Els Monsaert, Christof Vulsteke. geintegreerd Kankercentrum Gent Klinische Studiedienst Oncologie

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2 Els Monsaert, Christof Vulsteke geintegreerd Kankercentrum Gent Klinische Studiedienst Oncologie

3 5 jaar overleving Uitgezaaide tumoren Nood aan nieuwe behandelingen voor uitgezaaide tumoren! Surveillance, Epidemiology and End Results (SEER). Rosenberg et al. Sci Transl Med 2012

4 ONCE AGAIN Anti CTLA-4 (Ipilimumab) Anti PD-1 (Pembrolizumab, Nivolumab) Anti PD-L1 (Atezolizumab, Avelumab, Durvalumab)

5 Anti-PD-1/PDL-1 actief in meerdere kankers Objectieve tumor regressie gezien in patiënten met: Type kanker Respons ratio Melanoma % Longkanker % Nierkanker % Blaaskanker % Hoofd- en halskanker % FDA Hodgkin lymfoom % Merckel cel carcinoom % MSI-hi solid tumors 40 % Eierstokkanker, maagkanker, triple negatief mammacarcinoom, Hepatocellulair carcinoom, mesothelioma,

6 A common denominator, but not for all Prostaatkanker Pancreaskanker En groot percentage van de responderende kankers combinatie therapieën om tumorresistente kankers te overwinnen

7 A common denominator, but not for all Immunomodulerende antistoffen (anti-ctla4,-lag3, -TIM3,GITR, -OX40,-CD137,-CD27, ) Kanker vaccins COMBINATIE THERAPIEËN Tumoricide therapieën (chemotherapie, radiotherapie, Targeted therapy die immunogenen cel dood induceren (cf autologe vaccins) Metabole modulatie Epigenetische modulatie Manipulatie van het microbioom

8 Timeline of FDA approvals

9 MELANOMA

10 PIVOTAL TRIALS

11 Results of practice changing importance CkeckMate 066: phase 3, NIVO vs dacarbazine in BRAFw CheckMate 069: phase 2, NIVO+IPI vs IPI in BRAFw or BRAFmut ChecMate 067: phase 3, NIVO or NIVO+IPI in BRAFw or BRAFmut

12 CHEKCMATE 067 study design

13 Resultaten update Nivolumab betere OS dan dacarbazine in gemetastaseerd maligne melanoom (checkmate ) Betere ORR en PFS voor NIVO vs IPI en NIVO+IPI vs IPI, maar ook meer nevenwerkingen (Checkmate 069 2,3 en 067 4,5 ) Significante verbetering in OS met NIVO+IPI en NIVO alleen vs IPI CR in 18-20% bij pt met NIVO of NIVO+IPI Robert et al 1 en Posto et al 2,N Engl J Med 2015; Hodi et al 3 Lancet Oncol 2016; Larkin et al, N Engl J Med ; Larkin et al, AACR

14 Analyse van de CR patiënten Meerderheid van de patiënten blijft in complete respons na 40maanden mediaan follow up Patiënten die geen CR bereiken hebben vaker LDH>ULN, hersenmetastasen en high tumor burden bij start Na 3 jaar meer patiënten in CR behandelingsvrij in combo-arm dan in mono-arm

15 Evolutie naar genezing van gemetastaseerde patiënten?

16 Studies in eerste en tweede lijn

17 Wanneer het menselijk brein tekort schiet Alwetende professor Oncoloog AZMM INNOVATIECELLEN + AI

18 Promising: epacadostat

19 Promising: epacadostat

20 Late breaking abstracts ESMO Madrid 2017 IMMUNOTHERAPIE SCHUIFT OP NAAR ADJUVANS SETTING Stage IIIb/IIIc Hoge kans op relapse 68% herval na 5j bij IIIb 89% herval na 5j bij IIIc Fase III studie bij stage IIIb, IIIc en IV MM na volledige resectie met adjuvante behandeling Nivo vs IPI NIVO superieur tov IPI IPI had reeds superioriteit tov surveillance aangetoond in de EORTC18071 trial

21 RENAL CEL CARCINOMA

22 Tyrosine kinase inhibitoren (targeted therapy) Sunitinib, sorafenib, pazopanib, axitinib VEGF belangrijke driver bij mrcc VEGFi sedert meer dan 10jaar standard of care Nooit OS aangetoond, wel PFS!!

23 ESMO guideline first line

24 CHECKMATE 214: CHANGING PARADIGM? Checkmate 214 toont voor het eerst OS Nivo-IPI kan beschouwd worden als een nieuwe eerste lijns behandeling voor poor/intermediate risk

25 Responses Response ratio in deze poputatie is de hoogste ooit gerapporteerd De duur van respons is de langste ooit gerapporteerd De complete respons is hoogste ooit gerapporteerd

26 Second line Overall survival aangetoond in Tweede lijn vs mtori Terugbetaald 2017 Nieuwe therapeutische optie voor onze patiënten met kans op duurzame responsen

27 First line challengers IMMotion 150 Toont ook de noodzaak aan irecist vs RECIST!

28 First line challengers

29 GEMETASTASEERD UROTHEELCELCARCINOOM

30 Until 2016 Prognostische factoren: Laag Hb Viscerale metastasen Performantiestatus Cis-Gem mos 13.8months Tweede lijn Zeer beperkte activiteit Median OS rond de 7 maanden Derde lijn Zeer weinig data

31 First line challengers Immunotherapie Met targeted therapy Met chemotherapie

32 KEYNOTE 361

33 The new kids on the block: 2nd line Updated analyses KEYNOTE /09/2017, ESMO, Madrid OS van Duurzame responsen Terugbetaald in België 10/2017

34 The new kids on the block: 2nd line IMVigor cohort 2 (single arm phase II) Compassionate Use program Duurzame responsen geassocieerd met PDL1 expressie Checkmate 275 (single arm phase II) Terugbetaald in 2 de lijn

35 Cisplatinum ineligible Keynote 052 Terugbetaald 10/2017 IMvigor 210 (cohort 1)

36 SLOKDARM EN MAAGCARCINOOM

37 Immunotherapie en digestieve oncologie Evolutie in de ontwikkeling van efficiënte antitumorale immunotherapie binnen digestieve oncologie = relatief traag Assepoester gevoel in het oncologische landschap Reden? Immunotherapie is vooral nuttig bij tumoren met hoge immunogeniciteit Digestieve tumoren: gebrek aan T-cel respons, beperkte immunogeniciteit

38 Pembrolizumab for Advanced Gastric or GEJ Adenocarcinoma On September 22, 2017, the Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA, Merck & Co., Inc.) -> patients with recurrent locally advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 as determined by an FDA-approved test. Patients must have had disease progression on or after two or more prior systemic therapies, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy.

39 KEYNOTE-059 Follow-up analysis of phase II KEYNOTE-059 trial (data cutoff: April 21, 2017) Pts with recurrent or metastatic gastric or GEJ adenocarcinoma; ECOG PS 0/1; HER2/neu negative*; no prior PD-1/PD-L1 tx, systemic steroids, autoimmune disease, ascites, or active CNS mets (N = 315) Cohort 1 2 prior lines of CT Cohort 2 No prior tx Cohort 3 No prior tx, PD-L1+ Pembrolizumab 200 mg Q3W Pembrolizumab 200 mg Q3W + Cisplatin 80 mg/m 2 Q3W + 5-FU 800 mg/m 2 Q3W or Capecitabine 1000 mg/m 2 BID Q3W Pembrolizumab 200 mg Q3W Tx continued for 35 cycles (~ 2 yrs) or until PD, intolerable toxicity, or withdrawal of consent; survival follow-up until study end, death, or withdrawal *HER2/neu positive allowed in cohort 1 if prior trastuzumab administered. Primary endpoints: ORR (RECIST v1.1 by central review), safety Additional endpoints including: DCR, DoR, PFS, OS.

40 KEYNOTE-059: Efficacy Outcome ORR, % CR PR SD PD Cohort 1 (n = 259) Cohort 2 (n = 25) Cohort 3 (n = 31) DCR mdor, mos (range) 14.2 (2.4 to 19.4+) 4.6 (2.6 to 20.3+) 9.6 (2.1 to 17.8+) mpfs, mos (95% CI) 2.0 ( ) 6.6 ( ) 3.3 ( ) mos, mos (95% CI) 5.5 ( ) 13.8 (8.6-NR) 20.7 ( ) ORR higher in PD-L1 positive vs PD-L1 negative pts (cohort 1: 16% vs 6%; cohort 2: 69% vs 38%)

41 Keynote-059: summary and conclusions Pembrolizumab continues to demonstrate, in patients with advanced G/GEJ cancer Promising antitumor activity and durable response as monotherapy in patients whose disease has progressed after 2 prior lines of therapy Encouraging antitumor activity in combination with chemotherapy in previously untreated patients Encouragin antitumor activity as monotherapy in previously untreated patients with PDL1 positive tumours Responses were regardless of PDL1 expression, but higher in patients with PDL1 positive tumors in cohort 1 and 2

42 Ongoing trials

43 COLORECTAAL CARCINOOM

44 Historiek CRC -> niet-immunogeen i.e. niet in staat immuun gemedieerde actie te induceren.maar..

45 Mismatch repair deficient tumors Tumoren met mutaties in een of meerdere DNA MMR genen -> groot aantal DNA replicatie fouten en hoge levels van DNA MSI -> tumoren zijn hypergemuteerd -> productie van neo-antigenen -> sterk immunogeen Geassocieerd met HNPCC, doch ook bij sporadisch CRC Goede kandidaten voor immuun checkpoint blokkade Micro Satellite Instability (MSI) -> eerste waardevolle biomarker voor immunotherapie in CRC 3 tot 5% van gemetastaseerd CRC

46 On May 23, 2017, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA, Merck & Co.) for adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dmmr) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options or with MSI-H or dmmr colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. MSI-H and dmmr

47 Paradigma shift for cancer care! the first FDA approval of a cancer drug for treating tumors with a certain genetic defect regardless of where the tumor appears in the body, rather than for a specific tumor type.

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49 MSI-H and dmmr On July 31, 2017, the U.S. Food and Drug Administration granted accelerated approval to nivolumab (OPDIVO, Bristol-Myers Squibb Company) for the treatment of patients 12 years and older with mismatch repair deficient (dmmr) and microsatellite instability high (MSI-H) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

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51 QUID MICROSATELLITE STABLE COLORECTAL CANCER? one of the main focuses of research is how to turn these cold tumors, where immune cells aren t getting to the tumors sufficiently or aren t recognizing the tumors, into hot tumors that are infiltrated by immune cells and for in which immunotherapy is more likely to work.

52 Besluit Untill recent Depiction of Kaplan-Meier survival curve with genomically targeted agents (blue line) as compared to standard therapies (purple line), indicating an improvement in median overall survival but lack of durable responses Hype Improved median overall survival and durable responses in a fraction of patients treated with immune checkpoint therapy (green line); Future possibility for improved median overall survival with durable responses for the majority of patients in the setting of combination treatment with genomically targeted agents and immune checkpoint therapy (red line) (Source: Sharma, Allison: Cell, April 2015)

53 THANK YOU