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R.S. Herbst



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    Immunotherapies and targeted therapies in advanced NSCLC (ID 39)

    • Event: ELCC 2017
    • Type: Proffered Paper session
    • Track:
    • Presentations: 1
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      83O - A phase II study of durvalumab (MEDI4736) for previously treated patients with stage IV squamous NSCLC (SqNSCLC): Lung-MAP Sub-study SWOG S1400A (ID 279)

      14:45 - 15:00  |  Author(s): R.S. Herbst

      • Abstract
      • Presentation
      • Slides

      Background:
      Durvalumab (MEDI4736) is an engineered human IgG1 mAb targeting programmed cell death ligand-1 (PD-L1). Treatment with other anti-PD-1/PD-L1 antibodies has demonstrated meaningful clinical benefit in patients with advanced NSCLC.

      Methods:
      As part of the Lung Master Protocol S1400, a National Clinical Trials Network group "umbrella" trial for second-line SqNSCLC we conducted a phase II study of durvalumab in patients with Stage IV squamous NSCLC (ECOG PS 0-2; ≥1 prior systemic treatment regimens, including one platinum-based), EGFR/ALK wild-type. The primary endpoint was overall response rate (ORR) (RECIST v1.1); secondary endpoints included duration of response (DoR), ORR among PD-L1 positive patients, disease control rate (DCR), investigator-assessed progression-free survival (PFS), overall survival (OS) and safety (CTCAE v4.03). The initial protocol was a randomized phase II/III comparison of durvalumab to docetaxel, and was amended to be a single arm phase II trial of single agent durvalumab. PD-L1 positive tumors were defined by ≥ 25% of tumor cells with membrane staining.

      Results:
      Of the 68 eligible patients (median [range] age 66 [35-92] years, PS 0/1/2 26%/62%/12%), 11 were responders (16% ORR, 95% Confidence Interval [CI] 7%, 25%). DCR was 54% (CI 43%, 66%), median OS was 11.5 months (CI 10.1-12.4 mos), and median PFS was 2.9 mos (CI 2.0-4.1 mos). Of the 11 responders, median time to response and DoR were 3.6 mos (CI 2.8-4.2 mos) and 18.6 months (95% CI 4.4-NR mos), respectively. Of the 14 PDL1-positive patients, 2 were responders (14% ORR, 95% CI 0%, 33%), DCR was 57% (CI 31%, 83%), median OS and PFS were 10.7 mos (CI 9.2-10.7 mos) and 2.3 mos (CI 1.4-4.9 mos), respectively. Durvalumab showed a manageable safety and tolerability profile; most adverse events (AEs) were low grade and resolved with treatment delay and/or immunosuppressive interventions. Grade ≥3 treatment-related AEs occurred in 23(34%) of patients. Drug-related AEs led to discontinuation in 6 patients (9%, 95% CI 2%, 16%).

      Conclusions:
      Durvalumab demonstrated clinical benefit and durable responses in a previously treated metastatic NSCLC population with manageable toxicity profile. Results are comparable with other anti-PD-1/PD-L1 therapies in metastatic, relapsed NSCLC.

      Clinical trial identification:
      NCT02766335

      Legal entity responsible for the study:
      Southwest Oncology Group/NCTN

      Funding:
      Lung-MAP supported in part by NIH/NCI grants CA180888, CA180819, CA180820, CA180821, CA180868, and by Amgen, AstraZeneca, Bristol-Myers Squibb Company Genentech and Pfizer through the Foundation for the National Institutes of Health, in partnership with Friends of Cancer Research.

      Disclosure:
      V. Papadimitrakopoulou: Advisory Role for: Eli Lilly&Co, Genentech, Janssen Global Sevices, Bristol-Myers Squibb, ARIAD, Astra Zeneca Pharmaceuticals, Novartis, Merck Corporate-sponsored research: Novartis, Astra Zeneca, Genentech, Merck, Janssen, ACEA, Bristol-Myers Squibb. H. Borghaei: Advisory: Bristol-Myers Squibb, Lilly, Genentech, Celgene, Pfizer, EMD-Serono, Boerhinger-Ingelheim, Trovagene, AstraZeneca, Research Support: Millenium, Merck, Celgene. K. Kelly: Advisory: Synta, AstraZeneca, Lilly, Clovis Oncology, ARIAD, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, G1 Therapeutics. Research: Millenium, Novartis, EMD Serono, Lilly, Genentech, Abbvie, Gilead, Celgene, Five Prime Therapeutics, Transgene. All other authors have declared no conflicts of interest.

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    Poster Display Session (ID 63)

    • Event: ELCC 2017
    • Type: Poster Display Session
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 5/07/2017, 12:30 - 13:00, Hall 1
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      143TiP - IMpower110: Phase III trial of 1L atezolizumab in PD-L1–selected chemotherapy-naive NSCLC (ID 364)

      12:30 - 12:30  |  Author(s): R.S. Herbst

      • Abstract

      Background:
      Despite poor survival and toxicities, chemotherapy is the standard of care and remains the main first-line option for patients (pts) with advanced NSCLC non-squamous (non-sq) and squamous (sq) histology without genetic driver alterations. Immunotherapies targeting PD-L1/PD-1 are available for 2L+ NSCLC but remain to be fully studied in the 1L setting. Atezolizumab (atezo), an anti–PD-L1 mAb, prevents PD-L1 interacting with PD-1 and B7.1, restoring tumor-specific T-cell immunity. Significant and clinically relevant survival benefit has been shown with atezo in previously treated NSCLC, regardless of PD-L1 expression on tumor cells (TC) and/or tumor-infiltrating immune cells (IC). IMpower110 (NCT02409342), a global Phase III randomized, multicenter, open-label trial, will evaluate efficacy and safety of 1L atezo vs cisplatin (cis)/carboplatin (carbo) + pemetrexed (pem) or gemcitabine (gem) in PD-L1–selected chemotherapy-naive pts with advanced non-sq or sq NSCLC, respectively.

      Trial design:
      Inclusion criteria include stage IV non-sq or sq NSCLC, measurable disease (RECIST v1.1), ECOG PS 0-1, no prior chemotherapy for advanced NSCLC and centrally assessed PD-L1 expression of ≥ 1% on TC or IC (TC1/2/3 or IC1/2/3 with VENTANA SP142 IHC assay; expected prevalence, ≈ 65%). Exclusion criteria include active or untreated CNS metastases, prior immune checkpoint blockade therapy or autoimmune disease. Pts will be randomized 1:1 to receive atezo or cis/carbo + pem (non-sq)/gem (sq) (4 or 6 21-day cycles are allowed). Pts receiving atezo may continue until loss of clinical benefit, while pts in the comparator arm can receive pem maintenance (non-sq) or best supportive care (sq) until disease progression. Stratification factors are sex, ECOG PS, histology (non-sq vs sq) and centrally assessed PD-L1 expression by IHC. Co-primary endpoints are PFS and OS. Key secondary endpoints are ORR, DOR, IRF-assessed PFS (RECIST v1.1) and TTD in pt-reported lung cancer symptoms. Safety and PK will also be evaluated. Tumor biopsies at progression will be assessed for immunologic biomarkers associated with responses to atezo and to differentiate unusual responses from radiographic progression. Approximately 570 pts will be enrolled.

      Clinical trial identification:
      NCT02409342

      Legal entity responsible for the study:
      F. Hoffmann-La Roche Ltd/Genentech Inc., a member of the Roche Group

      Funding:
      F. Hoffmann-La Roche Ltd/Genentech Inc., a member of the Roche Group

      Disclosure:
      J. Jassem: Speaker: AstraZeneca, Roche, Pfizer; Advisory roles: AstraZeneca, Boehringer, BMS, Celgene, G1 Therapeutics, Merck, Pfizer, Pierre Fabre, Roche; Travel support: Roche, Boehringer. F. de Marinis: Consultation fees received from Roche/BMS/Boehringer/Novartis/Pfizer/MSD/Astrazeneca. D.R. Spigel: Consulting/Advisory Role: Genentech (uncompensated); Travel, accommodation, expenses: Genentech. S. Lam, S. Mocci, A. Sandler, A. Lopez-Chavez, Y. Deng: Employee, stock: Roche/Genentech. G. Giaccone: Consulting or Advisory Role: Clovis, Boehringer-Ingelheim; Celgene; Research grants: Karyopharm, Astra-Zeneca; Eli-Lilly. R.S. Herbst: Consultant and research support from Genentech

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    Targeted therapies and immunotherapies (ID 46)

    • Event: ELCC 2017
    • Type: Poster Discussion session
    • Track:
    • Presentations: 1
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      90PD - Previously treated advanced NSCLC cohort from a multi-disease phase 1 study of ramucirumab (R) plus pembrolizumab (P): Efficacy and safety data (ID 169)

      14:45 - 14:45  |  Author(s): R.S. Herbst

      • Abstract

      Background:
      R (anti-VEGFR2) and P (anti-PD-1) are active in previously treated advanced NSCLC. Median progression-free survival (PFS) reported in KEYNOTE-001 (previously treated; PD-L1 all comers) was 3.0 months (95%CI, 2.2-4.0) and ORR was 18%. This is the first study to combine R with P.

      Methods:
      Ongoing, multi-cohort, phase 1a/b trial enrolled pts with confirmed NSCLC with prior progression on systemic therapy, measurable disease, ECOG PS 0-1 and baseline tumor tissue. PD-L1 was classified strongly positive (tumor proportion score [TPS] ≥50%), weakly positive (TPS=1-49%), or negative (TPS <1%) using the DAKO PD-L1 22C3 IHC pharmDx assay. Primary objective- assess safety and tolerability of R + P; preliminary efficacy will be examined.

      Results:
      As of 21-Nov-2016, 27 pts with previously treated advanced NSCLC received R at 10 mg/kg on Day 1 with P 200 mg on Day 1 q3W. Median age was 65, 78% male, 96% had a history of smoking, 78% had adenocarcinoma and 15% had squamous-cell carcinoma. Sixteen (59%) pts received ≥2 and 4 (15%) received ≥3 prior treatment regimens for their disease. Median duration of treatment was 7.0 mo (IQR 3.0-12.4) and 8.3 mo (IQR 3.3-12.4) for R and P, respectively. Treatment related adverse events (TRAEs) occurred in 25 (93%) pts, most commonly hypertension (26%) and asthenia (19%). Five (19%) pts experienced grade 3 TRAEs (adrenal insufficiency, delirium, hypertension [n = 2], hyponatremia, infusion related reaction, proteinuria, and respiratory failure). No grade 4-5 TRAEs occurred. ORR was 30% with a median time to response of 2.1 mo. Duration of response has not been reached. Responses occurred in PD-L1 unknown (n = 1), negative (n = 2), and strong positive (n = 5) groups as well as both histologies. Median PFS was 9.7 mo (95% CI 4.6-11.5) and overall survival rate at 6 mo was 84.9%. Disease control rate was 85%. Ten (37%) pts remain on study treatment, including all responders.

      Conclusions:
      R + P demonstrated encouraging antitumor activity independent of PD-L1 and histology. The safety profile was consistent with monotherapy treatment for each drug, with no additive toxicities. The study was amended and is now enrolling pts with treatment naïve advanced NSCLC.

      Clinical trial identification:
      NCT02443324 JVDF

      Legal entity responsible for the study:
      Eli Lilly and Company, Indianapolis, IN

      Funding:
      Eli Lilly and Company, Indianapolis, IN

      Disclosure:
      R.S. Herbst: Personal fees from Eli Lilly, outside the submitted work. E. Calvo: Institutional research funding: multiple- available upon request; Travel expenses: Lilly, PsiOxus, Novartis; Consultant: Novartis, GSK, Astellas, Genentech, Lilly, Nanobiotich, Pfizer; SB: Novartis. N. Isambert: Honoraria: Pfizer, Novartis; Consulting/Advisory: Merck Serono. J. Bendell: Institutional research funding: From multiple and available upon request, including Lilly and Merck. P. Cassier: Personal fees from Roche/Genentech, Novartis, Astra-Zeneca, Amgen, Plexxikon; non-financial support from Roche/Genentech, Merck Sharp Dohme, Astra-Zeneca, Plexxikon; and grants from Merck Sharp Dohme and Astra-Zeneca, outside the submitted work. J. Jin, G. Mi, J. Rege: Employee and stock holder at Eli Lilly and Company. L. Paz-Ares: Consultant/Advisory role: Roche, Lilly, Novartis, MSD, BMS, Amgen, Clovis, AZ, BI, Pfizer. All other authors have declared no conflicts of interest.