The future of recurrent high-grade glioma treatment: what should we expect from the new agents? Andrew S. Chi, MD, PhD Assistant Professor of Neurology Standard Treatment Options for Recurrent GBM Re-resection Re-irradiation • SRS Cytotoxic chemotherapy • Lomustine • Carboplatin • Dose-dense temozolomide Bevacizumab Bevacizumab for recurrent GBM Accelerated US FDA-approval based on independent review of 2 historically-controlled, single-arm or non-comparative phase II trials: • Friedman et al. JCO 2009: • ORR: 26%, Median duration of response: 4.2 months • Kreisl et al JCO 2009: • ORR: 20%, Median duration of response: 3.9 months Wen and Kesari N Engl J Med (2009) Bevacizumab + Standard Therapy Combinations • BELOB randomized Phase II trial (ASCO 2013) • Bevacizumab: OS9 = 38% (mOS 8 mo) • CCNU (110 mg/m2): OS9 = 43% (mOS 8 mo) • CCNU (90 mg/m2) + bevacizumab: OS9 = 59% (mOS 11 mo) • EORTC 26101 phase III trial • EORTC 26091 (TAVAREC) randomized trial for recurrent grade II/III glioma • Temzolomide vs Temozolomide + Bevacizumab • RTOG 1205 re-irradiation trial • Randomized Phase II trial of RT + bevacizumab vs. bevacizumab Recent Considerations in GBM Trials • Limited success in “first generation” of targeted therapy trials • Anti-angiogenic agents have dominated recent clinical trials • Bevacizumab US FDA approved for recurrent GBM • Increased awareness of inter- and intra-tumoral heterogeneity • Number of potential therapeutic targets and targeted agents have significantly increased • Increased understanding of how tumors change after therapy Intratumoral Heterogeneity Snuderl et al. Cancer Cell (2011) Tumor Evolution Throughout Therapy Johnson et al. Science (2014) Strategies in Recent GBM Trials • Bevacizumab approval for recurrent GBM • May have established a new “standard therapy” control • Combinations with bevacizumab have proliferated • Targeted therapy combinations are being emphasized • Novel clinical trial designs (e.g. adaptive randomization) • “Basket” Trials with genetic selection • Immune checkpoint inhibitors (e.g. PD-1) have emerged Currently Enrolling Trials for Malignant Glioma at MGH Drug Target / Mechanism Selection Criteria MK-1775 Wee1 None BKM120 pan-PI3K Activated PI3K pathway EGFRvIII / vaccine EGFRvIII pan-HER EGFR amplification EGFRvIII + DM1 drug conjugate EGFRvIII Plerixafor + Bevacizumab stem cells, VEGF None GDC-0084 PI3K and mTOR None MLN0128 TORC1/2 None ANG1/2 and VEGF None Endoglin (angiogenesis) None HSP / vaccine None Rindopepimut (CDX-110) Dacomitinib (PF-00299804) AMG595 AMG386 + Bevacizumab TRC105 HSPPC-96 vaccine + Bevacizumab vs Bevacizumab “Basket” Trials Enrolling GBM patients at MGH Drug Target / Mechanism Selection Criteria Crizotinib MET, ALK, ROS MET, ALK, ROS MGA271 B7-H3 (immune checkpoint) B7-H3 expression c-Met, VEGFR2, VEGFR3 MET amplification AG-120 IDH1 R132H IDH1 R132H Vemurafenib BRAF V600E BRAF V600E BGJ398 FGFR FGFR amplification or mutation Neratinib EGFR, HER2, HER3 EGFR, HER2, HER3 mutations or EGFR amplification E7050 + E7080 Selected MGH Experience - Targeted Therapy METamplified EGFRamplified Crizotinib x 6 cycles Dacomitinib x 6 cycles Targeted Therapy Combinations Trametinib (MEK) + Dabrafenib (BRAF) for BRAF V600E melanoma • Based on sound biological rationale and robust preclinical validation Flaherty et al. NEJM (2012) Immune Checkpoint Inhibitors Holzel et al. Nature Reviews Cancer (2013) Immune Checkpoint Inhibitors Nivolumab (BMS) (PD1) Randomized Phase II in recurrent GBM • Nivolumab vs. Nivolumab + Ipilimumab vs. Bevacizumab MK-3475 (Merck) (PD-1) likely will enter into trial in recurrent GBM Holzel et al. Nature Reviews Cancer (2013) Initial MGH Experience - Pseudoprogression Baseline Cycle 2 Novel Clinical Trial Design • Genetically-enriched targeted therapy trials • Mandate tissue acquisition / genetic analysis prior to enrollment? • Consortia-run • Bayesian Adaptive Randomization • Multi-arm balanced randomized design • More patients randomly assigned to effective treatment arms • Results in trials with fewer overall patients with no loss in statistical power • “Basket” trials are gaining popularity in industry What should we expect? • Combinations may be required for targeted therapies • Likely to be effective if mechanistic basis is sound • Synergistic and unanticipated toxicities may emerge • Achieving therapeutic doses may be a challenge • Robust pre-clinical validation of targets in clinically relevant models is required • Genetically-enriched trials and basket trials • Immune-based therapies will proliferate
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