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Immunotherapy for Metastatic Triple Negative Breast Cancer

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Sylvia Adams, MD, medical oncologist, and associate professor at the NYU School of Medicine, discusses the latest research including the role of immunology in the treatment of triple negative metastatic breast cancer. This webinar was hosted on October 19, 2016.

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Immunotherapy for Metastatic Triple Negative Breast Cancer

  1. 1. Immunotherapy for Metastatic Triple Negative Breast Cancer Sylvia Adams, MD Associate Professor of Medicine Breast Cancer and Cancer Immunotherapy Programs New York University School of Medicine
  2. 2. Disclosures No relevant financial conflicts Global Principal Investigator, Keynote-086 Steering Committee Member, Impassion-130
  3. 3. FDA approvals for immune checkpoint antibodies 8/5/16 Pembrolizumab met H&N ca Breast Cancer? 10/19/16 Atezolizumab met NSCLC
  4. 4. Presented by: Shaveta Vinayak, M.D., M.S. Adams et al, J Clin Oncol 2014 Breast Tumor-Infiltrating Lymphocytes (TIL) iTILs sTILs
  5. 5. Immune Response against Cancer CD4+ T cell CD8+ T cell Tumor bed Tumor bed CD8+ T cell CD8+ T cell CD4+ T cell CD4+ T cellCD40 CD4+ T cell CTLA-4CD137 OX40 PD-1 PD-L1 CD80 CD86 DEC-205 Ag Release of Cancer Antigens & Antigen presentation T cell priming and activation T cell trafficking, tumor infiltration, recognition and killing
  6. 6. Presented by: Shaveta Vinayak, M.D., M.S. Adams et al, J Clin Oncol 2014 Breast Tumor-Infiltrating Lymphocytes (TIL) iTILs sTILs
  7. 7. TIL in breast cancer- the subtype matters Loi S, et al. J Clin Oncol 2013 Luen, et al, Breast, 2016 Stanton, Adams, Disis. Jama Onc 2016
  8. 8. 500 patients with TNBC Median age: 49 years (24-85), 59% positive LN Adjuvant treatment with anthracycline/taxane Median follow-up 10.6 years. Baseline surgical sample assessed on H&E section, TIL graded in deciles Higher sTIL were associated with better prognosis: For every 10% increment in sTIL: •14% reduction of risk for recurrence or death (P=0.02) •18% reduction of risk for distant recurrence (P=0.04) •19% reduction of risk of death (P=0.01) Prognostic value retained in multivariate model sTIL are prognostic in TNBC treated with adjuvant chemotherapy: E2197 and E1199 0% 80%
  9. 9. Randomized Ph III BIG 02-98 ECOG 2197 and 1199 FINHER Gustave Roussy Trial A CMF, AC CMF AC-T, AC, AT Docetax or Vinorelb FEC CAF/CEF vs none 256 TNBC 481 TNBC 134 TNBC 199 TNBC 8-year f/u 10.6- year f/u 5.2- year f/u 12.7-year f/u all LN pos 59% LN pos 89% LN pos 43% LN pos Methods REMARK & pre-specified analysis H&E full section, analyzed in deciles (continuous) and categorical (LPBC vs not) sTIL per 10% DFS univariate OS HR 0.84 (p=0.02) HR 0.86 (p=0.02) HR 0.79 (p=0.03) n/a HR 0.82 (p=0.02) HR 0.81 (p=0.01) HR 0.80 (p=0.08) HR 0.89 (p=0.1) sTIL per 10% DFS multivariate OS HR 0.85 (p=0.02) HR 0.84 (p=0.005) HR 0.77 (p=0.02) n/a (DFS) HR 0.83 (p=0.02) HR 0.79 (p=0.003) HR 0.81 (p=0.14) HR 0.85 (p=0.04) sTIL are a robust prognostic biomarker in TNBC Summary of prospective studies ~ level I evidence Loi S, et al. J Clin Oncol 2013, Adams S, et al, J Clin Oncol 2014 Loi S, et al. Ann Oncol 2014, Dieci MV, et al, Ann Oncol 2015
  10. 10. • Stromal TIL in 80% of TNBC, ~ 10% are lymphocyte-predominant (more lymphocytes than tumor cells) • Pre-existing TIL indicative of an endogenous adaptive anti-tumor immune response and determine survival • Consensus guidelines for evaluation of TIL in breast cancer published by our group  Target and harness the immune system to improve cure rates in TNBC TNBC is immunogenic - Implications Salgado et al, 2014, Annals of Oncology
  11. 11.  Immune checkpoint inhibitors are drugs – often made of antibodies – that re- invigorate an immune attack on cancer cells.  Programmed death 1 (PD-1) receptor and its ligand PD-L1 are expressed in the tumor and TILs to protect against immune destruction (‘inhibitory’)  Anti PD-1/PD-L1 antibodies can block that these inhibitory pathways, restoring functional killer T cells. The PD-1:PD-L1 Pathway– Immune checkpoints
  12. 12. Anti-PD-1, Nanda, SABCS 2014/JCO 2016 N=32, heavily pretreated IHC >1% in tumor or stroma, 58% of screened MK-3475 at 10 mg/kg q 2 weeks (Keynote-012) •Acceptable safety (6/32 G3 or higher) •Median follow-up: 9.9 months •ORR 18.5% (5/27), including 1 CR •Responses durable, with the median response duration not reached (range, 15 to 40+ weeks) and 3 of 5 responders on treatment for ≥11 mos •Median time to response: 18 weeks (q 8 scans) •Median time on study: 8.5 weeks PD-1/PD-L1 Blockade in metastatic PD-L1-positive TNBC Anti-PD-L1, Emens, SABCS 2014/AACR2015 N=21 IHC >5% immune cells, 23% of screened patients MPDL3280A at 15-20 mg/kg q 3 weeks • Acceptable safety (1/12 G3) • Median follow-up: 40 wks • ORR 19% (4/21), including 1 CR • Responses durable, median duration of responses not yet reached (range 18+ to 56+ weeks), • Median time to response: 6 weeks (q 6 scans) • Median time on study: 9 weeks
  13. 13. KEYNOTE-086: Pembrolizumab Monotherapy for Metastatic TNBC • Primary Endpoint: – ORR (RECIST 1.1) in first line PD-L1+BC – ORR (RECIST 1.1) in 2+ line BC – Safety, tolerability • Secondary Endpoints: – PFS, DOR, OS 1L PD-L1-positive mTNBC n=80 Pembrolizumab 200 mg IV q 3 weeks Pembrolizumab 200 mg IV q 3 weeks 2+L mTNBC n=160 Conditional expansion in PD-L1-positive Adams, et al, TIP, SABCS 2015
  14. 14. SWOG S1418/NRG BR006 RPhIII Pembrolizumab for Residual TNBC post NAC • Hypothesis: – Pembrolizumab reduces IDFS by 33% c/w observation alone • Primary Endpoint: – Invasive DFS in PD-L1-positive and overall cohort • Secondary Endpoints: – Toxicity – OS – DRFS – QOL (PROMIS, PRO-CTCAE forms, inflammatory markers) – Tissue banking Pembrolizumab 200 mg IV q 3 weeks x 1y Observation TNBC with >/=1 cm residual invasive breast cancer or any + LN after neoadjuvant chemotherapy N=1000 PIs: Pusztai/Mamounas • Registration: – Central PD-L1 testing • Stratification: – Nodal stage ypNo vs ypN+ – Residual tumor >2 vs < 2cm – PD-L1 pos vs neg – Prior adjuvant chemo yes vs no 1:1
  15. 15. 15 • Cytotoxic chemotherapy can maintain clinical stability with these highly aggressive tumors as well as lower tumor burden, a known predictive factor for immunotherapy success • Preclinical data for synergy of chemo- and immunotherapy • Immune effects of paclitaxel can be harnessed  Can increase TIL in neoadjuvant setting (Demaria et al., 2001).  Enhances antigenicity of cancer cells by increasing the expression of MHC class I molecules.  Reduce local immunosuppressive mechanisms such as intratumoral MDSCs, transforming growth factor β (TGF-β), IL-10 and regulatory T cells (reviewed in Zitvogel et al 2013).  Can increase PD-L1 expression (Gong et al 2011). • Nab-paclitaxel does not require steroid premedication, FDA-approved for metastatic breast cancer. PD-1:PD-L1 Blockade Combined with Chemotherapy Rationale Adams et al, ASCO 2016
  16. 16. 16 Rationale: • Cytotoxic chemotherapy can maintain clinical stability with these highly aggressive tumors as well as lower tumor burden, a known predictive factor for immunotherapy success • Preclinical data for synergy of chemo- and immunotherapy • Immune effects of paclitaxel can be harnessed • Nab-paclitaxel does not require steroid premedication, FDA-approved for metastatic breast cancer Main eligibility: • Up to two cytotoxic regimens for metastatic TNBC, no taxane within 6 months • Measurable disease, biopsy-accessible Treatment: • Nab-paclitaxel (125 mg/m2 IV over 30 minutes on Days 1, 8, and 15 q 28 days). • Atezolizumab (MPDL3280A, 800 mg flat dose) every 2 weeks (Days 1 and 15 q 28 days), starting with cycle 2 for serial biopsies Objectives: • Primary: safety and tolerability, • Secondary: PK, RR and PD, tissue correlates Phase Ib Nab-paclitaxel with atezolizumab (a PD-L1) Adams et al, ASCO 2016
  17. 17. 17 • 32 patients enrolled • All 32 patients who received ≥ 1 dose of atezolizumab were evaluable for safety (data cutoff date of January 14, 2016) • No unusual toxicities observed above what is expected for the single agents • All patients experienced ≥ 1 adverse event (AE) of any cause • No deaths related to study treatment • Fatigue and pyrexia frequent • Neutropenia, thrombopenia, anemia, neuropathy • 1 patient with new onset Type I diabetes • 1 patient discontinued atezolizumab after prolonged asymptomatic Grade 2 AST elevation • 6 patients discontinued nab-paclitaxel due to a treatment-related AE: n = 1: peripheral sensory neuropathy (Grade 1), asthenia (Grade 2), fatigue (Grade 2), pneumonia (Grade 3), n = 2 for peripheral neuropathy (1 each Grade 2 and 3) Phase Ib Nab-paclitaxel with atezolizumab (a PD-L1) Safety Adams et al, ASCO 2016
  18. 18. 18 • 32 patients enrolled • Best overall response by RECIST 1.1 • 2 patients experienced a decrease in tumor burden after an initial increase or the appearance of new lesions (irPR) • 2/15 at NYU NED at 2 years, off abraxane >1 year • PFS data are not mature, median DOR not been reached • Median overall survival not mature: NE (95% CI, 8.0-NE) • Planned evaluation of modulators of PD-L1 expression • RPIII ongoing Phase Ib Nab-paclitaxel with atezolizumab (a PD-L1) Preliminary efficacy Adams et al, ASCO 2016 BORR 1L (n = 13) All Patients (n = 32) Confirmed ORR 46% (19-75) 38% (21-56) CR 8% 3% PR 38% 34% SD 38% 44% PD 15% 16% By line of therapy:
  19. 19. • Baseline levels of TILs showed a trend with increased response • PD-L1 expression? • HR deficiency, MMR, mutational load? TILs as a percentage of total tumor area. Adams S, et al. ASCO 2016 PD-1:PD-L1 Blockade Combined with Chemotherapy Predictive markers?
  20. 20. Response/Pseudoprogression to Atezolizumab/Nab-Paclitaxel Adams S, et al. ASCO 2016
  21. 21. IMpassion130 (WO29522) Randomized Phase 3 trial: Front-line Metastatic TNBC • Primary Endpoint: – PFS (RECIST 1.1) and OS • Secondary Endpoints: – PFS (mRECIST), ORR, DOR, HRQoL • Key efficacy populations: – ITT and PD-L1+ • FDA-registration trial 1L mTNBC n=900 (1:1; double-blinded) Atezolizumab 840 mg q2wk + Nab-paclitaxel 100 mg/m2 qwk 3/4 wks Placebo q2wk + Nab-paclitaxel 100 mg/m2 qwk 3/4 wks Stratification factors: Liver mets: Y/N Prior Taxane: Y/N PD-L1 IHC (IC 1/2/3) Emens, Adams, et al, TIP, SABCS 2015
  22. 22. NYU 15-00441: PhII Pembrolizumab and Nab-paclitaxel in mBC • Primary Endpoint: – Safety run in in first 12 patients – ORR in TNBC • Secondary Endpoints: – PFS (mRECIST), DOR, OS – ORR in HR+ – Predictive biomarkers • Tumor biopsy baseline, after abraxane alone and after combination • Serum, PBMC, stool baseline, p c 2, 4 1L-3L metastatic BC - TNBC n=30 - HR+/HER2- n=20 Nab-paclitaxel 100 mg/m2 d1, d8 q 3w + Pembrolizumab 200 mg q3w (added with second cycle) Eligibility: Measurable disease Serial biopsy-accessible tumor Up to 2 prior chemoRx lines for mBC Taxane washout 3 months No active brain metastases No pneumonitis Metaplastic BC PI: Adams Clinicaltrials.gov NCT# 02752685
  23. 23. For TIL-rich tumors: Therapies targeting immune inhibitory pathways which are often also increased For Non-infiltrated tumors: Interventions to trigger innate immune activation, T cell priming and effector T cell trafficking Immunotherapeutic Approaches based on Tumor Microenvironment CD4+ T cell CD8+ T cell Tumor bed Tumor bed CD8+ T cell CD8+ T cell CD4+ T cell CD4+ T cellCD40 CD4+ T cell CTLA-4CD137 OX40 PD-1 PD-L1 CD80 CD86 DEC-205 Ag Release of Cancer Antigens & Antigen presentation Vaccines, RT, chemo, TLR agonists T cell priming and activation CTLA-4, OX40, HD IL-2, IL-7 T cell trafficking, tumor infiltration, recognition and killing
  24. 24. Summary 1. Subsets of breast cancer are immunogenic. 2. The anti-tumor immune response has prognostic significance, with level I evidence that TIL predict survival in TNBC. It also predicts chemotherapy efficacy in the neoadjuvant setting. 3. There are compelling reasons why immunotherapies should be studied in breast cancer, but specific to subtype. 4. Several modalities (TLR agonists, radiotherapy, trastuzumab etc) can be harnessed to TIL-poor into TIL+ tumors. 5. Immune checkpoint blockade is emerging as highly promising strategy in breast cancer. Combination studies are ongoing to improve response rates. > 100 studies available nationally (see www.clinicaltrials.gov).
  25. 25. Thank you! NYU Langone Bellevue

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