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What’s New in Biology, Treatment and Clinical Trials for Metastatic Triple-Negative Breast Cancer

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Triple-negative breast cancer is an area of very active research, with many exciting new agents and approaches in the pipeline.

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What’s New in Biology, Treatment and Clinical Trials for Metastatic Triple-Negative Breast Cancer

  1. 1. What’s New in Biology, Treatment and Clinical Trials for Metastatic Triple-Negative Breast Cancer Nancy Lin, MD Susan F. Smith Center for Women’s Cancers Clinical Director, Breast Oncology Center Geoffrey Shapiro, MD, PhD Director, Early Drug Development Center Dana-Farber Cancer Institute
  2. 2. Outline • Definitions: What is TNBC? • Treatment: How do we treat TNBC? • New Directions: What are some approaches being tested in clinical trials? • Clinical Trials: Which, why, how, when?
  3. 3. • There are three main subtypes of breast cancer • Within these, there are other ways to further sub-divide breast cancers • Oncologists use the breast cancer subtype to guide the kinds of treatments to recommend • Clinical trials often will focus on specific subtypes Breast Cancer Subtypes
  4. 4. Breast Cancer Subtypes Breast Cancer Subtypes ER-positive HER2-positive Triple-negative TALK to your doctor if you are not sure what type of breast cancer you have
  5. 5. “Triple Negative” Breast Cancer (TNBC) • Defined as negative for estrogen, progesterone, and HER2 receptors • Represents about 15% of all breast cancer • More likely to present in younger women and in women of African ancestry • May be associated with an inherited mutation in BRCA1 – National guidelines recommend consideration of genetic testing in women younger than age 60 with TNBC, regardless of family history – But--most patients with triple negative breast cancer do not carry a hereditary BRCA1 mutation
  6. 6. Hormonal therapy Hormonal therapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Herceptin + perjeta + chemotherapy TDM1 Lapatinib + Capecitabine Herceptin + chemotherapy Herceptin + chemotherapy Hormone receptor positive Triple-negative HER2-Positive *Note, these are just examples. Each patient is different and treatment is tailored accordingly. How Do We Treat Metastatic Breast Cancer?
  7. 7. Chemotherapy for Metastatic TNBC Many active and tolerable chemotherapy choices
  8. 8. • Order of chemotherapy does not appear to influence survival • Choose chemotherapy based on: – Activity level seen in clinical trials – Amount of active cancer/need for rapid response – Prior treatments – Route of administration (pills versus IV) – Side effect profile – BRCA 1/2 status – Other health problems • Blood counts, neuropathy, diabetes, heart problems, liver function Choice of Chemotherapy in Metastatic TNBC
  9. 9. Drug Route Hair loss Diarrhea Neuropathy Hand foot redness Effect on blood counts Paclitaxel (Taxol) IV weekly 2 or 3 wks in a row Then off 1 wk Yes No Yes No + Capecitabine (Xeloda) Oral twice daily 2 wks in a row Then off 1 wk No Yes No Yes + Eribulin (Halaven) IV weekly 2 wks in a row Then off 1 wk Sometimes No Yes No ++ Choice of Chemotherapy in Metastatic TNBC: One example •What chemotherapies have been given previously? How long ago? •Able to take and absorb pills? •How is the liver function? •How important is avoidance of hair loss? •Any baseline neuropathy and how severe?
  10. 10. Is all TNBC the same? ER-negative, PR-negative HER2-negative
  11. 11. Heterogeneity of TNBC TNBC is not just one disease— Different subtypes likely have different “Achilles’ heels” VEGF EGFR PTEN loss BRCA1- Basal-like AR Immune infiltrate
  12. 12. Many Approaches Under Evaluation for TNBC in Clinical Trials Pathway/Drug type Drugs in development DNA repair PARP inhibitors (olaparib, rucaparib, veliparib), platinum agents (cisplatin, carboplatin) PI3K/Akt/mTOR PI3K inhibitors (buparlisib, taselisib, GDC0941, AZD8186, many others); Akt inhibitors (GDC0068, others), mTOR inhibitors (everolimus, others) Androgen (testosterone) signaling Anti-androgens (bicalutamide, enzalutamide) Immune CTLA4 blockade (ipilumumab), PD1/PD-L1 blockade (nivolumab, pembrolizumab, atezolizumab), Antibody-drug conjugates IMMU-132, SGN-LIV1A, PF06647263, CDX-011 Cell cycle Dinaciclib, seleciclib Chk1 GDC0575 Bromodomain TEN-101, GSK525762 Heat shock (stress) Ganetespib, others Angiogenesis Ramucirumab, cedirinib
  13. 13. Targeting DNA repair
  14. 14. Environmental Insults Cause DNA Damage Cross-linking agents Cross-links DNA Damage leads to mutations that can contribute to development of cancer
  15. 15. Chemotherapy and radiation used in cancer treatment also damage DNA Normal Cells Cancer cells Six normal DNA repair pathways + + + + + + Cancer cells are often deficient in one or more DNA repair pathway − + + + + +
  16. 16. Cancer cells may become hyper-dependent on a second DNA repair pathway Six normal DNA repair pathways Normal cells One defective pathway leads to hyper-dependence on a second pathway Cancer cells + + + + + + − + + + + +
  17. 17. The status of the six DNA Repair Pathways can drive treatment decisions (Precision Medicine) Cancer Status Clinical Decision One pathway is defective Use a chemotherapy drug that requires that pathway for repair Pathway is restored and the cancer becomes resistant Use a chemotherapy drug + an inhibitor of the restored pathway to re-sensitize the cancer (combination treatment) One pathway is defective and the cancer is hyper-dependent on a second pathway Use an inhibitor of the second pathway
  18. 18. TNBC may be defective in the homologous recombination (HR) repair pathway Cancer Status Clinical Decision HR pathway is defective (inherited or acquired BRCA mutation) Sapacitabine or cisplatin damage DNA in a way that requires HR for repair; cancer cells defective in HR are highly sensitive to these agents HR pathway is restored and the cancer becomes resistant Use sapacitabine or cisplatin + a 2nd drug that disrupts HR (e.g. CDK inhibitor, HSP90 inhibitor, PI3-Kinase inhibitor) Cell defective in the HR pathway become hyper-dependent on a second pathway called alt-NHEJ Alt-NHEJ requires the PARP enzyme. A PARP inhibitor blocks alt-NHEJ and is lethal to an HR-defective cancer cell.
  19. 19. Basis of Use of PARP inhibitors in HR- deficient breast cancer (BRCA-mutated)
  20. 20. Concept of Synthetic Lethality Cancer Status Inhibition of PARP1 Repair Status Cellular Outcome HR-proficient (BRCA WT) – PARP repairs SSBs Cancer and Normal Cell Survival HR-proficient + HR (BRCA1/2) repairs DSBs Cancer and Normal Cell Survival HR-deficient (BRCA mutated) – PARP repairs SSBs Cancer and Normal Cell Survival HR-deficient (BRCA mutated) + HR is defective Alt-NHEJ cannot compensate No Repair Normal Cell Survival Cancer Cell Death DNA Damage Single-Strand Break Double-Strand Break
  21. 21. Concept of Synthetic Lethality has translated to positive clinical outcomes in patients treated with a PARP inhibitor (olaparib)
  22. 22. Platinum Agents and Breast Cancer • Include the drugs cisplatin and carboplatin • DNA cross-linking agents—so there is reason to believe they may be especially effective in patients with BRCA ½ mutations and/or with triple negative breast cancer • These drugs are active in breast cancer in general….but the questions is:
  23. 23. Platinum Agents and Breast Cancer • Include the drugs cisplatin and carboplatin • DNA cross-linking agents—so there is reason to believe they may be especially effective in patients with BRCA ½ mutations and/or with triple negative breast cancer • These drugs are active in breast cancer in general….but the questions is: How does platinum chemotherapy compare with other chemotherapy drugs?
  24. 24. TNT Trial Metastatic TNBC Or BRCA ½ associated breast cancer Platinum chemotherapy Taxane chemotherapy
  25. 25. Tutt et al, SABCS 2014
  26. 26. PARP Inhibitors •Tumors of BRCA 1/2+ patients lose 2 important ways to repair DNA when treated with a PARP inhibitor •Multiple trials testing PARP vs chemo in BRCA 1/2 carriers •Trials combining PARP with other drugs in BRCA 1/2 non-carriers
  27. 27. Phase 3 Trials Ongoing Inherited BRCA 1 or BRCA2 mutation Up to 2 previous types of chemotherapy for MBC PARP inhibitor Choice of standard chemotherapy -Capecitabine -Vinorelbine -Eribulin -Gemcitabine (allowed in BRAVO and EMBRACA)Olaparib – OLYMPIAD – NCT02000622 Niraparib – BRAVO – NCT01905592 BMN673 – EMBRACA – NCT01945775 Completed accrual, awaiting results Accruing Accruing
  28. 28. Targeting the Androgen Receptor
  29. 29. Androgen Receptor Function: The Basics Testosterone Androgen Receptor
  30. 30. Androgen Receptor Function: The Basics Testosterone Androgen Receptor DNA
  31. 31. Targeting AR in the Clinic • Bicalutamide – 21% had stable disease > 6 months • Enzalutamide – 20% of patients had stable disease > 6 months – “PredictAR” gene signature sorted patients to those with average disease control 2 months vs 10 months – Phase III study (ENDEAR) to be launched will compare Taxol vs enza vs combination of Taxol + enza for predictAR+ve patients Gucalp et al, CCR 2013; Traina et al, ASCO 2015
  32. 32. Modulating the immune system
  33. 33. The Immunity Cycle
  34. 34. APC-T Cell Interaction T"cell TCR CD28 CTLA4 APC MHC CD28 B7 T"cell&inhibition T"cell TCR CD28 CTLA4 APC MHC B7 T"cell&activation T"cell TCR CD28 CTLA4 APC MHC B7 T"cell&potentiation Antibody binds CTLA"4 X B7-CTLA-4 interaction is an immune checkpoint. CTLA-4 antibodies (e.g. ipilimumab) produced the first prolongation in survival in patients with advanced melanoma
  35. 35. The Immunity Cycle
  36. 36. T-Cell – Tumor Cell Interaction
  37. 37. Adaptive Immune Resistance • PD-1 – PD-L1 interaction is an immune checkpoint. • PD-1 or PD-L1 antibodies re-activate the T cells in order to attack the cancer cells • PD-1 antibodies: Opdivo (nivolumab), Keytruda (pembrolizumab) • PD-L1 antibody: Tecentriq (atezolizumab) • Drugs approved for melanoma, lung cancer, renal cell cancer, bladder cancer
  38. 38. Durability of Responses is driving the excitement for this anti-cancer strategy Data in > 1800 melanoma patients treated with ipilimumab
  39. 39. aKaplan-Meier estimate. Analysis cut-off date: November 10, 2014. 0 8 16 24 32 40 48 56 Time, weeks Responder Nonresponder CR PR SD PD PD after CR, PR, or SD Last dose Treatment ongoing Best overall response A Phase Ib Study of Pembrolizumab (MK-3475,anti-PD-1 Ab) in Patients With Advanced Triple-Negative Breast Cancer. Nanda et al. Overall response rate 18.5% Median time to response 17.9 weeks Median duration of response not yet reached Nanda et al, JCO 2016
  40. 40. Challenges in Breast Cancer I: Weak activation of T Cells
  41. 41. Strategy: Stimulate anti-tumor immunity • Chemotherapy • Radiation • PARP inhibitors • Combinations with other immunotherapy agents
  42. 42. Atezolizumab (anti-PDL1) + nab-Paclitaxel Adams S, et al. SABCS 2015 Best Overall Response 1L (n=9) 2L (n=8) 3L+ (n=7) All patients (n=24) ORR (95% CI) CR PR 67% (30, 93) 11% 78% 25% (3, 65) 0 75% 29% (4, 71) 0 43% 42% (22, 63) 4% 67% SD 11% 25% 29% 21% PD 0 0 29% 8%
  43. 43. Challenges in Breast Cancer II: Complexity of the Immune Microenvironment Anti- Tumor T Cell Several other cell types may prevent activation and proliferation of the T cells (CD8 cells) capable of killing tumor cells. Strategy: Administer agents capable of disabling T-Regs MDSCs or of reprogramming macrophages
  44. 44. Challenges in Breast Cancer III: Other Immune Checkpoints Turn off T Cells in addition to PD-1 – PD-L1 Strategy: Anti-LAG-3 and Anti-TIM-3 antibodies
  45. 45. Summary of Additional Immune Targets
  46. 46. Antibody-Drug Conjugates
  47. 47. Antibody Drug Conjugates 1. Antibody that recognizes a marker on tumor cells that is not/less present on normal cells 2. Linker that is stable in circulation but releases the drug in target cells 3. Potent drug designed to attack the cancer cell when internalized and released
  48. 48. Antibody Drug Conjugates Tumor cell
  49. 49. Antibody Drug Conjugates Tumor cell
  50. 50. Antibody Drug Conjugates Tumor cell
  51. 51. Antibody Drug Conjugates Tumor cell
  52. 52. Antibody Drug Conjugates Tumor cell
  53. 53. Antibody Drug Conjugates in Development for TNBC • IMMU-132 – Target: Trop2 – Phase 1/2 trial completed, phase III trial planned • CDX-011 – Target: TPNMB – Phase 2 completed, phase 3 trial ongoing • SGN-LIV1A – Target: LIV-1 – Ph1 in breast ca ongoing • PF-06647263 – Target: EFNA4 – Phase 1 in breast cancer ongoing 53
  54. 54. 255-022 111-029 255-008 255-025 252-004 255-028 111-018 255-018 252-009 255-005 252-014 254-012 255-019 252-007 111-006 111-030 254-019 252-001 181-004 255-021 255-027 111-013 254-016 255-011 252-010 255-023 204-005 255-029 254-017 255-024 254-009 255-026 252-003 111-002 254-021 255-015 255-004 255-010 111-033 204-009 -1 0 0 -8 0 -6 0 -4 0 -2 0 0 2 0 4 0 6 0 8 0 1 0 0 BestResponse (%changeintargetlesionfrombaseline) Prior chemotherapies = 4 (median; range=1-11) IMMU-132 54 Objective response = 15/49 = 31% Disease control = 37/49 = 76% Clinical benefit ratio [CR+PR+(SD ≥4 mo)] = 63%* 15 May 2015 Bardia et al
  55. 55. How Can We Make Progress? Support Clinical Trials! • “One reason I chose to participate in a clinical trial was to help women with triple-negative breast cancer. It is thanks to women who have enrolled in clinical trials that we have the treatments that give us hope.” – Natalia (LBBC, Guide to Understanding TNBC)
  56. 56. Clinical Trials: FAQs • When should I consider a clinical trial? – Clinical trials may be an option for you as early as the first treatment you receive for metastatic breast cancer, but may also be an option further into the course of your disease. – If you are interested in trials, getting connected early to a treatment team who can help identify potential trials for you is key. • Will I have to pay more to be on a trial? – All normal procedures are billed to insurance; anything beyond normal care is paid for by the trial. There should be no “upcharge” for being in a trial • Is being on a trial busy? – Each trial is different and has a different schedule • Will I know what medicine I am getting? I don’t want a placebo. – In most trials, both patient and provider know exactly what treatment is being given. – Some larger trials use randomization and placebos, and in some cases neither patient nor provider know identity of study drug. – But in almost every trial with placebo, at minimum a patient receives best standard of care.
  57. 57. How to learn about trials? • Know what subtype of breast cancer you have • Learn about your family history and consider BRCA testing • Talk to your doctor and/or nurse • Consider receiving care and/or consultation in a center with a focus on clinical trials • Consider on-line resources
  58. 58. Advanced TNBC: Conclusions • TNBC is unique compared to other types of breast cancer • Not all TNBC is the same • Chemotherapy works for TNBC, and there are a number of standard options • No single best target has been identified so far; however, TNBC is an area of very active research; many exciting new agents and approaches in the pipeline • Speak to your provider about whether a trial is an option for you • Future progress depends on.....Making every woman count!

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