Nieuwe patiëntenselectie met longcarcinoom als role model voor de medisch oncoloog Anne-Marie Dingemans POST ASCO NVMO 18 juni 2015

Nieuwe patiëntenselectie met longcarcinoom als role model voor de medisch oncoloog Anne-Marie Dingemans POST ASCO NVMO 18 juni 2015

Dingemans l post ASCO NVMO 18 juni 2015

Disclosure belangen Dingemans

(potentiële) belangenverstrengeling

Zie hieronder

Voor bijeenkomst mogelijk relevante relaties met bedrijven

Bedrijfsnamen

 

Sponsoring of onderzoeksgeld Honorarium of andere (financiële) vergoeding

 Roche  Eli Lilly  Boehringer Ingelheim  Astra Zeneca  Pfizer  BMS  Amgen  Astra Zeneca  Novartis  MSD



Oncogene “Drivers” in Adenocarcinoma

Kerr KM. J Clin Pathol. 2013;66(10):832-838.


1st ESMO Consensus Conference in Lung Cancer: Lugano 2010

Felip, et al. Ann Oncol 2011


Resistentie mechanismen

Yu HA, et al. Clin Cancer Res. 2013;19(8):2240-2247.


3de generatie EGFR-TKI Mutatie specifiek, ook T790M Minder effect op EGFR-WT = minder bijwerkingen

AZD9291: Best Percentage Change in Target-Lesion Size.

Jänne PA et al. N Engl J Med 2015;372:1689-1699.


Efficacy of rociletinib (CO-1686) in plasma-genotyped T790M-positive NSCLC patients • Study objective –

To report data on the safety and efficacy of rociletinib, an oral inhibitor of mutant EGFR, on a subset of NSCLC patients with the T790M resistance mutation detected by plasma genotyping treated with rociletinib 500−1000 mg BID

• Study design –

An overall Phase I/II study was performed on 456 enrolled patients diagnosed with EGFR-mutant NSCLC

–

In Phase II, T790M positive by central tumour genotyping was required

–

Plasma EGFR status was assessed by BEAMing (Sysmex), a quantitative assay using emulsion PCR then flow cytometry

• Key results –

456 patients received rociletinib and were included in the safety analysis

–

243 and 147 patients were T790M positive by centrally-confirmed tissue genotyping and plasma testing, respectively, and were analysed for efficacy

Sequist et al. J Clin Oncol 2015; 33 (suppl): abstr 8001

Quantitative and Sensitive BEAMing Test (Sysmex Inostics) Used for Plasma EGFR Mutation Testing

Presented By Lecia Sequist at 2015 ASCO Annual Meeting

Plasma Testing for T790M has Good Sensitivity and Likely Good Specificity


Best Response to Rociletinib (All Doses) in Plasma T790M+ Patients


T790M Plasma Testing is a Viable Alternative to Tissue Testing


Rociletinib Activity Observed in Central T790M Negative Patients


Slide 21

Presented By Alex Adjei at 2015 ASCO Annual Meeting



Oncogene “Drivers” in Adenocarcinoma

Kerr KM. J Clin Pathol. 2013;66(10):832-838.

Progression-free and Overall Survival.

Crizotinib versus chemotherapie eerste lijn

70% cross-over crizotinib

Solomon BJ et al. N Engl J Med 2014;371:2167-2177.


A Common Scenario

Baseline

After 9 months of crizotinib


A Common Scenario Most common site of progression on crizotinib – 70%!

Baseline

After 9 months of crizotinib

Next Generation ALK TKIs

50% maximal inhibitory concentration (IC50) values of Ba/F3 cells dependent on expression of EML4-ALK (native) or kinase domain mutated EML4-ALK variants (n = 10). Data for each cell line are derived from at least 4 independent experiments (error bars = standard deviation). Dashed horizontal lines indicate the mean steady-state exposure concentrations of each drug corrected for the functional effects of protein binding at the recommended phase 2 doses: aCrizotinib: 250 mg BID, 259 nM9; AP26113: b180 mg QD, 899 nM and c90 mg QD, 264 nM10; dCeritinib: 750 mg QD, 456 nM11; eAlectinib: 600 mg BID, 277 nM12; fn = 2

Ou SH. Drug Des Devel Ther. 2011;5:471-485. Shaw AT, et al. N Engl J Med. 2014;370(13):1189-1197. Ou S, et al. Eur J Cancer. 2013;49(Suppl 2): Abstract 44.


Activity of Other ALK TKIs

ALK TKI Ceritinib LDK378 (Novartis) Alectinib CH5425802 (Roche) AP26113 (Araid)

RR, % (n) Crizotinib Naïve

RR, % (n) Crizotinib Resistant

72% (83)

56% (163)

9.0 (6.9-18.4)

93.5% (46)

60% (47)

>14

100% (7)

69% (45/65)

13

mPFS, m

N=16

Felipe E, et al. Ann Oncol. 2014; Abstract 4380. Shaw AT, et al. N Engl J Med. 2014;370(26):2537-2539. Gadgeel SM, et al. Lancet Oncol. 2014;15(10):1119-1128. Nakagawa K, et al. J Clin Oncol. 2013;31(Suppl): Abstract 8033; Gettinger, S, et al. ESMO 2014: Abstract 5146

Abstract 8008
Efficacy and safety of the ALK inhibitor alectinib in ALK+ non-small-cell lung cancer (NSCLC) patients who have failed prior crizotinib: an open-label, single-arm, global phase 2 study (NP28673)

Presented By Sai-Hong Ou at 2015 ASCO Annual Meeting

Long median progression-free survival in crizotinib-resistant ALK+ NSCLC patients


Marked activity of alectinib in ALK+ NSCLC patients with measurable CNS metastases



What About Resistance? Crizotinib RR 65% to 75%; Median PFS 8-11 Months

Courtesy A. Shaw.


Ceritinib resistance is associated with ALK G1202R

Ding eman sl post ASC O NVM O 18 juni 2015


Gerichte therapie: wat doen we na ASCO 2015 Re-biopsie bij progressie! EGFR mutatie • T790M • Hersenmetastasen • Rol liquid biopsy ALK = lastige ziekte: • Dynamisch komen en gaan van mutaties • Let op hersenmetastasen RET/BRAF/MET etc: • Trials! • Verwijzen • DRUP


Non-oncogene driven NSCLC Or non-druggable (KRAS?) = still majority of our patients


Docetaxel > BSC

Shepherd F A et al. JCO 2000;18:20952103 Shepherd F A et al. JCO 2000;18:2095-2103

O NVMO 18 juni 2015

https://www.mmv.nl/nieuws/effectief-tegen-kanker-maar-niet-te-betalen


Mutations in Cancer Cells Make Them Appear Different to the Immune System

High mutational rates may contribute to increased immunogenicity Especially in smokers Lawrence MS, et al. Nature. 2013


Telegraaf


Lung cancer immunotherapy Landscape Cancer immunotherapy: any interaction with the immune system to treat cancer Active: priming of the immune system

Antigen-

specific

-> AG-specific antibodies & cytotoxic T cells

Monoclonal antibodies

Non-antigen-specific -> enhancement of immune system cytokines checkpoint inhibitors

HOPE: • • Promising phase II data!

Cancer vaccination therapy

Passive: delivery of compounds that may use immune system

Cancer immunomodulation therapy

• •

Adoptive cell transfer

cetuximab trastuzumab •

Targeted antibodies immunotherapy

T cells engineering • CARs Dendritic cells •

Cellular immunotherapy


Lung cancer vaccination phase 3 trials NSCLC Stage

IB-IIIA Stage IIIA-B following CRT

IIIb/IV following ChT

Trial

Status

MAGE-A3 ASCI MAGRIT target 2270

Recruited

Tecemotide (L-BLP25) START target 1300

Recruited

Belagenpumatucel-L STOP target 700

Recruited

rEGF target 1000

Ongoing

TG4010 TIME target 1000

Ongoing

Racotumomab (1E10) target 1082

Ongoing


Lung cancer immunotherapy Landscape Cancer immunotherapy: any interaction with the immune system to treat cancer Active: priming of the immune system

Antigen-

specific

-> AG-specific antibodies & cytotoxic T cells

Monoclonal antibodies

Non-antigen-specific

• •

Cancer vaccination therapy

Passive: delivery of compounds that may use immune system

-> enhancement of immune system cytokines checkpoint inhibitors

Hype: phase I at ASCO!

Cancer immunomodulation therapy

•

•

Adoptive cell transfer

cetuximab trastuzumab

Targeted antibodies immunotherapy

T cells engineering • CARs Dendritic cells •

•

Cellular immunotherapy


Nivolumab phase I

Updated by Brahmer ASCO 2014 Abstract 8112 N=129 NSCLC across doses (1-3-10mg/kg): - ORR 17% - Median duration response 74 weeks - OS 9.6 month - 1- and 2-year survival 42% and 24% 3mg/kg ORR 9/37, OS 14.9 month

Topalian SL et al. N Engl J Med 2012;366:2443-2454


Brahmer J. et al. NEJM, June 2, 2015


Ding eman sl post ASC O NVM O 18 juni 2015

RPh III Nivolumab vs Docetaxel in 2nd line Sq NSCLC

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125527s000lbl.pdf


Nivolumab geeft significante verlenging overleving



Clinical activity of nivolumab vs docetaxel as second line treatment in advanced NSCLC



Tumor response and duration



Treatment related adverse events in > 5% of patients



En verlenging PFSree and overall survival



OS by PD-L1 Expression

Presented By David Spigel at 2015 ASCO Annual Meeting


LCSS Average Symptom Burden Index:
Mean Change From Baseline While on Treatment

Presented By David Spigel at 2015 ASCO Annual Meeting


NIVOLUMAB 2de lijn Plaveiselcelcarcinoom


And not only in squamous….


Checkmate 057: phase III study nonsquamous NSCLC 2nd line stage IIIb/IV nonsquamous NSCLC

Randomize 1:1

Nivolumab 3 mg Q 2wks Docetaxel 75 g Q 3wk

End points: Primary: OS Secundary: PFS ORR Correlation PD-L1 Paz–Arez, LBA 109 ASCO 2015


Nivolumab in non-squamous cell lung cancer


ASCO 2015 30-5-15 studie stop na interim analyse nivolumab

docetaxel

N

292

290

ORR

19%

12%

PFS

2.3

4.2

0.92 (0.77-1.11)

OS

12.2

9.4

0.73 (0.59-0.89) P=0.0015

OS PDL1+

HR

0.59 (0.43-0.82)


Slide 30

Presented By Scott Gettinger at 2014 ASCO Annual Meeting


SELECTION OF PATIENTS Histology PD-L1 expression Mutational status


IMMUNOTHERAPIE: DAGELIJKSE PRAKTIJK = morgen


NVALT: Immunotherapie voor Longkanker Criteria voor centra 1. > 20 pt per jaar 2. Regelmatig MDO waarin specialisten zitting nemen die bij immunotherapie noodzakelijk zijn (dermatoloog, MDL-arts, immunologisch georienteerd arts)

3. Patienten registratie verplicht 4. Ervaring met immunotherapie door deelname aan studies


CENTRUM- EN PARTNERZIEKENHUIZEN Centrumziekenhuizen voor longkanker:

1.

Universitair Medisch Centrum Groningen

2.

Universitair Medisch Centrum Maastricht

3.

Erasmus Medisch Centrum Rotterdam

4.

VU Medisch Centrum Amsterdam

5.

NKI / Antoni van Leeuwenhoekziekenhuis Amsterdam

Partnerziekenhuizen: 1.

St. Antonius ziekenhuis, Nieuwegein

2.

Catharina ziekenhuis, Eindhoven

3.

Jeroen Bosch ziekenhuis, Den Bosch

4.

Rijnstate ziekenhuis, Arnhem

5.

Amphia ziekenhuis, Breda

6.

Isala klinieken, Zwolle

7.

Wever ziekenhuis, Heerlen


Goldman Sachs top disruptive themes






Van hype naar hoop naar werkelijkheid Of waarom u longarts had moeten worden….

Nieuwe patiëntenselectie met longcarcinoom als role model voor de medisch oncoloog Anne-Marie Dingemans POST ASCO NVMO 18 juni 2015

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