Virtual Library

Start Your Search

Matthew G Krebs



Author of

  • +

    OA 14 - New Paradigms in Clinical Trials (ID 681)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Clinical Design, Statistics and Clinical Trials
    • Presentations: 1
    • +

      OA 14.06 - Entrectinib in Patients with Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small Cell Lung Cancer (NSCLC) (ID 8564)

      11:00 - 12:30  |  Author(s): Matthew G Krebs

      • Abstract
      • Presentation
      • Slides

      Background:
      Entrectinib is a potent, investigational, CNS-active, oral inhibitor of ROS1 with a biochemical IC~50~ (0.2 nM) ~30 times more potent than crizotinib, the only agent approved for the treatment of ROS1-positive NSCLC. Previously, we reported an objective response rate of 85% in 13 ROS1 inhibitor-naïve NSCLC patients who were treated in Phase 1 studies (Drilon and Siena et al, Cancer Discov 2017), including 2 of 3 (67%) patients with CNS disease. Responses were durable, with 1 patient remaining on study for more than 3 years. Entrectinib was well tolerated, with predominantly Grades 1 or 2 adverse events that were reversible with dose modification.

      Method:
      Patients with ROS1 inhibitor-naïve NSCLC were enrolled across Phase 1 and 2 studies of entrectinib. Patients were screened for ROS1 gene fusions either locally or centrally at Ignyta’s diagnostic laboratory using next generation sequencing. Entrectinib was administered orally at 600 mg once-daily in 4-week cycles. Safety was assessed by monitoring adverse events, laboratory tests, and clinic visits. Tumor assessments were performed at the end of Cycle 1 and every 8 weeks thereafter. All scans were read locally (INV) and by blinded independent central review (BICR) using RECIST v1.1. INV results will be presented except where noted.

      Result:
      As of 24 May 2017, a total of 32 patients were evaluable for response (median age 52 years, 72% female). At a median follow-up of 12 months, objective responses were observed in 24 of 32 (75% [95% CI: 56.6, 88.5]; 3 complete responses) patients, including 7 of 11 (64% [95% CI: 30.8, 89.1]) patients with CNS disease at baseline. Five of 7 patients with evaluable CNS lesions by BICR experienced confirmed RECIST intracranial responses, for a CNS response rate of 71% (95% CI: 29.0, 96.3). With 19 (59%) patients remaining on study, the median duration of response was 17.2 months (95% CI: 6.5, 36.0) and progression-free survival was 19.1 months (95% CI: 6.5, 36.6). The most common (>15%) treatment-related adverse events were fatigue/asthenia (34%), dysgeusia (34%), dizziness (24%), weight increase (21%), paresthesia (19%), nausea (18%), constipation (18%), and diarrhea (16%). All data will be updated at the time of presentation.

      Conclusion:
      Entrectinib is well tolerated and has shown promising antitumor activity in ROS1 inhibitor-naïve NSCLC, including patients with CNS disease. Patients with ROS1+ NSCLC and other tumor types continue to be enrolled in STARTRK-2 (NCT02568267) in order to support a potential regulatory filing for entrectinib in this population.

      Only 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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

  • +

    P1.15 - SCLC/Neuroendocrine Tumors (ID 701)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
    • +

      P1.15-004 - An Open-Label, Multitumor Phase II Basket Study of Olaparib and Durvalumab (MEDIOLA): Results in Patients with Relapsed SCLC (ID 9388)

      09:30 - 16:00  |  Presenting Author(s): Matthew G Krebs

      • Abstract
      • Slides

      Background:
      The prognosis of small cell lung cancer (SCLC) remains poor and there is a high unmet need for effective therapies. Poly (ADP-ribose) polymerase (PARP) inhibitors and immunotherapies hold promise due to expression of PARP and high mutational burden in SCLC. PARP inhibition leads to upregulation of anti-programmed cell death ligand-1 (PD-L1) and enhanced cancer immunosuppression. This led us to investigate the combination of olaparib and the PD-L1 inhibitor, durvalumab in SCLC (NCT02734004).

      Method:
      Individuals with relapsed SCLC at least 12 weeks after platinum-based therapy were eligible. Patients received olaparib tablets 300 mg PO BID for a 4-week run-in, followed by a combination of olaparib 300 mg PO BID and durvalumab 1.5 g IV q 4 weeks. The combination was continued until progressive disease by RECIST 1.1. Tumor assessments were done at baseline, 4 weeks and every 8 weeks thereafter. The primary endpoints were disease control rate (DCR) at 12 weeks, as well as safety and tolerability. The secondary endpoints included DCR at 28 weeks, objective response rate (ORR), duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Biomarker endpoints included PD-L1 expression and evaluation of tumor infiltrating lymphocytes (TILs). A target DCR of 60% was used to calculate the sample size in a Bayesian predictive probability design.

      Result:
      Among the 38 patients, the median age was 63 years (range 44-76) and median line of prior chemotherapies 1 (range 1-3). At the time of analysis, each patient was followed up for at least 12 weeks. The most common grade 3 or higher AEs included anemia (34.2%), hyponatremia (10.5%), lymphopenia (10.5%), chronic obstructive pulmonary disease (5.3%), increased GGT (5.3%) and increased lipase (5.3%). DCR at 12 weeks was 29%. Confirmed responses included one partial response and one complete response. Three additional patients had unconfirmed responses. The updated primary and secondary endpoints, as well as biomarker and PK data will be presented.

      Conclusion:
      Although AEs of all grades were seen commonly, the combination of olaparib and durvalumab was relatively well tolerated, as most of the AEs were attributed to underlying disease. While efficacy of the combination in this SCLC population did not reach the target DCR and is below the futility boundary (<40%), a minority of patients obtained significant benefit and will be followed up for further clinical and translational analyses.

      Only Active 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 or select "Add to Cart" and proceed to checkout.