Toxicity as a Biomarker

Transcription

1 Toxicity as a Biomarker Frede Donskov, M.D., PhD Chair, Danish Renal Cancer Group, DARENCA Aarhus University Hospital Denmark Thirteenth International

2 COI Research funding from Novartis, GSK, Pfizer and Roche

3 Hypothyroidism in Patients With Ren Cell Carcinoma: The interpretation of toxicity should be reconsidered sunitinib and sorafenib sorafenib only Schmidinger M. Cancer 2011; 117:

4 X 6 X 5 X 4 HTN within 12 weeks Management JNCI 2011; 103:

5 Sunitinib may induce neutropenia and thrombocytopenia through binding to the Fms-like tyrosine kinase 3 (FLT-3) expressed on the surface of hematopoietic cells ECCO-ESMO 2011

6 JC0 2006; 24: Thirteenth International JC0 2009; 27:

7 Shen, Hu, Donskov. PLoS One. 2014; 9: :e98259 Donskov, Sem Cancer Biol 2013; 23: Thirteenth International Heng JCO 2009; 27:

8 ECCO-ESMO 2011

9 Neutropenia and thrombocytopenia during therapy as biomarkers of efficacy Neutropenia gr > 1 = <1.5 Thrombocytopenia gr >1 = < 75 ECCO-ESMO 2011

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11 Comparative Assessment of Sunitinib-associated Adverse Events as Independent Biomarkers of Efficacy in Patients with Metastatic Renal Cell Carcinoma Frede Donskov, M. Dror Michaelson, Igor Puzanov, Mellar P. Davis, Georg A. Bjarnason, Robert J. Motzer, David Goldstein, Xun Lin, Darrel P. Cohen, Robin Wiltshire, and Brian I. Rini No TSH measurements

12 Final multivariate models of associations between adverse events and objective response for mrcc patients receiving sunitinib on Schedule 4/2 or any dose/schedule Schedule 4/2 Any dose/schedule Adverse event at any time point Endpoint Odds Odds ratio 95% CI P-value a ratio 95% CI P-value a Neutropenia OR < Hypertension OR < < Hand foot syndrome OR Asthenia/fatigue OR Thrombocytopenia OR

13 Final multivariate models of associations between adverse events and survival endpoints for mrcc patients receiving sunitinib on Schedule 4/2. Adverse event at any time point Adverse event by the 12-week landmark Adverse event Endpoint HR 95% CI P-value a HR 95% CI P-value a Neutropenia PFS OS Hypertension PFS OS < < Hand foot syndrome PFS OS Asthenia/fatigue PFS OS < Thrombocytopenia PFS OS Same results on any dose/schedule Dose reduction was not associated with outcome

14 Evaluation of eight different clinical scenarios ( 8-group analysis) on efficacy outcomes, based on combined baseline neutrophil count and neutropenia grade and hypertension status during treatment for mrcc patients receiving sunitinib on any dose/schedule Median time to progression/survival event, months (95% CI) Group a n PFS OS OR, n (%) Baseline neutrophil count / neutropenia during treatment / hypertension during treatment >ULN / nadir grade 1 / no HTN ( ) 4.9 ( ) 0 >ULN / nadir grade >1 / no HTN (NA) 13.5 (NA) 0 >ULN / nadir grade 1 / yes HTN ( ) 24.5 ( ) 9 (27.3) >ULN / nadir grade >1 / yes HTN ULN / nadir grade 1 / no HTN ( ) 9.8 ( ) 3 (4.4) ULN / nadir grade >1 / no HTN ( ) 16.8 ( ) 7 (17.5) ULN / nadir grade 1 / yes HTN ( ) 19.1 ( ) 74 (28.7) ULN / nadir grade >1 / yes HTN ( ) 37.1 ( ) 172 (53.3) Same results on schedule 4/2 Thirteenth International

15 Evaluation of eight different clinical scenarios ( 8-group analysis) on efficacy outcomes, based on combined baseline thrombocyte count and thrombocytopenia grade and hypertension status during treatment for mrcc patients receiving sunitinib on Schedule 4/2 Median time to progression/survival event, months (95% CI) Group a n PFS OS OR, n (%) Baseline thrombocyte count / thrombocytopenia during treatment / hypertension during treatment >ULN / nadir grade 1 / no HTN ( ) 4.4 ( ) 0 >ULN /nadir grade >1 / no HTN ( ) 2.5 ( ) 0 >ULN / nadir grade 1 / yes HTN ( ) 14.8 ( ) 14 (45.2) >ULN /nadir grade >1 / yes HTN ( ) 16.0 (13.3 NA) 5 (55.6) ULN / nadir grade 1 / no HTN ( ) 10.6 ( ) 6 (10.2) ULN / nadir grade >1 / no HTN (1.1 NA) 13.5 ( ) 2 (25.0) ULN / nadir grade 1 / yes HTN ( ) 31.8 ( ) 147 (49.7) ULN / nadir grade >1 / yes HTN ( ) 37.6 ( ) 68 (66.0) Same results on any dose/schedule Thirteenth International

16 Sunitinib-induced hypertension, neutropenia and thrombocytopenia as predictors of good prognosis in metastatic renal cell carcinoma patients Juhana Rautiola, Frede Donskov, Katriina Peltola, Heikki Joensuu and Petri Bono No TSH measurements BJU Int 2014 Epub ahead of print

17 Neutropenia gr > 1 = < mg 4/2 39 (22%) 37.5 mg cont 80 (44%) 25 mg cont 62 (34%) Thrombocytopenia gr >0 = < LLN Hypertension 60 (33%) Neutropenia 88 (49%) Thrombocytopenia 135 (75%) Neutropenia was associated with improved PFS and OS in all sunitinib doses, and a trend was seen for hypertension and thrombocytopenia MVA: Hypertension and neutropenia associated with PFS and OS Thrombocytonenia associated with PFS 12-week landmark: hypertension and thrombocytopenia associated with PFS and OS Only 4 patients with baseline neutrophils > ULN achieved neutropenia BJU Int 2014 Epub ahead of print Thirteenth International

18 Biomarker profile based on Hypertension, Neutropenia and Thrombocytopenia: Favourable profile: all 3 biomarkers, poor profile: no biomarkers NR Response Rate: Fav vs Int vs poor biomarker profile: 47% vs 21% vs 4% BJU Int 2014 Epub ahead of print

19 ESMO 2014

20 Motzer, JCO 1999; 17: Schutz, Eur Urol 2014; 65: Thirteenth International

21 Sorensen, Eur J Cancer 2014 Feb;50(3): TSH not significant submitted

22 5 random biomarkers 4 random biomarkers 3 random biomarkers 2 random biomarkers 1 random biom Good biomarker profile: 3-5 biomarkers. Med OS 23.5 mo Poor biomarker profile: 0-2 biomarkers. Med OS 9.6 mo Thirteenth International C-index Heng + 5-factor biomarker profile 0.68 C index Heng alone 0.63 submitted

23 Suggested model VEGF inhibition / modulation in tumor biology Decreased nitric oxide production from endothelial cells (1) Modulation in tumor microenvironment Vasculature constriction Reduction in sodium renal excretion (2) Reduced # tumor educated immune cells Hypertension and normal sodium Neutropenia and thrombocytopenia the majority of VEGF is contained within neutrophils, approximately 10% in thrombocytes and only 1% of the total VEGF is free in serum (Kusumanto, Angiogenesis. 2003;6(4):283 7) (1) Erdogan, J Vasc Res 2005; 42: (2) Van Heeckeren, JCO 2007; 25:

24 Conclusions The interpretation of toxicity should be reconsidered Hypertension, neutropenia, thrombocytopenia, hand-foot syndrome, normal sodium, LDH < 1.5 ULN, and elevated TSH, developed during therapy, are predictive markers of favourable outcome and should no longer be perceived as unwanted side effects Lack of hypertension and neutropenia within 12 weeks could be incorporated as a stratification factor in prospective studies assesing whether dose adjustments or switching to an alternative treatment startegy may change clinical outcome