Author of

• 11745

  +

  P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Medical Oncology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11749

    +

    P2.11-004 - A Phase Ib, open label, dose escalation study of the safety and pharmacology of PI3-Kinase (PI3K) Inhibitor GDC 0941 in combination with either Paclitaxel (Pac) and Carboplatin (Carbo) with or without Bevacizumab (Bev), or Pemetrexed (Pem), Cisplatin (Cis), and Bev in patients with advanced Non–Small Cell Lung Cancer (NSCLC). (ID 885)

    09:30 - 09:30  |  Author(s): J.A. Ware
    • Abstract

    Background
    The PI3K pathway has been implicated as a mechanism for cell survival and resistance to chemotherapy. PI3K may be an important target in NSCLC based on genetic alterations such as PIK3CA amplification, PTEN loss and PI3K mutations. Preclinical NSCLC models show that concurrent dosing of GDC-0941 improved activity of taxanes, platinums, and anti-VEGF therapy. This Phase 1b study aims to establish the safety and tolerability of GDC-0941 in combination with four frontline standard of care regimens in patients with advanced NSCLC.

    Methods
    This study contains two Carbo/Pac containing arms: Arm A (GDC-0941 + Carbo + Pac), open to squamous (Sq) patients and Bev-ineligible non-squamous (NSq) patients; and Arm B (GDC-0941 + Carbo + Pac + Bev) for NSq patients. The study also aims to evaluate two Cis/Pem containing arms in NSq patients: Arm C (GDC-0941 + Cis + Pem + Bev); and Arm D (GDC-0941 + Cis + Pem). Study objectives are to evaluate safety and pharmacokinetics (PK), and to determine the maximum tolerated/administered dose (MTD or MAD) of GDC-0941 in combination with chemotherapy regimens in all arms. Patients received GDC-0941 with 4-6 cycles of chemotherapy every 3 weeks (Q3W): Pac (200 mg/m[2]), Carbo (AUC 6 mg/mL·min), Cis (75 mg/m2), Pem (500 mg/m2), and Bev(15 mg/kg) . In all arms, GDC was given PO qd on Days 1-14 of a 21-day cycle. GDC-0941 +/- Bev were given until progression or toxicity.

    Results
    As of 1 February 2013, Arms A, B and C have completed enrollment, with 18, 24 and 13 patients, respectively; no patients have been enrolled in Arm D to date. The most common Grade 3/4 treatment-related adverse events (TAEs) reported in ≥10% of patients were as follows: Arm A: neutropenia (50%), anemia (17%), febrile neutropenia (17%), leukopenia (11%) and thrombocytopenia (11%); Arm B: neutropenia (38%), lymphopenia (13%); Arm C: fatigue (31%), dehydration (15%) and hypertension (15%). The MTD/MAD in Arms A, B and C is 340 mg GDC-0941 in combination with either Carbo + Pac +/- Bev or with Cis + Pem + Bev, respectively. PK characteristics in all Arms were similar to historical profiles for the respective chemotherapy agents, as well as to the single-agent GDC-0941 profile. Confirmed partial responses (PRs) for patients with at least one post-baseline scan are as follows: 6 of 10 (60%) Sq patients; 11 of 28 (39%) NSq (Arms A and B) and 9 of 12 (75%) NSq patients (Arm C).

    Conclusion
    The combinations of GDC-0941 with either Pac + Carbo (+/- Bev), or Cis + Pem + Bev have been well tolerated at doses consistent with target PK exposures based on preclinical activity. Promising responses rates have been observed with all combinations evaluated. Evaluation of GDC-0941 + Cis + Pem is ongoing. A randomized Phase 2 study of GDC-0941 + Pac + Carbo (+/- Bev) in NSq and Sq patients is ongoing.