AVANCES EN EL TRATAMIENTO SISTEMICO DE LOS TUMORES BRCA-DEFICIENTES

Transcription

1 AVANCES EN EL TRATAMIENTO SISTEMICO DE LOS TUMORES BRCA-DEFICIENTES Dra. Judith Balmaña Servicio de Oncología Médica Hospital Universitario Vall Hebron Barcelona

2 Preclinical evidence of chemomodulation by BRCA BRCA: prognostic or predictive factor? Role of platinums in BRCA associated tumors PARP inhibitors Challenges and future steps

3 Narod and Foulkes, Nat Rev Cancer 2004

4 BRCA1 and DNA damage

5 CISPLATIN PACLITAXEL HCC1937: BRCA1-mutant t t breast cancer cell line MCF-7: BRCA1-wild type + hormone sensitive MDA-MB: MB: BRCA1-wild type + hormone insensitive Tassone et al, Br J Cancer 2003

6 Restoration of BRCA1 function induces resistance to cisplatin i and restores sensitivity i i to paclitaxel Tassone et a, Br J Cancer 2003

7 Is BRCA deficiency predictive of chemosensitivity?

8 Study Study population Survival Lee, 1999 Ash Jewish BRCA1/2 vs Similar Robson, 1998 Ash Jewish BRCA1/2 vs Similar Chappuis, 2000 Ash Jewish BRCA1/2 vs Worse Eerola, 2001 BRCA1/2 vs sporadic Similar Goode, 2002 BRCA1/2 vs sporadic Similar El Tamer, 2004 Jewish desc BRCA1/2 vs Similar Robson, 2004 AshJewish BRCA1/2vs BRCA1: worse if nochemo BRCA2: similar Rennert, 2007 Ash Jewish BRCA1/2 vs BRCA1: better if chemo BRCA2: similar Goodwin, 2011 BRCA1/2 vs sporadic BRCA1: worse if no chemo (NS) BRCA2: worse if no chemo

9 Análisis de 26 estudios observacionales Supervivencia a los 5 años: no portadoras: 36% (IC 95%:34-38%) BRCA1: 44% (IC 95 %: 40-48%) BRCA2: 52% (IC 95%:46-58%)

10 Chappuis et al, 7 BRCA1, 4 BRCA2, 27 control. Neoadj chemo with AC 2002 pcr: 44% BRCA vs 4% sporadic (p=0.009) Delaloge et al, BRCA1, 5 BRCA2, 57 control. Neoadj chemo with AC pcr: 53% BRCA1, 0% BRCA2, 14% control Hubert et al, BRCA1, 7 BRCA2 (Ashkenazi mut ) Neoadj chemo with FAC, FEC, or AC pcr: 13% BRCA1, 0% BRCA2 Byrski et al, 2008 Arun, JCO BRCA1, 12 control. Neoadj chemo with AT Clinical response: 40% BRCA1, 100% controls 57 BRCA1, 23 BRCA2. Neoadjuvant chemotherapy. pcr: Anthracycline based (no taxane): 44% BRCA1, 0% BRCA2 AT: 46% BRCA1, 17% BRCA2

11 Overall RR: 23% No prior chemotherapy: 26% Priorchemotherapy chemotherapy: 7% Cisplatin arm less likely: tumors >2cm N+ prior chemotherapy Byrski, JCO 2010

12 Byrski, Breast Cancer Res Treat BRCA1. Neoadj chemo with cisplatin, pcr 90% Gronwald et al, ASCO BRCA1. Neoadj chemo with cisplatin, pcr 72% Silver et al, JCO TNBC (2 were BRCA1+) Neoadj chemo with Cisplatin 75 mg/m² pcr: 22%, 2 BRCA1+ (100%)

13 BRCA1 BRCA2 Sporadic (n=93) (n=28) (n=121) Anthracycline based 59% 64% 61% CMF 31% 25% 26% Taxane based 8% 4% 11% Platinum based 1% 0 1% Objective response 66% 89% 50% Kriege et al, JCO 2009

14 20 BRCA1 founder mutation carriers 4 prior chemotherapies Cisplatin 75mg/m 2 every 3 w x 6 cycles 1st line: 89% ORR: 80% PFS:12 months OS: 30 months

15 PI: Nadine Tung

16 BRCA1/2 mutation carrier, 1st metastatic relapse from breast cancer Randomise 2:1 Carboplatin Response rate Docetaxel AUC 6 q3w Toxicity 100mg/m 2 6 cycles Time to progression 6 cycles Upon progression Docetaxel 100mg/m 2 6 cycles Response rate Toxicity Time to progression Carboplatin AUC 6 q3w 6 cycles PI: Andrew Tutt

17 BRCA associated tumors are sensitive to DNAdamaging agents Standard regimens (anthracycline ± taxanes) used for BC treatment have shown to be effective There is no definitive evidence of the superiority of platinums in BRCA associated BC BRCA status is a prognostic and predictive factor in OvC

18 CONVERTIR LA ALTERACIÓN CONVERTIR LA ALTERACIÓN GENÉTICA EN OPORTUNIDAD TERAPÉUTICA

19

20 DNA damage endogenous, cytotoxics, radiation, etc. If PARP is inhibited, SSB repair prevented, leading to increased double strand DNA breaks

21

22 Normal or heterozygote for HR defect DNA DAMAGE DNA DAMAGE HR deficient e.g. BRCA1/2 -/- HR NHEJ SSA BER NER etc x PARPi HR NHEJ SSA BER NER etc x x PARPi Lethality Error prone repair Genomic instability Cell death

23 Increased levels of chromosomal aberrations in PARP inhibitor treated BRCA2 -/- cells BRCA2 -/- Control + PARP inhibitor Farmer H et al. Nature 2005;434: Alan Ashworth, personal communication

24 PARPi Olaparib (AZD2281) Rucaparib (AGO14699) Veliparib (ABT888) Company, First trial Astra Zeneca 2005 Pfizer/Clovis 2003 Abbott 2006 IC 50 phase route 5nM (PARP1) 1nM (PARP2) 1.5 µm (Tankyrase 1) I II oral 1.4nM (PARP1) I II Iv oral 5.2nM (PARP1) 2.9nM (PARP2) I II oral CEP 9722 Cephalon nM (PARP1) 6nM (PARP2) I oral E7016 Eisai 50nM (PARP1/2) I oral 2010 BMN 673 Biomarin 0.57nM (PARP1) I oral 2011

25 Escalation phase (n=60) Various tumour types; BRCA carrier status not mandatory 10 dose level cohorts: 10mg daily given for 2 out of 3 weeks 600 mg bid continuous dosing 22 carriers of a BRCA1 or 2 mutation Expansion phase (n=50) at 200 mg bid continuous: Confirmed BRCA mutation carriers with ovarian, primary peritoneal and fallopian cancer Fong, NEJM 2009; Fong, JCO 2010

26 95% toxicities were grade 1 2: Nausea and vomiting 18%, dysgeusia 13%, anorexia 12%, fatigue 28% Grade 3 4 toxicities were rare: Myelosupression (<5%) Nausea and vomiting (2 3%) CNS dizziness or moodchanges (2 3%) Pattern of toxicity very similar in BRCA mutation carriers MTD = 400mg bid Fong, NEJM 2009

27 Total Platinum Platinum Platinum sensitive resistant refractory # of evaluable pts Responders by RECIST 14 (28%) 6 (46%) 8 (33%) 0 Responders by GCIG 17 (34%) 8 (61%) 7 (29%) 2 (15%) CA125 Responders by either 20 (40%) 8 (61%) 10 (41%) 2 (15%) RECIST or GCIC criteria SD (>4 cycles) 3 (6%) 1 (7%) 1 (4%) 1 (7%) Median duration of response in weeks (range) 28 (23 33) 28 (20 37) 28 (19 38) NE Fong, JCO 2010

28 Tutt, Lancet 2010

29 Tutt, Lancet 2010

30 Tutt, Lancet 2010

31 Recurrent (stage IIIB/IIIC/IV) ovarian cancer after failure of 1 prior platinum based chemotherapy Patients Sequential cohorts Confirmed germline BRCA1 or BRCA2 mutation Measurable disease ECOG performance status 0 2 Cohort 1 Olaparib 400 mg po bid (MTD) (28-day cycles) (n=33) Cohort 2 Olaparib 100 mg po bid (28-day cycles) (n=24) Audeh, Lancet 2010

32 Audeh, Lancet 2010

33 Audeh, Lancet 2010

34 Kaye, ESMO 2010

35 Kaye, J Clin Oncol. 2012

36

37 Kaye, J Clin Oncol. 2012

38

39 Gelmon et al, Lancet 2011

40 1. Fong et al, J Clin Oncol Audeh et al, Lancet Gelmon, Lancet Oncol 2011

41 N Engl J Med 2012;366:

42

43 N Engl J Med 2012;366:

44 Oza, ASCO 2012

45 Oza, ASCO 2012

46

47 Ovarian cancer: Benefit in OS not reached within the sporadic population. Need of an FDA approved companion diagnostic test to target population Breast cancer: Relatively small fraction of breast cancer cases, but not as small to receive orphan designation: single arm phase II trial would not satisfy the FDA/EMA Requirement of an FDA approved companion diagnostic test Population sensitive to conventional therapies

48 75 pts, 200mg bid olaparib, 54 BRCA1/21 BRCA2 Platinum resistance pre PARPi: 49%; Olaparib RR: 39% REGIMEN Platinum (single or combined) 16/37: 43% Taxane (single) 4/9: 44% PLD (single) 1/8: 12% Others 1/4: 25% TOTAL 22/58: 38% RESPONSE RATE (RECIST) OS post PARPi CT: 7.9m Predictors of OS: Non progression to prior PARPi (HR 0.28) Optimal initial debulking (HR 0.36) Plat S pre PARPi (HR 0.46) Ang et al, ASCO 2012

49 PI: Bella Kaufman

50 Platinum chemotherapy PARP inhibitors Target BRCA and HR Interstrand t crosslink repair Replication fork collapse deficient cancers SSB Xenograft studies with BRCA deficient models suggest additive effects maintaining doses in combination Rottenberg PNAS 2008, Drew JNCI 2011 Single agent PARP inhibitor Well tolerated Large therapeutic window synthetic lethality PARP inhibitor Platinum combo Potential for improved response But chemo-sensitization is nonspecific May not enhance therapeutic window

51 BRCA status Tumour type Prior chemo 54% Known BRCA1/2 mutation 26% Known negative 20% Unknown 78% Breast cancer 19% Ovary Median 3 prior lines (1 11 range) Balmaña et al, ASCO 2012

52 39 (70%) patients had interruption or dose modification 31 (57%) patients t experienced daes that t ldt led to olaparib ibdose modification 18 (33%) patients experienced hematologicalaes mostlyneutropenia Confirmed responses 41% (not broken down by BRCA1/2 status) Durable responses (>1 year) withcontinued single agent olaparib Durable responses (>1 year) with continued single agent olaparib observed in both breast and ovarian cancer patients. Balmaña et al, ASCO 2012

53 Dose Levels L1 L2 L3 L4 L5 Carbo AUC ABT-888 mg 50 BID 50 BID 100 BID 150 BID 200 BID Patients treated 7 (1 ineligible) DLTs Delaysfor G3/4thrombocytopeniafrequent ~55% of cycles Carboplatin at an AUC of 5 given Q 21 days and ABT 888 at doses of 150 BID daily are likely to be the MTD Response rate 50% (9/18 patients) in cohorts 1 4

54

55

56 Isakoff, SABCS 2011

57

58 Target Therapy Tumor Predictive RR Disease type Marker % control rate % Study C kit Imatinib GI stromal C kit expr Demetri, 2002 EGFR Gefitinib NSCLC EGFR mut Mok, 2009 ALK Crizotinib NSCLC ALK EML fusion gene BRAF BRAF inhibitor Melanoma BRAF V600E mut Kwak, Flaherty, 2010 PARP Olaparib Breast Germline Ttt2010 Tutt, BRCA1/2 mut

59

60 Edwards, Nat 2008; Sakai, Nat 2008

61 64 Primary OC: 3% secondary mutations 25% vs 0 46% 46 Recurrent OC: 28% secondary mutations 5% 10% vs 0 Not all secondary mutations tti are associated with resistance to platinum No Norquist et al, JCO 2011

62 CDK1 Narod and Foulkes, 2004

63 CDK1 inhibitor PARP1 inhibitor Johnson et al, Nat Genet 2011

64 Ecteinascidins

65 Trabectedin in BRCA carriers: ORR 5 27% ; median PFS months (Delaloge, ASCO 2009; Pharmamar)

66

67 BRCA associated tumors have a great chemosensitivity, especially to DNA damaging agents There is no definitive evidence of the superiority of platinums in BRCA BC. Randomized clinical trials are ongoig PARP inhibitors are promising in monotherapy. Combination with chemotherapy h may narrow the therapeutic window New targeted therapies towards the DNA repair deficiency are being tested