic drugs for lung cancer with ALK+. Long-term outcomes and prognostic factors, however, in surgically resected cases are unclear. We evaluated the survival rate, and investigated association between prognosis of surgically resected lung adenocarcinoma (AC) with ALK+ and clinicopathological features.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From 1996 to 2013, clinical data of 62 AC patients with ALK+ were retrospectively analyzed. The median follow up time was 73 months. Relationships between the patients’ clinicopathological features (i.e. age, gender, smoking history, operative procedure, administration of adjuvant therapy, tumor size, c-stage, p-stage, pleural invasion, Ly/V invasion, intrapulmonary metastasis, histologic predominant subtypes, and histologic grade), and their recurrence-free survival (RFS), post-recurrence survival (PRS) and overall survival (OS) rates were assessed.

      4c3880bb027f159e801041b1021e88e8 Result

      The 5-year RFS and OS were 69% and 92%, respectively. For OS, advanced p-stage (IIIA and IV) and pleural invasion were independent poor prognostic factors in multivariate analyses, but 5-year OS for even Stage IIIA was 85%, nevertheless (Figure).figure. os for each stages..jpg

      20 patients had recurrence. 8 of the 20 patients were treated with ALK-tyrosine kinase inhibitors (TKIs), and 12 were without. The median PRS was 54 months. Patients treated with AKL-TKIs had longer PRS and OS than without (65 vs. 38 months, p=0.01, and 80 vs. 74 months, p=0.04, respectively).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Long-term outcomes in surgically resected ALK+ AC were excellent even so advanced stage. ALK-TKIs are certainly effective for post-recurrence status. For the resectable ALK+ AC treatment strategy, ALK-TKIs might play an important role.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • 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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      P2.13-18 - A Multicenter Prospective Biomarker Study to Explore Mechanisms of Afatinib Resistance Based on Digita PCR and Next-Generation Sequencing (ID 12187)

      16:45 - 18:00  |  Author(s): Makoto Nishio

      • Abstract

      Background

      Afatinib is an oral irreversible blocker of ErbB-family kinases and shows a pronounced anti-tumor efficacy for advanced non–small cell lung cancer (NSCLC) positive for activating mutations of EGFR. We applied digital polymerase chain reaction (dPCR) and next-generation sequencing (NGS) to explore mechanisms of afatinib resistance.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible patients had advanced lung adenocarcinoma with EGFR activating mutations. Tumor and plasma samples were collected before afatinib treatment and after treatment failure with disease progression (systemic progressive disease, SPD). DNA from the samples was analyzed by dPCR and NGS.

      4c3880bb027f159e801041b1021e88e8 Result

      Thirty-five patients were enrolled, with a median follow-up time of 15.8 months. Among 25 patients with SPD, tumor, plasma, or both samples were available for 18, 23, and 16 individuals, respectively. dPCR and NGS detected EGFR T790M mutation in 13 (56.5%) and 11 (47.8%) of 23 plasma samples at SPD, with sensitivity and specificity compared with tumor samples being 83.3% and 70.0% (dPCR) and 50.0% and 70.0% (NGS), respectively. Applying the ratio of the number of T790M alleles to that of activating mutations (T/A) for determination of the T790M positivity improved the sensitivity and specificity of plasma analysis compared with tumor analysis to 83.3% and 100% (dPCR) and 57.1% and 100% (NGS), respectively. Among 25 patients with SPD, the T790M mutation of EGFR alone (n = 11), copy number gain (CNG) of NRAS (n = 1), CNG of MET (n = 1), CNG of EGFR plus T790M (n = 1), and CNG and E545K of PIK3CA plus T790M of EGFR (n = 1) were identified by NGS as putative resistance mechanisms against afatinib. No tumor showed transformation to small cell carcinoma. Median progression-free survival was longer in patients with than in those without T790M at SPD (15.1 versus 10.9 months, P =0.25). Median time to SPD was much longer in patients with than in those without T790M at SPD (17.9 versus 10.9 months, P =0.18).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Assessment of T/A ratio with dPCR or NGS improved specificity of plasma analysis for determination of T790M positivity compared with tumor analysis. dPCR and NGS analysis in tumor and plasma samples shed light on exploring mechanisms of afatinib resistance.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.01-75 - RELAY+, an Exploratory Study of Gefitinib with Ramucirumab in Untreated Patients with EGFR Mutation-Positive Metastatic NSCLC (ID 12637)

      12:00 - 13:30  |  Presenting Author(s): Makoto Nishio

      • Abstract
      • Slides

      Background

      RELAY is a randomized, double-blind phase 1b/3 study investigating the efficacy and safety of the addition of ramucirumab (a human IgG1 monoclonal antibody that binds to Vascular Endothelial Growth Factor (VEGF) Receptor 2) to erlotinib (an EGFR TKI) in treatment-naïve EGFR-mutant metastatic NSCLC. Results from the Phase 1b cohort showed that combining ramucirumab with erlotinib was safe with encouraging clinical activity and a median PFS of 17.1mo (Reck et al., Clinical Lung Cancer 2017). While enrolment for the RELAY Phase 3 cohort has been completed, the RELAY+ cohort was recently added to explore the safety and efficacy of the combination of ramucirumab with gefitinib, a frequently used EGFR TKI in East Asia.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      RELAY+ is an open-label, 2-period, single-arm exploration of the efficacy and safety of the addition of ramucirumab to gefitinib in previously untreated East-Asian patients with EGFR mutation-positive metastatic NSCLC (Period 1) and of ramucirumab to osimertinib in patients whose disease progressed in Period 1 and harbors the T790M mutation (Period 2). The trial is planned to be conducted in Japan, Taiwan and South-Korea and is currently open for enrollment. Approximately 80 patients will be enrolled.

      In Period 1 patients will receive ramucirumab (10mg/kg) every two weeks and gefitinib (250mg/day) until disease progression, unacceptable toxicity or other withdrawal criteria are met. The study objectives are to determine the 1-yr PFS rate, safety and patient reported outcomes (Lung Cancer Symptom Scale and EQ-5D-5L]). In Period 2 the efficacy and safety of ramucirumab (10mg/kg) every two weeks with osimertinib (80mg/day) will be explored.

      Both RELAY+ and RELAY participants will be enrolled in a liquid biopsy exploratory substudy. ctDNA (circulating tumor DNA) from plasma samples will be used for ddPCR (droplet digital PCR) and NGS (Next Generation Sequencing) to characterize mechanisms of acquired resistance and to test the hypothesis if the addition of ramucirumab to an EGFR TKI delays or modifies the emergence of EGFR TKI resistance.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    PL02 - Presidential Symposium - Top 5 Abstracts (ID 850)

    • Event: WCLC 2018
    • Type: Plenary Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 08:15 - 09:45, Plenary Hall
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      PL02.07 - IMpower 133: Primary PFS, OS and Safety in a PH1/3 Study of 1L Atezolizumab + Carboplatin + Etoposide in Extensive-Stage SCLC (ID 12892)

      09:00 - 09:10  |  Author(s): Makoto Nishio

      • Abstract
      • Presentation
      • Slides

      Background

      First-line (1L) standard-of-care treatment for extensive-stage small cell lung cancer (ES-SCLC) is platinum (carboplatin or cisplatin) with etoposide. Despite high initial response rates, there has been limited progress in the last two decades and outcomes remain poor with a median overall survival (OS) of ~10 months. IMpower133 (NCT02763579), a global Phase 1/3, double-blind, randomized, placebo-controlled trial evaluated efficacy and safety of adding atezolizumab, a humanized monoclonal anti–PD-L1 antibody, or placebo to 1L carboplatin and etoposide in ES-SCLC.

      Patients with measurable (RECIST v1.1) ES-SCLC, ECOG performance status 0 or 1, who had not received prior systemic treatment for ES-SCLC were enrolled. PD-L1 immunohistochemical testing was not required. Patients were randomized 1:1 to receive four 21-day cycles of carboplatin (AUC 5 mg/mL/min IV, Day 1) plus etoposide (100 mg/m2 IV, Days 1-3) with either atezolizumab (1200 mg IV, Day 1) or placebo, followed by maintenance therapy with atezolizumab or placebo until intolerable toxicity or progressive disease per RECIST v1.1. Patients meeting predefined criteria could receive treatment beyond progression. Co-primary endpoints were OS and investigator-assessed progression-free survival (PFS). Adverse events (AEs) were graded per NCI-CTCAE v4.0. Blood-based tumor mutation burden (bTMB) was assessed using prespecified cutoffs of ≥16 vs. <16 and ≥10 vs. <10 mutations/Mb.

      In total, 201 patients were randomized to the atezolizumab group, and 202 to the placebo group. Median follow-up was 13.9 months. Median OS was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio [HR] 0.70 [95% confidence interval (CI): 0.54, 0.91; P=0.0069]). Median PFS was 5.2 months and 4.3 months, respectively (HR 0.77 [95% CI: 0.62, 0.96; P=0.017]). OS and PFS benefits were consistent across key patient subgroups. Investigator-assessed confirmed objective response rates were 60.2% and 64.4% in the atezolizumab and placebo groups, respectively; median duration of response, 4.2 and 3.9 months. Exploratory analyses showed OS survival benefits in subgroups above and below prespecified bTMB cutoffs. Grade 3-4 treatment-related AEs were reported in 56.6% vs. 56.1% patients in atezolizumab vs. placebo groups, respectively; serious treatment-related AEs occurred in 22.7% and 18.9% patients, respectively.

      Addition of atezolizumab to carboplatin and etoposide provided a significant improvement in OS and PFS in 1L ES-SCLC in an all-comer patient population. No unexpected safety signals were identified. Atezolizumab plus carboplatin and etoposide may represent a new standard regimen for patients with untreated ES-SCLC.

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