SUCCESS AND FAILURES OF COMBINED MODALITIES IN GBM:OLD PROBLEMS AND NEW DIRECTIONSDR MUKTI

Do not repeat the tactics which have gained you one victory, but let your methods be regulated by the infinite variety of circumstances.

(Sun Tzu 6.28)

Chinese General, Military strategist, and Philosopher of ancient China

Author of The Art of War

A widely influential work of military strategy that has affected both western and eastern philosophy.

GLIOBLASTOMA MULTIFORME (GBM)

GBM is an aggressive intracranial tumor characterized by local and distant brain relapse despite aggressive therapy.

Current standard treatment includes surgical resection RT with concurrent Temozolomide adjuvant Temozolomide (TMZ)

CHALLENGES IN THE MANAGEMENT OF GBM Extent of Resection

Blood-brain barrier(BBB) penetration

Tissue Sensitivity

Therapeutic Resistance

CHALLENGES IN THE MANAGEMENT OF GBM

Extent of resection: Eloquent location:

Unacceptable levels of morbidity and mortality if removed.

Infiltrative nature of tumours': Virtually impossible to resect all viable tumor.

Blood-brain barrier(BBB)penetration: Many therapeutic agents, regardless of their tumor selectivity and potency, cannot cross the BBB.

CHALLENGES IN THE MANAGEMENT OF GBM

Tissue sensitivity: Cytotoxic agents, Radiation and many systemic DNA damaging chemotherapies, can induce significant acute toxicities.

Profound late effects including cognitive dysfunction.

Therapeutic resistance: GBMs appear to contain substantial radio-resistant and chemo-resistant populations of tumor cells, as well as significant intratumoral heterogeneity at the molecular level

Why are we presenting this paper? Anything new to learn or the same old

story….. To summarize the key elements of combined modality therapy.

To summarize selected examples of successes and failures along the path to enhance OS.

To discuss emerging opportunities for new t/t combinations.

Finally, we will present a series of open questions for consideration in the future for the design of new t/t regimens.

To begin with a Case Discussion….

• Impaired speech• Change in personality/ emotion/

behaviourCHIEF

COMPLAINTS

• Gadolinium contrast enhanced MRI-Left frontal lobe SOL

• Enhanced on T2. Marked edemaDIAGNOSIS

• awake craniotomy with speech mapping during the procedure.

• Radical but subtotal resection was performed.

SURGERY

• Glioblastoma multiforme, Grade IV of left frontal lobe HPR

Treatment….Received RT and concurrent TMZ, follwed by adjuvant TMZ for 6 months.

1st relapse approximately 6 months after t/t completion, which occurred within the original T1 post-contrast enhancing site of disease.

Treated with Irinotecan with Bevacizumab.

Post treatment scan 6 months later revealed near-complete resolution of T1 post-contrast enhancing disease but a persistent FLAIR abnormality.

Treatment for Relapse….Within 2 months he experienced a 2nd relapse.

Was treated with Lomustine chemotherapy but progressed immediately after initiation of therapy, again at the primary site.

Enrolled in Phase I clinical trial testing a novel DNA repair inhibitor with reirradiation (NCT02202993).

3rd relapse within 6 months, which was outside of both the initial and repeat irradiation treatment fields and succumbed to his disease shortly thereafter.

What we have learnt from this case???

This case summarizes many of the key features of GBM and the profound difficulties.

Local recurrences occur in nearly all patients.

Recurrences are often found near or within the T1 post contrast enhancing regions of disease.

Antiangiogenic agents can reduce T1 post contrast enhancing disease.

But infiltrative disease in the FLAIR abnormality is unaffected.

Primary site of relapses persist despite local interventions, including high-dose re-irradiation and cytotoxic chemotherapies.

Interval between each relapse narrows.

Even if local control can be sustained, distant relapses eventually would occur, presumably via migration of isolated tumor cells along white matter tracts.

For these reasons, it is likely that no single t/t would cure GBM, and multimodality approaches are needed.

COMBINED MODALITY THERAPY (CMT)

Combined modality therapy is defined as “the treatment of a disease or condition by several different means simultaneously or sequentially.”

Cornerstone of oncology t/t ,with notable success.

Combined modality therapy has 2 major goals:Enhancement of tumor control by the use of multiple, non overlapping or partially overlapping t/t

modalities.Attenuation of t/t related Side Effects, by decreasing the intensity of each therapy with in a

combination regimen

C M T: SurgerySurgical resection is the first, and most critical element of multimodality therapy.

Surgery provides a definitive HPR, and it is well established that the extent of resection correlates with OS.

Early studies simply classified the extent of GBM resection into 3 categories: Gross total Subtotal Partial resection.

EVIDENCE…Lacroix et al: a direct correlation between OS and the extent of T1 contrast enhancing

tumor resection > 98% vs < 98% resection: 4.2 month Median Survival advantage *

Subsequent study extended this OS benefit to subtotal resections as low as 78% of the tumor volume. Maximum benefit if resection >95% or more. **

*Lacroix M, Abi-Said D, Fourney DR, et al: A multivariate analysis of 416 patients with glioblastoma multiforme: Prognosis, extent of resection, and survival. J Neurosurg 95(2):190-198, 2001.

* *Sanai N, Polley MY, McDermott MW, et al: An extent of resection threshold for newly diagnosed GBM. JNeurosurg115(1):3-8, 2011 10.

EVIDENCE…Li et al: more extensive resections, which include the regions of FLAIR abnormality may provide a further OS benefit.complete resection of T1 contrast enhancing tumor(100%) still had a median survival of only 15.1 months, suggesting that local control is only one of many barriers to achieving durable disease control.*

Kelly et al: revealed isolated tumor cells in the MRI defined abnormalities on T2-weighted sequences, which typically are well beyond the resection cavity. **

*Li YM, Suki D, Hess K, et al: The influence of maximum safe resection of GBM on survival in 1229 patients: Can we do better than gross- total resection?J Neurosurg:1-12,2015

**Kelly PJ, Daumas-DuportC, Scheithauer BW, etal: Stereotactic histologic correlations of computed tomography-and magnetic resonance imaging-defined abnormalities in patients with glial neoplasms. Mayo ClinProc62(6):450-459,1987

C M T: RADIATION THERAPY - EVIDENCE Brain Tumor Study Group evaluated the use of BCNU and RT (Whole Brain RT 60 Gy), either alone or in combination vs supportive care alone.*

◦ RT vs supportive care alone: OS Benefit (35 vs 14 weeks, respectively)*◦ BCNU did not significantly improve OS as a single agent or when combined with RT. *

Subsequent Brain Tumor Study Group trial: RT with Semustine**

RT doses of 60 Gy to whole Brain was used. * WalkerMD, Alexander Jr. E, Hunt WE, et al: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg 49(3):333-343, 1978. **Walker MD, Green SB, Byar DP, et al: Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 303(23):1323-1329, 1980

Subsequent studies indicated majority of glioma recurrences after WBRT occurred within 2 cm of the primary tumor site. Use of smaller RT fields to the tumor bed, which were not associated with higher rates of failure in

comparison to patients treated with WBRT.

Use of 3DCRT => IMRT are used.

o Walkeretal established a dose-effect relationship in RT for GBM 60 Gy was required for maximal disease control

However, dose escalation > 60 Gy: No clear OS benefit.

Doses as high as 90 Gy to the primary site: nearly universal local recurrence. There is still a chance that dose escalation in the era of IMRT and concurrent TMZ may shift the balance towards a relevant benefit with RT dose escalation

CMT: CHEMOTHERAPY-EVIDENCEInitially: Nitrosureas in GBM were negative.

RT + Chemotherapy: trend towards improved OS.

TMZ as the first chemotherapy to show a clear OS benefit in GBM.

For any systemically administered agent: Blood Brain Barrier. Only small molecules < 500 daltons in size lipid soluble, can readily penetrate CNS.

BBB-associated efflux transporters

Brain tumors themselves can disrupt the BBB

SUCCESSS STORIES-TMZ+RTEarly 1990s: Adjuvant PCV chemotherapy was beneficial after RT for high-grade gliomas.

oOS benefit for both Grade III and IV gliomas, but statistical significance in Grade III only

BCNU in combination with (6-Thioguanine and 6Mercaptopurine): Negative

TMZ emerged as the drug of choice for this disease in the 1990s.

THE ORIGIN OF TMZEarly 1980s novel series of Imidazotetrazinones - Potent antitumor activity in preclinical models.

Mitozolomide was the most potent compound in this series: some clinical activity but profound thrombocytopenia Bone marrow toxicity was attributed to DNA cross-linking action associated with the chloroethyl

substituent of mitozolomide

TMZ differed by a methyl group at this position which abrogated DNA cross-linking activity.TMZ demonstrated substantial in vivo antitumor activity in preclinical models excellent oral bioavailability.Phase I clinical trial (Cancer Research Campaign in the UK): established the safety of a 5-day TMZ

dosing regimen in monthly cycles. Subsequent clinical studies evaluated the pharmacokinetics profile and the maximum tolerated dose

of TMZ in patients with a range of solid tumors.

Integration of TMZ into the GBM Therapeutic RegimenPhase II trials in predominantly recurrent glioma patients: favorable responses with TMZ as a monotherapy.

Yung et al: pivotal, randomized Phase II trial recurrent glioma patientsTMZ vs Procarbazine.Statistically significant difference in 6 month PFS: 21% vs 9% (No clear OS benefit)

1999: TMZ received FDA approval in Refractory Anaplastic Astrocytoma.

RTOG 9813 : TMZ in the upfront setting for anaplastic astrocytoma. .

RTOG 9813 (Paper presented at: 2015 ASCO Annual Meeting, 2015)

TMZ in the upfront setting for anaplastic astrocytoma.

Phase III trial, randomized

(RT with TMZ) vs (RT with nitrosurea – BCNU)RT 59.4 GyTMZ dose: 5-day , monthly/ BCNU dose: 3 days every 8 weeks Concurrently with RT and in the adjuvant setting, for a total of 12 months.

BCNU was also tested in combination with TMZ, but this regimen was found to be too toxic.

This trial was closed early because of poor accrual and did not show a clear winner,

But it did show that the RT with TMZ was better tolerated than RT with BCNU.

No difference in OSIDH mutation was associated with better survival outcome

Stupp regimen-LandmarkBrock et al, Phase I trial: continuous dosing of TMZ over 6-7 weeks primarily in glioma patients ;

1998 Maximum tolerated dose of 75 mg/m2/d was established, 2-fold greater exposure of the drug compared to the 5-day dosing regimen in monthly cycles acceptable levels of reversible myelosuppression. Favorable responses were observed in glioma patients (41%, and an additional 25% had stable disease).

Phase II trial by Stupp et al: in newly diagnosed GBM (JCO, 2002)Stupp regimen: 75 mg/m2/d, 7-days of the week during the 6 weeks of RT, followed by TMZ

monotherapy,150-200 mg/m2/d for 5 days, every 28 days, for 6 cycles. Well-tolerated, median survival was 16 months.

Phase III trial of the EORTC – NCI of Canada Trials Group (NEJM, 2005): 573 patients, 85 centresRT alone vs RT with Stupp regimen.OS was superior in the chemoradiotherapy group (Median Survival 14.6 vs 12.1 months; 2 year OS 26.5 vs 10.4 months)

NEW STANDARD OF CARE ESTABLISHED FOR THIS DISEASE.

TMZ5-3-

(methyltriazen-1-yl) imidazole-

4carboximide at physiologic pH

Methyldiazonium Cation

Transfers Methyl

Groups To DNA

N7- and N3-methyl guanine (meG)

Base Excision Repair (Non

Lethal)

Mismatch repair (MMR) “futile cycles” excises the newly synthesized strand,

with persistence of the original O6-meG

Mispair with thymidine instead of cytosine

O6-meG (can only be repaired by the MGMT enzyme)

Only 5%-10%

FUTURE DIRECTIONSTMZ : greatest improvements in OS for GBM over last several decades.

RTOG 0525 tested a Dose Dense (Days 1-21 every 28 days) TMZ regimen compared to the standard schedule => showed no additional benefit.

60% of Pt with MGMT unmethylated GBM, there is great interest in developing novel methods to sensitize these tumors to this treatment.

O6-benzylguanine is an inhibitor of MGMT activity, and preclinical studies suggested that it could be administered with TMZ to resensitize tumor cells to alkylator therapies.

While this approach showed initial promise in recurrent glioma, other studies indicated that myelosuppression limited the clinical utility of this combination.

Other approaches for TMZ sensitization: including BER inhibitors.

TMZ analogues are in development and may overcome resistance in MGMT unmethylated tumors. Eg. the bifunctional DP68 and monofunctional DP86 imidazotetrazines were recently described as TMZ analogues with antiglioma activity independent of MGMT and MMR status

SUCCESS STORIES - ANTITUMOUR VACCINEGlioblastoma : relatively anti-immunogenic malignancy because of the immunosuppressive adaptations

levels of T-cell responsiveness and monocyte or dendritic function, decreased IgG or IgA immunoglobulins, and an increase in T-reg cell fraction. major histocompatibility complex (MHC) molecule down regulation,

production of immuno-inhibitory cytokines,

infiltration of immunosuppressive lymphocytes,

impairment of T-cell function due to unfavorable factors such as hypoxia.

Despite this, promising treatment modality with favourable early results from clinical trials

Immunotherapy with radiation may enhance the efficacy

Antitumor vaccines are particularly attractive because of their ability to induce potent antitumor immunity with long lasting immunologic memory while sparing normal tissues.

antitumor vaccine strategies: peptide vaccines, heat shock protein (HSP) vaccines, dendritic cell (DC) vaccines, whole tumor vaccines, human umbilical vein endothelial cell vaccines.

RINDOPEPIMUTMost successful: RINDOPEPIMUT ( Celldex Therapeutics),

Antitumor Peptide Vaccine synthetic mutated EGFRvIII peptide conjugated to the immune adjuvant keyholelimpet hemocyanin.

EGFRvIII is found in approximately 25%-30% of GBMs and appears to be an independent negative prognostic factor in GBM.

This constitutively active mutated EGFRvIII represents an attractive vaccine target because of its extracellular epitope location and specificity for brain tumors.

In Phase II testing, the Rindopepimut vaccine was well tolerated in patients with resected EGFRvIII-positive GBM Median OS - 21.8-26.0 months, 3-yearOS of 26%.

RINDOPEPIMUT It produced robust antiEGFRvIII immune responses despite TMZ-induced lymphopenia.

EGFRvIII was routinely eliminated in post treatment tumor samples obtained at recurrence, suggesting that this antitumor vaccine can eradicate its target cell population.

Recently results from the ReACT trial (NCT01498328) presented the first randomized immunotherapy trial to demonstrate a survival benefit in GBM patients.

RINDOPEPIMUT – ReACT trial:Bevacizumab-naïve patients with relapsed EGFRvIII-positive GBM (previously treated with conventional chemoradiation)

Bevacizumab and Rindopepimut with GM-CSF or placebo vaccine.

Rindopepimut arm well tolerated. median OS 11.3 months (vs 9.3 months) (HR- 0.53, P = 0.014). Persistent “tail” present on the OS curve for the patients receiving Rindopepimut 2-year OS was 24% compared with 0% in the control arm.

Advantage: long-term PFS, objective response rate, and steroid requirement.

It was also shown that higher anti-EGFRvIII antibody titres predicted for improved OS(HR= 0.17, P=0.0001).

RINDOPEPIMUTfurther validation in ACT IV (NCT01480479)

Phase III double-blinded trial in the upfront setting

EGFRvIII-positive GBM following total or subtotal resection and RT with TMZ.

Randomly assigned to Rindopepimut Or control keyhole limpet hemocyanin along with adjuvant TMZ.

However, the trial was recently discontinued after interim analysis showed no significant benefit of the vaccine on OS

Final results are pending

FUTURE DIRECTIONSDC vaccination: harvesting DCs from peripheral blood and culturing them with tumor-specific antigen(s) to induce DC maturation before reinfusion back into the patient.

Phase I: autologous DC vaccine (ICT-107) pulsed with cancer stem cell-targeted antigens, investigators observed an impressive median OS of 38.4 months and 2-year PFS of 43.8% in 16 newly diagnosed GBM patients.

subsequent Phase III randomized, double-blinded, trial is planned for patients with newly diagnosed GBM but has not yet opened enrollment (NCT02546102).

DCs pulsed with cytomegalovirus phosphoprotein65(pp65)RNA, which is expressed in more than 90% of GBM specimens, showed improved PFS and OS when the patients were preconditioned with the tetanus or diphtheria toxoid before the DC vaccine.

preconditioning with a potent recall antigen may help to improve the antitumor response with DC vaccines. Cytomegalovirus pp65 DC vaccine would be tested in a Phase II randomized, doubleblinded trial (ATTAC-II),

which is not yet open for enrollment (NCT02465268).

FUTURE DIRECTIONS: HSPHSPs : stress-induced molecular chaperones, aid in protein folding and transport.

HSP peptide - 96 ( HSPPC-96) interacts with antigen presenting cells and leads to presentation of gp-96 chaperoned proteins by Class I and II MHC.

Phase I dose-escalation trial: Recurrent GBM - treated with an autologous HSPPC-96 vaccine derived from surgically resected tumor samples. Immune responders (11 of 12 patients treated) had a median survival of 47 weeks, compared with 16 weeks for the

non responder.

Phase II study: newly diagnosed GBM - HSPPC-96 was delivered following standard treatment with radiation and TMZ. -> reported a median OS of 23.8 months.Low PD-L1 expression Median OS: 44.7 months High PD-L1 expression Median OS: 18.0 months suggesting that systemic immunosuppression driven by PD-L1 may play an important role in mitigating vaccine efficacy.

This vaccine approach is now being studied in a Phase II trial in recurrent, resected GBM with Bevacizumab compared with bevacizumab alone

FAILURE STORIESlate 1980s and early 1990s consensus:

1. RT was the standard of care for GBM after resection, and it was clear that2. local recurrence was the major barrier. 3. RT dose-escalation attempts were ineffective,

Thus a focus was directed to combining agents with RTHypoxic sensitizers, S-phase sensitizers, and targeted agents.

Almost all of these studies were negative, leading many to believe that radiosensitizers were “dead in the water.”

FAILURE STORIESHypoxic tumor cell radiosensitizers eg. imidazoles, RSR13 (efaproxiral) and tirapazamine.

RTOG 94-17 tested Tirapazamine in a single-arm Phase II trial for newly diagnosed GBM, with no clear benefit in PFS or OS compared to historical controls.

Halogenated pyrimidines were also tested as GBM radiosensitizers. incorporated into the DNA of dividing cells in place of thymidine and the incorporated molecules are more

susceptible to DNA breaks caused by RT-induced free radicals.

tested clinically: bromo-deoxyuridine and iodo-deoxyuridine. Negative in GBM and anaplastic gliomas.

Motexafin Gadolinium is a reactive oxygen species (ROS) generator, which appears to selectively concentrate into tumor cells, showed promise in early-phase GBM clinical trials. However, a single-arm Phase II trial failed to show a benefit compared to historical controls.

Hypoxia in tumors is an established phenomenon, but it is heterogeneous and fluid in nature within the tumor.

This raises a number of questions

1. Will sensitization of this fraction of the tumor lead to a clinical benefit? ◦ bromo-deoxyuridine and iodo-deoxyuridine are meant to sensitize replicating tumors cells but largely

would spare tumor cells in G1 and G2/M

2. What is the magnitude of this effect?

3. What is the consequence of sparing tumor cells outside of S-phase? o ROS generation can tip the balance to induce cell death, but the amount that is needed for selective

tumor cell kill is poorly established

3. Is there really a therapeutic index with this approach?

THE INITIAL PROMISE-BEVACIZUMABBevacizumab: recombinant humanized monoclonal antibody -> all isoforms of VEGF -> decreases tumor vascularization -> inhibits tumor growth.

Initial Phases I and II trials of Bevacizumab demonstrated objective tumor responses.

However the first randomized placebo-controlled Phase III trial of Bevacizumab combined with chemotherapy in previously treated metastatic breast cancer patients failed to show improvement in PFS or OS.

Breakthrough Phase III study in metastatic colorectal cancer patients showed a 4.7 month increase in OS

BEVACIZUMABConcern in Intracranial tumors: perceived risk of cerebral haemorrhage

(based on a case report of a fatal intracranial haemorrhage from a previously undiagnosed brain metastasis while on bevacizumab).

However, a report of patients with recurrent GBM treated with bevacizumab and irinotecan showed acceptable safety and excellent efficacy.

First Phase II Clinical Trials by Vredenburgh: Bevacizumab + Irinotecan in recurrent high-grade glioma.

6 month survival of 77% (57% of patients having at least a partial response to treatment) Established the safety of bevacizumab in recurrent glioma with only 1.5% of patients experiencing

intracerebral hemorrhage.

Single agent Bevacizumab in Recurrent GBM

Friedman et al

Bevacizumab alone (A)or in combination with Irinotecan (B)

estimated 6-month PFS: 42.6% (A) vs 50.3% (B)Median OS: 9.2 months (A) vs 8.7 months (B)

Kreisl et al

Single agent Bevacizumab followed by Bevacizumab + Irinotecan at tumour Progression

6-month PFS : 29% (95% CI, 18% to 48%)Median PFS: 16 weeks (95% CI, 12 to 26 weeks)6 month OS - 57% (95% CI, 44% to 75%) Median OS - 31 weeks (95% CI, 21 to 54 weeks)

FDA granted accelerated approval to single agent

Bevacizumab for patients with recurrent GBM in 2009

FAILURE STORIESNewly diagnosed GBM: In Feb, 2014, results from 2 Phase III trials

(New England Journal of Medicine)

Avastin in Glioblastoma (AVAglio) trial

RTOG 0825.

February 20, 2014 Vol. 370 No. 8

AVAGLIORT + TMZ +

Avastin/ Placebo

TMZ (adj) + Avastin/

Placebo (6 cycles)

Maintenance Avastin/ Placebo

RTOG 0825 RT + TMZ TMZ (adj) (12 cycles)

Maintenance Bevacizumab/ Placebo

FINDINGS: AVAGLIO:Median PFS 10.6 months vs. 6.2 months

Overall survival did not differ significantly between groups

Stratified hazard ratio for progression or death 0.64 (p<0.001)

Grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%

Maintenance of baseline quality of life and performance status

RTOG 0825:Progression-free survival was longer in the bevacizumab group (10.7 months vs. 7.3 months)

No significant difference in the duration of overall survival (15.7 and 16.1 month)

Hazard ratio for progression or death, 0.79

Modest increases in adverse events

Increased symptom burden, worse quality of life, and a decline in neurocognitive function

It is unclear exactly why prolongation of median PFS did not translate into an improvement in OS in these studies.

• Patient crossover diluted a bevacizumab mediated survival advantage

• PFS advantage was observed because of the ability of bevacizumab to decrease tumor blood-vessel permeability which would effectively limit the appearance of progression on MRI while having little effect on true tumor progression.

Despite the lack of survival benefit observed in these trials, bevacizumab may still prove to have a role in select populations with newly diagnosed GBM.

ongoing studies of combination therapy in the upfront setting:

The Avastin + Radiotherapy in Elderly Patients with Glioblastoma ( ARTE ) study (NCT01443676) To explore the efficacy of bevacizumab combined with RT compared to

RT alone in the treatment of newly diagnosed GBM in the elderly

Phase II study: Novo TTF system in combination with TMZ, RT and Bevacizumab in newly diagnosed, unresectable GBM (NCT02343549).

portable battery or power-supply operated device which produces changing electrical fields,

applied to the head of the patient by electrically-insulated surface electrodes

TTFields for 12 months for an average of 18 hours per dayMay take a treatment break for a total of 3 days per month

Bevacizumab Therapy for Radiation Necrosis

The etiology of radiation necrosis is still under investigation,

But recent evidence supports a role of VEGF as a contributor to radiation necrosis pathogenesis.

First report to describe the efficacy of bevacizumab for radiation necrosis was published by gonzalezet al.

Other studies found: (BootheD et* al and TorcuatorR et al**)o Bevacizumab is an effective treatment for radiation necrosis o consistently showed reduction in steroid requirement o improvement in MRI abnormalities.

*BootheD et al:Bevacizumabasatreatmentfor radiationnecrosisofbrainmetastases post stereotactic radiosurgery. Neuro Oncol15(9):1257-1263,2013

**TorcuatorR,ZunigaR,MohanYS,etal:Initialexperiencewith Bevacizumab treatment for biopsy confirmed cerebral radiationnecrosis. J Neurooncol94(1):63-68,2009

Levin VA et al: Randomized double-blind placebo- controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system. Int J Radiat Oncol Biol Phys 79(5):1487-1495, 2011

14 patients with cerebral radiation necrosis

Bevacizumab or placebo administered at 3-week intervals.

Improvement in neurologic symptomsAll Bevacizumab treated patients None of the placebo treated patients

These findings suggest that bevacizumab should be first line therapy in the treatment of histologically confirmed radiation necrosis.

Other Angiogenesis Inhibitors as Radiosensitizers Monoclonal antibodies targeting VEGF : bevacizumab,

Small molecule inhibitors of VEGF : vandetanib and sorafenib,

Protein kinase C beta inhibitors: enzastaurin

Integrin inhibitors: cilengitide Rationale:

◦ drugs like bevacizumab may improve tumor oxygenation through vascular normalization. By supplying the tumor with increased oxygen, the cytotoxic effects of radiation amplified◦ radiation-induced VEGF secretion may contribute to radio- resistance of GBM through the reduction of the damaging effect of RT on endothelial cells

Phase I study: sorafenib + RT +TMZ in newly diagnosed high-grade glioma found significant dose-limiting toxicities with the addition of sorafenib including thrombocytopenia, diarrhea, hypercholesterolemia.

Hottinger AF etal: BrJCancer110(11):2655-2661,2014

Vandetanib: potentiate the cytotoxic effect of ionizing radiation by reducing tumor hypoxia through vascular normalization◦ Phase II trial by Lee et al: no significant prolongation of OS when compared to the control

arm

Cilengitide: selectively inhibits the αvβ3 and αvβ5 integrins◦ CENTRIC Phase III trial: MGMT methylated GBM were randomized to RT +TMZ with or

without cilengitide -> No clinical Benifit

EMERGING CMT OPPORTUNITIESPromising new therapeutic strategies for GBM:

The 2 examples are: Rationally Designed Radiosensitizers Immune Check Point Modulation.

Radiosenitizers: demonstrate extraordinary selectivity and potency for various DNA repair pathway protein targets.

Immune Check Point Modulation: based on recent leaps in immunotherapy

PARP INHIBITORSoPARP inhibitors (PARPi) block Base Excision Repair => increased single-strand breaks (SSBs).

oUnrepaired SSBs are eventually converted to double-strand breaks (DSBs) in S-phase,

oPARPi are thought to preferentially damage actively replicating tumor cells.

oSynthetic lethal interaction with Hr-deficient Breast Cancer cells.

oSynergistic interactions between PARPis and TMZ, and also RT.

oSensitize both MGMT methylated and unmethylated GBM.

oControversy exists regarding whether a clinically effective dose of both drugs can be administered.

oAmerican Brain Tumor Consortium (ABTC) recently tested the addition of the PARPi, VELIPARIB (ABT-888), to the Stupp regimen. o This study found that concurrent administration of Veliparib with standard RT and daily TMZ was not tolerable

as a result of hematologic toxicity

DNA Damage Checkpoint InhibitorsThe most exciting developments for GBM radiosensitization are related to the development and clinical testing of small molecules targetting key DNA damage response checkpoint proteins, including ATM, ATR, Chk1, Chk2, and Wee1.

These pathways may be hyperactivated in GBM stem cells, and there are now a wealth of highly selective inhibitors targeting each of these proteins .

The ATR/Chk1 and Wee1 axes mediate the IR-induced S- and G2/M checkpoints, respectively,

targeting these proteins may offer an inherent therapeutic index over normal tissue

ABTC 1202 is testing this concept in newly diagnosed GBM, in which the Wee1 inhibitor MK-1775, is being added to the Stupp regimen

Immune Checkpoint ModulationFocused on 2 T-cell surface proteins,

1. cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4)2. programmed cell death protein 1 (PD-1) along with its ligands (PD-L1 and PD-L2).

CTLA-4 interrupts CD28 signaling

inhibits early steps of T-cell activation

dampening antigen-specific T-cell activation

PD-1 binding blocks activation

of T cell (Later stage)

Suppression of T-cell effector

function

Acts within peripheral

organs

Anti-CTLA-4 (ipilimumab)

anti-PD-1 Ab(nivolumab & pembrolizumab)

potentiating the immune response

enhance the antitumor immune responses

intratumoral T-cell infiltration

increase expression of Fas and intercellular adhesion molecule-1

on tumor cellsIncreasing quantity & diversity

of intracellular peptide

Increase production & presentation of tumor antigens

Induction of MHC class I expression

IONIZING RADIATION

Combining radiation with either peripheral tumor vaccines or immune checkpoint blockade is more effective than either treatment alone in murine brain tumor models.

clinical trials combining immunotherapy and radiation for GBM. NCT02311920: Newly Diagnosed Glioblastoma: Randomized after concurrent chemoradiation to

Treatment With TMZ Alone/TMZ + Nivolumab/ TMZ + Nivolumab & Ipilimumab CheckMate 143 trial: recurrent GBM randomized to nivolumab/ nivolumab + ipilimumab/

bevacizumab (NCT 02017717).CheckMate 498: unmethylated MGMT GBM nivolumab vs TMZ in combination with RT in the upfront

setting (NCT02617589).

Multiple other strategies incorporating immunotherapy are undergoing clinical investigation, including GBM vaccines and adoptive T-cell transfer therapy with chimeric antibody receptor.

Open Questions for Consideration

1. Hypofractionation—Better or Worse for Combined ModalityTherapy??

2. Can Poor BBB Penetration of Small Molecule Radiosensitizers Be Overcome??

3. Tumor Heterogeneity—Does One(Treatment) Size Fit All??

HYPOFRACTIONATION: in Elderly Hypofractionated treatment has been shown to provide similar outcomes to standard fractionation in elderly patients with GBM who receive radiation alone.

1. Malmstrom A, Lancet Oncol 13(9):916-926, 2012: Elderly (> 60 years); TMZ (200mg/ m2; 5 days q28; 6 cycles) vs RT_std (60 Gy/30 #) vs RT_hypo (34 Gy/ 10 #) RT_std => poor outcomes, especially in patients older than 70 years. Both TMZ and RT_Hypo should be considered as standard treatment options in elderly patients (spl >70 years) MGMT promoter methylation status might be a useful predictive marker for benefit from TMZ.

2. Roa W J Clin Oncol 22 (9):1583-1588, 2004 : elderly (>60 years) standard RT (60 Gy in 30 fractions) or a shorter course of RT (40 Gy in 15 fractions) no difference in survival reasonable treatment option for older patients with GBM.

3. Roa W, J Clin Oncol 33(35):4145-4150, 2015 : optimal radiotherapy regimen for elderly and/or frail patients frail = 50 years ; KPS of 50% - 70%; elderly and frail = 65 years ; KPS 50% - 70%; elderly = 65 years KPS 80% - 100% 25 Gy / 5#/ 1 week vs 40 Gy /15#/ 3 weeks No differences in OS, PFS, and QOL

HYPOFRACTIONATION: with RADIOSENSITIZERHypofractionation + Radiosensitizers: safe ?? effective ??Phase I trial: Hypo_RT 52.5 Gy / 15 fractions + peri-RT TMZ

no instances of irreversible grade 3 or higher acute toxicity (J Clin Neurosci 21(4):633-637, 2014 )

In a Phase II: Hypo_ high-dose IMRT with concurrent TMZ -> adjuvant TMZ necrosis was noted in nearly half of the treated patients in the high-dose field and also in the subventricular zone

=> deterioration in the performance status of long-term survivors. (Int J Radiat Oncol Biol Phys 88(4):793-800, 2014)

NCIC CTG CE.6/EORTC 26062–22061/TROG 08.02: Phase III≥65 yrs of age, ECOG 0-240gy/15 RT vs 40gy/15 RT with concomitant TMZ + monthly adjuvant TMZ until progression or 12 cyclesFinal results will add to our knowledge on the optimal treatment of these patients

Ongoing Phase I: Novel radiosensitizer MIBEFRADIL with hypofractionated RT in recurrent GBM (NCT02202993) safety

HYPOFRACTIONATION: fraction size

Little is known about how radiation fraction size impacts the antitumor immune response

Combining stereotactic or hypofractionated radiation regimens with immunotherapy have resulted in dramatic clinical responses

◦ Hiniker SM, Chen DS, Reddy S, et al: A systemic complete response of metastatic melanoma to local radiation and immunotherapy. Transl Oncol 5(6):404-407, 2012

◦ Postow MA, Callahan MK, Barker CA, et al: Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 366 (10):925-931, 2012 ◦ SeungSK,CurtiBD,CrittendenM,etal:Phase1 study of stereotactic body radiotherapy and interleukin-2—Tumor and immunological

responses.SciTranslMed4(137):137ra74,2012

Preclinical data also appear to support a hypofractionated approach when compared to single fraction treatment

Current hypofractionation regimens for GBM: ◦ 2.67 Gy/fraction ◦ This is considerably less than what has been shown to be effective in the preclinical immunotherapy studies.

Ongoing Phase I/II trial at Stanford: (NCT01120639) ◦ in patients with GBM using concurrent TMZ and RT ◦ doses ranging from 5-8 Gy/fraction◦ to define safe dose levels that can then be translated into studies with immunotherapy.

POOR BBB PENETRATION - SMALL MOLECULE RADIOSENSITIZERS>98% of drugs with molecular weights as low as 500 Da cannot pass through the BBB. This significantly limits the ability to deliver radiosensitizing agents to the brain.

Strategies : Direct Intratumoral Delivery via convection enhanced delivery, ultrasound-mediated delivery,

and peptide carrier-mediated delivery.

Convection enhanced delivery (CED): catheter placed directly into the tumor under stereotactic guidance -> drug infused into the brain tissue under positive pressure. This produces high local concentrations of drug while overcoming the toxicities of systemic.

This technique has been studied in Phase I-III clinical trials for malignant glioma and is also being evaluated for use in children with diffuse intrinsic pontine glioma ( NCT 015 02917).

Advantage: allows for delivery of novel drug formulations such as nanoparticle-encapsulated radiosensitizers.

Nanoparticles offer the potential for delayed drug release within the tumor and interstitium while avoiding toxicities associated with systemic delivery.

TUMOR HETEROGENEITY—DOES ONE (TREATMENT) SIZE FIT ALL?Analysis of The Cancer Genome Atlas (TCGA) identified 4 subtypes of GBM based on gene expression–based molecular classification. IDH1 mutation and alterations of platelet derived growth factor A (Proneural) EGFR amplification (Classical) NF1 loss (Mesenchymal) Expression of neuron markers such as NEFL, and GABRA1 (Neural)

The link between treatment response in these 4 molecular subtypes is not completely understood.Proneural subtype is also associated with 1p and 19q co-deletion and TP53 mutations.

This subtyping is useful because of its prognostic ability and the relative ease of testing.

Attempts to block EGFR signaling with small molecule inhibitors and monoclonal antibodies. Though limited success has been observed to this point.

Recent clinical success with Rindopepimut. Published reports of Phase III clinical trials in the recurrent (ReACT trial) and upfront settings (ACT IV trial) are pending.

Vaccine targeting mutant IDH1 was shown to induce antitumor immunity - future target for combination therapy with radiation.

CONCLUSIONSLittle change in OS for GBM

Combination of a variety of therapeutic strategies are necessary to substantially improve OS for this disease

Surgery – extent of resection: cornerstone

RT is likely to remain the backbone of adjuvant treatment - GBM Doses, fields, and RT modalityRadiosensitizer

TEMOZOLOMIDE (Stupp regimen)

New developments in multiple therapeutic realms hold great promiseNovel targets and targeted therapySpecial devices

Specific molecular subtypes of GBM – find out the best specific approach

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