Systemic Therapy: Chemotherapy Immune Therapy / Targeted Therapy in HNSCC Immunotherapy Alain Algazi, MD Assistant Clinical Professor UCSF Melanoma & Head and Neck Oncology Targeted therapy alain.algazi@ucsf.edu 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? 1
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 2
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 + HER2 TKI R/M 18% (8%) J Clin Oncol 30, 2012 suppl J Clin Oncol 28:15s, 2010 suppl; abstr 5501 3
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 MEK AKT ERK TORC1 TORC2 Targeted therapy example cetuximab + BYL719 Targeted therapy example cetuximab + BYL719 4
Targeted therapy example cetuximab + BYL719 Targeted therapy example cetuximab + BYL719 Targeted therapy example cetuximab + BYL719 Targeted therapy example cetuximab + BYL719 5
Some agents in ph I/II for head and neck cancer SCCHN: Open Trials EGFR: EGFR/VEGF: VEGF: VEGF/PDGF: IGF: mtor: PARP: erlotinib, gefinitib, zalutumumab vandetanib cediranib, bevacizumab sorafenib, sunitinib cixutumumab everolimus, sirolimus veliparib, iniparib Cetuximab + BYL719 (oral PI3K inh) Cetuximab + MM-121 (mab ErbB3 inh) CC-115 (oral dual DNA-PK/mTORi inh) Papillary Thyroid Carcinoma (38% BRAF V600E ) BRAF V600E Thyroid carcinoma: Open Trials Vemurafenib for Metastatic/Unresectable PTC Vemurafenib Neoadjuvant for Locally Advanced Thyroid Cancer Dabrafenib + Trametinib for Metastatic/Unresectable BRAF V600E PTC 6
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 7
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 May predict response PDL-1 expressed in HPV + tumor cells KEYNOTE-012 Study Design (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) 8
Objectives Eligibility Patient Overview PD-L1 IHC Pre-screening of KEYNOTE 12 HNSCC Tumor Samples 9
PD-L1 Screening Results Summary of Drug-related Adverse Events Incidence > 5%* Pre-specified Adverse Events* Efficacy: Waterfall Plot* 10
Best Overall Response* Time on treatment and disposition* Ipilimumab + Radiation The Abscopal Effect Slide 19 Postow et al. 2012. 11
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 12