Antiangiogenic Agents in NSCLC Where are we? Which biomarkers? Martin Reck Department e t of Thoracic c Oncology ogy Hospital Grosshansdorf Germany 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):401-410. Jain RK, et al. Nat Clin Pract Oncol. 2006;3(1):24-40. Inoue M, et al. Cancer Cell. 2002;1(2):193-202. 1
Targets of Antiangiogenic Therapy VEGF Antibodies VEGF Receptor TKI Scappaticci, F. A. J Clin Oncol; 20:3906-3927 2002 Antiangiogenic treatment in NSCLC Anti VEGF antibodies Anti VEGF TKIs and other approaches 2
Bevacizumab: First-Line Trials Inclusion N Patients Control Bevacizumab Trial Period Analyzed Randomization Arm Dose AVF-0757g 1 1998 1999 98 1:1:1 Cp, P Arm A: 7.5 mg/kg Arm B: 15 mg/kg ECOG 4599 2 2001 2005 878 1:1 Cp, P 15 mg/kg AVAiL 3 2005 2006 1043 1:1:1 Ci, G, Pl (low or high h dose) Arm A: 7.5 mg/kg Arm B: 15 mg/kg JO19907 4 2007 2008 175 2:1 Cp, P 15 mg/kg 1. Johnson DH, et al. J Clin Oncol. 2004;22:2184-2191. 2. Sandler A, et al. N Engl J Med. 2006;355(24):2542-2550. 3. Reck M, et al. J Clin Oncol. 2009;27(8):1227-1234. 4. Ichinose Y, et al. Eur J Cancer Suppl. 2009;7(2): Abstract O-9008. Bevacizumab Metaanalysis OS PFS Soria JC et al, ESMO 2010 3
Bevacizumab Metaanalysis Soria JC et al, ESMO 2010 Antiangiogenic treatment in NSCLC Anti VEGF antibodies Predictive Markers? Anti VEGF TKIs and other approaches 4
Individualized Approach Safety Driven? Exclusion criteria: Histology (squamous cell carcinoma) Invasion of central blood vessels History of gross hemoptysis Active, relevant cardiovascular disease ECOG 4599: Survival and Hypertension Dahlberg S et al, J Clin Oncol 2010 5
No correlation between hypertension and bevacizumab efficacy Systematic analysis of HTN and clinical outcome in 5,900 patients across 6 clinical trials of bevacizumab In 5 of the 6 studies, HTN during treatment was not predictive of clinical benefit or prognostic for the course of disease AVF2107g NO16966 AVADO RIBBON-1 AVAiL AVOREN Prognostic HR (p value) for PFS 1.20 (0.14) 1.00 (>0.99) 1.09 (0.66) 1.16 (0.34) 0.95 (0.69) 1.11 (0.45) for OS 1.36 (0.02) 0.89 (0.49) 1.02 (0.95) 1.40 (0.11) 0.85 (0.33) 0.87 (0.45) Predictive HR (p value) for PFS 0.55 (0.0008) 0.81 (0.18) 0.91 (0.72) 0.82 (0.26) 1.04 (0.83) 0.81 (0.29) for OS 0.43 (<0.0001) 0.80 (0.36) 0.91 (0.85) 0.62 (0.05) 1.32 (0.21) 0.98 (0.95) Hurwitz, et al. ASCO 2010 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 6
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 Bevacizumab 7.5mg/kg until progression + up to six 21-day cycles of Carboplatin/Gemcitabine it bi (CG)* PD or Carboplatin/Paclitaxel (CP)* (n=150) No cross-over permitted Bevacizumab 15mg/kg q3w + up to six 21-day cycles of Carboplatin/Gemcitabine (CG)* or Carboplatin/Paclitaxel (CP)* (n=150) PD Bevacizumab 15mg/kg until progression Primary endpoint: exploration of correlation between candidate biomarkers and overall response rate to chemotherapy plus bevacizumab *Chemotherapy regimen was not randomly allocated but was chosen by the Investigator 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 Mok T et al, ESMO 2011 Biomarker evaluable population*: baseline characteristics Characteristic, n (%) Bev 7.5mg + chemo (n=144) Bev 15mg + chemo (n=143) Gender Female 53 (37) 55 (38) Male 91 (63) 88 (62) Ethnicity Caucasian Asian Other Smoking status Never smoker Former smoker Current smoker ECOG PS 0 1 122 (85) 22 (15) 0 (0) 49 (34) 54 (38) 40 (28) 52 (36) 92 (64) 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 7
Secondary efficacy outcomes Bev 7.5mg + Bev 15mg + HR chemo chemo (95% CI) (n=151) a (n=140) a ORR (CR+PR), % 37.1 46.4 DCR (CR+PR+SD), % 76.8 78.5 Duration of response, months 5.8 5.6 (n=154)(itt) (n=149)(itt) Median PFS, months 6.8 6.7 b Median OS, months 13.4 13.7 1.01 (0.78 1.31) 1.16 (0.87-1.53) 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 Choice of chemotherapy? Shaked Y et al, Cancer Cell 2008 8
Exploratory analysis of PFS by bevacizumab dose level and chemotherapy regimen * PFS estimate 1.0 0.8 0.6 0.4 0.2 Regimen n Median PFS (months) 6-month PFS rate Bev 15mg/kg g + CP 62 7.1 68% Bev 7.5mg/kg + CP 66 6.3 52% Bev 15mg/kg + CG 87 6.1 51% Bev 7.5mg/kg + CG 88 6.8 63% 0 0 3 6 9 12 15 18 21 24 CG = carboplatin/gemcitabine; CP = carboplatin/paclitaxel Time (months) *Chemotherapy regimen was not randomly allocated but was chosen by the Investigator. Approximately 60% of patients received CG Mok T et al, ESMO 2011 Challenges (Shaked 2008) Challenging technology (Fresh samples needed) d) Technology not standardized Markers to define CECs/CEPs are in discussion Multiple Factors which contribute to change of CEC/CEP count (timing of VEGF-Inhibitor) 9
Primary endpoint: overall response rate relative to baseline candidate biomarker status Low BM level N Responders, % bfgf 142 45 E-SELECTIN 142 39 ICAM 142 44 PLGF 146 44 VEGFA 140 44 VEGFR1 142 49 VEGFR2 143 39 High BM level N Responders, % 141 43 141 48 141 43 56 43 140 45 141 39 140 49 Logistic regression OR* 95% CI P value 1.07 0.63 1.80 0.813 1.81 1.06 3.08 0.029 1.09 0.64 1.85 0.748 1.16 0.58 2.33 0.676 1.22 0.72 2.09 0.460 0.77 0.46 1.29 0.319 1.44 0.85 2.45 0.176 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 0.007 (0.05/7 adjusted for multiple testing) Mok T et al, ESMO 2011 Exploratory analysis of PFS relative to candidate biomarker status N Low BM level No. of Median events, n (%) PFS, months bfgf 142 116 (82) 7.2 E-SELECTIN 142 119 (84) 6.6 ICAM 142 118 (83) 7.0 PLGF 146 122 (84) 6.7 VEGFA 140 111 (79) 7.4 VEGFR1 142 119 (84) 7.2 VEGFR2 143 120 (84) 6.7 N High BM level No. of Median events, n (%) PFS, months 141 124 (88) 6.5 141 121 (86) 6.8 141 122 (87) 6.3 56 51 (91) 6.3 140 126 (90) 6.1 141 121 (86) 6.2 140 120 (86) 6.9 Cox regression HR 95% CI P value 1.21 0.92 1.59 0.170 0.94 0.72 1.24 0.684 1.18 0.89 1.56 0.250 1.20 0.85 1.71 0.308 1.57 1.17 2.09 0.002 1.14 0.87 1.49 0.351 0.95 0.72 1.26 0.724 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 0.007 (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 10
Exploratory analysis of PFS relative to baseline plasma VEGFA levels PFS estimate 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 00 0.0 Biomarker value level: Low (median PFS 7.4m) High (median PFS 6.1m) HR=1.57 (1.17 2.09) p=0.002 0 3 6 9 12 15 18 21 24 No. at risk Time (months) Low 140 121 90 50 24 13 7 1 0 High 140 115 71 27 10 4 0 0 0 Lower plasma VEGFA at base line was associated with a longer PFS Mok T et al, ESMO 2011 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 11
Antiangiogenic treatment in NSCLC Anti VEGF antibodies Anti VEGF TKIs and other approaches 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 OS OS 40% 26% 27.4% 24% 5.6 5.4 (HR 0.79) 4.6 5.4 (HR 0.99) 13.0 11.0 (HR 0.9) 10.7 10.6 (HR 1.15) Cis/Gem 60 6.0 12.4 +/- OS Na 5.5 12.5 Sorafenib (HR 0.83) (HR 0.98) Negative Negative Negative 12
Sorafenib + KRAS Mutation? 37 pretreated patients (Second / Third line) 8% Squamous Cell NSCLC K-Ras Mutation Rate: 32% EGFR Mutation Rate: 22% Response: 6% DCR: 65% Kelly RJ et al, Clin Cancer Res 2011; 17: 1190-99 Sorafenib + KRAS Mutation? KRAS Mut + KRAS Mut - PFS (m) 2.6 P:0.51 OS (m) 7.2 3.6 13.2 P: 0.59 All 3.4 11.6 Kelly RJ et al, Clin Cancer Res 2011; 17: 1190-99 13
VEGF-TKI Second Line Therapy Randomized Phase III Trials Reference Schedule Prim EP RR PFS (m) OS (m) Outcome Scagliotti Erlotinib +/- 10.6% OS ESMO 2010 Sunitinib 6.9% Herbst Lancet Oncol 2010 De Boer J Clin Oncol 2011 Natale J Clin Oncol 2011 Novello WCLC 2011 Doce +/- Vancetanib Pem +/- Vandetanib Erlotinib v Vandetanib Doce +/- Aflibercept PFS PFS PFS OS 17% 10% 19.1% 7.9% 12% 12% 23.3% 8.9% 3.6 9.0 2.0 8.5 (HR 0.8) (HR 0.92) 4.0 3.2 (HR 0.79) 2.6 2.0 (HR 0.98) 2.6 2.0 (HR 0.98) 5.2 4.1 (HR 0.82) 10.6 10.0 6.9 7.8 6.9 7.8 10.0 10.4 (HR 1.0) Negative Positive Negative Negative Negative VITAL Trial: PFS (ITT) 1.0 Symbol=Censor Placebo/Docetaxel 0.9 Aflibercept/Docetaxel Kaplan-Meier Estimate 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Stratified HR (95%CI) = 0.819 (0.716-0.937) 0.937) P = 0.0035 Median PFS: Placebo + docetaxel = 4.11 mos. Aflibercept + docetaxel = 5.19 mos. N Aflibercept + Docetaxel Placebo + Docetaxel RR 23.3% 8.9% P-value <0.00010001 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 Number at Risk Time (Months) Placebo 457 258 145 80 48 Afli 456 302 181 113 62 Cut-off date= Jan 26, 2011;Median follow-up = 22.97 months WCLC, 07July 2011 Novello et al. J Thorac Oncol 6: 2011 (suppl; abstr O43.06) 14
VITAL Trial: Overall survival (ITT) 1.0 Symbol=Censor Placebo/Docetaxel 0.9 Aflibercept/Docetaxel Kaplan-Meier Estimate 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Stratified HR (95.1%CI) = 1.01 (0.868-1.174) P = 0.8985 Median OS: Placebo + docetaxel = 10.41 mos. Aflibercept + docetaxel = 10.05 mos. 0.1 log-rank p = 0.8985 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Number at Risk Time (Months) Placebo 457 404 321 252 197 97 35 Afli 456 375 310 252 194 97 41 Cut-off date= Jan 26, 2011;Median follow-up = 22.97 months WCLC, 07July 2011 Novello et al. J Thorac Oncol 6: 2011 (suppl; abstr O43.06) 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 / 13 59 / 65 69 / 37 / 108 *This is an investigational agent. Its efficacy and safety have not been established Hilberg F, et al. Cancer Res 2008;68:4774 4782 15
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 PD173074 in 83 cell lines Weiss J et al, Science Transl Met 2010, 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 1120 + standard docetaxel th Placebo + standard docetaxel th BIBF 1120 + standard pemetrexed therap Placebo + standard pemetrexed therap therapy therapy therapy 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. 16
Conclusion Confirmed efficacy of anti VEGF antibody bevacizumab b in eligible ibl patients t Role of VEGF-TKI remains to be defined Further drugs are in clinical investigation Up to now no predictive marker available 17