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ASCO 2006 Update Novel Therapeutics in Prevention and Treatment for Breast Cancer

ASCO 2006 Update Novel Therapeutics in Prevention and Treatment for Breast Cancer. Hope S. Rugo, MD Clinical Professor of Medicine Director, Breast Oncology Clinical Trials Program UCSF Comprehensive Cancer Center. Discussion Outline. Endocrine Therapy Prevention 5: STAR NSABP P-2

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ASCO 2006 Update Novel Therapeutics in Prevention and Treatment for Breast Cancer

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  1. ASCO 2006 UpdateNovel Therapeutics in Prevention and Treatment for Breast Cancer Hope S. Rugo, MD Clinical Professor of Medicine Director, Breast Oncology Clinical Trials Program UCSF Comprehensive Cancer Center

  2. Discussion Outline • Endocrine Therapy • Prevention • 5: STAR NSABP P-2 • Adjuvant therapy • Updates from IES, ARNO95, GROCTA4/ITA, MA17 • Bone health substudy from ATAC • Neoadjuvant • Metronomic chemotherapy (SWOG 0012) • Adjuvant trastuzumab • Update on the HERA trial • New treatments for HER2+ disease – Lapatanib • Phase III trial with capecitabine • 502: Inflammatory breast cancer • 503: Treatment of CNS disease • 583: Risk of cardiac toxicity

  3. The Study of Tamoxifen and Raloxifene (STAR): Initial Findings from the NSABP P-2 Breast Cancer Prevention Study TAMOXIFEN 20 mg/day X 5 years • Eligibility: • Postmenopausal women at moderate to high risk • 5-year breast cancer risk by modified Gail score = 1.66% RALOXIFENE 60 mg/day X 5 years • Accrual (July 1999-Nov 2004) – 19,747 women randomized • Interim results at 327 invasive breast cancer cases • Average follow-up 47.3 months Wickerham, ASCO 2006, LBA#5

  4. Patient Population Age: <49: 9%; 50-59: 50%; 60-69: 32%; 70+: 9% Prior hysterectomy: 51.5% Prior LCIS: 9.2% Prior Atypical Hyperplasia: 22.7% NSABP P-2: Results Wickerham, ASCO 2006, LBA#5 * Gail Model Projected Incidence: 312

  5. SAFETY *P=.01 Wickerham, ASCO 2006, LBA#5

  6. STAR Trial: Summary • Raloxifene compared to tamoxifen for breast cancer prevention in postmenopausal women was • As effective in preventing invasive disease • Not as effective in preventing in situ disease • And resulted in: • Fewer thromboembolic events • Fewer cataracts • Fewer endometrial cancers • Patient reported outcomes • More musculoskeletal symptoms, weight gain, dyspareunia with raloxifene • More vasomotor symptoms, bladder problems, leg cramps, gynecologic symptoms with tamoxifen • The future of prevention trials? • Comparison of aromatase inhibitors to placebo • Map 3 – exemestane vs placebo (4560 pts) • IBIS-2 – anastrozole vs placebo (6000 pts)

  7. RANDOMIZE IES Trial Design Exemestane 5162* Post Treatment Follow-up 10335* Tamoxifen 4724 Tamoxifen 5294* 2-3 years study treatment 2-3 years Start of study Diagnosis Total 5 years endocrine therapy * Total women years Coombes, # LBA527

  8. First Mature Survival Analysis of the IES Trial: Switching to Exemestane after 2-3 Years of Adjuvant Tamoxifen Coombes, # LBA527 122 pts found to be ER- on central review, 2.4 vs 2.8% Median Follow-up: 55.7 months, 4.6 yrs

  9. Exemestane Tamoxifen Cumulative Hazard Rate - OS ITT ER+/Unknown End of treatment End of treatment

  10. IES: Cardiovascular Safety Coombes, # LBA527

  11. IES: Safety

  12. ARNO 95: Survival Benefit of Switching to Anastrozole after 2 yrs Tamoxifen vs Continued Tamoxifen Kaufmann, # 547 • Small trial, small number of events • N = 979 • No adjuvant chemotherapy given, 74% node negative • Median follow-up 30 months • Results • Switching to anastrozole reduced risk of recurrence (HR 0.66; P=.049) • 3-year DFS • Absolute difference of 4.2% (93.5% vs 89.3%) • Switching to anastrozole improved OS (HR 0.53; P=.045) • Serious adverse events were reported less frequently with anastrozole (22.7% vs 30.8%; P=.0065) • Vascular events 9.2% A vs 8.8% T • Musculoskeletal events 16.8% A vs 8.0% T • Endometrial events 4.5% A vs. 15.9% T

  13. Pooled Analysis of Grocta 4 and ITA Trials:Mortality Benefit of Switching to an AI Boccardo, # 548 • Two consecutive small phase III trials • Tamoxifen for 2-3 yrs followed by either aminoglutethimide or anastrozole for a total of 5 yrs • N=813 (pooled) • 415 tamoxifen for 5 years • 413 tam followed by either A • Results • All-cause mortality • HR 0.61 favoring switch, P = .007 • Breast cancer mortality • HR 0.61 favoring switch, P =0.25 • Breast cancer unrelated deaths HR = 0.62; P=.10 • Small studies, hard to evaluate P values in pooled analyses, encouraging results!

  14. Updated analysis of NCIC CTG MA.17 (letrozole vs. placebo to letrozole vs placebo) post unblindingRobert, # 550 Letrozole n= 2593 Letrozole n = 2457 Tamoxifen N = 5187 R Placebo (PLAC) n = 613 Placebo n= 2594 5 years Letrozole (PLAC-LET) n = 1655 0-3 mo Median F/U (mo) 30 54 Unblinding • Purpose: compare PLAC-LET vs PLAC to determine benefits/safety of starting letrozole after prolonged periods (1-5 y) off tamoxifen • Patients: those who switched (PLAC-LET) were younger, had more advanced disease, and were more likely to have had adjuvant chemotherapy than PLAC patients

  15. Updated analysis of NCIC CTG MA.17 (letrozole vs. placebo to letrozole vs placebo) post unblinding PLAC-LET to PLAC Hazard Ratio P=0.05 P<0.0001 P=0.002 P=0.012 • Safety • PLAC-LET vs PLAC: no significant increase in fractures (P=0.60); more new osteoporosis (P=0.007); no difference in cardiovascular disease (P=0.84) OS = overall survival; CBC = contralateral breast cancer. Robert, ASCO 2006 # 550

  16. NCIC CTG MA.17: Intent to treat analysis (ITT) of randomized patients after a median follow-up of 54 monthsIngle, # 549 • Advantage of letrozole for DFS, DDFS and contralateral breast cancer reduction maintained despite 73% of patients on placebo opting to receive letrozole after study unblinding

  17. Effect of Anastrozole on Bone Mineral Density: 5-year Results from the ATAC Trial SubStudyColeman, # 511 • Bone subprotocol: Anastrozole N=81, Tamoxifen N=86 • More bone loss reported with anastrozole in lumbar spine (P<.0001) and hip (P<.0001) • No patients with normal bone at baseline became osteoporotic while on treatment • 17% on anastrozole became osteopenic versus 3% on tamoxifen • Of patients osteopenic at baseline • 5% became osteoporotic on anastrozole versus 1% on tamoxifen • On the ATAC trial, a total of 11% of patients on anastrozole experienced bone fracture, versus 7.7% on tamoxifen (HR 1.49; P<.0001)

  18. SWOG 0012Standard AC vs Weekly A and Daily C, followed by Weekly T, a Randomized Phase III Comparison as Neoadjuvant Therapy of Inflammatory and Locally Advanced Breast CancerEllis, # LBA537 RANDOMIZE A (60 mg/m2) with C(600 mg/m2) q 3 wks x 5 → Paclitaxel 80 mg/m2 wkly x 12 SURGERY Inflammatory or Locally Advanced BC N=265 (IBC 31%) A (24/m2/wk) with C (60/m2/day) + G-CSF wkly x 15 → Paclitaxel 80 mg/m2 wkly x 12 Primary endpoint: Pathologic CR

  19. SWOG 0012Results Ellis, ASCO 2006 # LBA537

  20. Conclusions • We need to carefully select patients for adjuvant clinical trials testing different chemotherapy regimens • Differences in regimens will be magnified in specific patient groups • Topoisomerase II gene amplifications and deletions associated with response to anthracyclines • Genes associated with cellular proliferation correlate with response to chemotherapy • Aromatase inhibitors should be part of adjuvant hormonal therapy for postmenopausal women and are beneficial even late after diagnosis • Careful attention should be paid not only to side effects, but risk factors that predispose women to adverse events

  21. Randomization Observation After ASCO 2005, option of switch to trastuzumab HERA Trial: Median F/U 2 yrs Women with locally determined HER2-positive invasive early breast cancer Surgery + (neo)adjuvant CT ± RT Centrally confirmed IHC 3+ or FISH+ and LVEF ≥ 55% X 2 years trastuzumab 8 mg/kg 6 mg/kg 3 weekly schedule 1 year trastuzumab 8 mg/kg  6 mg/kg 3 weekly schedule 861 observation patients are known to have switched to trastuzumab Smith et al, ASCO 2005

  22. Patient Characteristics % patients Observation(n=1698) 1 year trastuzumab(n=1703) Prior (neo)adjuvant CT No anthracyclines 5.9 5.9 Anthracyclines, no taxanes 68.1 67.8 Anthracyclines + taxanes 26.0 26.3 Hormone receptor status Negative 50.4 50.5 Positive 49.6 49.5 Nodal status Neoadjuvant CT 10.5 11.4 Negative 32.7 31.9 1-3 28.928.5 >4 27.9 28.1 539 events observed in the 2 arms (347 at ASCO 2005)

  23. 6 12 18 24 30 36 Disease-free survival (ITT)Median FU 2 yrs Patients(%) 100 1 yeartrastuzumab 80 6.3% Observation 60 3-yearDFS 40 Events HR 95% CI p value 80.6 218 0.54, 0.76 <0.0001 0.64 20 74.3 321 0 0 Months from randomisation No. at risk 1703 1591 1434 1127 742 383 140 1698 1535 1330 984 639 334 127

  24. 6 12 18 24 30 36 Overall survival (ITT) Median FU 2 yrs 1 yeartrastuzumab Patients(%) 100 2.7% Observation 80 60 3-yearOS 40 Events HR 95% CI p value 92.4 0.47, 0.91 0.0115 0.66 59 20 89.7 90 0 0 Months from randomisation No. at risk 1703 1627 1498 1190 794 407 146 1698 1608 1453 1097 711 366 139

  25. Secondary efficacy end points(ITT analysis) 1 year trastuzumab Observation TTR TTDR OS HR 1.0 0.66 0.62 0.60 No. events 305 198 255 160 90 59 0 95% CI p value (log rank) 3-year percent, % 0.52, 0.74 <0.000175.4 vs 82.1 0.49, 0.73 <0.000179.4 vs 85.7 0.47, 0.91 0.011589.7 vs 92.4 TTR, time to recurrence; TTDR, time to distant recurrence; OS, overall survival

  26. Annualized DFS hazards - ITTobservation and 1 year trastuzumab groups Months since randomisation

  27. HERA N=5102 Analyzed=3387 Chemo  T 2 year BCRIG006 N=3222 Analyzed=3222 N9831 N=2766 Analyzed=1736 NSABP-B31 N=2046 Analyzed=1615 Chemo  T 1 year C +D x 6 + T 1y ACx4P wk x 12 + T 1y FINHER N=232 Analyzed=232 AC x 4 D x 4 + T 1y ACx4 Pwk x 12 + T 1y ACx4Px4 + T 1y Chemo  Nil AC x 4 D x 4 D or V+T 9wksFECx3 ACx4  Px4 ACx4P wk x 12 D or VFEC 12 m 24 m 24 m 24 m 39 m F-up (months) Control arms w/o trastuzumab (T) Trastuzumab single agent following anthracycline  taxane Trastuzumab with taxane following anthracycline regimen Trastuzumab with chemo, avoiding or preceding anthracycline regimen ADJUVANT TRASTUZUMAB TRIALS Total randomized : 13,365 Total analyzed : 10,192 T=trastuzumab D=Docetaxel P=paclitaxel V=Vinorelbine AC=adriamycin+ cyclophosphamide

  28. Lapatanib Mechanism of Action Lapatinib • Binds to intracellular ATP binding site of EGFR (ErbB-1) and HER2 (ErbB-2) preventing phosphorylation and activation • Blocks downstream signaling through homodimers and heterodimers of EGFR (ErbB-1) and HER2 (ErbB-2) • Dual blockade of signaling may be more effective than the single-target inhibition provided by agents such as trastuzumab 1+1 2+2 1+2 Downstream signaling cascade Rusnak et al. Mol Cancer Ther 2001;1:85-94; Xia et al. Oncogene 2002;21:6255-6263; Konecny et al. Cancer Res. 2006;66:1630-1639

  29. Phase I Trial of Lapatanib and Capecitabine vs Cabecitabine in Advanced or Metastatic Breast Cancer • Progressive, HER2+ MBC or LABC • Previously treated with anthracycline, taxane and trastuzumab* • No prior capecitabine R A N D O M I Z E Lapatinib 1250 mg po qd continuously + Capecitabine 2000 mg/m2/d po days 1-14 q 3 wk Capecitabine 2500 mg/m2/d podays 1-14 q 3 wk • Stratification: • Disease sites • Stage of disease Patients on treatment until progression or unacceptable toxicity, then followed for survival N=528 *Trastuzumab must have been administered for metastatic disease Geyer et al, ASCO 2006

  30. IRC Per Protocol IRC TTP Events Number of Investigator Defined TTP Events Required for IA: 133 + 10% = 144 321 Patients Accrued by Time of Data Lock N=321 Number of Events: 114 103 Progressive BC 11 BC Related Deaths Imaging &photograph assessments sent to IRC Protocol Specified Interim Analysis Plan

  31. IDMC Recommendations March20th,2006 • Agreed with superiority and futility boundaries • Unanimous recommendation for termination of study enrollment based on : “clinically meaningful, statistically significant advantage in primary endpoint (TTP) in the capecitabine + lapatinib arm vs capecitabine alone arm” • No safety or tolerability concerns • Accrual as of 3/20/06: 392 of 528

  32. Disease Characteristics and Prior Treatment • Patients must have relapsed w/in 6 mo of adjuvant therapy or have progression of metastatic disease • Tumor • 35-38% hormone receptor positive • 96% stage IV disease, 50% > 3 metastatic sites • Prior treatment • 98% prior anthracylines, 98% prior taxanes • 97% prior trastuzumab • 91-93% metastatic • 4-6% adjuvant • 97-99% progressed on prior trastuzumab • Median duration of prior trastuzumab 43 wks • No difference in interval from last dose of T to randomization (66-70% > 4 weeks)

  33. Lapatinib + Capecitabine Capecitabine No. of pts 160 161 Progressed or died* 45 (28%) 69 (43%) 90 Median TTP, wk 19.7 36.9 80 Hazard ratio (95% CI) 0.51 (0.35, 0.74) 70 P-value (log-rank, 1-sided) 0.00016 60 50 40 30 20 10 0 10 20 50 0 30 60 40 Time (weeks) Time to Progession – ITT Population % of patients free from progression* 100 70 * Censors 4 patients who died due to causes other than breast cancer

  34. Progression-Free Survival - ITT Population Lapatinib + capecitabine 100 Capecitabine Cumulative Progression-Free Survival, % No. of pts 160 161 90 Progressed or died 45 (28%) 73 (45%) 80 Median PFS, wk 36.9 17.9 70 Hazard ratio (95% CI) 0.48 (0.33, 0.70) P-value (log-rank, 1-sided) 0.000045 60 50 40 30 20 10 0 10 20 0 30 70 50 40 60 Time (weeks)

  35. Response Rate - ITT Population *P-value (Fisher’s exact, 2-sided) = 0.113

  36. Brain Metastases as Site of Progression *P-value (Fisher’s exact, 2-sided)= 0.110

  37. Investigator Assessed Endpoints ITT Population 0.017

  38. Most Frequent Adverse Events All Grades 100 90 Severity Gr 4 % of Patients 80 Gr 3 70 Gr 2 L+C 60 1 Gr 1 12 50 L+C C 6 L+C C 40 19 C 11 2.5 5 30 7 13 28 15 20 20 11 26 19 10 13 12 9 9 0 Diarrhea PPE Rash and/or Skin Reaction L = lapatinib; C = capecitabine.

  39. Mean LVEF at Scheduled Assessments 80 Lapatinib + Capecitabine Capecitabine 75 70 65 Mean LVEF (%) 60 55 n=108n=92 n=84 n=67 n=160n=160 n=37 n=26 n=63 n=37 n=15 n=9 n=7 n=1 50 Week 24 Screening Week 6 Week 12 Week 18 Week 36 Week 48 Assessment

  40. Conclusions • The planned interim analysis crossed pre-specified reporting boundary and demonstrated a clinically meaningful and statistically significant improvement in median TTP • Lapatinib + capecitabine 8.5 mo vs capecitabine 4.5 mo • Lapatinib + capecitabine well tolerated; declines in LVEF were infrequent, asymptomatic, reversible • Fewer patients developed brain metastases as first site of progression in the group receiving lapatinib • Trials evaluating lapatinib in earlier stages of HER2+ breast cancer are warranted

  41. Two Stage Green-Dahlberg Design Pre-treatment tumor biopsy Administer lapatinib (1500 mg/d) Clinical Evaluation: according to RECIST criteria and *chest wall/skin response documented by Canfield digital photography *(CR: complete resolution of disease; PR >50% reduction; SD 20-49% reduction Phase II Trial of Lapatanib in Patients with Relapse/Refractory Inflammatory Breast Cancer Cohort A ErbB2+ Cohort B ErbB1+/ErbB2- Spector et al. ASCO 2006;Abstract 502

  42. Baseline Characteristics/ Demographics Spector et al. ASCO 2006;Abstract 502

  43. 17% PD 17% pending PTEN deficient 58% PD 100% 69% 17% SD 8.3% 100% of responders are ErbB2 (IHC 3+/FISH+)p-ErbB2 positive Preliminary Results: Treatment Response 100% 21% SD 50% 62% clinical responders 62% PR 0% Cohort A ErbB2+ 24 patients Cohort B ErbB1+/ErbB2- 12 patients 5 enrolled patients were not evaluable (did not express target or died prior to Day 28) Spector et al. ASCO 2006;Abstract 502

  44. Responses (RECIST and Skin) Spector et al. ASCO 2006;Abstract 502

  45. Summary Summary Lapatinib monotherapy is clinically active in heavily pre-treated IBC patients • 62% response rate in ErbB2 overexpressors Lapatinib is well tolerated • Generally grade 1/2 GI and skin toxicity Preliminary biomarker analysis suggests • Correlation of ErbB2 (IHC3+ or FISH+) with response • Responders are more likely to be p-ErbB2 positive • (which appears to correlate with FISH +) • Co-expression of IGF-IR does not appear to preclude response • PTEN deficiency does not appear to preclude response Spector et al. ASCO 2006;Abstract 502

  46. Phase 2 Trial of Lapatanib for Brain Metastases in Patients with HER2+ Breast Cancer • Lapatinib given in four week cycles • 750 mg PO BID • response assessed every 2 cycles • Dose modifications • grade 3 or 4  hold until grade 0 or 1 and reduce one level • grade 3 or 4 LVEF dysfunction or interstitial pneumonitis off study Lin et al, ASCO 2006, #503

  47. Patients and Toxicity • 39 patients enrolled, all off study by 5/06 • Prior CNS radiation in 95% (37) • 51% WBRT, 15% SRS, 28% both • Toxicity • No grade 4 • 21% grade 3 diarrhea, 22% grade 2 • Other common toxicities • Fatigue • Headache • Mild rash

  48. Best CNS Response (RECIST)(N=39) Complete Response (CR) 0 Partial Response (PR) 2 (5.1%) [95% CI 1% to 17%] *Both received prior WBRT and SRS TTP 49 and 23 weeks 16 measurable disease, 4PR Lin et al. ASCO 2006;Abstract 503

  49. Best CNS Response (RECIST)(N=39) Complete Response (CR) 0 Partial Response (PR) 2 (5.1%) Baseline Week 8 Lin et al. ASCO 2006;Abstract 503

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