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G.I. Shapiro



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    MA16 - Novel Strategies in Targeted Therapy (ID 407)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
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      MA16.09 - Antitumor Activity and Safety of Crizotinib in Patients with MET Exon 14-Altered Advanced Non-Small Cell Lung Cancer (ID 5162)

      15:14 - 15:20  |  Author(s): G.I. Shapiro

      • Abstract
      • Presentation
      • Slides

      Background:
      MET alterations leading to exon 14 skipping occur in ~4% of non-squamous non‑small cell lung cancer (NSCLCs) and 20–30% of sarcomatoid lung carcinomas, resulting in MET activation and sensitivity to MET inhibitors in vitro.[1–4] Crizotinib, initially developed as a MET inhibitor, is currently approved for the treatment of ALK-rearranged and ROS1-rearranged advanced NSCLC. We present crizotinib antitumor activity and safety data in patients (pts) with MET exon 14-altered advanced NSCLC.

      Methods:
      Advanced NSCLC pts positive for MET exon 14-alteration status determined locally by molecular profiling were enrolled into an expansion cohort of the ongoing phase I PROFILE 1001 study (NCT00585195) and received crizotinib at a starting dose of 250 mg BID. Objective responses were assessed using RECIST v1.0.

      Results:
      As of the data cut-off of Feb 01, 2016, 21 pts with MET exon 14-altered NSCLC received crizotinib treatment (18 response-evaluable, 3 not yet evaluable). Median age was 68 y (range: 53−87). Tumor histology was: 76% adenocarcinoma, 14% sarcomatoid adenocarcinoma, 5% adenosquamous carcinoma, and 5% squamous cell carcinoma. Sixty-two percent (62%) of pts were former-smokers, 38% never-smokers, and there were no current smokers. Duration of treatment ranged from 0.2 to 12.2 mo, with 76% of pts (16/21) still ongoing. Five pts discontinued treatment (1 due to AE, 3 due to clinical or disease progression, and 1 preferred alternative treatment formulation). PRs were observed in 8 pts, for an objective response rate of 44% (95% CI: 22–69); 9 pts had stable disease. Median time to response was 7.8 weeks (range: 7.0–16.3), which was the approximate time of the scheduled first on treatment tumor scans for patients. Median progression-free survival could not be calculated. The most common (≥25%) treatment-related AEs (TRAEs) were edema (43%) diarrhea (33%), nausea (33%), vision disorder (33%), and vomiting (29%). Most TRAEs were grade 1/2 in severity and consistent with the known safety profile of crizotinib. Four grade 3 TRAEs (edema, bradycardia, anemia, and weight increased) and no grade 4 or 5 TRAEs were reported. Enrollment of pts with MET exon 14-altered NSCLC continues, and updated data will be available at the time of presentation.

      Conclusion:
      Crizotinib has clinically meaningful antitumor activity in pts with MET exon 14-altered advanced NSCLC. The drug has a tolerable AE profile, consistent with that previously reported for pts with ALK-rearranged or ROS1-rearranged advanced NSCLC. Further study of crizotinib in this pt population is warranted.

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    P1.07 - Poster Session with Presenters Present (ID 459)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      P1.07-002 - G1T28, a Cyclin Dependent Kinase 4/6 Inhibitor, in Combination with Topotecan for Previously Treated Small Cell Lung Cancer: Preliminary Results (ID 5213)

      14:30 - 14:30  |  Author(s): G.I. Shapiro

      • Abstract

      Background:
      Chemotherapy-induced bone marrow and immune system toxicity causes significant acute and long-term consequences. G1T28 is a potent and selective CDK4/6 inhibitor (CDK4/6i) in development to reduce chemotherapy-induced myelosuppression and preserve immune system function in small cell lung cancer (SCLC) patients. Hematopoietic stem and progenitor cells (HSPC) are dependent upon CDK4/6 for proliferation, and preclinical models demonstrated that transient G1T28-induced G~1~ cell cycle arrest renders them resistant to chemotherapy cytotoxicity, allowing faster hematopoietic recovery, preservation of long-term stem cell and immune system function, and enhancement of chemotherapy anti-tumor activity.

      Methods:
      Objectives of this ongoing multicenter Phase 1b/2a study are to assess the dose limiting toxicities (DLTs), safety, hematological profile, PK, and anti-tumor activity of G1T28 in combination with topotecan (NCT02514447). The study consists of a limited open-label, dose-finding portion (Part 1; up to 40 patients), and an open‑label, single-arm expansion portion (Part 2; 28 patients). Eligible patients had histologically/cytologically confirmed SCLC, adequate organ function, ECOG performance status 0-2, 1-2 prior lines of chemotherapy, and no symptomatic brain metastases. G1T28, at a starting dose of 200 mg/m[2] (derived from the Phase 1a healthy volunteer study and expected to maintain HSPC G1 arrest beyond topotecan exposure), was administered IV prior to IV topotecan on days 1-5 every 21-days.

      Results:
      21 patients (median age 68, 5 females, 20 white and 1 African-American) have been enrolled across 5 cohorts. DLTs due to Grade 3/4 myelotoxicity occurred in the first two cohorts and were associated with supra-therapeutic topotecan exposures due to decreased topotecan clearance by G1T28. Reducing the topotecan dose achieved exposures in the therapeutic range and was well tolerated. No episodes of febrile neutropenia or bleeding have occurred to date. For the 17 evaluable patients, there were 5 PR, 8 SD, and 4 PD. In the 6 platinum refractory patients there were 1 PR, 3 SD, and 2 PD.

      Conclusion:
      G1T28, a novel CDK4/6i, combined with topotecan for previously treated SCLC patients has been well tolerated, without any episodes of febrile neutropenia or bleeding. There are encouraging early signs of anti-tumor activity, with a response rate of 29% overall (36%, 4/11 in sensitive and 17%, 1/6 in refractory) and a clinical benefit rate (CR+PR+SD) of 76% overall (82%, 9/11 in sensitive and 67%, 4/6 in refractory). This novel approach, allowing the administration of chemotherapy with preservation of hematopoietic function and cellular immunity, could potentially improve treatment outcomes of patients with CDK4/6-independent tumors. Updated data will be presented.