Upload
phungtuong
View
213
Download
0
Embed Size (px)
Citation preview
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
Heinz Ludwig 2013 ©
Intratumor heterogenity and branched evolutionrevealed by multiregion sequencing
Gerlinger M et al., NEJM 2012
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
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 %
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
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
Heinz Ludwig 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.
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
Advances in breast cancer
� T-DM1
� Pertuzumab + Trastuzumab
� Tratstuzumab + Lapatinib
� Everolimus and Aromatase inhibitors
� Genome and transcriptome studies identify new BC subgroups
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
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.
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
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
Heinz Ludwig 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
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
Colorectal Cancer: Regorafenib, Afliberceptand Bevacizumab beyond progression improve
outcome
Regorafenib:
• oral multi-kinase inhibitor
• targets angiogenic, stromal and oncogenic RTKs
• VEGFR2-TIE2 tyrosine kinaseinhibition
Heinz Ludwig 2013 ©
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%)
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
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)
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
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)
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
Is the increase in PFS worth the effort?QoL decreases during Bevacizumab therapy (ICON 7 trial)
Stark D et al., Lancet Oncology 2013
Heinz Ludwig 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%)
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
Intraarterial infusion of p53 (Gendicine)results in tumor shrinkage
Li Y et al., ASCO abstract 2012
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
Heinz Ludwig 2013 ©
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%
Li Y et al., ASCO abstract 2012
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
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
Jänne PA et al., Lancet Oncology 2013
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
Selumetinib + Docetaxel improves PFS comparedto Placebo+ Docetaxel in kras mutated
relapsed/resistant NSCL
Jänne PA et al., Lancet Oncology 2013
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
Melanoma
Established treatments
� Ipilimumab
� Verumafenib
New drugs
� MEK inhibitor: Trametinib
� Programmed death-1(PD-1)
programmed death-1 ligand (PD-L1 )
Heinz Ludwig 2013 ©
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)
Heinz Ludwig 2013 ©
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
Heinz Ludwig 2013 ©
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%)
Heinz Ludwig 2013 ©
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