ESMO 2017 I I TUMORI CEREBRALI Dr. Tiziana Falbo Oncologia medica Istituto Neurotraumatologico Italiano Grottaferrata (Roma)
Introduction What is a low- grade glioma Weller, Nat Rev Primers 2015 Ostrom, neuro Oncol, 2014 (1)Shaw, Neurosurg, 2008 Buckner, NEJM 2016 (2)Stupp, NEJM 2005
WHO 2016 Update : «Integrated diagnosis «Histological Criteria & grade+ Molecular Markers
The (long standing) standard of care for GBM Stupp et al. New Eng J Med. 2005 Weller et al. Lancet Oncol. 2017
A decade of negative GBM drug trials Chinot et al. New Eng J Med. 2014 Stupp et al. Lancet Oncol 2014 Weller et al. Lancet Oncol 2017
Highlight topics in Madrid 2017 - Regorafenib in recurrent glioblastoma - Safety of nivolumab with RT ± TMZ in newly diagnosed glioblastoma - EGFR amplification rate in glioblastoma
REGOMA: a randomized, multicenter, controlled openlabel phase II clinical trial evaluating regorafenib activity in relapsed glioblastoma patients Lombardi Giuseppe 1, De Salvo Gian Luca 2, Brandes A. Alba 3, Eoli Marica 4, Rudà Roberta 5, Faedi Marina 6, Lolli Ivan 7, Pace Andrea 8, Rizzato Simona 9, Germano Domenico 10, Pasqualetti Francesco 11, Farina Miriam 2, Magni Giovanna 2, Pambuku Ardi 1, Bergo Eleonora 1, Cabrini Giulio 12, Indraccolo Stefano 13, Gardiman Marina P. 14, Zagonel Vittorina 1 1 Department of Clinical and Experimental Oncology, Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy; 2 Clinical Trials and Biostatistics Unit, IOV-IRCCS, Padua, Italy; 3 Medical Oncology Department, USL-IRCCS Scienze Neurologiche, Bologna, Italy; 4 Besta Institute, Milano, Italy; 5 Department of Neuro-Oncology, University of Turin and City of Health and Science Hospital, Torino, Italy; 6 Medical Oncology Unit, IRST-IRCCS, Meldola, Italy; 7 Medical Oncology Unit-IRCCS, Castellana Grotte, Bari, Italy; 8 Neuroncology Unit, Regina Elena, Roma, Italy; 9 Medical Oncology Unit, Udine, Italy; 10 Medical Oncology Unit, Benevento, Italy; 11 Radiotherapy Unit, Pisa, Italy; 12 Molecular Pathology Unit, Verona, Italy; 13 Immunology and Molecular Oncology Unit, IOV-IRCCS, Padua, Italy; 14 Pathology Department, Padova, Italy Regione del Veneto
Background
Regorafenib a pan kinase inhibitor Inhibition of multiple tyrosine kinases FGFR, Ang-2, VEGFR, KIT Inhibits in preclinical model tumor vasculature/ angiogenesis tumor growth Safe and effective in metastatic colon-rectal cancer 1, hepatocellular carcinoma(2) and GIST(3) patients Regorafenib inhibits tumor vasculature and tumor growth in a rat GS9L glioblastoma model 4 1 Grothey et al. Lancet 2013 2 Bruix et al. Lancet 2017 3 Demetri et al. Lancet 2013 4 Wihelm SM et al. Int J Cancer 2011
REGOMA - A randomized, multicenter, controlled open-label phase II clinical trial rgbm after RT/TMZ PD by RANO criteria at least 12 weeks after completion of radiotherapy, unless the recurrence is outside the radiation field or has been histologically documented At least 1 bi-dimensionally measurable target lesion with 1 diameter of at least 10mm Histologically confirmed GBM ECOG PS 0-1 (KPS 70) R 1:1 Regorafenib 160mg/die (3 weeks on, 1 week off) Lomustine 110mg/m2 day1 (every 6 weeks) Treat until PD (RANO criteria) Stratification factors: center and surgery at recurrence Study location: 10 centers in Italy
Objectives of the study Primary Objective Overall Survival (OS) Secondary Objectives 6-month Progression Free Survival (6m-PFS) (assessed by RANO criteria) Disease control rate (DCR) Objective Response Rate (ORR) Safety (assessed by CTCAE v4.0) Quality of Life (assessed by EORTC QoL C30 and BN-20) Exploratory Analyses Analysis of angiogenic and metabolic tissue biomarkers as possible predictors of response to regorafenib
Baseline Patient Characteristics
Overall Survival Arm Total Failed Regorafenib 59 32 Lomustine 60 41 Median OS months (95%CI) 6.5 (5.6-12.0) 5.5 (4.7-8.0) 6-month OS (95%CI) 55.6 (40.9-68.0) 43.6 (29.8-56.6) 12-month OS (95%CI) 36.8 (22.2-51.4) 12.7 (3.9-26.9) Log-Rank p-value 1-side 0.0284 Hazard Ratio (80%CI) 0.64 (0.47-0.87)
Progression-free survival Arm Total Failed Regorafenib 59 52 Lomustine 60 54 Median PFS, months (95%CI) 2.0 (1.9-3.6) 1.9 (1.8-2.1) 3-month PFS (95%CI) 44.1% (31.2-56.2) 25% (14.9-36.4%) 6-month PFS (95%CI) 15.5% (7.4-26.2) 8.3% (2.8-17.7%) Log-Rank p-value 0.0514 Hazard Ratio (95%CI) 0.69 (0.47-1.01)
Response Rates Regorafenib Lomustine Complete Response 1.7% 1.8% Partial Response 3.4% 1.8% Objective Response Rate 5.1% 3.6% Stable Disease 39% 17.5% Disease Control Rate 44.1% 21.1% Progressive Disease 55.9% 78.9% Chi-square test p-value=0.0083
Post progression treatment
SAFETY
Conclusions Primary endpoint of a better OS estimate with regorafenib versus lomustine was met This was a large academic, multicenter, randomized trial in patients with relapsed glioblastoma reporting for the first time on regorafenib activity and efficacy Regorafenib adverse events were manageable and expected. Quality of life analyses are ongoing Regorafenib efficacy should be confirmed in a subsequent randomized phase 3 study
Nivolumab in Combination With Radiotherapy ± Temozolomide: Updated Safety Results From CheckMate 143 in Patients With Methylated or Unmethylated Newly Diagnosed Glioblastoma Michael Lim, 1,a Antonio Omuro, 2,a Gordana Vlahovic, 3 David A. Reardon, 4 Solmaz Sahebjam, 5 Timothy Cloughesy, 6 Joachim Baehring, 7 Nicholas Arthur Butowski, 8 Von Potter, 9 Ricardo Zwirtes, 9 Prashni Paliwal, 9 Michael Carleton, 9 John Sampson, 3,b Alba A. Brandes 10,b 1 The Johns Hopkins Hospital, Baltimore, MD; 2 Memorial Sloan Kettering Cancer Center, New York, NY; 3 Duke University Medical Center, Durham, NC; 4 Dana-Farber Cancer Institute and Harvard University School of Medicine, Boston, MA; 5 Moffitt Cancer Center and Research Institute, Tampa, FL; 6 University of California Los Angeles, Los Angeles, CA; 7 Yale School of Medicine, New Haven, CT; 8 University of California San Francisco, San Francisco, CA; 9 Bristol-Myers Squibb, Princeton, NJ; 10 AUSL-IRCCS Institute of Neurological Sciences, Bologna, Italy a Co-lead authors. b Co-senior authors.
S 1 2 Antigen release and antigen uptake Tumour cell Antigenpresenting cell Antigen-presenting cell migration and lymph drainage Cervical lymph node Glioblastoma tumour 5 4 Figure 1 Overview of the immune response and major immune checkpoint molecules in the immune cycle of glioblastoma. Antigens released from degenerating tumour cells are taken up by antigen-presenting Nature cells, Reviews microglia and Neurology macrophages (1). Antigens are trafficked to lymph nodes via migration of antigen-presenting cells, and via drainage through lymphatic vessels in the meningeal sinuses (2). In the lymphatic tissues, antigen presentation and T-cell priming takes place. This interaction is tightly regulated by a multitude of co-inhibitory (CTLA4) and co-stimulatory (CD80, CD86, CD28) immune checkpoint molecules, and could be modulated by specific therapeutic antibodies, such as the CTLA4 inhibitor ipilimumab (3). Activated T cells reach the tumour via the blood stream and migration through the blood brain or blood tumour barrier (4). Tumour-associated immunosuppressive factors, including immune checkpoint molecules, inhibit tumour cell destruction by T cells. PDL1 is expressed on tumour cells and microglia and inhibits T cells via binding to PD1. PD1 PDL1 inhibitors (for example, nivolumab, pembrolizumab) block this immunosuppressive mechanism and thereby increase tumour cell lysis by The inflammatory microenvironment in glioblastoma Interaction between T cell and tumour cell or antigen-presenting cell Tumour cell PD1 PDL1 inhibitor T-cell traff c with migration through the blood brain barrier and blood tumour barrier 3 Antigen presentation and T-cell priming CTLA4 inhibitor + T cell Microglia Antigen CD80/ 86 CD28 TCR CTLA4 MHC PDL1 PD1 Tight regulation of inflammatory processes in the CNS Low density of tumor associated lymphocytes in glioblastoma compared to brain metastases 1 Activation of immune system under investigation in gliomas: dendritic cells, vaccination, Immune-checkpoint inhibitors, CAR-T-cells Preusser et al, Nat Rev 2015
Cohorts 1c and 1d Study Design CheckMate 143: Nivolumab With RT ± TMZ in Newly Diagnosed GBM Newly Diagnosed GBM a Cohort 1c Part A (non-randomized): Any MGMT methylation status Part B (randomized to 1c or 1d): Unmethylated MGMT status Cohort 1d Part A (non-randomized); Part B (randomized to 1c or 1d): Unmethylated MGMT status Standard RT (60 Gy) b + Concurrent TMZ (75mg/m 2 daily) Nivolumab 3 mg/kg Q2W Adjuvant TMZ (150 200 mg/m 2 5/28 d for 6 cycles) Weeks 1 3 10 14 37+ Standard RT (60 Gy) b Nivolumab 3 mg/kg Q2W Treatment until: Confirmed disease progression Unacceptable toxicity Discontinuation due to other reason Follow-up: Safety for 100 days Progression Survival every 3 months Primary Endpoint: Safety and tolerability (CTCAE v4.0) Data Cutoff for Analysis: July 13, 2017
Safety Summary CheckMate 143: Nivolumab With RT ± TMZ in Newly Diagnosed GBM Grade 3 4 a AE, adverse event; SAE, serious adverse event; TRAE, treatment-related adverse event. a Per CTCAE v4.0.
Conclusions CheckMate 143: Nivolumab With RT ± TMZ in Newly Diagnosed GBM Nivolumab in combination with RT ± TMZ was well tolerated, with no new safety signals The use of TMZ in combination with nivolumab and RT did not lead to significant additional safety events, other than those known to occur with TMZ alone The cohort not receiving TMZ did not show any significant additional immune-mediated AEs The incidence of grade 3 4 neurological TRAEs was relatively low (< 5%) and consistent with our previous experience in GBM These results suggest that nivolumab in combination with RT and nivolumab in combination with RT and TMZ are safe for further clinical evaluation in patients with newly diagnosed GBM 24
EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) AMPLIFICATION RATES OBSERVED IN SCREENING PATIENTS FOR RANDOMIZED CLINICAL TRIALS IN GLIOBLASTOMA Martin J. van den Bent 1, Lisa Roberts-Rapp 2, Peter Ansell 2, James Lee 3, Jim Looman 2, Earle Bain 2, Christopher Ocampo 2, Kyle D. Holen 2, Erica J. Gomez 2, Andrew B. Lassman 4 1 Department of Neuro-Oncology, Erasmus MC Cancer Institute, Rotterdam, NL; 2 AbbVie Inc., North Chicago, IL, USA; 3 Abbott Molecular Inc., Des Plaines, IL, USA; 4 Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA esmo.org
EGFR signals EGFR abnormalities in glioblastoma EGFR amplification EGFR protein expression EGFR viii CEP 7 signals - Controversial association of EGFR abnormalities and prognosis - Treatment target for - EGFR viii: Rindopepimut vaccination: negative phase III trial - EGFR amplification: antibody-drug conjungate ABT-414/Depatux-m
EGFR tyrosine Kinase inhibitors are (almost) inactive in glioblastoma (apparently) irrespective of EGFR status
Antibody-drug conjugate Depatux-M (ABT-414)
INTELLANCE 1 Study Design M13-813/RTOG 3508, Phase II/III, 1L GBM Patient Population Histologically confirmed de novo GBM (primary) or gliosarcoma Tumor demonstrates EGFR amplification Chemoradiation therapy start within 7 wks of diagnosis Karnofsky performance score 70 1:1 Randomization Placebo-controlled N = 360 RT/TMZ RT/TMZ N = 360 RT/TMZ + depatux-m INTELLANCE 2 Study Design M14-483/EORTC-1410-BTG, Phase II, 2L GBM Patient Population Histological confirmed recurrent de novo (primary) GBM Tumor demonstrates EGFR amplification 1 line of chemotherapy WHO score 0-2 No prior EGFR- or EGFRvIII-directed therapy 1:1:1 Randomization Open-label N = 80 Arm 1: depatux-m + TMZ N = 80 Arm 2: depatux-m N = 80 Arm 3: Lomustine or TMZ
Study sites INTELLANCE 1 INTELLANCE 2
Pooled INTELLANCE 1/2 screening results ROW EGFRamplified Nonamplified Total Positive Africa 4 5 9 44% Americas 244 218 462 53% Asia 70 133 203 35% Europe 676 516 1192 57% Middle East 22 20 42 52% Oceania 78 104 182 43% Total 996 1094 2090 52%
EGFR amplification in glioblastoma EGFR amplification is present in 52% of patients with GBM Largest cohort ever screened (2090 patients) Lower EGFR amplification rate in patients with GBM from Asia (35%) INTELLANCE 1 and INTELLANCE 2 explore the antibody-drug conjugate depatuxizumab mafodotin (depatux-m, ABT-414) in newly diagnosed and recurrent glioblastoma
Take home messages - Regorafenib showed signs of activity in recurrent glioblastoma - Nivolumab in combination with RT ± TMZ is well tolerated - EGFR amplifications are a potential treatment target in glioblastoma, but are less common in the Asian patient population
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