Targeted therapies beyond the EGFR gene mutation therapies beyond the EGFR gene mutation ... Phase...
Transcript of Targeted therapies beyond the EGFR gene mutation therapies beyond the EGFR gene mutation ... Phase...
SAMO Interdisciplinary Workshop onChest & Head/Neck Tumors
Targeted therapiesbeyond the EGFR gene mutationbeyond the EGFR gene mutation
Enriqueta Felip
Vall d’Hebron University Hospital, Barcelona; Spain
Lucerne, 19-20 November 2010
Lung cancer: personalized treatment
Lung ADC from East-Asian never-smokers
52 resected lung ADC from never-smokers analyzed for EGFR,KRAS, NRAS, HRAS, HER2; BRAF, ALK, PIK3CA, TP53 andLKB1
41 tumors EGFR muts, 3 EML4-ALK, 2 HER2, 1 KRAS, all mutsmutually exclusivemutually exclusive
4 tumors contained PIK3CA muts, always together with EGFRmuts
Majority of ADC from never-smokers can be defined molecularlyby targetable oncogenic mutant kinases
Sun JCO 10
Targeted therapiesbeyond the EGFR gene mutation
EGFR monoclonal antibodies
Anti-angiogenesis inhibitors
Pan-HER irreversible inhibitors
ALK inhibitors ALK inhibitors
c-MET inhibitors
KRAS inhibitors
PARP inhibitors
EGFR monoclonal antibodiesCetuximab
Lancet 09
• RR shows benefit for cetuximab + 9% (increase by 53%)
• PFS by independent review did not reach statisticalsignificance
EGFR monoclonal antibodies: cetuximab1st line NSCLC: taxanes/carbo +/- cetuximab
Taxane / carbo +Taxane / carbo
Taxane / carbo +
cetuximabTaxane / carbo
RR by independentreview (IRRC)
26% 17%
PFS by IRRC
PFS by Investigator
4.4 mo
4.3 mo
4.2 mo
3.8 mo
MS in pts receiving cetuximab / CT, 9.7 mo, compared to 8.4 mo withCT alone (HR 0.89, p=0.17)
Lynch JCO 10
EGFR monoclonal antibodiesCetuximab
FLEX trial:
– Pts included express EGFR by IHC
– Similar survival benefit with cetuximab across differenthistologic subtypes
– Pts developing rash, better outcome– Pts developing rash, better outcome
– KRAS not predictive marker of cetuximab benefit
At present cetuximab is not approved for NSCLC treatment byregulatory agencies
Accurate identification of pts likely to benefit from cetuximabneeded
Anti-angiogenesis inhibitorsBevacizumab
Phase III trials in non-SCC (E4599 and AVAiL, Sandler NEJM 2006, Reck
Ann Oncol 2010)
Outcome PC/Bev 15
N: 417
PC
N: 433
CG/Bev 7.5
N: 345
CG/Bev 15
N: 351
CG/plac
N 347
ORR, % 35* 15 38* 35* 22
MedianPFS, mo
6.2*; HR 0.66 4.5 6.8*; HR 0.75 6.6*; HR 0.85 6.2
MedianOS, mo
12.3*; HR 0.79 10.3 13.6; HR 0.93 13.4; HR 1.03 13.1
*= p value < 0.05
Bevacizumab combined to platin-based CT isa treatment option in PS 0-1 pts with non-SCC histology
Anti-angiogenesis inhibitorsBevacizumab
Bevacizumab treatment duration:
– Should bevacizumab be continued when CT stops?
– Should bevacizumab be continued after 1st line treatmentPD?
In EGFR-mut pts, potential contribution of adding bevacizumabto EGFR TKIs (those with concomitant T790M?)
Identification of predictive markers needed
Phase II pazopanib trialOral angiogenesis inhibitor targeting VEGFR, PDGFR, c-KIT
TEXT
Patients included at 8 sites in the United States and Spain
Altorki JCO 10
Pazopanib trial: patient demographics
Patients (N = 35)
Median age, years (range) 64 (49 - 81)
Sex, n (%)FemaleMale
22 (63)13 (37)
Tumour histology, n (%)Adenocarcinoma 22 (63)AdenocarcinomaSquamous cell carcinoma
Other
22 (63)4 (11)9 (26)
Clinical disease stage, n (%)IAIBIIAIIB
19 (54)14 (40)1 (3)1 (3)
• Median duration of pazopanib therapy, 16 days(range: 3 to 29 days)
Altorki JCO 10
Tumor volumetric response
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• 85.7% pts achieved reduction in tumor volume
• RR according to RECIST: 3 PRs; 8.6%
• Phase II randomized trial of pazopanib/pem vs cis/pem in 1stline closed for higher toxicity in the pazopanib/pem arm
• Monotherapy; EORTC maintenance trial; French adjuvant trial
Patients
Pan-HER irreversible inhibitors
HKI-272 EGFR/HER2
BIBW2992 EGFR/HER2
PF-299804 EGFR/HER2/HER4
Wong CCR 09
HKI-272
EGFR mutations found in the 6 NSCLC pts with SD > 24 wks
BIBW2992 irreversible inhibitor EGFR/HER2
Phase III BIBW2992 vs placebo in pts failing CT and EGFR TKIs
− BIBW2992 improves PFS but not OS
Study enriched for EGFR-mut pts
– Median time of previous EGFR TKI treatment, 10 mo; 45% CR/PR
– >10 mo OS in both arms (pts in 3-4th line)
Majority of pts received treatment at PD (68% in BIBW2992 / 79% inplacebo)
Active drug, negative trial:
– BIBW2992 now being analyzed in 1st line EGFR-mut pts
– Other studies needed (pts with HER2 expression?)
Miller Presidential Symposium ESMO 2010
PF299804 irreversible inhibitor EGFR/HER2/HER4
2nd line (ASCO 2010)
– PF299804 vs erlotinib in pts with NSCLC after CTfailure
• 188 pts randomized
• PF299804 significantly longer PFS vs erlotinib• PF299804 significantly longer PFS vs erlotinib(p=0.017)
1st line in EGFR-mut pts (Mok ESMO 2010)
HER2 in lung cancer
• HER2 IHC: 1+ in 20%, 2+ in 15%, 3+ in 5%• HER2 FISH+: 2% / mut: 2-3%• Positivity depends on histology: ADC 15-40%, SCC 0-5%
• Two studies using trastuzumab in HER2+ (IHC +1,+2,+3); majorityIHC+1, trend to better results in IHC+3IHC+1, trend to better results in IHC+3
• Pt with HER2 amplification, no EGFR/HER2/KRAS mut; responseto PF-299804 (irreversible inhibitor of EGFR, HER2 and HER4) andtrastuzumab (Kelly JCO 10)
• Anti-HER2 treatments should be analyzed in selected groups of pts(HER2 FISH+, mut)
ALK inhibitors
EML4-ALK fusion gene detected in subset of NSCLC pts,promising candidate for therapeutic target (Soda Nature 2007)
EML4-ALK
• EML4-ALK is oncogenic both in vitro and in vivo and ALKinhibitors are effective in preclinical models (Soda PNAS USA 2008)
• EML4-ALK-positive tumors more frequent in never/lightsmokers and ADC pts (Koivunen CCR 2008)
• EML4-ALK positivity associated to resistance to EGFR TKIs(Shaw JCO 2009)
• EML4-ALK mutually exclusive of EGFR, KRAS and ERBB2muts (Sun JCO 2010)
EML4-ALK
• 105 ALK-positive NSCLC pts, determined by FISH, treated with PF-02341066 (crizotinib, inhibitor of ALK and MET/HGF) (ESMO 2010; Kwak
NEJM 10)
– Median number of prior regimens, 3
– Most pts ADC (96%) and never-smokers (76%)
– RR 57%– RR 57%
– PFS: 9.2 months
– Good safety profile, GI toxicities the most frequent AES
• Ongoing phase III study in 2nd line vs CT (PROFILE 1007); phase IIIstudy in 1st line planned / pending activation
• Secondary mut in one pt who had PD after ALK-inhibitor (Choi NEJM 10)
Clinical trials in pts ALK+ translocationExperience at Vall d’Hebron Hospital
Phase III trial of PF-02341066 vs doc/pem in pts with ALK+
14 pts screened:
– 9 pts ALK-
– 3 pts insufficient tumor tissue
– 2 pts ALK+ (14%):
• 2 pts included (14%) in study and randomized to CT arm
Clinical trials in pts ALK+ translocationExperience at Vall d’Hebron Hospital
Phase III trial of PF-02341066 vs doc/pem in pts with ALK+
Clinical characteristics of the 2 ALK+ pts
Man, 67 yrs old, former smoker. Diagnosed October 2009 ADC Man, 67 yrs old, former smoker. Diagnosed October 2009 ADC
stage IVA, EGFR-wt
Received carbo/paclitaxel (PR). At PD, randomized to CT
Woman, 39 yrs old, never-smoker. Diagnosed September 2009
ADC stage IVA, EGFR-wt
Received 6 cycles cis/pem (PR). At PD, randomized to CT
Clinical trials in pts ALK+ translocationExperience at Vall d’Hebron Hospital
Phase II trial of PF-02341066 in pts with ALK+
31 pts screened
– 21 pts ALK-
– 7 pts insufficient tumor tissue
– 3 pts ALK+ (9.7%):
• 2 pts included in study (6.5%) and treated with crizotinib
• 1 pt not included, no evaluable disease
Clinical trials in pts ALK+ translocationExperience at Vall d’Hebron Hospital
Phase II trial of PF-02341066 in pts with ALK+
Clinical characteristics of 2 ALK+ pts included
Man, 52 yrs old, never-smoker. Diagnosed June 2009 ADC stage IVBEGFR-wt
Started cis/pem (PR), at PD erlotinib (early PD), carbo/pac (PD). MayStarted cis/pem (PR), at PD erlotinib (early PD), carbo/pac (PD). May2010 - bone, liver and pleural disease; started crizotinib achieving PR(ongoing)
Woman, 63 yrs old, never-smoker. Diagnosed November 2009 ADCstage IV B (brain, liver), EGFR-wt
Started pem/pazopanib (SD). June 2010-liver and lung PD; startedcrizotinib achieving PR (ongoing)
Research Project at Vall d’Hebron Hospital
Oncology Department / Pathologist Department / Molecular lab
Tumor samples from 110 NSCLC patients with advanceddisease diagnosed in our Institution (2007-09) and screened forEGFR-mut, and being tested for:
– ALK by FISH (using a break-apart probe to the ALK gene– ALK by FISH (using a break-apart probe to the ALK gene[Vysis LSI ALK Dual Color, Abbott Molecular], FISH+ cases:
rearrangements detected in > 15% of cells, definition of Shawet al)
– ALK by IHC using the cell-signaling antibody
On-site pathologists were blinded for results provided by Pfizer ofpts referred for possible inclusion in the Crizotinib trials
ALK: challenges
Diagnosis
– Know the incidence of ALK+ in Europe and the clinicalcharacteristics of pts with this translocation
– Gain experience for immediate implementation of ALKdetermination
– Evaluate IHC and precise link to FISH results
– Standardization and quality control of these techniques
Share information among research groups
Treatment
– ALK inhibitors in combination with other agents
– Treatment at PD
IPI-504, Hsp90 inhibitor
• Heat-shock protein 90 (Hsp90) regulates stability of keyproteins through its role as a protein chaperone
• Phase II in 76 pts previously treated with EGFR TKIs and withtumor sample available (Sequist JCO 10)
− 7% PR− 7% PR− 10% PR in EGFR-wt and 4% in EGFR-mut with acquiredresistance− in 3 ALK+ pts, 2 PR and 1 prolonged SD > 7 mo, no previousALK inhibitor treatment
• Preclinical studies showed that ALK is Hsp90 client
Importance of tissue availabilitywhen analyzing targeted therapies
C-MET receptor inhibitors
• MET amplified, mutated, and overexpressed in many tumors
− Associated with worse prognosis in NSCLC
• MET activation, implicated in resistance to EGFR inhibition
• MET inhibitors in NSCLC: ARQ 197 and MetMAb (ESMO 10)
Erlotinib/placebo verlotinib/ARQ 197
Erlotinib/placebo verlotinib/MetMAb
Met inhibitor TKI, daily PO Mab, Iv q 3W
Trial phase, design Randomised Phase II, Placebo Randomised Phase II, Placebo
N pts 167 128
Eligibilitty > 1 prior line 2nd-3rd line
Tissue required
End-point PFS PFS-all pts
PFS in “Met High” pts
ARQ 197-209
Phase II MetMAbMet-high: > 50% + cells with 2+ or 3+ staining intensityTissue evaluable from 95% of pts54% of pts Met-high
KRAS
Targeting mutant KRAS in NSCLC
• Most commonactivatedoncogene
• Currently no
Mutations in NSCLC cell lines
PDGFR
PIK3CA
ALK
MET
ROS
EGFR
ERBB2
BRAF
MEK1
• Currently notherapiesspecificallytargeting rasmutations
Sharma Nat Rev Cancer 10
PI3K and MEK inhibitiona rational strategy for targeting KRAS mutant NSCLC
• Scientific rationale
– ras activates both PI3Kand Raf/MEK/ERKpathways
– extensive cross-talk
PP
PP
RasPI3K
RTK
GF
PTEN– extensive cross-talk
between pathwaysS
ca
ff
ol
dRaf
MEK
ERK
Cell proliferationCell survivalInvasiveness
Enhanced metabolism
PDK1
mTORS6K
AKT
Battle trial
• 255 pts, new biopsy for analysis of 11 markers of 4 pathways /treatment with sorafenib, vandetanib, erlotinib/bexaroteneaccording to result
• Repeat biopsies for biomarkers; safe and feasible
• 105 pts received sorafenib / 59 erlotinib− Pts with KRAS-mut treated with sorafenib: 61% diseasecontrol at 8 weeks− Pts with KRAS-mut treated with erlotinib: 31% disease controlat 8 weeks
Sorafenib in KRAS-mut pts?
Kim AACR 2010; Herbst ASCO 2010
PARP inhibitors
• Why PARP inhibitors may be important in NSCLC− Subgroup of pts low levels of BRCA1 (Rosell PLoS One 09)
− BRCA1 crucial in DNA repair− Cis induces DNA damage / crucial agent in NSCLC− Synergy platinum+PARP inhibitors
• PARP inhibitors in clinical trials: BSI-201, olaparib, veliparib…− Phase II randomized trial cis/gem +/- BSI-201 in 1st line finished
• Potential role− In combination with platinum-doublets− In selected pts with low BRCA1 expression− Phase I-II trial olaparib/gefitinib in EGFR-mut (ETOP trial; PI R Rosell)
Targeted therapiesbeyond the EGFR gene mutation
• Relevance of personalized treatment in NSCLC− Establish the molecular profile of the tumor− Availability of tumor tissue, essential
• Targeted therapies beyond EGFR mut, a reality:• Targeted therapies beyond EGFR mut, a reality:− Positive studies with bevacizumab and cetuximab− ALK rearrangement provides useful molecular target; RRand survival outcomes with ALK-inhibitors impressive
• Promising agents under investigation, pan-HER, c-MET, PI3K,PARP inhibitors…