Highlights in Oncology 31012013 - oncoconferences.ch · VTE: 5% vs 3% Diarhea: 10% vs 8% Asthenia: 6% vs 4% OS from start of first-line TX 23·9 vs. 22.5 months, p=0·17 (ML18147)

Heinz Ludwig 2013 ©

Highlights in Oncology 2012/13

Prof. Dr. Heinz Ludwig1. Medizinische Abteilung –Zentrum für Onkologie, Hämatologie und PalliativmedizinWilhelminenspital, 1160 WienE-Mail: [email protected]: www.onkologie.at


Intratumor heterogenity and branched evolutionrevealed by multiregion sequencing

Gerlinger M et al., NEJM 2012


Intratumor heterogenity and branchedevolution revealed by multiregion sequencing

Genome analysis of a single tumor specimen underesti mates tumorheterogeneity

Reconstructing tumor clonal architectures and the i dentification of commonmutations located in the trunk of the phylogenetic t ree may contribute to more robust biomarkers and therapeutic approaches.

Gerlinger M et al., NEJM 2012


Approval of Anticancer DrugsGeneric Name Trade Name Indications

Axitinib Inlyta Advanced kidney cancer

Vismodegib Erivedge Locally advanced basal cell cancer

Pertuzumab Perjeta HER2-positive metastatic breast cancer

Carfilzomib Kyprolis Second line treatment in multiple myeloma

Ziv-aflibercept Zaltrap In combination with FOLFIRI in metastaticcolorectal cancer

Enzalutamide Xtandi Metastatic castration-resistant prostate cancer

Regorafenib Stivarga Metastatic colorectal cancer

Ruxolitinib Jakavi Intermediate or high-risk myelofibrosis

Decitabine Dacogen AML

Brentuximabvedotin

Adcetris Hodgkin lymphoma and systemic anaplasticlarge cell lymphoma

Bosutinib Bosulif CML

Ponatinib Iclusig CML, ALL


Ponatinib is active in resistant CMLincluding T315 mutations

Ponatinib: orally active Bcr-Abl TKI effective against the T315I mutation

inhibits, on nanomolar scale, Src and Bcr-Ablkinases including many common imatinib resistant Bcr-Abl mutations.

Cortes JE et al., NEJM 2012


Ibrutinib rescues treatment resistant CLL

oral Ibrutinib, fixed doses 420mg or 840mg daily until PD

Ibrutinib: highly active

well tolerated

durable remissions in R/R

CLL including HR disease

Bryd J et al. ASH 2012, Abstract No 189

Treatment naive

Relapsed/refractory >= 2 prior TX

High risk

CR 10 % 3 % 0

PR 61 % 64 % 50 %


Ibrutinib in treatment naïve and relapsed/refractory and/or high risk CLL Patients

Response or Survival Outcome, %

Treatment-Naive Patients ≥ 65 Yrs of Age

(n = 31)

Relapsed/Refractory and High-Risk

Relapsed/Refractory Patients (n = 85)

ORR�CR�PR

681058

712

68

PR with lymphocytosis

13 18

SD 13 4

PD 0 2

Estimated 26-mo PFS

96 75*

Estimated 26-mo OS

96 83†

Byrd JC, et al. ASH 2012. Abstract 189*P = .0256†P = .0937


Ibrutinib has significant activity in patients withrelapsed/refractory B-Cell Malignancies

Ranjana HA et al., JCO 2013

3922PR

148CR

%No.Best response – different dose levels

53ASCT

2715Radiotherapy

4525Anthracycline based

8447Alkylator based

9352Rituximab

3 (1-10)Median No. (range)

%No.Prior therapy

74Waldenström macroglobulinemia

74Marginal zone/mucosal-associated lymphoid tissuelymphoma

137DLBCL

169Mantle-cell lymphoma

2916CLL/SLL

2916Follicular lymphoma

%No.Histologic subtype


Ibrutinib is cytotoxic to myeloma and potentlyenhances bortezomib and lenalidomide

activities through NF- κB

10µM Ibrutinib for 48h – significant cell death 7-46% in primary MM

cells

Ibrutinib augments cytotoxicactivity of lenalidomide and bortezomib in primary MM cells

Rushworth SA et al., Cellular Signaling 2013


Blinatumomab targets CD19and rescues patients with resistant ALL

Nagorsen D & Baeuerle PA, Experimental Cell Research 2011

Blinatumumab: monoclonal antibody, bi-specific T-cell engager (BiTEs); directs immune system to act against tumor cells; target s CD19 antigen on B cells.


Blinatumomab induces a high CR rate in relapsed/refractory B-precursor ALL

Results: (> 2 cycles)

Hematological CR 26/36 (72%)

Molecular CR 24 (66%)

ORR:

First relapse 20 (95%)

Later relapse 6 (40%)

OS: 14.1 mos. in responders

6.6 mos. in non responders

36 Patients

Blinatumomab (5µµµµg/m2/day week 1, therafter 15µµµµg/m2/day continous

infusion for 28 days, x 2 (2 week TX free interval)

Top MS et al., abstract 614, ASH 2012

Toxicity

Cytokine release syndrome

CNS events (seizures,

encephelopathy, all of which

resolved)

Pyrexia, headache, tremor,

fatigue


Advances in breast cancer

� T-DM1

� Pertuzumab + Trastuzumab

� Tratstuzumab + Lapatinib

� Everolimus and Aromatase inhibitors

� Genome and transcriptome studies identify new BC subgroups


Breast cancer subgroups defined bygenomic and transcriptomic characterisation

Curtis Ch et al., Nature 2012

997 discovery and 995 validation setbreast cancer tissue of patientswith long time follow up


New insights into breast cancer pathology

ZNF703, a luminal B specific driverTranscriptional corepressor, does not bind directly to DNA regulates transcription through recruitment of HDACs to gene promoters. Regulates cell adhesion, migration and proliferation.

Somatic deletion events affecting key subunits of t hePP2A holoenzyme complex and MTAP, which have previously been under-explored in breast cancer

CAN (copy number abnormality) rare but relevant

IGF1R, KRAS and EGFR amplifications

CDKN2B, BRCA2, RB1, ATM, SMAD4, NCOR1 and UTX homozygous deletions.


Exemestane + Everolimus vs. Exemestane + Placebo in patients resistant to Anastrozole or

Letrozole

724 patients, HR+, HER2- refractory

to anastrazole or letrozole (recurrent during

or <12 months after adjuvant TX, or PD

during or <1 month after hormone TX for

MBC

other previous HT or chemotherapy allowed

Parameter Exemestane+ Everolimus

Exemestane + Placebo

P value

RR 7.0 0.4 <0.001

PFS 10.6 4.1 0.001

Deaths 10.7% 13%

Stomatitis 8% 1%

Exemestane 25mg daily, Everolimus 10mg daily

Baselga J et al., San Antonio Breast Cancer Conference 2011


Letrozole + Temsirolimus vs. Letrozole + Placebo in locally advanced or MBC

1112 patients, HR+, HER2- AI naïve, advanced

(stage IIIA and B) MBC, or had adjuvant AI

therapy, discontinued > 12months

40% had prior adjuvant hormone therapy

Parameter

Letrozole + Temsiroli

mus

Letrozole+ Placebo

P value

RR 17.0% 17.0% ns

PFS 8.9 mos 9.0 mos ns

Letrozole 2.5mg daily, Temsirolimus 30mg (oral) 5 day s q 2 weeks

Wolf AC et al., JCO 2013


Letrozole + Temsirolimus vs. Letrozole + Placebo in locally advanced or MBC,

stratification by age ( ≤ 65 vs. > 65 years)

Parameter

Letrozole + Temsirolim

us

Letrozole + Placebo

P value

Age ≤ 65 years

9.0 mos 5.6 mos 0.009

Age > 65 years

8.5 mos% 10.1 mos 0.17

Wolf AC et al., JCO 2013

≤ 65 years

> 65 years


Anaplastic Oligodendroglioma

Codeletion of 1p/19q associated with longer OS with combined radio PCV-CHT2 studiesCaimcross GJ abstract JCO 2012Van Den Bnet MJ abstract JCO 2012

Previously reported: Better outcome inMGMT and IDH mutated patients

Promoter methylation of the MGMT genepredicts for superior OS with temozolomidcompared to RT

No methylation predicts for RT sensitivity


Combined Chemo-Radiotherapy prolongs OS in Esophageal Cancer

vanHagen P et al., NEJM

Carboplatin and Paclitaxel

Radiation dose: 41.4 Gy, 23 fractions of 1.8 Gy each , 5 fractions/week, starting on day 1of first CHT cyc le


Colorectal Cancer: Regorafenib, Afliberceptand Bevacizumab beyond progression improve

outcome

Regorafenib:

• oral multi-kinase inhibitor

• targets angiogenic, stromal and oncogenic RTKs

• VEGFR2-TIE2 tyrosine kinaseinhibition


Regorafenib compared to BSC extends survival in metastatic CRC

OS not correlated with any of thecommon risk factors

1052 Patientsresistant/relapsing < 3 months after last therapy, pre-exposed to Pyrimidin, Oxaliplatin, Irinotecan, Bevacizumab

if kras wild type pretreatment with Cetuximab or Panitumomab

Regorafenib 160mg daily + BSC or placebo + BSC

Grothey A et al. CORRECT trial, Lancet 2012

OS 6.4 vs. 5.0 months, p=0.0052

AE 93% vs. 61%G 3 hand-foot skin reactions (17%), fatigue (48.1%) , diarrhea (16.7%),hypertension (36.7%), rash and desquamation (29.6%)


Aflibercept

Aflibercept:• Fusion protein• Inhibitor of VEGF1 and 2• Binds to VEGF-A,

VEGF-B and PIGF*

TruncatedVEGFR1

Fc

TruncatedVEGFR2

*Phosphatidylinositol-glycanbiosynthesis class F protein anchors proteins to cell surfaces


Aflibercept + Irinotecan improves OS in Oxaliplatin pretreated patients with CRC

� ORR: 19.8% vs. 11.1%, p=0.0001

� PFS: 6.9 vs 4.67 months, p<0.0001

� OS: 13.5 vs 12.1 months, p=0.00329

� AE: 99.2% vs 99.7%, G3/4 AE: 83.5% vs 63.5%

Typical for anti VEGF therapyVanCutsem E et al., JCO 2012


Bevacizumab beyond progression

Bevacizumab:• Angiogenesis inhibitor• Slows down growth of new blood

vessels• Monoclonal antibody • Inhibits VEGF-A

920 patients with CRC with PD

up to 3 months after

discontinuing first-line CHT +

Bevacizumab

Second-line CHT+ Bevacizumab

Second line CHT

R


Bevacizumab beyond progression extends survival

Bennouana J et al., Lancet Oncology 2013

OS: 11.2 vs- 9.8 months, p=0.0062PFS: 5.7 vs. 4.1 months, p<0·0001

AE grade 3-5: Bleeding: 2% vs. <1%GI perforation: 2% vs. <1%VTE: 5% vs 3%Diarhea: 10% vs 8%Asthenia: 6% vs 4%

OS from start of first-line TX23·9 vs. 22.5 months, p=0·17

(ML18147)


Enzalutamide improves Survival in men with chemotherapy treated prostate cancer

Arbiraterone in men with castration-resistant

PC who have not received prior CHT

PFS: 11.1 vs 5.6 months

OS: strong trend for improved OS

Less pain, functional declineRyan CJ et al., JCO 2012 Abstract LBA4518

Alpharadine

Alpha emitting radium 223

OS: 14.9 vs 11.3 monthsParker C et al., ESMO 2012 Abstract 898PD


Enzalutamide improves Survival in men with chemotherapy treated prostate cancer

OS: 18.4 vs 13.6 months, p<0.001)

AE, grade 3: 45.3% vs 53.1%

But more fatigue, diarrhea, hot flashes,

musculoskeletal pain, headache

Cardiac disorders 6% vs 8%

Hypertension: 6.6% vs 3.3%

Scher HI et al., NEJM 2012

Enzalutamide:

• Androgen receptor antagonist

• treatment of metastaticcastration-resistant PC


Anti-angiogenic first line therapy increases PFS in ovarian cancer

Authorstudy

# of pts.

TreatmentPFS

Comments+BEV Placebo/

control

Aghajanianet al.

OCEANS

484 Gemcitabine+Carboplatin +/- BEV or Placebo

12.4 mos 8.4 mos OS: not given

p<0.001

Perren et al.

ICON7

1528 CarboplatinAUC5/6Paclitaxel 175mg/m²+/- BEV 7.5mg/kg q3w 18 cycles

24.1 mos 22.4 mos OS: 36.6 mos vs. 28.8 mosp=0.098

p=0.04

High risk patients:

18.1 mos 14.5 mos

Burger et al.

GOG-0218 Trial

1873 Paclitaxel 175mg/mCarboplatinAUC 6, cycles 1-6BEV cycles 2 -22, q 3w

11.2 mos/ 14.1 mos(BEV only)

10.3 mos OS:p-value not significant

p=0.16 and p<0.001 (BEV only)


Anti-angiogenic second line therapy increases PFS in ovarian cancer

Author/study

# of patients

TreatmentPFS

p-value Response Rate+BEV

Placebo/ control

Second line

Pujade-Lauraineet al.

AURELIA

361CT alone or with BEV (10 mg/kg q2w or 15 mg/kg q3w on CT)

6.7 mos 3.4 mos p<0.00130.9% vs. 12.6%

p=0.001


Is the increase in PFS worth the effort?QoL decreases during Bevacizumab therapy (ICON 7 trial)

Stark D et al., Lancet Oncology 2013


Regorafenib after failure to Imatinib orSunitinib extends PFS in GIST

Demetri GA et al., Lancet Oncology 2013

240 patients screened, 133 were randomized to Regorafinib and 66 to BSC,Crossver ti Regorafenib after failure to BSC was allowed (85%)


Head and neck cancer

Drivers: Activating mutations: MET, PI3K

Loss of function: p53, p16, PTEN

HPV status important

Li Y et al., ASCO abstract 2012

Stratification/selection for HPV status necessary

Multiple arteries perfuse H&N tumors (thrombosis)

Single-gene driver mutations are rare in HNC and loss of suppressor events are common

Multiple targets within signaling pathways are bein g identifiedcombination of biologics with traditional (effectiv e) chemotherapy is warranted


Intraarterial infusion of p53 (Gendicine)results in tumor shrinkage


Gendicine: a non replication competent adenovirus carrying a functional p53 gene

60% of SCC H&N cancers carry p53 mutations

Gendicine induces apoptosisImmune responseReduces VEGF production

1012 Virus particlesApplication: intratumural, intraarterial, Intraveno us

P53 expression detectable 3 hrs after administration and up to 14 days


Head and neck cancer

99 patients with H&N cancer, stage III-IV

� Intraarterial rAdV-p53 q 3 d x 6

� CHT for SCC: Oxaliplatin d 1, 200mg/m2 Bleomycin 8mg/ m2, d 2,3,6

Metothrexate 30mg/m2 d 1, 8

� CHT for Adeno Ca: Oxaliplatinn 200mg/m2, da, 5-FU 200 mg/m2 d 1,3

and Cyclophosphamide 400mg/m2, d 2,8

Treatment CRR ORR OS@ 3 years

rAd-p53 16.7% 54.5% 60.6%

rAd-p53 + CHT 48.5% 88.6% 82.9%

CHT 17.3% 51.6% 58.1%



Kras mutations found in 20-30% of patientswith NSCLC

Jänne PA et al.; Lancet Oncology 2013

Patients with kras mutations:Do not responde to EGFR inhibitorsNo/little benefit from adjuvant TX

Selumetinib – selective MEK inhibitor


KRAS-mutant NSCLC

• KRAS is the most frequently mutated oncogene in NSCLC outside Asia– Mutations in ~20% of

tumors

• Effectiveness of chemotherapy may be reduced in patients with KRAS-mutant NSCLC

• KRAS-mutant NSCLC patients do not respond to EGFR targeted therapies

Jänne PA et al., Lancet Oncology 2013

EGFR

KRAS

ALKFusions

Unknown

HER2

BRAF

P1K3CA AKT1

MAP2K1NRAS

ROS1 fusionsKIF5B-RET

EGFR

KRAS

ALKFusions

Unknown

HER2

BRAF

P1K3CA AKT1

MAP2K1NRAS

ROS1 fusionsKIF5B-RET


Selumetinib

Selumetinib: potent and selective allostericinhibitor of MEK 1/2 )

• KRAS mutation Hyperactivation of MAPK/ERK pathway

Tendency for greater sensivitity to Selumetinib in BR AF/RAS-mutant celllines

Ras

Raf

MEK 1/2

ERK 1/2

Selumetinib



Phase II, double-blind, randomized, placebo-controlled, multi-center trial; NCT00890825

Patients

Locally advanced or metastatic NSCLC (stage IIIB-IV)

Failed first-line therapy

Confirmed KRASmutant tumor

WHO PS 0-1

Excluding symptomaticbrain metastases

Endpoints

Primary: OS

Secondary:• PFS• ORR• Duration of response• Change in tumor size• Alive and progression-free

at 6 months• Safety and tolerability

Selumetinib75 mg BID

+ Docetaxel75mg/m²

Placebo BID + Docetaxel

75mg/m²

Randomization (1:1 ratio)

•Docetaxel was administrated every 21 days; selumetinib/placebo administrated daily

•Following completion of patient enrollment, the primary endpoint was changed from PFS to OS, without changing the sample size.

•OS analysis was planned for after approx. 58 events; HR 0.57, 80 % power assuming a 1-sided 10 % significance level


Selumetinib + Docetaxel improves PFS comparedto Placebo+ Docetaxel in kras mutated

relapsed/resistant NSCL



Crizotonib (Xalkori ®) shows high activity in ALK positive NSCLC and anaplastic large cell

lymphoma

Crizotinib:•Small molecule inhibitor of

ALK and c-Met

• ALK (anaplasticlymphoma kinase) and

• ROS1 inhibitor• found in 2% of NSCLC(c-ros oncogene1, receptor tyrosine kinase )

Shaw AT et al., JCO 2012 Abstract 7508


Crizotinib improves survival in ALK positive NSCLC

Shaw AT et al., Lancet Oncology 2011

ALK positive (n=82)OS@ 2 years: 55%

ALK negative (n=30)OS@ 2 years: 12%

23 ALK positive NSCLC treated in 2 or 3rd line TX with Crizotonibvs.

23 ALK positive patients treated with various 2nd line T X


Response to Crizitonib in ALK positive NSCLCand toxicity data

149 ALK positive patientsORR 61%Time to response: 7.9 weeksDuration of response: 49.1 weeksPFS: 9.7 months

Camidge DR et al., Lancet Oncol 2012


Melanoma

Established treatments

� Ipilimumab

� Verumafenib

New drugs

� MEK inhibitor: Trametinib

� Programmed death-1(PD-1)

programmed death-1 ligand (PD-L1 )


The MEK inhibitor Trametinib results in increased PFS compared to CHT

Most frequent AEs: •skin rash, diarrhea, edema, hypertension,•fatigue

Trametinib

inhibits MEK1 and MEK2

Robert C et al., ASCO 2012; JCO, 2012

METRIC study: 322 patients with BRAFV600E/K mutant advanced or metastatic melanoma

Trametinib (2mg, d) vs. Dacarbacine orPaclitaxel

PFS: 4.8 mos vs. 1.4 mos (ITT population)OS: HR: 0.53 (95% CI 0.30–0.94; p=0.0181)


Anti–PD-L1 Antibody results in tumor regression in patients with advanced cancer

or tumor cell

Tumors induce tolerance by nduction of ligands engging re ceptorsleading to inhibition of T cell function

or tumor


Anti–PD-L1 antibody results in tumor regression in patients with advanced cancer

anti–PD-L1 antibody (0.3 -10mg/kg), i.v, 14 d, 6 wk cyclesfor up to 16 cycles

MelanomaCR or PR in 17%, 9/52 patients Duration of TX: 12 wks (2-111)

NSCLC

ORR: 10% 5/49 patients

Adverse Events: fatigue, infusion, reactions, diarr hea, arthralgia, rash, nausea, pruritus, and headache. Gade 3 or 4: 9 of 20 7 (9%)



Envisioning Cancer Care in 2030ASCO

� An immense amount of data of an individual patient and his tumor will be collected and correlated with myriads of data from simi lar cases

� Only IT based systems will be able to document, store and comparethe data

� Only IT based systems will be able to draw appropriate co nclusionsfor clinical managment of individual patients

� Combination targeted therapy will be the standard o f care for most cancers

� Routine quality measurement and improvement will be embedded firmly in oncology practice

� Public reporting of oncologists’ quality of care wil l be routine� Other health care providers will play a large role in routine oncology

care

Documents

Highlights in Oncology 31012013 - oncoconferences.ch · VTE: 5% vs 3% Diarhea: 10% vs 8% Asthenia: 6% vs 4% OS from start of first-line TX 23·9 vs. 22.5 months, p=0·17 (ML18147)