Immunotherapy Update in Metastatic Breast Cancer

Transcription

1 ANZBCTG Annual Meeting 2017 Immunotherapy Update in Metastatic Breast Cancer Sherene Loi, MBBS (Hons), FRACP, PhD Peter MacCallum Cancer Centre, Melbourne, Australia

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3 EFFICACY OF CHECKPOINT BLOCKADE IN BREAST CANCER

4 Is breast cancer immunogenic? Higher levels of immune infiltrate observed in PRIMARY TNBC and HER2+ BC samples Loi 2013, 2014, Denkert 2010, 2016 High TILs= surrogate for activated CD8+ T cells

5 Change From Baseline in Tumor Size, % Change From Baseline in Tumor Size, % Pembrolizumab Demonstrates Broad Antitumor Activity Melanoma 1 (N=655) KEYNOTE NSCLC 2 (N=262) KEYNOTE H&N 3 (N=132) KEYNOTE Urothelial 4 (N=33) KEYNOTE Gastric 5 (N=39) KEYNOTE TNBC 6 (N=32) KEYNOTE chl 7 (N=29) KEYNOTE Mesothelioma 8 (N=25) 80 KEYNOTE Daud A et al ASCO; 2. Garon EB et al. ESMO 2014; 3. Seiwert T et al ASCO; 4. Plimack E et al ASCO; 5. Bang YJ et al ASCO; 6. Nanda R et al. SABCS 2014; 7. Moskowitz C et al ASH Annual Meeting; 8. Alley EA et al AACR; 9. Varga A et al ASCO; 10. Ott PA et al ASCO; 11. Doi T et al ASCO Ovarian 9 (N=26) KEYNOTE SCLC 10 (N=20) KEYNOTE Esophageal 11 (N=23) KEYNOTE-028 Courtesy Merck

6 Avelumab- anti-pd-l1- anti-tumor activity in PD-L1 unselected previously treated metastatic BC patients Tumor shrinkage by 30% was observed in 16 patients (9.5%) in overall MBC population, including 2 patients with PD by RECIST who had PRs by modified irrc 8.6% (5/58) of TNBC patients had an ORR [44% with >10% PD-L1+ on TILs) 2.8% (2/72) ER+ BC patients had an ORR 3.8% (1/26) HER2+ BC patients had an ORR Dirix et al, SABCS 2015

7 Change From Baseline, % Pembrolizumab (PD-1) antitumor activity in previously treated (A) and previously untreated (B) mtnbc- phase II study Cohort A (N = 170): Previously Treated, Regardless of PD-L1 Expression ORR:4.6% All patients responding are still alive Median TTR:3.0mo Median duration of response: 6.3mo Plots include patients with 1 evaluable postbaseline assessment (n = 143 for cohort A, n = 50 for cohort B). 1. Adams S, et al. ASCO Annual Meeting; Jun 2-6, 2017; Chicago, IL; Abstr 1088.

8 O S, % % 100% 64.6% 100% 89.6% 39.0% Events/Pts, n CR or PR 0/8 SD 6/35 PD 66/103 Median (95% CI) Not reached (NR-NR) Not reached (12.7-NR) 7.1 mo ( ) N o. a t r is k T im e, m o n th s NR, not reportable. Patients with response that was nonevaluable (n = 5) or not assessed (n = 19) per RECIST v1.1 by central review are not included. Data cutoff date: Nov 10, 2016.

9 Change From Baseline, % Change From Base l ine, % Pembrolizumab antitumor activity in previously treated (A) and previously untreated (B) mtnbc- phase II study Cohort A (N = 170): Previously Treated, Regardless of PD-L1 Expression Cohort B (N = 52) 1 : Previously Untreated, PD-L1 Positive ORR:4.6% All patients responding are still alive Median TTR:3.0mo Median duration of response: 6.3mo ORR:23.1% Plots include patients with 1 evaluable postbaseline assessment (n = 143 for cohort A, n = 50 for cohort B). 1. Adams S, et al. ASCO Annual Meeting; Jun 2-6, 2017; Chicago, IL; Abstr 1088.

10 Atezolizumab (PD-L1) Antitumor Activity in Previously Treated and Previously Untreated mtnbc- phase II study 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% Phase 2 Atezolizumab monotherapy 10% 26% SD 26% 42% SD 22% SD 4% 8% overall 1L 2L 3L+ 19% SD ORR SD N= 96 were alive 6 wks or more (83%) 20% died within 6 weeks Objective Responses were higher in the 1L setting PD-L1 levels did not make a difference Schmid et al AACR 2017

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12 Pembrolizumab antitumor activity in previously treated met ER+BC- phase II study: KN Change From Baseline in Sum of Longest Diameter of Target Lesion, % PD SD PR ORR 12% ( %) PD-L1+ rate was 19.4% Met ER+ BC is not immunogenic Only patients with 1 evaluable postbaseline tumor assessment are included (n = 22). Data are presented for 20 patients; 2 patients were excluded due to non-evaluable postbaseline lesions. Data cutoff date: July 1, Rugo et al, SABCS 2015

13 Why modest efficacy in metastatic TNBC? Majority of metastases lack T cell infiltrate no immunity present P<0.001 TIL work done in primary BCs Metastatic TNBC grows too fast Large tumor burden Immune escape (subclones) Largely immunosuppressive microenvironment Unmatched primary (n=111) and metastatic sites (n=34) Unpublished work Loi Lab

14 Pembrolizumab graduated in all HER2- Primary HR+/HER2- and TN BC Signature All HER2- TNBC HR+/HER2- Estimated pcr rate (95% probabilty interval) Pembro 0.46 ( ) 0.60 ( ) 0.34 ( ) Control 0.16 ( ) 0.20 ( ) 0.13 ( ) Probability pembro is superior to control Predictive probability of success in phase 3 > 99% 99% >99% >99% >99% 88% The Bayesian model estimated pcr rates appropriately adjust to characteristics of the I-SPY 2 population. The raw pcr rates (not shown) are higher than the model estimate of in TNBC.

15 Improving outcomes to checkpoint blockade for advanced breast cancer patients 1. Primary Resistance: Tumor burden/prior treatment/tempo Tumor mediated immunosuppression Combinations of checkpoint agents will not overcome the fact that there are no T cells present 2. Secondary resistance: some immunity present- How to create a more durable response Immune escape tumor related- oncogenic pathways immune- checkpoint related metabolic- adenosine pathway

16 Chemotherapy combinations: possible synergy between Taxane + Atezolizumab in metastatic TNBC 1L ORR=66% ORR PDL1+ IC=0 (n=7) IC1/2/3 (n=9) Unk (n=8) CR % PR 57.1% 77.8% 62.%% SD 42.9% 22.2% 0 PD % 2L=25% 3L=28% Patients with baseline higher TILs did better No change in TILs seen on serial biopsies Adams et al, SABCS 2015

17 Phase III study ongoing: ImPassion130 Roche-Genentech WO29522 NCT

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19 Other directions Combinations Radiotherapy+IO AZTEC study (TROG) Combinations with targeted agents i.e. anti- HER2+: (Panacea, Diamond studies) Combinations with MEKi (immunoadjuvant) Colet study

20 MEK inhibition and induction of immunity MHC-I MHC-II PD-L1 *p<0.01 in vitro cell lines AT3-ova * * Red: vehicle Black- MEKi Orange: anti-pd1 Ab Purple: anti-ctla4 Ab Green: MEK+anti-PD1 Ab Blue: MEKi + anti-ctla4 Ab in vivo as measured on TILs FACs Day 15 Loi et al, CCR 2016; Dushyanthen et al, Nat Comms

21 COLET study WO29479

22 Is there a difference between anti-pd(l)-1 agents? Efficacy so far looks similar Immune toxicity looks largely comparable More infusion reactions with avelumab More fever with atezol Dosing schedule different

23 Toxicity (%) AE Nivo any Nivo G3 Pembro any Pembro G3 Atezo Any Atezo G3 Avel any Avel G3 Any AE Diarrhea Fatigue Pruritus NG 0 Nausea Pyrexia Hypo-thyroidism Pneumonitis Nivolumab= Larkin et al, NEJM 2015; Pembrolizumab= Garon et al, NEJM 2015; Atezolizumab= Herbst et al, Nature 2014; Avelumab= Dirix et al, SABCS 2015

24 CAN BIOMARKERS HELP IDENTIFY RESPONDERS TO CHECKPOINT BLOCKADE?

25 What biomarkers? PD-L1 IHC T cells/ immune signatures Mutational load

26 IHC PD-L1+ assays Merck (pembrolizumab) PD-L1+ 1% tumor or TILs BMS (nivolumab) PD-L1 5% tumor cells Roche-Genentech (atezolizumab) IHC 0/1 <5% TILs; IHC 2/3 5% TILs Merck Serono/Pfizer (avelumab) various! Medimmune/AZ (durvalumab) IHC 25% tumor cells PD-L1 positivity certainly enriches for responders? What cut-off, what about those PD-L1 neg who respond

27 PD-1 blockade responders requires a preexisting adaptive CD8+ immune response TILs (CD8+) matter! PD-L1 high with high TILs PD-L1 high with no TILS Tumeh et al, Nature 2014

28 Evaluate TILs in the tumor stroma Report TILs as %- see figure Intra- pathologist reproducibility study published Modern Pathology Quantity is important Do TILs or pre-existing immunity predict response to checkpoint blockade? Wait for ESMO 2017 Salgado, Denkert et al, 2014 Denkert et al 2016

29 Association of response to PD-1 blockade with IFNγ gene signature Ribas et al, ASCO 2015

30 mrna correlates of TILs: higher TILs on H&E= more T cell activation/exhaustion N=580 Denkert et al, JCO 2015

31 Mutational burden: somatic mutations could act as tumor antigens No relationship between mutations and TILs in MEL or BC Spranger, PNAS 2016 Luen SJ et al Breast 2016 Lawrence et al, Nature 2013

32 Factors in an effective immune response Tumor factors Tumor burden (LDH) Tempo of growth Chemotherapy/RT Tumor evolution Loss of MHC1/2 Prior-treatment Other SNP/ethnicity microbiome T T T T Breast cancer Immunosuppression estrogen T T LN T Quantity of T cells Right type of T cells Localization- danger signals Chemo-DNA damage Radiotherapy Oncolytic virus; vaccines Quality of T cells Longevity Checkpoints

33 Conclusions Some types of breast cancer are immunogenic HER2+, TNBC, BRCA+ primary vs metastatic setting is important for efficacy TILs quantity will be important for responders as well as PD-L1 expression Simply quantified on a H&E slide In advanced disease, combinations will be needed for the majority of breast cancer patients How can we convert low TILs (non-responders) to high TILs? Is it even possible? Best place to evaluate will be primary disease setting- who does not needs it?

34 Acknowledgements LOI LAB Peter Savas Balaji Virassamy Chris Mintoff, Stephen Luen Sathana Dushyanthen Courtney Van Geelen Franco Caramia, Christophe LeFevre Joyce Teo, Stephanie Versaci, Luke Percy Mariam Mansour, Ann Bryne, Tania Tan Terry Speed and WEHI Paul Neeson HITRL Phil Darcy, Paul Beavis, Mike Kershaw Breast Unit, Pathology Dept Peter Mac Roberto Salgado, Stephen Fox Mark Smyth, John Stagg Geoff Lindeman, Jane Visvader, Daniel Gray