Combinations in immunotherapy
TJN Hiltermann Longarts UMCG Groningen
Leek symposium 9-11-2016
Financial disclosures • Adviesraad BMS, AZD, Merck, Boehringer, Pfizer
Tijd (maanden)
Ove
rlevi
ng (%
)
Betere selectie patiënten en/of combinatie PD1 + RTx/biological?
PD1/ PD-L1
Biological o f Chemotherapie
HOE VERDER?
Hoe verder met immunotherapie
• PD-L1 als biomarker • Combinatie studies • Mogelijke rol histologie
2nd line treatment NSCLC: Nivolumab checkmate studies
17 (squamous)
57(non squamous)
Brahmer N Engl J Med 2015
Median Overall survival 1-Yr Overall survival
EMA approval independent of PD-L1
Borghaei N Engl J Med 2015
1st line treatment NSCLC: pembrolizumab
Reck N Engl J Med 2016
Selection: PD-L1≥50%
Keynote 24
500 (26%) PD-L1≥50% 305 (16%) in study 2nd line keynote-10: 442 (16%) PD-L1≥50%
PD-L1 as biomarker
• Obligatory in first line treatment (aprox 16% of patients)
• Not needed for second line treatment
• Enrichment of patients by higher cut off levels (RR 40-50%)
Moving forward?
• Studies combining PD-(L)1 inhibitor with chemotherapy
• Studies combining PD-(L)1 inhibitor with other checkpoints
• Studies combining PD-(L)1 inhibitor with radiotherapy
Combining 2nd line chemotherapy with PD-1
Langer Lancet Oncology 2016
Naiyer A. Rizvi et al. JCO 2016;34:2969-2979
Combining firstline chemotherapy and PD-1 inhibitor in NSCLC
N=11 N=15 N=15 N=13
No clear association could be discerned between PD-L1 expression and PFS or OS (Data Supplement), including assessments of higher expression levels of PD-L1
Fase III studies in NSCLC combining PD-(L)1 inhibitor with other checkpoint inhibitor
• Mystic trial (first line): durvalumab vs durvalumab + tremelimumab vs chemotherapy
• Neptune trial (first line) durvalumab+tremelimumab vs chemotherapy • Arctic trial (2nd line): Chemotherapy vs durvalumab vs durvalumab and
tremelimumab vs tremelimumab • CheckMate 227 (first line) Nivolumab, or nivolumab + ipilimumab, or
nivolumab + chemotherapy, vs chemotherapy • Checkmate 722 (2nd line EGFRm): Nivolumab + chemotherapy or nivolumab +
ipilimumab vs chemotherapy
Radiotherapy and immunotherapy
• Meerdere studies lopen hiernaar • Volgt evt studie UMCG
KAN HET SLIMMER?
No response to immuno Rx as shown by rebiopsy
Biomarker status and response to PD-L1 inhibitor
RS Herbst et al. Nature 515, 563-567 (2014)
Potential characteristics of immunogenic and nonimmunogenic tumors
P. Sharma and J.P. Allison Science 2015;348:56-61
Om tot response te komen heb je combinatie Rx nodig bij niet immunogene tumor
Daniel S. Chen and Ira Mellman
The cancer immune cycle
The tumor immunity continuum
Priti S. Hegde et al. Clin Cancer Res 2016;22:1865-1874
Immune exhausted
Inflamed
Immune Desert (ignorant)
+ =
Agents that promote effective priming Eg OX40, αCTLA4, CD137
Agents that promote tumor cell death Eg Chemotherapy, CAR-T vaccines, Radiotherapy, STING Targeted therapy Talimogene Laherparepvec=T-VEC
Address the barriers to T-cell entry into the tumor Eg αVEGF, chemokine agonists/antagonis, TCBs
Increase responses in PD-L1+ tumors: Eg αLAG-3, αTIGIT, αIDO, OX40
AACR 2016 Hegde PS
The tumor immunity continuum and cancer immune cycle
Conclusies
• Door patiënten en met name tumor goed te karakteriseren zullen we verder kunnen komen met de behandeling van gemetastaseerde kanker patiënten: − PD-L1 is niet het (hele) verhaal − Biopten voor behandeling steeds relevanter (inflamed vs
non-inflamed, Treg, TAM, MDSC etc) voor begrip van tumor responsen
− Combinaties van behandelingen (gestuurd door immunohistologie) zijn volgende stap in behandeling
PD-(L)1 inhibitors may become the backbone in treatment of (Lung)
cancer
Sent us your patients
Behandeling wordt steeds complexer
Motto: Makkelijker kunnen we het u niet maken
Multiple choice vragen
1. Belangrijkste parameter voor succes bij immunotherapie met checkpoint inhibitors is op dit moment:
a) PD-(L)1 status van tumor b) Histologie van tumor c) Aanwezigheid van tumor infiltrerende ontstekingscellen d) Type ontstekings infiltraat in tumor
2. Belangrijkste parameter voor verbetering succes bij immunotherapie met checkpoint inhibitors wordt
a) PD-(L)1 status van tumor b) Histologie van tumor c) Aanwezigheid van tumor infiltrerende ontstekingscellen d) Type ontstekings infiltraat in tumor
Herbst et al Lancet 2016; Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, NSCLC (KEYNOTE-010)
1224 (45%) no PD-1
=30% 1665 (62%)
Selection of patients
442 (16%) PD-L1≥50%
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