Immunterapi til behandling af kræft. Lars Bastholt Onkologisk afd Odense Universitets Hospital 28. maj 2019

Transkript

1 Immunterapi til behandling af kræft Lars Bastholt Onkologisk afd Odense Universitets Hospital 28. maj 2019

2 Immunterapi Immunterapi Kemoterapi Target host immunity Target host tumor

3 Immunsystemet og kræft

4 Ved immunterapi til behandling af kræft udnyttes at: Kræftceller indeholder kræftproteiner der adskiller dem fra normale celler Immunsystemet kan finde frem til kræftceller via kræftproteinerne Immunsystemet kan specifikt dræbe kræftceller der indeholder kræftproteiner Immunsystemet har en hukommelse der kan medfører langvarig behandlingseffekt Immunterapi er i stand til at skubbe til balancen mellem kræften og immunsystemet til fordel for ovennævnte

5 Kan immunsystemet genkende kræftceller? IL-2 = interleukin 2 GM-CSF = granulocyte-macrophage colony-stimulating factor Adapted from Armstrong A, et al. Br Med J 2001; 323: 1289

6 Effekt af immunterapi Standard therapy

7 The DAnish Metastatic MElanoma Database DAMMED

8 Organization in DK - Medical treatment for melanoma Three centers with close collaboration Agreement on national guidelines Agreement on clinical trials

9 DAMMED - Medical treatment for melanoma Results Yearly report with anonymized data involved colleagues supporting medical companies (Merck MSD, BMS, Novartis and Roche) DAMMED Danish Metastatic Melanoma Database Report on the Treatment of Danish Patients with Metastatic Melanoma 2018 Research Retrospective data with real-world evidence Inge Marie Svane, MD Henrik Schmidt, MD Lars Bastholt, MD Ulrich Heide Køhler, Datamanager

10 Results DAMMED Danish DAMMED Metastatic Melanoma - Medical Database treatment for melanoma Report on the Treatment of Danish Patients with Metastatic Melanoma 2018 Yearly report with anonymized data involved colleagues supporting medical companies (Merck MSD, BMS, Novartis and Roche) Research Retrospective data with real-world evidence Inge Marie Svane, MD Henrik Schmidt, MD Lars Bastholt, MD Ulrich Heide Køhler, Datamanager

11 IL2 in Denmark pts ( ) Bastholt et al: Eur J Cancer, 2019; 115:61-67

12 Overview: The Antitumor Immune Response Tumor Step 4: Lymphocytes kill tumor cells Tumor cells Step 1: Antigen processing CTL DC Step 3: Lymphocyte activation T-cell receptor Antigen- MHC DC Step 2: Antigen presentation T cell Lymph node

13 Rationale for CTLA4 Blockade Releasing a Brake for T-Cell Activation MHC Antigen TCR Dendritic cell B7 CD28 T cell CTLA4 Antibody to CTLA4 prevents interaction with B7 and blocks the negative signal.

14 First check point inhibitor: ipilimumab 2 nd line therapy for metastatic melanoma 3 mg/kg iv every 3 rd week 4 times. Clinical response: 10-15% Treatment can be repeated if response lasts more than 6 months Schadendorf, JCO 2015

15 DAMMED - Ipilimumab

16 Immune Checkpoint Inhibitors clinicaloptions.com/oncology CTLA-4 and PD-1/L1 Checkpoint Blockade Priming phase (lymph node) Effector phase (peripheral tissue) Dendritic cell T cell T-cell migration T cell Cancer cell MHC TCR TCR MHC Dendritic cell B7 B7 CD28 CTLA-4 T cell T cell PD-1 PD-L1 Cancer cell Ribas A. N Engl J Med. 2012;366:

17 DAMMED - Pembrolizumab Median OS: 24,4 mths (21,0-31,2) 2-year OS: 50,9% (46,7-55,0) 3-year OS: 42,8% (38,1-47,4) 4-year OS: 37,5% (31,7-43,3)

18 CheckMate 067: Study Design 4-year follow up of a randomized, double-blind, phase 3 study to compare NIVO+IPI or NIVO alone with IPI alone a Unresectable or metatastic melanoma Previously untreated 945 patients R 1:1:1 Stratify by: BRAF status AJCC M stage Tumor PD-L1 expression <5% versus 5% n = 314 n = 316 NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses then NIVO 3 mg/kg Q2W NIVO 3 mg/kg Q2W + IPI-matched placebo Treat until progression or unacceptable toxicity Co-primary endpoints a were PFS and OS in the NIVO-containing arms versus IPI alone n = 315 IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo Database lock: May 10, 2018; minimum follow-up of 48 months for all patients a The study was not powered for a comparison between NIVO+IPI and NIVO 18

19 PD-L1 <1% vs > 1% Hodi, Lancet Oncol 2018

20 DAMMED Ipi/Nivo Median OS: not reached 1-year OS: 71,0% (61,5-78,5) 2-year OS: 61,7% (49,9-71,5) Hodi, Lancet Oncol 2018

21 DAMMED Ipi/Nivo Brain metastases

22 Forbedret overlevelse hos kræftpatienter i takt med udvikling af immunterapi immunterapi 2. Immunterapi 1. Immunterapi

23 Effekt - Immunterapi Pseudoprogression

24 Pseudoprogression Screening Week 96 Durable & ongoing response without signs of IRAEs Week 12 Initial increase in total tumour burden (mwho PD) Week 16 Responding Courtesy of K. Harmankaya, Vienna Harmankaya et al. Presented at EADO 2009, Vienna, Austria

25 Pseudoprogression Ribas A et al. Clin Cancer Res 2009;15(23):7116 8) 2009;15:

26 Questions?

27 Immunterapi På hvilket sygdomsstadie? Udbredt sygdom Forebyggende mod tilbagefald efter operation Før operation

28 100 RFS ipi vs placebo (EORTC 18071) Ipi vs Nivo (CM 238) Nivo Ipi Ipi Placebo Years

29 Risk / benefit ratio in the adjuvant setting 100% Overall Survival Adjuvant arm Adjuvant did not change outcome: patient death Adjuvant benefit 0% Control arm Time Adjuvant did not change outcome: patient is cured Olivier Michielin, MD-PhD

30 Risk stratification based SLNB Verver et al: Eur J Cancer 2018; 96:25-33

31 Case Story Adjuvant Therapy Melanoma Jan 19: surgery for metastatic lymph node metastases left axilla. Unknown primary Feb 19: Info on possible adjuvant treatment with Nivolumab Shared decision making essential 50% risk equals 50% chance for being cured by surgery alone Risk of irreversible toxicity emphasized 1. course of Nivolumab given based on normal blood samples 31

32 Bivirkninger af immunterapi Knæk Cancer Odense 25. oktober 2018 Lars Bastholt

33 Immunterapi Immun homeostase: Kritisk for at opretholde tolerancen overfor egne molekyler (SELF), og dermed Undgå autoimmunitet Checkpoint hæmmere: Skaber potentielt en ubalance i tolerancen overfor SELF, og det Kan føre til reaktioner, der ligner autoimmunitet Immune-related adverse events (iraes)

34 Spectrum of toxicity of immune checkpoint blockade agents. S. Champiat et al. Ann Oncol 2016;27:

35 Behandling af iraes Tæt monitorering Ambulant el indlæggelse SE PATIENTEN!!! Pausér el stop immun-terapien? Steroid-behandling Topical eller systemisk? Lav, moderate or høje doser? Anden immunosuppressiv terapi Infliximab anti TNF Mycofenolat hæmmer DNA-syntesen i B- og T-lymfocytter Multidisciplinært Alle specialer skal vide hvordan man håndterer iraes

36 Steroider Ofte langvarigt, derfor Calcium m D-vitamin fra starten Tjek b-glucose Ofte lang aftrapningsfase, pga risiko for recidiv Kan vi fortsætte el genoptage immunterapien? Er det sikkert? Er det nødvendigt? Influerer det på behandlingens effektivitet? Risiko for sekundær binyrebarkinsufficiens?

37 Monitorering De fleste iraes er potentielt reversible Resolution kinetik Hurtig bedring GI, renale, hepatiske Langsom bedring Hud, endokrin toxicitet Endokrin toxicitet Ofte nødvendigt med langvarig og ofte livslang substitution

38 Immunterapi udløste bivirkninger - budskabet Alvorlige men håndterbare bivirkninger Risikoen er højst ved kombinationsbehandling Timing er uforudsigelig Patienterne skal uddannes godt Tidlig indgriben er vigtig Selvom behandling stoppes på grund af bivirkninger, kan der være vedvarende og god effekt af immunterapien

39 CAREGIVER GUIDE Retningslinjer for sygeplejersker for at øge sikkerheden for patienten ved behandling med immunterapi

40 Caregiver Guide - Diare Identifikation: Problemet? Hvor mange afføringer per dag? Hvor mange dage? Er det vandtyndt? Blod i afføringen? Abdominal smerter? Kvalme? Opkastninger? Feber? CTC kriterier Grade 1: Imodium (loperamid) Sygeplejerske følger op dagen efter Fortsat diare: pt skal ses i afdelingen. Grade >= 2: Pt skal vurderes i afdelingen Grade 1: 3 diarreer per dag Grade 2: 4-6 diareer per dag Grade 3:

41 Care Giver Guide an example CTC skema

42 PROMelanoma Ph.d.-projekt ved spl. Lærke Tholstrup Kan sikkerheden øges ved ugentlig indrapportering af bivirkninger?

43 Vurdering og håndtering af bivirkninger relateret til immunterapi

44 Checkpoint inhibitors Nov 2018 Anti-CTLA4 Ipilimumab (BMS) Tremelimumab (Astra Zeneca) Anti PD-1 Nivolumab (BMS) Pembrolizumab (Merck MSD) Pidilizumab (Cure Tech - Pfizer) Spartalizumab (Novartis) Cemiplimab (Sanofi) Anti- PD-L1 Durvalumab (Astra Zeneca) Atezolizumab (Roche) Avelumab (Merck)

45 Checkpoint inhibitors Nov 2018 Anti-CTLA4 Ipilimumab (BMS) Tremelimumab (Astra Zeneca) Anti PD-1 Nivolumab (BMS) Pembrolizumab (Merck MSD) Pidilizumab (Cure Tech) Spartalizumab (Novartis) Cemiplimab (Sanofi) Anti- PD-L1 Durvalumab (Astra Zeneca) Atezolizumab (Roche) Avelumab (Merck)

46 Immunterapi indikationer forår 2019 Malignt melanom RCC NSCLC Urotheliale cancere Hoved-halscancer SCC i huden Merkelcelle carcinom i huden

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48 Spørgsmål?