11/7/2014
Systemic Therapy:
Immune Therapy / Targeted Therapy in HNSCC
Chemotherapy
Immunotherapy
Alain Algazi, MD Assistant Clinical Professor UCSF Melanoma & Head and Neck Oncology
Targeted therapy
[email protected]
Carbo/5FU +/- Cetux Median OS 7.4 vs 10.1 mos Median PFS 3.3 vs 5.6 mos
Now what? 4 drugs? 5 drugs? Fatalism / hospice?
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Carbo/5FU +/- Cetux -- Toxic
Targeted therapy challanges
– Molecular target – Drug – Acquired resistance – Heterogeneity
Vemurafenib in melanoma: Partial response and natural selection
Targeted Therapy – EGFR
– Found in high levels in normal proliferating tissue – Aberrant expression associated with cell proliferation, survival, angiogenesis, invasion, metastasis – High nuclear localization (nEGFR) in epithelial cancers including SCCHN – Nuclear translocation induced by radiation, cisplatin – Increased nEGFR correlates with clinical outcomes
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In SCC of the Head and Neck: nEGFR is associated with decreased OS and response rate, increased recurrence rate
Metastatic SCC – Cetuximab BORR = 12-13%
Discov Med 2011 Nov;12(66):419-32)
Metastatic SCC – Cetuximab PFS ~ 2.5 months
Cetuximab: a non-optimal EGFR inhibitor? Agent
Target
Type
Pop’n ORR
OS (vs Cetux)
Panitumumab EGFR
mAb
R/M
HPV+ 11 mo (12.6) HPV+ 11.7 mo (8.6)
Afatinib
EGFR + TKI HER2
R/M
18% (8%)
J Clin Oncol 30, 2012 suppl J Clin Oncol 28:15s, 2010 suppl; abstr 5501
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EGFR MAb – Combinations?
EGRF / PI3K Combination Erlotinib (EGFR) + Temsirolimus (mTOR) Closed early due to toxicity J Clin Oncol 30, 2012 suppl; abstr 5549
EGFR RAS PI3K
RAF PTEN
AKT TORC1
Targeted therapy example – cetuximab + BYL719
MEK ERK
TORC2
Targeted therapy example – cetuximab + BYL719
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Targeted therapy example – cetuximab + BYL719
Targeted therapy example – cetuximab + BYL719
Targeted therapy example – cetuximab + BYL719
Targeted therapy example – cetuximab + BYL719
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Some agents in ph I/II for head and neck cancer EGFR: EGFR/VEGF: VEGF: VEGF/PDGF: IGF: mTor: PARP:
erlotinib, gefinitib, zalutumumab vandetanib cediranib, bevacizumab sorafenib, sunitinib cixutumumab everolimus, sirolimus veliparib, iniparib
Papillary Thyroid Carcinoma (38% BRAFV600E)
SCCHN: Open Trials • Cetuximab + BYL719 (oral PI3K inh) • Cetuximab + MM-121 (mAb ErbB3 inh) • CC-115 (oral dual DNA-PK/mTORi inh)
BRAFV600E Thyroid carcinoma: Open Trials • Vemurafenib for Metastatic/Unresectable PTC • Vemurafenib Neoadjuvant for Locally Advanced Thyroid Cancer • Dabrafenib + Trametinib for Metastatic/Unresectable BRAFV600E PTC
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Thyroid Cancer – Vandetanib: TKI of RET, VEGFR, EGFR
MTC Cabozantinib: TKI of cMET, VEGFR2, RET PFS 11.2 mo vs 4 mo (PFS > 6 mo in 68%) BORR 28% vs 0 ORR
PFS 11.1 mo vs. 5.9 mo
Leboulet, Schlumberger et al Lancet Oncol 2012; 13: 897-905)
MTC Cabozantinib: TKI of cMET, VEGFR2, RET
Immunotherapy • Ipilimumab (mAb CTLA-4) in SCC lung – PII IIIB/IV NSCLC vs carbo/taxol – irPFS HR 0.55 in SCC vs 0.82 in NSC – Phase III: OS in squamous NSCLC – PD-1 combos in HNSCC J Clin Oncol 2012 Jun 10;30(17):2046-54
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PD-1 / PD-L1 Abs
Immune Therapy – Anti-PD1 antibody in melanoma Targeted by nivolumab / MPDL3280A / MK3475
Impressions • Far less toxic than ipilimumab • More durable responses than BRAF / MEK
When the data came out, we were giddy There were 300-400 proposals for combinations with MK3475 Okazaki et al. Nature Immunology 14, 1212–1218 (2013)
Immunotherapy mAb PD-1 or PDL-1 mAbs – rationale – PDL-1 expression KEYNOTE-012 – Study Design
• May predict response • PDL-1 expressed in HPV+ tumor cells (Cancer Res 2013 Mar 15;73(6):1733-41)
• anti-PD-1 mAb inhibits SCC in vitro (Oral Oncol 2006 Mar;42(3):268-74)
Open phase I trial: MPDL3280A (mAb PD-1 inh) Presented By Tanguy Seiwert at 2014 ASCO Annual Meeting
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Objectives
Eligibility
Presented By Tanguy Seiwert at 2014 ASCO Annual Meeting
Presented By Tanguy Seiwert at 2014 ASCO Annual Meeting
Patient Overview
PD-L1 IHC Pre-screening of KEYNOTE 12 HNSCC Tumor Samples
Presented By Tanguy Seiwert at 2014 ASCO Annual Meeting
Presented By Tanguy Seiwert at 2014 ASCO Annual Meeting
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PD-L1 Screening Results
Summary of Drug-related Adverse Events Incidence > 5%*
Presented By Tanguy Seiwert at 2014 ASCO Annual Meeting
Presented By Tanguy Seiwert at 2014 ASCO Annual Meeting
Pre-specified Adverse Events*
Efficacy: Waterfall Plot*
Presented By Tanguy Seiwert at 2014 ASCO Annual Meeting
Presented By Tanguy Seiwert at 2014 ASCO Annual Meeting
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Best Overall Response*
Time on treatment and disposition*
Presented By Tanguy Seiwert at 2014 ASCO Annual Meeting
Presented By Tanguy Seiwert at 2014 ASCO Annual Meeting
Ipilimumab + Radiation – The Abscopal Effect
Slide 19
Presented By Tanguy Seiwert at 2014 ASCO Annual Meeting
Postow et al. 2012.
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Conclusions
• Overall survival is limited in metastatic / unresectable HNSCC • Targeted therapy combinations can draw on prior data to address resistance • EGFR / PI3K combinations show signs of synergy • Immune checkpoint inhibitors are active in HNSCC • Checkpoint inhibitors work best in the context of inflammation • NRG study to test anti-PD-1 Ab with XRT
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