VEGF-Inhibitors in NSCLC. Martin Reck Department of Thoracic Oncology Hospital Grosshansdorf Germany

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1 VEGF-Inhibitors in NSCLC Martin Reck Department of Thoracic Oncology Hospital Grosshansdorf Germany

2 Conflicts of interest Advisory Board: AstraZeneca Bristol-Myers Squibb Daiichi Sankyo Eli Lilly Merck Pfizer Roche Honoraria for lectures: AstraZeneca Daiichi Sankyo Eli Lilly Roche

3 VEGF Is the Only Angiogenic Factor Present Throughout the Tumor Life Cycle VEGF, vascular endothelial growth factor Bergers G, et al. Nat Rev Cancer. 2003;3(6): Jain RK, et al. Nat Clin Pract Oncol. 2006;3(1): Inoue M, et al. Cancer Cell. 2002;1(2):

4 Targets of Antiangiogenic Therapy VEGF Antibodies VEGF Receptor TKI Scappaticci, F. A. J Clin Oncol; 20:

5 Antiangiogenic treatment in NSCLC Anti VEGF antibodies Anti VEGF TKIs and other approaches

6 Bevacizumab: First-Line Trials Trial Inclusion Period AVF-0757g N Patients Analyzed Randomization Control Arm Bevacizumab Dose 98 1:1:1 Cp, P Arm A: 7.5 mg/kg Arm B: 15 mg/kg ECOG :1 Cp, P 15 mg/kg AVAiL :1:1 Ci, G, Pl (low or high dose) Arm A: 7.5 mg/kg Arm B: 15 mg/kg JO :1 Cp, P 15 mg/kg 1. Johnson DH, et al. J Clin Oncol. 2004;22: Sandler A, et al. N Engl J Med. 2006;355(24): Reck M, et al. J Clin Oncol. 2009;27(8): Ichinose Y, et al. Eur J Cancer Suppl. 2009;7(2): Abstract O-9008.

7 Bevacizumab Metaanalysis OS PFS Soria JC et al, ESMO 2010

8 AVAPERL: Patient disposition Arm A: Bevacizumab Patients screened (n=414) First-line induction with Bev-cis-pem (n=376) CR/PR/SD by RECIST Patients randomized to maintenance a (n=253) b (n= 125) 5 patients not treated Median follow-up time for this analysis: 11 months PD Not eligible for randomization (n=123) 123 patients not randomized 50 discontinued due to AEs 49 discontinued due to PD 9 patients died 7 withdrew consent 5 discontinued for other reasons 3 did not start treatment Arm B: bevacizumab + pemetrexed (n=128) 3 patients not treated a RECIST-related end points measured from the preinduction phase. b Intent-to-treat population Barlesi F, et al, ESMO ECCO 2011

9 Progression -free survival from date of randomization(%) AVAPERL: PFS from randomization a Bev+pem 7.4 months (81 events) Bev 3.7 months (104 events) HR, 0.48 ( ); P <.001 Cont. maintenance bev+pem (n=128) Cont. maintenance bev (n=125) Time (months) Pts at risk Bev+pem Bev a Median follow-up time in ITT population (excluding induction): 8.28 months (bev+pem arm), 7.95 months (bev arm) bev, bevacizumab; cont., continuation; HR, hazard ratio; ITT, intent to treat; pem, pemetrexed; pts, patients. Barlesi F, et al, ESMO ECCO 2011

10 Antiangiogenic treatment in NSCLC Anti VEGF antibodies Predictive Markers? Anti VEGF TKIs and other approaches

11 Predictive Markers Antiangiogenic Agents Current Approaches Imaging: PET Dynamic Contrast Enhanced (DCE) MRI Alternative RECIST Criteria Infiltrating Myeloid Cells (Heng, JCO 2009) Circulating Endothelial cells VEGF Polymorphisms Lung?? Circulating Vascular Marker

12 BO21015 (ABIGAIL) study design and endpoints Previously untreated, stage IIIB, IV or recurrent nonsquamous NSCLC (n=300) Stratified by stage, gender, PS, chemotherapy regimen Bevacizumab 7.5mg/kg q3w + up to six 21-day cycles of Carboplatin/Gemcitabine (CG)* or Carboplatin/Paclitaxel (CP)* (n=150) Bevacizumab 15mg/kg q3w + up to six 21-day cycles of Carboplatin/Gemcitabine (CG)* or Carboplatin/Paclitaxel (CP)* (n=150) Bevacizumab 7.5mg/kg until progression PD No cross-over permitted PD Bevacizumab 15mg/kg until progression Primary endpoint: exploration of correlation between candidate biomarkers and overall response rate to chemotherapy plus bevacizumab Secondary endpoints: PFS; ORR; DCR; duration of response; OS and safety Key exploratory endpoints: changes in candidate biomarkers across time, correlation of tumour volume changes with RECIST *Chemotherapy regimen was not randomly allocated but was chosen by the Investigator Mok T et al, ESMO 2011

13 Biomarker evaluable population*: Characteristic, n (%) Gender Female Male Ethnicity Caucasian Asian Other Smoking status Never smoker Former smoker Current smoker ECOG PS 0 1 baseline characteristics Bev 7.5mg + chemo (n=144) 53 (37) 91 (63) 122 (85) 22 (15) 0 (0) 49 (34) 54 (38) 40 (28) 52 (36) 92 (64) Bev 15mg + chemo (n=143) 55 (38) 88 (62) 122 (85) 20 (14) 1 (<1) 38 (27) 68 (48) 37 (26) 49 (34) 94 (66) Histology Adenocarcinoma 133 (86) 126 (88) Biomarker evaluable population (BEP) represents 95% of ITT population reasons for exclusion: 7 patients did not have a baseline biomarker sample; 9 patients did not receive at least one dose of bevacizumab * all patients who received at least one dose of bevacizumab with a valid baseline plasma sample Mok T et al, ESMO 2011

14 Secondary efficacy outcomes Bev 7.5mg + chemo (n=151) a Bev 15mg + chemo (n=140) a HR (95% CI) ORR (CR+PR), % DCR (CR+PR+SD), % Duration of response, months (n=154)(itt) (n=149)(itt) Median PFS, months b Median OS, months ( ) 1.16 ( ) a Population evaluable for response b final OS analysis (clinical cut off 10 months after PFS analysis, as per protocol) Mok T et al, ESMO 2011

15 Choice of chemotherapy? Shaked Y et al, Cancer Cell 2008

16 PFS estimate Exploratory analysis of PFS by bevacizumab dose level and chemotherapy regimen * Regimen n Median PFS (months) 6-month PFS rate Bev 15mg/kg + CP % Bev 7.5mg/kg + CP % Bev 15mg/kg + CG % Bev 7.5mg/kg + CG % Time (months) CG = carboplatin/gemcitabine; CP = carboplatin/paclitaxel *Chemotherapy regimen was not randomly allocated but was chosen by the Investigator. Approximately 60% of patients received CG Mok T et al, ESMO 2011

17 Primary endpoint: overall response rate relative to baseline candidate biomarker status Low BM level N Responders, % bfgf E-SELECTIN ICAM PLGF VEGFA VEGFR VEGFR High BM level N Responders, % Logistic regression OR* 95% CI P value After adjustment for multiple testing, none of the candidate biomarkers correlated with overall response rate according to baseline plasma level Definition of candidate biomarker (BM) level: low median; high > median; *Odds ratio: high vs low BM level BEP population patients pooled; all patients received bevacizumab; covariates: treatment, biomarker level (dichotomized) and baseline prognostic factors; statistically significant if p (0.05/7 adjusted for multiple testing) Mok T et al, ESMO 2011

18 Exploratory analysis of PFS relative to candidate biomarker status Low BM level High BM level Cox regression No. of Median No. of Median N events, n (%) PFS, months N events, n (%) PFS, months HR 95% CI P value bfgf (82) 7.2 E-SELECTIN (84) 6.6 ICAM (83) 7.0 PLGF (84) 6.7 VEGFA (79) 7.4 VEGFR (84) 7.2 VEGFR (84) (88) (86) (87) (91) (90) (86) (86) Lower plasma VEGFA at base line was associated with a longer PFS BEP patients pooled : all patients received bevacizumab. Covariates: treatment, biomarker level (dichotomized) and baseline prognostic factors; statistically significant if p (0.05/7 adjusted for multiple testing) N.B. Absence of control arm precludes determination of predictive and/or prognostic value of the tested BM candidate Mok T et al, ESMO 2011

19 PFS estimate Exploratory analysis of PFS relative to baseline plasma VEGFA levels Biomarker value level: Low (median PFS 7.4m) High (median PFS 6.1m) HR=1.57 ( ) p= No. at risk Time (months) Low High Lower plasma VEGFA at base line was associated with a longer PFS Mok T et al, ESMO 2011

20 Abigail ongoing research Changes in Candidate Biomarker across time (Dynamic Sampling) Correlation of tumor volume changes with RECIST Analyses of tumor samples Individual Expression profiles

21 Epidermal Growth Factor-Like-7: EGFL7 Tumor-enriched vascular extracellular matrix (ECM) protein that supports endothelial cell survival, particularly under stress Forms peri-vascular tracks that persist along tumor blood vessels damaged by anti-angiogenic therapy

22 Anti-EGFL7 (MEGF0444A) 22 Humanized antibody inhibits endothelial cell-egfl7 interaction Tumor-selective anti-vascular and antiangiogenic activity Inhibits tumor vascular re-growth following anti-vegf treatment Improves OS in combination with anti- VEGF in a high-bar NSCLC genetically engineered mouse model (GEMM): Spontaneous tumorigenesis driven by KRAS G12D and loss of p53 Tumors develop in native lung tissue Heavy tumor burden (~10-50 carcinomas/ lung) Models human responses to targeted therapy well* *Singh et. al, Francia and Kerbel, Nature Biotech, 2010

23 Biomarkers of Anti-EGFL7 Activity: Circulating Progenitor Cells (CPCs) Circulating Progenitor Cells (CPCs): CD34 Hi CD31 Low CD45 Low Differentiate into endothelial cells Express high levels of EGFL7 EGFL7 increases CPC survival Anti-EGFL7 reduces CPCs in tumorbearing anti-egfl7-sensitive mice Anti-VEGF does not affect CPCs

24 Start Arm B Anti-EGFL7 Phase 1b Design (MEGF0444A) Arm A Anti-EGFL7 2 mg/kg bevacizumab 10 Anti-EGFL7 5 mg/kg bevacizumab Arm B Anti-EGFL7 2 mg/kg Bev 10 + pac* Anti-EGFL7 5 mg/kg Bev 10 + pac 3 9 Design Pts with advanced solid tumors Standard 3+3 dose escalation Dosing IV q2wks Arm A: + bev Arm B: + bev/pac Bevacizumab-type exclusion criteria DCE-MRI in expansion cohorts Anti-EGFL7 10 mg/kg Anti-EGFL7 10 mg/kg bevacizumab 10 6 Bev 10 + pac 6 Expansion Cohorts 10 5 and 10 mg/kg Flat dosing (600 mg) + Rapid Infusion bevacizumab *90 mg/m 2 qw Naumovski L et al, ASCO 2011, abstract 2514

25 Anti-EGFL7 Phase 1b Patient Characteristics (MEGF0444A) All Patients (N=40) a Age in years, Median (range) 62 (24-78) Gender, n (%) Female Male ECOG PS, n (%) 0 1 Prior Therapies b Diagnosis colorectal sarcoma breast gastric kidney ovarian bladder liver lung other n (43) 23 (57) 13 (33) 27 (67) Prior VEGF-Axis Inhibitor, n a Data as of 26 January 2011; b Prior therapies not available for one patient Naumovski L et al, ASCO 2011, abstract 2514

26 Biomarkers: Circulating Progenitor Cells CPC modulation supports 5 mg/kg q2wk dose 40-60% reduction in CPCs at 5 mg/kg Naumovski L et al, ASCO 2011, abstract 2514

27 Imaging Biomarkers: DCE-MRI Changes in K trans support 5 mg/kg q2wk dose DCE-MRI: K trans parameter reflects tumor perfusion and vascular permeability Changes in log transformed K trans data summarized by LME model Trend towards combination activity with bevacizumab and anti-egfl7 * Scales cannot be directly compared Fredrickson J et al, ASCO 2011, abstract 2539

28 Antiangiogenic treatment in NSCLC Anti VEGF antibodies Anti VEGF TKIs and other approaches

29 VEGF-TKI First Line Therapy Randomized Phase III trials Reference Schedule Prim EP RR PFS (m) OS (m) Outcome Scagliotti ASCO 2011 Scagliotti J Clin Oncol 2010 Gatzemeier ESMO 2010 Carbo/Pac +/- Motesanib Carbo/Pac +/- Sorafenib Cis/Gem +/- Sorafenib OS OS OS 40% 26% 27.4% 24% Na (HR 0.79) (HR 0.99) (HR 0.83) (HR 0.9) (HR 1.15) (HR 0.98) Negative Negative Negative

30 VEGF-TKI Second Line Therapy Randomized Phase III Trials Reference Schedule Prim EP RR PFS (m) OS (m) Outcome Scagliotti ESMO 2010 Herbst Lancet Oncol 2010 De Boer J Clin Oncol 2011 Natale J Clin Oncol 2011 Novello WCLC 2011 Erlotinib +/- Sunitinib Doce +/- Vancetanib Pem +/- Vandetanib Erlotinib v Vandetanib Doce +/- Aflibercept OS PFS PFS PFS OS 10.6% 6.9% 17% 10% 19.1% 7.9% 12% 12% 23.3% 8.9% (HR 0.8) (HR 0.79) (HR 0.98) (HR 0.98) (HR 0.82) (HR 0.92) (HR 1.0) Negative Positive Negative Negative Negative

31 Kaplan-Meier Estimate VITAL Trial: PFS (ITT) Symbol=Censor Placebo/Docetaxel Aflibercept/Docetaxel Stratified HR (95%CI) = ( ) P = Median PFS: Placebo + docetaxel = 4.11 mos. Aflibercept + docetaxel = 5.19 mos. N Aflibercept + Docetaxel Placebo + Docetaxel RR 23.3% 8.9% P-value < Number at Risk Time (Months) Placebo Afli Cut-off date= Jan 26, 2011;Median follow-up = months WCLC, 07July 2011 Novello et al. J Thorac Oncol 6: 2011 (suppl; abstr O43.06)

32 VITAL Trial: Overall survival (ITT) Kaplan-Meier Estimate Symbol=Censor Placebo/Docetaxel Aflibercept/Docetaxel log-rank p = Stratified HR (95.1%CI) = 1.01 ( ) P = Median OS: Placebo + docetaxel = mos. Aflibercept + docetaxel = mos Number at Risk Time (Months) Placebo Afli Cut-off date= Jan 26, 2011;Median follow-up = months WCLC, 07July 2011 Novello et al. J Thorac Oncol 6: 2011 (suppl; abstr O43.06)

33 BIBF 1120* inhibits VEGFR, PDGFR and FGFR In vitro Potent inhibitor of VEGFR, FGFR and PDGFR in enzymatic and cellular assays VEGFR 1 / 2 / 3 PDGFR α / FGFR 1 / 2 / 3 IC 50 / EC 50 (nm) 34 / 21 / / / 37 / 108 *This is an investigational agent. Its efficacy and safety have not been established Hilberg F, et al. Cancer Res 2008;68:

34 FGFR1 Amplification in Squamous Cell NSCLC Systematic search for genetic alterations in 232 lung cancer specimen 155 Squamous Cell Lung Cancer samples with frequent FGFR1 Amplification Testing of FGFR1 Inhibitor PD in 83 cell lines Weiss J et al, Science Transl Met 2010,

35 BIBF 1120: LUME-Lung study programme LUME-Lung 1 and 2: large, multinational, randomized, double-blind, Phase III, placebo-controlled clinical trials assessing the efficacy of BIBF 1120* 200 mg BID with second-line chemotherapy in patients with advanced or recurrent NSCLC Patients with: histologically or cytologically confirmed NSCLC; stage IIIB/IV or recurrent NSCLC; failure of one previous first-line chemotherapy for advanced and/or metastatic disease; eligibility for docetaxel or pemetrexed therapy BIBF standard docetaxel therapy Placebo + standard docetaxel therapy BIBF standard pemetrexed therapy Placebo + standard pemetrexed therapy Maintenance BIBF 1120 Maintenance placebo Maintenance BIBF 1120 Maintenance placebo 1 o endpoint PFS; 2 o OS, RR, QL, safety LUME-Lung 1 N=1300 fully accrued 1 o endpoint PFS; 2 o OS, RR, QL, safety LUME-Lung 2 N=1300 ongoing *This compound is an investigational agent. Its efficacy and safety have not been established.

36 Conclusion Confirmed efficacy of anti VEGF antibody bevacizumab in eligible patients Role of VEGF-TKI remains to be defined Further drugs are in clinical investigation Up to now no predictive marker available