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…
