I tumori cerebrali

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

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

Regione del Veneto 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

REGOMA: a randomized, multicenter, controlled open- label phase II clinical trial evaluating

regorafenib activity in relapsed glioblastoma patients

Background

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

• 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

Regorafenib – a pan kinase inhibitor

• Stratification factors: center and surgery at recurrence

• Study location: 10 centers in Italy

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)

Regorafenib

160mg/die (3 weeks on, 1 week off)

R _{until PD} ^Treat

(RANO criteria)

1:1 Lomustine

110mg/m2 day1 (every 6 weeks)

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

Median OS months (95%CI)

6-month OS (95%CI)

12-month OS (95%CI)

Log-Rank p-value 1-side

Hazard Ratio (80%CI) Regorafenib 59 32 6.5

(5.6-12.0)

55.6 (40.9-68.0)

36.8 (22.2-51.4)

0.0284 0.64 (0.47-0.87)

Lomustine 60 41 5.5

(4.7-8.0)

43.6 (29.8-56.6)

12.7

(3.9-26.9)

Progression-free survival

Arm Total Failed

Median PFS, months (95%CI)

3-month PFS (95%CI)

6-month PFS (95%CI)

Log-Rank p-value

Hazard Ratio (95%CI) Regorafenib 59 52 2.0

(1.9-3.6)

44.1%

(31.2-56.2)

15.5%

(7.4-26.2)

0.0514 0.69 (0.47-1.01)

Lomustine 60 54 1.9

(1.8-2.1)

25%

(14.9-36.4%)

8.3%

(2.8-17.7%)

Response Rates

Chi-square test p-value=0.0083

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%

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

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

Nivolumab in Combination With

Radiotherapy ± Temozolomide: Updated Safety Results From CheckMate 143 in Patients With Methylated or

Unmethylated Newly Diagnosed Glioblastoma

1

The Johns Hopkins Hospital, Baltimore, MD;

Memorial Sloan Kettering Cancer Center, New York, NY;

3

Duke University Medical Center, Durham, NC;

Dana-Farber Cancer Institute and Harvard University School of Medicine, Boston, MA;

Moffitt Cancer Center and Research Institute, Tampa, FL;

University of California Los Angeles, Los Angeles, CA;

7

Yale School of Medicine, New Haven, CT;

University of California San Francisco, San Francisco, CA;

9

Bristol-Myers Squibb, Princeton, NJ;

AUSL-IRCCS Institute of Neurological Sciences, Bologna, Italy

aCo-lead authors.

bCo-senior authors.

The inflammatory microenvironment in glioblastoma

• 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

506 | SEPTEMBER 2015 | VOLUME 11 www.nature.com/ nr neurol

data suggest a correlation between treatment response and immune-related adverse events, although this associ- ation requires further investigation.⁴² Adverse effects are particularly common in patients treated with the CTLA4 inhibitor ipilimumab: severe cases of colitis, pneumoni- tis and hypophysitis have been reported, among other serious immune-related toxicities.^8,9,43–45 Patients receiv- ing ipilimumab monotherapy for melanoma were much more likely to discontinue treatment because of adverse events—such as diarrhoea, colitis, rash, or fatigue—than were patients treated with nivolumab (13.2% vs 5.1%, respectively). Combination therapy with nivolumab plus ipi limumab was associ ated with par ticularly high rate of discontinuation because of severe adverse effects (29.4%).⁴⁵

Adverse events have also been reported with the PD1 inhibitors nivolumab and pembrolizumab, although these agents seem to have a more favourable safety profile, perhaps suggesting a more restricted role of PD1 in inhibiting the immune response.8,10,11,30–32,46 Because of these experiences, detailed algorithms have been developed to manage specific immune-related adverse events—such as skin-related, gastrointestinal, hepatic and endocrine events—and these algorithms are now well established in clinical practice.⁴⁷

A key challenge in the development of immunother- apy for CNS tumours will be to balance the intensity of the immune response with the potential for inflamma- tory and autoimmune events, including autoimmunity directed at the brain (allergic encephalomyelitis).^46,48,49 Moreover, any increase in intracranial pressure and cere- bral oedema that is associated with enhanced inflamma- tory response against tumour manifestations, owing to effective immune checkpoint inhibition, could reduce tol- erability.⁴⁹ Of note, autoimmune events in the CNS have not been reported in the approximately 250 patients with brain metastases from melanoma who were treated with ipilimumab, though long-term follow-up data from such patients have not yet been published.^25,26,28

Biomarkers for response to checkpoint inhibition In several cancer types, including melanoma and lung cancer, expression of PDL1 in the tumour positively cor- relates with response to inhibitors of the PD1–PDL1 axis, although responses have also been observed in patients with PDL1-negative tumours and the true predictive role of this marker is under intense investigation.^10,50 Importantly, several immunohistochemical assays for the assessment of PDL1 expression exist and evaluation of PD1 as potential predictive biomarker will require Nature Reviews | Neurology Antigen release

and antigen uptake

Tumour cell

Antigen- presenting cell

Antigen-presenting cell migration and lymph drainage

Cervical lymph node

T-cell traff c with migration through the blood–brain barrier and blood–tumour barrier Antigen presentation and T-cell priming Interaction between T cell and tumour cell or antigen-presenting cell

Tumour cell

Microglia

Glioblastoma tumour

– – PD1–PDL1

inhibitor 1

3 4 5

2

Antigen CD80/ 86 CD28 TCR CTLA4 MHC PDL1 PD1

T cell

CTLA4 inhibitor – +

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 cells, microglia and 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 lymphocytes (5). Abbreviations: CTLA4, cytotoxic T-lymphocyte-associated antigen 4; MHC, major histocompatibility complex;

PDL1, programmed cell death 1 ligand 1; PD1, programmed cell death protein 1; TCR, T-cell receptor.

REVIEWS

© 2015 Macmillan Publishers Limited. All rights reserved

Data Cutoff for Analysis: July 13, 2017

Cohorts 1c and 1d Study Design

CheckMate 143: Nivolumab With RT ± TMZ in Newly Diagnosed GBM

Primary Endpoint: Safety and tolerability (CTCAE v4.0) Cohort 1c

Part A (non-randomized):

• Any MGMT methylation status Part B (randomized to 1c or 1d):

• Unmethylated MGMT status

Nivolumab 3 mg/kg Q2W

Standard RT (60 Gy)

+ Concurrent TMZ

(75mg/m

daily)

Adjuvant TMZ (150–200 mg/m

5/28 d

for ≥6 cycles)

Cohort 1d

Part A (non-randomized); Part B (randomized to

1c or 1d):

• Unmethylated MGMT status

Nivolumab 3 mg/kg Q2W

Standard RT (60 Gy)

Treatment until:

•Confirmed disease progression

•Unacceptable toxicity

•Discontinuation due to other reason

Follow-up:

•Safety for ≥ 100 days

•Progression

•Survival every 3 months

Weeks 1 3 10 14 37+

Newly Diagnosed GBM

Safety Summary

CheckMate 143: Nivolumab With RT ± TMZ in Newly Diagnosed GBM

AE, adverse event; SAE, serious adverse event; TRAE, treatment-related adverse event.

aPer CTCAE v4.0.

Grade 3–4

• 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

Conclusions

CheckMate 143: Nivolumab With RT ± TMZ in Newly Diagnosed GBM

24

esmo.org

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

EGFR abnormalities in glioblastoma

EGFR signals

CEP 7 signals

EGFR amplification EGFR protein expression EGFR vIII

- 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

INTELLANCE 2 Study Design

M14-483/EORTC-1410-BTG, Phase II, 2L GBM

1:1 Randomization Placebo-controlled

N = 360

Patient Population

RT/TMZ RT/TMZ

RT/TMZ + depatux-m Histologically confirmed

de novo GBM (primary) or gliosarcoma Tumor demonstrates

EGFR amplification Chemoradiation therapy start

within 7 wks of diagnosis

Karnofsky performance score

≥ 70

N = 360

1:1:1 Randomization Open-label Patient Population

N = 80 N = 80 N = 80

Arm 2: depatux-m

Arm 3: Lomustine or TMZ Arm 1: depatux-m + TMZ 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

Study sites

INTELLANCE 1

INTELLANCE 2

ROW EGFR- amplified

Non-

amplified 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%

Pooled INTELLANCE 1/2

screening results

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

Thanks for your attention!