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…