Navigating Breast Cancer Therapeutics in the Adjuvant and Metastatic Settings

Transcription

1 Navigating Breast Cancer Therapeutics in the Adjuvant and Metastatic Settings Helen K. Chew, MD, FACP Professor of Medicine UC Davis Comprehensive Cancer Center September 26, 2015

2 16th Annual Advances in Oncology 2015 September 25-26, 2015 Sacramento, CA Navigating Breast Cancer Therapeutics in the Adjuvant and Metastatic Settings Helen K. Chew, M.D. No relevant financial relationships in the past twelve months by presenter or spouse/partner. The speaker will directly disclosure the use of products for which are not labeled (e.g., off label use) or if the product is still investigational.

3 Objectives To discuss recent trials that inform us on the treatment of adjuvant and advanced: Triple negative breast cancer (TNBC) HER2 positive breast cancer Hormone receptor positive breast cancer

4 Schema of randomized phase II CALGB (Cancer and Leukemia Group B) trial. ddac, dose-dense doxorubicin plus cyclophosphamide. William M. Sikov et al. JCO 2015;33: by American Society of Clinical Oncology

5 CALGB Stage II/III non-inflammatory TNBC ER and PgR <10% HER2 0 or 1+ by IHC or nonamplified No grade >2 neuropathy or contraindications to bevacizumab Primary outcome: pcr rates

6 (A) Pathologic complete response (pcr) breast (ypt0/is); (B) pcr breast/axilla (ypt0/is N0); 95% CIs shown in parentheses. William M. Sikov et al. JCO 2015;33: by American Society of Clinical Oncology

7 Once-per-week paclitaxel (wp) and dose-dense doxorubicin plus cyclophosphamide (ddac) treatment by delivery arm. William M. Sikov et al. JCO 2015;33: by American Society of Clinical Oncology

8

9 CALGB The addition of either carboplatin or bevacizumab increased pcr compared to standard chemotherapy; the addition of both was associated with the highest pcr rate. However, two, large adjuvant trials of bevacizumab (BEATRICE and E5103) failed to demonstrate any DFS or OS benefit.

10 NRG BR003

11

12 Rationale 15% of unselected TNBC is associated with BRCA1 or 2 mutations. BRCA-mutated and some TNBCs may be deficient in homologous recombination repair, conferring a greater sensitivity to platinum agents.

13

14

15

16

17

18

19

20 Conclusion In unselected TNBC, there is no clinical benefit of carboplatin compared to docetaxel. However, in patients who harbor a BRCA 1 or 2 mutation, the ORR and PFS were significantly greater among those who received carboplatin versus docetaxel.

21 Triple Negative Breast Cancer TNBC is a heterogeneous entity and currently, no experimental/targeted therapies have improved DFS or OS over standard chemotherapy. There is compelling evidence for carboplatin in metastatic, BRCA-mutated tumors; large, prospective data are challenged by a small population.

22 Objectives To discuss recent trials that inform us on the treatment of adjuvant and advanced: Triple negative breast cancer (TNBC) HER2 positive breast cancer Hormone receptor positive breast cancer

23

24 Adjuvant HER2 directed therapy Based on the prospective adjuvant trials, chemotherapy and a year of trastuzumab is standard. What about small, node negative tumors? Maintenance HER2 directed therapy?

25 Original Article Adjuvant Paclitaxel and Trastuzumab for Node- Negative, HER2-Positive Breast Cancer Sara M. Tolaney, M.D., M.P.H., William T. Barry, Ph.D., Chau T. Dang, M.D., Denise A. Yardley, M.D., Beverly Moy, M.D., M.P.H., P. Kelly Marcom, M.D., Kathy S. Albain, M.D., Hope S. Rugo, M.D., Matthew Ellis, M.B., B.Chir., Ph.D., Iuliana Shapira, M.D., Antonio C. Wolff, M.D., Lisa A. Carey, M.D., Beth A. Overmoyer, M.D., Ann H. Partridge, M.D., M.P.H., Hao Guo, M.S., Clifford A. Hudis, M.D., Ian E. Krop, M.D., Ph.D., Harold J. Burstein, M.D., Ph.D., and Eric P. Winer, M.D. N Engl J Med Volume 372(2): January 8, 2015

26 Single institution phase II study Tumors <2 cm, node negative, HER2 positive 406 patients received weekly paclitaxel x 12 weeks with weekly trastuzumab to complete a year. Non-randomized results appeared promising.

27 Probabilities of Disease-free Survival and Recurrence-free Interval. Tolaney SM et al. N Engl J Med 2015;372:

28 Neratinib after adjuvant chemotherapy and trastuzumab in HER2-positive early breast cancer: Primary analysis at 2 years of a phase 3 randomized, placebo-controlled trial (ExteNET)

29 Study Design

30 Primary Endpoint: Invasive DFS (ITT)

31 Safety (Adverse Events 10%)

32 MARIANNE Study Design

33 Statistical Considerations

34 Progression-Free Survival by IRF

35 Grade 3 AEs Occurring in 3% in Any Treatment Arm

36 MARIANNE TDM-1 and TDM-1 + pertuzumab were not superior to taxane + trastuzumab. The addition of pertuzumab did not improve PFS compared to TDM-1 alone. These results affected the now closed KAITLIN trial of adjuvant taxane and trastuzumab + pertuzumab (control) versus TDM-1 + pertuzumab.

37 HER2+ breast cancer In the neo/adjuvant setting, chemotherapy and trastuzumab (+ pertuzumab) are recommended. Limited data on single agent paclitaxel and trastuzumab. Adjuvant neratinib s toxicities outweigh early, small benefits. In MBC, pertuzumab and TDM-1 have broadened treatment options.

38 Objectives To discuss recent trials that inform us on the treatment of adjuvant and advanced: Triple negative breast cancer (TNBC) HER2 positive breast cancer Hormone receptor positive breast cancer

39

40

41

42 Original Article Adjuvant Ovarian Suppression in Premenopausal Breast Cancer Prudence A. Francis, M.D., Meredith M. Regan, Sc.D., Gini F. Fleming, M.D., István Láng, M.D., Eva Ciruelos, M.D., Meritxell Bellet, M.D., Hervé R. Bonnefoi, M.D., Miguel A. Climent, M.D., Gian Antonio Da Prada, M.D., Harold J. Burstein, M.D., Ph.D., Silvana Martino, D.O., Nancy E. Davidson, M.D., Charles E. Geyer, Jr., M.D., Barbara A. Walley, M.D., Robert Coleman, M.B., B.S., M.D., Pierre Kerbrat, M.D., Stefan Buchholz, M.D., James N. Ingle, M.D., Eric P. Winer, M.D., Manuela Rabaglio-Poretti, M.D., Rudolf Maibach, Ph.D., Barbara Ruepp, Pharm.D., Anita Giobbie- Hurder, M.S., Karen N. Price, B.S., Marco Colleoni, M.D., Giuseppe Viale, M.D., Alan S. Coates, M.D., Aron Goldhirsch, M.D., Richard D. Gelber, Ph.D., for the SOFT Investigators and the International Breast Cancer Study Group N Engl J Med Volume 372(5): January 29, 2015

43 Characteristics of Patients in the Primary Analysis, Overall and According to Chemotherapy Cohort. Francis PA et al. N Engl J Med 2015;372:

44

45 Primary Analysis Comparisons of Tamoxifen plus Ovarian Suppression (OS) with Tamoxifen Alone. Francis PA et al. N Engl J Med 2015;372:

46 Kaplan Meier Estimates of Freedom from Recurrence of Breast Cancer and Freedom from the Recurrence of Breast Cancer at a Distant Site after a Median Follow-up of 67 Months, According to Treatment Assignment. Francis PA et al. N Engl J Med 2015;372:

47 Key Targeted Adverse Events Reported during Follow-up, According to Treatment Assignment. Francis PA et al. N Engl J Med 2015;372:

48 Conclusions Adding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population. However, for women who were at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal, the addition of ovarian suppression improved disease outcomes. Further improvement was seen with the use of exemestane plus ovarian suppression.

49 Adjuvant endocrine therapy Options for premenopausal women include: -Tamoxifen x 10 years -OFS + AI x 5 years -OFS alone?

50 Abstract LBA502 <br /><br /> A Double Blind Phase 3 Trial of Fulvestrant With or Without Palbociclib in Pre- and Post-menopausal Women With Hormone Receptor-positive, HER2- negative Advanced Breast Cancer That Progressed on Prior Endocrine Therapy<br />(PALOMA3 Study) Presented By Nicholas Turner at 2015 ASCO Annual Meeting

51 Slide 2 Presented By Nicholas Turner at 2015 ASCO Annual Meeting

52 Palbociclib Presented By Nicholas Turner at 2015 ASCO Annual Meeting

53 PALOMA3 Study Design Primary endpoint: PFS Presented By Nicholas Turner at 2015 ASCO Annual Meeting

54 Adverse Events All Cause Presented By Nicholas Turner at 2015 ASCO Annual Meeting

55 Primary Endpoint: PFS (ITT Population) Presented By Nicholas Turner at 2015 ASCO Annual Meeting

56 Endocrine therapy in MBC Palbociclib is the first CDK 4/6 inhibitor approved (with letrozole) in the first line treatment of postmenopausal women with hormone receptor positive breast cancer. Phase III data to use palbociclib with fulvestrant beyond first-line.

57 Thanks. Questions?