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SHARE Webinar: Latest Research on Metastatic Breast Cancer from SABCS 2015

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Dr. Tiffany Traina, medical oncologist at Memorial Sloan-Kettering Cancer Center, presents the latest research on metastatic breast cancer reported at the San Antonio Breast Cancer Symposium in December 2015.

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SHARE Webinar: Latest Research on Metastatic Breast Cancer from SABCS 2015

  1. 1. Latest Research on Metastatic Breast Cancer from San Antonio Breast Cancer Symposium 2015 and beyond Tiffany A.Traina, MD Section Head,Triple Negative Breast Cancer Clinical Research Program Associate Member, Breast Medicine Service, Department of Medicine Memorial Sloan Kettering Cancer Center Assistant Professor of Medicine, Weill Cornell Medicine
  2. 2. Topics of interest from SABCS 2015 • Neoadjuvant carboplatin • IMMU-132 TNBC • TH3RESA trialHER2+ • JAVELIN • KEYNOTE Immunotherapy • ABCSG18 • CREATE-X Other
  3. 3. Neoadjuvant platinum for TNBC?
  4. 4. Why platinums inTNBC? • Platinum activity in BRCA- associated BC – BRCA1 is a key mediator of DNA damage response – BRCA deficient cells have impaired ability to repair damage • 80% of BRCA1-associated BC areTN • “BRCAness” ofTNBC – SporadicTNBC have genomic instability similar to BRCA1-associated breast cancer • High pCR rates inTNBC pilot trials Wilson C A , et al Nat Genet 1999;21:236
  5. 5. GeparSixto: Does carboplatin increase response? von Minckwitz et al Lancet Oncology 2014 Jun; 15(7) N = 315
  6. 6. Yes, Carboplatin increases pCR pCR (ypT0N0) von Minckwitz et al Lancet Oncology 2014 Jun; 15(7)
  7. 7. CALGB 40603: Does carboplatin increase pCR? Sikov et al, J Clin Oncol 2015 Jan 1;33(1):13-21 Paclitaxel 80 mg/m2 wkly x 12 ddAC x 4 Bevacizumab 10 mg/kg q2wks x 9 Bevacizumab 10 mg/kg q2wks x 9 CarboplatinAUC 6 q3wks x 4 CarboplatinAUC 6 q3wks x 4 Paclitaxel 80mg/m2 weekly x 12 Surgery XRT No Adjuvant Systemic Treatment Planned Paclitaxel 80 mg/m2 wkly x 12 Paclitaxel 80 mg/m2 wkly x 12 Paclitaxel 80 mg/m2 wkly x 12 ddAC x 4 ddAC x 4 ddAC x 4 N = 443 2 X 2 Randomization Primary Endpoint: pCR Breast (ypT0/is N any) Key Eligibility St II-III ER/PR <10% HER2 (-)
  8. 8. N=212 Yes, Carboplatin increases pCR 46% (40-53%) 60% (54-66%) Odds Ratio: 1.76 p = 0.0018 41% (35-48%) 54% (48-61%) Odds ratio: 1.71 p = 0.0029
  9. 9. PaclitaxelddAC Significant side effects limit tolerability Slide courtesy of Bill Sikov; SABCS 2013
  10. 10. Von Minckwitz et al S2-04 SABCS 2015 Geparsixto: DFS improved with addition of carboplatin 3 yr DFS: 76.1% vs. 85.8% HR 0.59 P=0.03
  11. 11. Sikov et al S2-05 SABCS 2015 CALGB: Carboplatin did NOT improve breast cancer related survival
  12. 12. CALGB: Carboplatin did NOT improve OS using a conventional anthracycline, cyclophosphamide and taxane containing regimen Sikov et al S2-05 SABCS 2015
  13. 13. Why the discrepancy? Challenge of pCR as a surrogate endpoint Berry D and HudisC, JAMAOncology, July 2015 • Trials were not powered to show survival advantage • Statistically, need a very large pCR difference to see a survival advantage Many unanswered questions re: the role of platinum inTNBC • Does the backbone regimen matter? • Does type of platinum matter?
  14. 14. For individual trials, no association between pCR and survival benefit Cortazar et al, Lancet July 2014
  15. 15. Is neoadjuvant platinum a new standard? No, data fell short and uncertainty remains • Await molecular/biomarker correlatives to narrowly select who may benefit – BRCA status – Other markers of DNA repair problems (HRD) • Carboplatin added to anthracycline/taxane reasonable when the goal of pre-op therapy is to reduce tumor volume • Would not routinely recommend platinum in the adjuvant setting forTNBC based on these data
  16. 16. IMMU-132
  17. 17. Sacituzumab Govitecan (IMMU-132) A next-generation irinotecan of interest inTNBC • Trop-2 expressed in >90% ofTNBC • IMMU-132 is a antibody-drug conjugate of humanized anti-Trop- 2 coupled with SN-38, the active metabolite of irinotecan • Phase I/II ongoing – N = 60 patients withTNBC – ≥2 prior chemotherapy regimens; median of 5 priors – ORR = 31% (18/58);CBR24 = 45% – Median PFS 6 months (95% CI: 4.1- 9.4mo) – Most common side effects: low white cells, diarrhea, fatigue, anemia – Serious diarrhea 3% (relatively rare) Bardia et al, Abstract #1016; ASCO 2015; SABCS 2015
  18. 18. FDA Assigns Sacituzumab Govitecan Breakthrough Designation forTNBC! February 8, 2016 "We believe breakthrough therapy designation for IMMU- 132 further validates this potential therapeutic for patients withTNBC, and we are delighted to receive this important recognition." Cynthia L. Sullivan President and CEO of Immunomedics “The planned phase III trial of sacituzumab govitecan, on which Immunomedics is working with the FDA, is a multicenter, international, randomized, open-label study that aims to accrue 328 patients with relapsed/refractory metastaticTNBC following ≥2 prior chemotherapies, including a taxane.The primary outcome measure will be PFS, with secondary endpoints includingOS,ORR, duration of response, and time to onset of response.”
  19. 19. HER2+ Breast Cancer
  20. 20. Hudis C. N Engl J Med 2007;357:39-51; Slamon et al NEJM 2001; Targeting HER2 improves breast cancer survival!
  21. 21. T-DM1 Average number DM1 molecules/monoclonal antibody=3.5 1. Beeram M., et al. J Clin Oncol. 2008; 26 (May 20 suppl; abstr 1028).
  22. 22. TDM1 vs.TPC in HER2+ MBC Wildiers et al; SABCS 2015
  23. 23. TDM1 improves OS in HER2+ MBC Wildiers et al; SABCS 2015
  24. 24. Immunotherapy
  25. 25. Immunotherapy rationale • Normal part of immune regulation • Antibodies that block the PD-1 pathway can reactivate T-cell activity and proliferation • Leading to enhanced antitumour immunity Wolchok & Chan Nature 2014 Pembrolizumab Nivolumab Atezolizumab
  26. 26. Immunotherapy forTNBC TNBCs have high PD-L1 Early but encouraging results Pembrolizumab (SABCS 2014) • PD1 inhibitor. Blocks ability of tumor to deactivate immune system • Small Phase 1 trial • Responses in ~20% of women with PD-L1+TNBC • Well tolerated Atezolizumab = MPDL3280A (AACR 2015) • PD-1 inhibitor • Small Phase 1 trial • Responses in ~20% of patients • Well tolerated
  27. 27. Many potential immunotherapy trials! Pembrolizumab 1. Pembrolizumab + capecitabine or paclitaxel (PI Heather McArthur) 2. Pembrolizumab + eribulin (industry) 3. Carboplatin +/- pembro (TBCRC: PI Hope Rugo) 4. Pembro vs.TPC (Industry) Atezolizumab (MPDL3280A ) • Carboplatin +/- atezolizumab (TBCRC: Vanderbilt) • Nab-paclitaxel +/- atezolizumab (Industry)
  28. 28. JAVELIN: Ph 1b of Avelumab in SolidTumors Trial Design • Fully humanized anti-PD1 antibody • Expansion cohort MBC – </= 3 lines of cytotoxic tx – PriorT + A – Unselected for PD-L1 expression or molecular subtype Patient Characteristics • TNBC 35% • ER+ 43% • HER2+ 15% • Median 3 regimens (0-10) Dirix et al; SABCS 2015
  29. 29. JAVELIN:Toxicity Dirix et al; SABCS 2015
  30. 30. Activity of avelumab in pts with MBC Dirix et al; SABCS 2015
  31. 31. KEYNOTE: Pembrolizumab in PD-L1+ ER+ MBC Pembrolizumab • Anti-PD-L1 antibody • Activity in PD-L1+TNBC – ORR 19% (5/27; Nanda SABCS 2014) – 3/5 responders on drug >11m • PD-L1 expression inversely correlated with ER expression KEYNOTE-028 • Phase 1b multicohort trial – ER+ HER2- MBC – Failure of or inability to receive standard therapy – PD-L1+ (≥1% tumor or stroma) – Measurable disease • Pembrolizumab 10mg/kg q2 weeks until 8 week scan – Confirmed POD after 4 weeks – CR/PR/SD to 24mo or POD or tox Rugo et al; SABCS 2015
  32. 32. KEYNOTE-028 Pt Characteristics • 19% (48) of 261 screened were PD-L1+ • N=25 on study – 44% had ≥5 prior lines Rugo et al; SABCS 2015
  33. 33. ABCSG-18: A role for “adjuvant” denosumab
  34. 34. ABCSG18: Background • Adjuvant bisphosphonates have been associated with a significantly reduced rate of breast cancer recurrence in bone and improved survival in postmenopausal women with breast cancer[1] • ABCSG18 trial: phase III trial of denosumab vs placebo in AI-treated postmenopausal women with early HR+ breast cancer – Primary analysis: significant reduction in fracture risk with denosumab vs placebo[2] • HR: 0.50 (95% CI: 0.39-0.65; P < .0001) – IDMC recommended unblinding following results of primary analysis, with DFS analysis to be completed before unblinding • SABCS report from the ABCSG18 study includes the impact of denosumab on DFS in postmenopausal pts with early HR+ breast cancer on AIs[3] 1. EBCTCG, et al. Lancet. 2015;386:1353-1361. 2. Gnant M, et al. Lancet. 2015;386:433-443. 3. Gnant M, et al. SABCS 2015. Abstract S2-02.
  35. 35. ABCSG-18: Study Design • Prospective, randomized, double-blind, placebo-controlled phase III trial • Primary endpoint: time to first clinical fracture • Secondary endpoints: % change in BMD, vertebral fractures, DFS, OS, BoneM+FS, safety Postmenopausal pts with early HR+ breast cancer receiving adjuvant AI therapy* (N = 3425) Denosumab 60 mg SC Q6M (n = 1711) Placebo SC Q6M (n = 1709) Gnant M, et al. Lancet. 2015;386:433-443. *Pts excluded if history of IV bisphosphonate, SERMS,Cushing’s disease, Paget’s disease, hypercalcemia, hypocalcemia, hyperprolactinemia, or other active metabolic bone disease.
  36. 36. ABCSG-18: Disease-Free Survival • ITT analysis consistent with sensitivity analysis in which pts switching to another bone-active treatment were censored – Hazard ratio, denosumab vs placebo: 0.807 (95% CI: 0.66-0.99; P = .0424) Gnant M, et al. SABCS 2015. Abstract S2-02. Impact of Denosumab vs Placebo on DFS (ITT) 100 90 80 70 60 0 Disease-FreeSurvival(%) Mos Since Randomization 900 6 12 18 24 30 36 42 48 54 60 66 72 78 84 93.8% 88.9% 83.5% 92.6% 86.8% 80.4% .0510Placebo Denosumab Number of Events/Patients HR (95% CI) vs Placebo P value 203/1709 167/1711 0.816 (0.66-1.00)
  37. 37. Denosumab improves DFS when consider cross-over Gnant et al; SABCS 2015
  38. 38. Indirect Comparison with EBCTCG, Lancet 2015
  39. 39. Denosumab data is consistent with EBCTG
  40. 40. 3% absolute reduction in breast cancer mortality in post-menopausal women (18%)
  41. 41. CREATE-X: Ph III trial of adjuvant capecitabine
  42. 42. Does capecitabine improve DFS after pre-op chemo? Lee S-J,Toi et al; SABCS 2015 Capecitabine 2,500 mg/m2/day po Day 1-14 in a 21-day cycle x6 cycles ** Safety interim analysis after N=50, IDMC recommended 8 cycles of tx
  43. 43. CREATE-XTrial Design Statistics • Primary endpoint 5y DFS – Estimate 62% vs 70% – HR 0.74, 2 sided alpha 5% – 352 events expected from 900 pts – Planned 1 interim analysis for DFS at 2 years Eligibility • Age 20-74 • Stage I-IIIB • HER2 negative • Non-pCR and/or LN+ after pre-operative chemotherapy • No prior oral 5-FU Lee S-J,Toi et al; SABCS 2015
  44. 44. CREATE-X Results Patient characteristics • Med age 48y • ~60% Premenopausal • ~40% Stage III • ~60% LN+ • ~63% ER+ • NeoadjTx Received – A+T/AT 94% – TC 1% – 5-FU containing 60% • Endocrine tx (67%) and radiation (72%) Capecitabine Compliance • Reduced: 24-37% • Discontinued: ~18-25% ≥Gr 3Tox Control Capecitabine Neutropenia 1.6% 6.6% Diarrhea 0.4% 3% HFS 10.9% Lee S-J,Toi et al; SABCS 2015
  45. 45. Capecitabine improves DFS/OS following pre- operative chemotherapy Lee S-J,Toi et al; SABCS 2015 5% improvement in overall survival! Across all subsets 42% improvement ifTNBC
  46. 46. Exciting innovation and technology…
  47. 47. Cutting edge technology to personalize cancer treatment!
  48. 48. Clinical trial enrolling now at MSK… Device Drugs Lead PI:Traina. NCT# 02521363
  49. 49. ThankYou!

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