Update on Breast Cancer

Transcription

1 Update on Breast Cancer William J. Gradishar, MD Professor of Medicine Robert H. Lurie Comprehensive Cancer Center Feinberg School of Medicine Northwestern University

2 Overview PARP Inhibitors Neoadjuvant Therapy in BRCA+ BC SLNB and Auxillary Recurrence Endocrine Therapy Studies Metastatic Breast Cancer Therapy DM-1 Neratanib RIBBON-1

3 PARP Inhibitors

4 PARP-1 is a key enzyme involved in repair of single strand DNA breaks DNA single strand break (SSB) PNK 1 damage pol β PARP XRCC1 During S-phase, replication fork is arrested at LigIII Inhibition of PARP-1 prevents recruitment of DNA repair enzymes leads to failure of SSB repair -accumulation of SSBs site of SSB Degeneration into double strand breaks

5 Selective effect of PARP-1 inhibition on cancer cells with BRCA1 mutation DSB in DNA Triggers activation of HR pathway to repair DSB Normal cell BRCA-deficient cancer cell Deficient HR repair Increases DSB that can t be repaired Cell survival HR homologous recombination; DSB double strand break Genomic instability and apoptosis

6 PARP Inhibitor Mechanism of Action 1. PLATINUM CHEMOTHERAPY Inflicts DNA damage via adducts and DNA crosslinking CG CG AT T TA CG GC A PARP1 2. PARP1 UPREGULATION Base-excision repair of DNA damage CG CG AT T TA C G A PARP1 BSI INHIBITION OF PARP1 PARP1 Disables DNA base-excision repair 4. REPLICATION FORK COLLAPSE Double strand DNA break BRCA1 BRCA2 Cell Survival Cell Death O Shaughnessy J, et al. ASCO Abstract 3.

7 Triple Negative BC Shares Clinical and Pathologic Features with BRCA1-Related BC Characteristics Hereditary BRCA1 Triple Negative/Basal-Like 1,2,3 ER/PR/HER2 status Negative Negative TP53 status Mutant Mutant BRCA1 status Mutational inactivation* Diminished expression* Gene-expression pattern Basal-like Basal-like Tumor histology Chemosensitivity to DNA-damaging agents Poorly differentiated (high grade) Highly sensitive Poorly differentiated (high grade) Highly sensitive *BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of HMG or ID Perou C, et al. Nature. 2000;408: Cleator S, et al. Lancet Oncology. 2007;8: Sorlie T, et al. Proc Natl Acad Sci USA. 2001;98: Miyoshi Y, et al. Int J Clin Oncol. 2008;13: O Shaughnessy J, et al. ASCO Abstract 3.

8 Phase II TNBC Study: Treatment Schema BSI-201: small molecule PARP inhibitor Metastatic TNBC N = 120 RANDOMIZE Gemcitabine (1000 mg/m 2, IV, d 1,8) Carboplatin (AUC 2, IV, d 1,8) 21-Day Cycle BSI-201 (5.6 mg/kg, IV, d 1,4,8,11) Gemcitabine (1000 mg/m 2, IV, d 1,8) Carboplatin (AUC 2, IV, d 1,8) O Shaughnessy J, et al. ASCO Abstract 3. Restaging Every 2 Cycles * Patients randomized to gem/carbo alone could crossover to receive gem/carbo + BSI-201 at disease progression

9 BSI-201: Preliminary Efficacy Results* Gem/Carbo (n = 44) BSI-201 +Gem/Carbo (n = 42) P-value Objective Response Rate, n (%) 7 (16) 20 (48).002 **Clinical Benefit Rate, n (%) 9 (21) 26 (62).0002 * Includes patients enrolled before September 30, 2008 and patients who had a confirmed response or disease progression **Clinical Benefit Rate = CR + PR + SD 6 months O Shaughnessy J, et al. ASCO Abstract 3.

10 BSI-201: Conclusions PARP1 was upregulated in most evaluated TNBC patients BSI gemcitabine/carboplatin was well tolerated and did not potentiate chemotherapy-related toxicities BSI-201 improved patients clinical outcomes Clinical Benefit Rate (62% vs. 21%; P =.0002) ORR (48% vs 16%; P = 0.002) Median PFS (6.9 months vs. 3.3 months; P < ) Median OS (9.2 months vs. 5.7 months; P = ) Promising safety and efficacy data from this Phase II study justify further investigation of BSI-201 in a Phase III study O Shaughnessy J, et al. ASCO Abstract 3.

11 Phase II Study with Olaparib: Rationale and Design To assess the efficacy and tolerability of oral olaparib in BRCA1/BRCA2 mutation carriers with breast cancer Multicenter proof-of-concept phase II study, single-arm sequential cohort design Confirmed BRCA1 or BRCA2 mutation Advanced refractory breast cancer (stage IIIB/IIIC/IV) after failure 1 prior chemotherapy for advanced disease Cohort 1 (enrolled first) Olaparib 400 mg po BID (MTD) 28-day cycles; n = 27 Cohort 2* Olaparib 100 mg po BID 28-day cycles; n = 27 *Following an interim review of the emerging efficacy of each cohort, patients ongoing in 100 mg BID cohort were permitted to crossover to receive the 400 mg bid dose MTD: determined during Phase I evaluation Tutt A, et al. ASCO Abstract 501.

12 Olaparib: Efficacy Results ITT cohort Tutt A, et al. ASCO Abstract 501. Olaparib 400 mg bid (n = 27) Olaparib 100 mg bid (n = 27) Overall Response Rate, n (%) 11 (41)* 6 (22)* Complete Response, n (%) 1 (4) 0 Partial Response, n (%) 10 (37) 6 (22) *An additional 1 patient in the 400 mg cohort and 3 patients in the 100 mg cohort had unconfirmed responses Per protocol cohort 400 mg bid (n = 26) 100 mg bid (n = 24) Overall Response Rate, n (%) 11 (42) 6 (25) Complete Response, n (%) 1 (4) 0 Partial Response, n (%) 10 (39) 6 (25) An additional 3 patients in the 100 mg cohort had unconfirmed responses

13 Olaparib: Conclusions First report of a targeted therapy trial designed for BRCA1/BRCA2 carriers with breast cancer Single agent oral olaparib 400 mg bid has substantial activity in heavily pre-treated BRCA1/BRCA2 carriers with advanced breast cancer Objective response rate ITT (RECIST): 41% Median PFS: 5.7 months Oral olaparib is well tolerated in BRCA1/BRCA2 carriers with a similar side effect profile to prior experience in non-carriers Clinical proof-of-concept for targeting BRCA1/BRCA2 mutations in both breast and ovarian 1,2 cancer

14 Neoadjuvant Therapy in BRCA+ Breast Cancer

15 Neoadjuvant Study: Design BRCA1 Mutation Carriers Primary Breast Cancer Cisplatin 75mg/m2 q 3wks IV x 4 cycles N = S U R G E R Y AC Primary Endpoint: pcr (in breast and axilla, DCIS permitted) Gronwald J, et al. ASCO Abstract 502.

16 Neoadjuvant Study: Response to Treatment Response No. % Clinical response Complete response Partial response 7 28 No change 0 0 Progressive disease 0 0 Pathologic response Complete pathologic response Partial response 7 28 No response 0 0 Residual disease in breast None < 1 cm cm 6 24 > 5 cm 0 0 Number of lymph nodes positive >9 0 0 Gronwald J, et al. ASCO Abstract 502.

17 Neoadjuvant Study: Conclusions Platinum-based chemotherapy is effective in a high proportion of patients with BRCA1-associated breast cancers Choice of breast cancer treatment may be better with BRCA1 testing Gronwald J, et al. ASCO Abstract 502.

18 Sentinel Lymph Node Biopsy and Auxillary Recurrence

19 Omission of Axillary Therapy in Patients with pn1mi or pn0i+ by Sentinel Node Biopsy: the MIRROR Study Patients with favorable primary tumor characteristics No indication for adjuvant systemic therapy Sentinel node procedure pn0, pn0(i+) or pn1mi N = 2680 after central pathology review Sentinel node biopsy only (SN only) N = 1218 Completion axillary lymph node dissection (calnd) N = 1314 Axillary radiotherapy (axrt) N = 148 Patients selected from the Netherlands Cancer Registry ( ) (N = 3205) Median follow-up: 4.7 years Tjan-Heijnen et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA506).

20 Omission of Axillary Therapy in Patients with pn1mi or pn0i+ by Sentinel Node Biopsy: the MIRROR Study Results: Multivariate Analysis Sentinel node status pn0 pn0 (i+) pn1mi Axillary therapy N 5-yr axillary recurrence HR 95 % CI calnd % 1.00 Reference SN only % calnd/axrt % 1.00 Reference SN only % calnd/axrt % 1.00 Reference SN only % 4.39* HR corrected for age, tumor size, grade, hormone receptor status, adjuvant systemic therapy and radiotherapy to the breast * Statistically significant compared to calnd/axrt Tjan-Heijnen et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA506).

21 Omission of Axillary Therapy in Patients with pn1mi or pn0i+ by Sentinel Node Biopsy: the MIRROR Study Conclusions Omission of axillary therapy appears feasible in pn0 disease Axillary therapy non-significantly decreased axillary recurrence in those with pn0(i+) disease Axillary therapy significantly decreased axillary recurrence in those with pn1mi disease Patients who received axrt showed no axillary recurrence, although number of events was too small for statistical analysis Tumor size, histological grade III, and negative ER/PgR status were significantly predictive of 5-year axillary recurrence by multivariate analysis Tjan-Heijnen et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA506).

22 Endocrine Therapy Studies: CYP2D6 Inhibition

23 Tamoxifen Metabolism H 2 O H 2 O TAMOXIFEN CH 2 O O CH 2 CYP3A4/5 CYP1A2 CYP2C9 CTYP2C19 CYP2B5 O NCH 2 H CYP2D6 CYP2B6 CYP2C9 CTYP2C19 CYP3A CYP2D6 H 2 O H 2 O 4-OH-TAM CH 2 O O CH 2 OH CYP3A4/5 O N CH 2 H OH SULT1A1 UGT SULT1A1 UGT NDM-TAM ENDOXIFEN Aubert RE, et al. ASCO Abstract 508.

24 Risk of breast cancer recurrence in women initiating tamoxifen with CYP2D6 inhibitors Eligibility: Continuous eligibility 6 mo prior to tamoxifen initiation Tamoxifen naïve (6 mo negative history) Tamoxifen duration 24 months Medication possession ratio of (n 0.7 = 1659) No CYP2D6 inhibitor therapy Weak CYP2D6 inhibitor therapy use or without overlap with tamoxifen Moderate-severe CYP2D6 inhibitor use with tamoxifen (n = 945) (n = 355) (n = 359) Retrospective cohort analysis of medical and pharmacy claims from the Medco Health Solutions integrated database Primary endpoint: hospitalization for breast cancer (event-free survival) Median duration of overlap between CYP2D6 inhibitors and tamoxifen: 287 days Aubert et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA508).

25 Risk of breast cancer recurrence in women initiating tamoxifen with CYP2D6 inhibitors N Breast cancer recurrence HR* P value No CYP2D6 inhibitors % reference reference Moderate/severe CYP2D6 inhibitors % 1.92 ( ).0002 SSRIs Weak 137 9% 1.07 ( ).677 Moderate/potent % 2.20 ( ).0002 * HR relative to no CYP2D6 inhibitor group Concomitant use of tamoxifen with moderate-severe CYP2D6 inhibitors significantly increases the risk of breast cancer recurrence Moderate-potent SSRIs double the risk of recurrence, while weak SSRIs were not associated with increased risk Aubert et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA508).

26 Concomitant CYP2D6 inhibitor use and tamoxifen adherence in early stage breast cancer Inclusion criteria: breast cancer resection Tamoxifen use 120 days CYP2D6 inhibitor use 60 days (n = 3147) Tamoxifen only (n = 1749) Tamoxifen + CYP2D6 inhibitor (n = 150) Retrospective pharmaco-epidemiologic study Databases: PHARMO, PALGA, Dutch Medical Register Univariate Cox regression of event-free time: CYP2D6 inhibitor use HR 95% CI P value No use 1.00 reference reference Use 60 days No difference when only strong CYP2D6 inhibitors included Dezentje et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA509).

27 Summary of concomitant CYP2D6 inhibitor use with tamoxifen in early stage breast cancer Registry studies give conflicting results regarding the effect of concomitant use on breast cancer recurrence CYP2D6 pharmacogenomics likely complicated; published data on CYP2D6 genotypes inconsistent Possession of drug does not necessarily indicate compliance Need further validation studies before recommendations for routine use can be made

28 Metastatic Breast Cancer

29 Trastuzumab-DM1 Target-dependent cytotoxic activity DM1-Derivative of maytansine: - Naturally occurring antitumor antibiotic - Significant preclinical activity, but significant clinical toxicity as free drug Trastuzumab-DM1 is designed to preferentially deliver DM1 to HER2+ tumor cells: - Improve therapeutic index of DM1 - Maintain biological effect of trastuzumab

30 Phase II T-DM1 Study Description A multi-institutional, open-label, single-arm Phase II US study in patients with locally confirmed HER2-positive MBC who progressed while receiving HER2-directed therapy Patients had received a median of 3 prior chemotherapy agents for MBC (range 1-12) 67/112 (60%) patients also received prior lapatinib T-DM1 (3.6 mg/kg) was given by IV infusion over minutes every 3 weeks (q3w) until progression Primary endpoint Objective response rate (ORR) per RECIST by independent review facility (IRF) Krop IE, et al. ASCO Abstract 1003.

31 Retrospective analysis of biomarkers for response to trastuzumab-dm1 in pretreated HER2+ MBC Study objective: Identify biomarkers that will predict for response to T-DM1 Study details: Retrospective analysis of phase II study evaluating trastuzumab- DM1 in patients with HER2+ MBC with progression on prior HER2- targeted therapy Examined HER2 (IHC, FISH, RT-PCR), HER2 extracellular domain (ECD), HER3, PI3K mutations, PTEN loss Efficacy Centrally confirmed HER2+ (n = 75) Centrally confirmed HER2 normal (n = 21) P value ORR* (95%CI) 32% (22-43%) 5% (<1-22%).01 PFS* 7.4 mo 2.6 mo NR * By independent review Krop et al. J Clin Oncol 2009; 27 (suppl): 15s (abstract 1003).

32 Retrospective analysis of biomarkers for response to trastuzumab-dm1 in pretreated HER2+ MBC Centrally-confirmed HER2+ Patients PI3K mutation or PTEN loss N Number with objective response ORR (95% CI) (%) Yes (6-45) No (20-70) Unknown ( ) HER2-positivity by central testing was strongly correlated with response to trastuzumab-dm1 In patients with HER2+ disease, numerically lower response rate in patients with either PI3K mutations or PTEN loss Response to trastuzumab-dm1 showed no correlation with levels of HER2 ECD, HER2 gene copy number, or HER3 levels Krop et al. J Clin Oncol 2009; 27 (suppl): 15s (abstract 1003).

33 A Phase II Study of Trastuzumab-DM1 in Patients With HER2+ Pretreated MBC: Efficacy Tumor response n IRF ORR % (95% CI) IRF CBR* % (95% CI) All evaluable patients ( ) 35 ( ) Patients previously treated with trastuzumab and lapatinib Patients with centrallyconfirmed HER2+ disease * CBR = CR+PR+SD 6 mo ( ) 36 ( ) ( ) 44 ( ) IRF = independent review facility; ORR = overall response rate Median PFS = 4.9 months Vogel et al. J Clin Oncol 2009; 27 (suppl): 15s (abstract 1017).

34 A Phase II Study of Trastuzumab-DM1 in Patients With HER2+ Pretreated MBC: Safety Adverse event (AE) (n = 112) Grade 3 (%) Grade 4 (%) Thrombocytopenia Hypokalemia 8 0 Fatigue Epistaxis 2 0 Musculoskeletal chest pain 2 0 Dyspnea 2 1 Pleural effusion 2 0 Confusional state 0 2 Cardiac safety (n = 108): No grade 3 or 4 LVEF dysfunction reported Only 2 patients had LVEF declines below 45% Treatment discontinuation: 83/112 discontinued (70 due to disease progression and 1 death due to progression) 5 patients discontinued due to AE, 4 that were possibly related to T-DM1 Vogel et al. J Clin Oncol 2009; 27 (suppl): 15s (abstract 1017).

35 Phase II results of the pan-her inhibitor neratinib (HKI- 272) in patients with advanced breast cancer 240 mg/day in women with stage IIIB,C or IV HER2-positive BC. Arm A: Prior (at least 6 weeks) trastuzumab treatment Arm B: No prior trastuzumab Most common grade 3/4 adverse event was diarrhea Prior Trastuzumab (n = 61) No Prior Trastuzumab (n = 66) Total (n = 127) ORR (95% CI) 26% (16-39) 56% (43-68) 42% (33-51) Clinical benefit rate* (95% CI) 36% (24-49) 68% (56-79) 53% (44-62) 16-week PFS rate (95% CI) 60% (46-72) 77% (64-86) NR PFS (95% CI) 23 weeks (16-39) 40 weeks (32-55) NR Burstein et al. Cancer Res 2009; 69 (suppl): (abstract 37).

36 Phase I/II trial of neratinib (HKI-272) + trastuzumab in advanced breast cancer Stage IIIB, IIIC, or IV HER2+ BC with progression following 1 trastuzumabcontaining regimen in any setting Part 1: Neratinib 160 mg qd (n = 4), 240 mg qd (n = 4) with trastuzumab 2 mg/kg weekly (4 mg/kg loading dose) Part 2: Neratinib 240 mg qd (n = 37) with trastuzumab 2 mg/kg weekly (4 mg/kg loading dose) Adverse events* N (%) All grades Grade 3/4 Diarrhea 41 (91) 7 (16) Nausea 23 (51) 2 (4) Anorexia 18 (40) NR Vomiting 17 (38) 2 (4) Asthenia 13 (29) NR Efficacy ORR 29% CR 7% PR 21% CBR* 36% 16 wk PFS rate 45% Median PFS * No significant changes in LVEF reported * CR+PR+SD 24wks 16 wks Swaby et al. J Clin Oncol 2009; 27 (suppl): 15s (abstract 1004).

37 RANDOMIZE 2:1 RIBBON-1: Study Design Previously untreated MBC (n = 1237) Stratification Factors: Disease-free interval Previous adjuvant chemotherapy Number of metastatic sites CHOICE OF CHEMO Capecitabine or Taxane or Anthracycline Chemo + bevacizumab q3w Chemo + placebo q3w Treat until PD Optional 2 nd -line chemo + bevacizumab Cape, T, or Anthra Capecitabine (1000 mg/m 2 BID x 14d) Taxane (docetaxel q3w or protein-bound paclitaxel q3w) Anthracycline-based chemotherapy (AC, EC, FAC, FEC) Placebo or bevacizumab (15mg/kg q3w) Robert N, et al. ASCO Abstract 1005.

38 RIBBON-1: Exploratory Endpoint - PFS by Chemotherapy Subgroups PL (n = 104) Taxane BV (n = 203) PL (n = 103) Anthra BV (n = 212) Median PFS, mo HR (95% CI) 0.75 ( ) 0.55 ( ) P-value.0547 <.0001 PFS = PFA by investigator Robert N, et al. ASCO Abstract 1005.

39 % RIBBON-1: Objective Response Rates Cape P =.0097 T/Anthra P = CR PR Measurable PL BV PL BV disease, (n) Includes only patients with measurable disease at baseline. Robert N, et al. ASCO Abstract 1005.

40 RIBBON-1: Overall Survival PL (n = 206) Cape BV (n = 409) PL (n = 207) T/Anthra BV (n = 415) % of deaths Median OS, mo HR (95% CI) 0.85 ( ) 1.03 ( ) P-value yr survival rate (%) P-value Robert N, et al. ASCO Abstract 1005.

41 RIBBON-1: Safety Summary Events (%) PL (n = 201) Cape Taxane Anthra BV (n = 404) PL (n = 102) BV (n = 203) PL (n = 100) BV (n = 210) Selected AEs* SAEs AEs leading to study drug (PL or BV) discontinuation AEs leading to death** *AEs previously shown to be associated with BV **Excludes AEs related to MBC progression Robert N, et al. ASCO Abstract 1005.

42 Conclusions RIBBON-1 provides a third randomized Phase III trial demonstrating the efficacy and safety of combining bevacizumab, a direct VEGF inhibitor, with first-line chemotherapy for MBC RIBBON-1 establishes the efficacy of combining bevacizumab with non-taxane chemotherapies used for first-line treatment of MBC. The safety profile of bevacizumab in combination with these chemotherapies was consistent with that reported from prior Phase III trials.

43