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Slide 1 ___________________________________ ___________________________________ Immunotherapy in Lung Cancer ___________________________________ Lyudmila Bazhenova, MD Associate Clinical Professor, Moores UCSD Cancer Center ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 2 ___________________________________ Disclosures ___________________________________ • No disclosures relevant to this talk ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 3 ___________________________________ Objectives ___________________________________ • Review immune pathways ▫ Immunology 101 • Review pitfalls of immunotherapeutic agents ▫ irRC ___________________________________ ▫ Flair phenomenon. • Review several agents in development ___________________________________ ___________________________________ ___________________________________ ___________________________________

Slide 4 ___________________________________ Evolution of L. Bazhenova, MD adenocarcinoma SCC Large cell carcinoma NOS • Chemotherapist ___________________________________ V 1.0 5% • Vocabulary: NSCLC 5% NSCLC 2002 • Visual aid: KRAS, 30% Unkn, 42% • Histopathologist V 2.0 30% • Vocabulary: CK 7, CK 20, TTF-1, CK 5/6, p63 2008 • Visual aid: ___________________________________ 60% • Molecular biologist EGFR, 15% V3.0 • Vocabulary: EGFR, KRAS, ALK, BRAF, C-MET, PI3K, HER2, MAPK 21, MEK, AKT, FISH, PCR….. 2010 • Visual aid: 100% ___________________________________ • Budding Immunologist MEK, 1% V 4.0 • Vocabulary: THL, CTLA4, MHC, B7, Antigen, TGF, IL-2 In the PIK3CA, 1% • Visual aid: works FGFR4, 2% HER EML4-ALK, 5% 2, 2% BRAF, 2% ___________________________________ ___________________________________ ___________________________________ Slide 5 ___________________________________ Current state of the art ___________________________________ • Several immunotherapy agents are now in phase III trials ▫ 1 just completed its accrual, another one is ___________________________________ expected to finish in 6 months • Increased interest after approval of sipuleucel-T and ipilimumab • Patients LOVE this studies. ___________________________________ ▫ No problems completing accrual ___________________________________ ___________________________________ ___________________________________ Slide 6 ___________________________________ Immunotherapeutic strategies ___________________________________ • Non specific immune stimulants • Vaccines ▫ Talactoferrin ▫ Dendritic cell vaccines ▫ Toll like receptor agonists ▫ Tumor cell vaccines  Cadi-05 (TRL2 agonist)  GM-CSF modified tumor cell ___________________________________ ▫ Anti CTL4 antibodies. vaccine  Belagenpumatucel-L  Ipilimumab ▫ Protein/peptide vaccines • Monoclonal antibodies to tumor  IDM -2101 antigens  MAGE A3 vaccine  L-BLP25 ___________________________________ ___________________________________ ___________________________________ ___________________________________

Slide 7 ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 8 ___________________________________ ___________________________________ [TITLE] ___________________________________ ___________________________________ Slide courtesy of Raffit Hassan. MD ___________________________________ ___________________________________ ___________________________________ Slide 9 ___________________________________ ___________________________________ [TITLE] ___________________________________ ___________________________________ Slide courtesy of Raffit Hassan. MD ___________________________________ ___________________________________ ___________________________________

Slide 10 ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 11 ___________________________________ Nov 2009 ___________________________________ Feb 17 2010 ___________________________________ ___________________________________ Started on Phase III Belagenpumatucel-L trial December 2009 ___________________________________ ___________________________________ ___________________________________ Slide 12 ___________________________________ Tissue biopsy ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________

Slide 13 ___________________________________ Pseudoprogression Nov 2009 ___________________________________ Feb 17 2010 ___________________________________ Mar 12 2010 ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 14 ___________________________________ Paradigm shift ___________________________________ Traditional chemotherapy- cytotoxic ___________________________________ Targeted therapy-cytostatic for unselected patients ___________________________________ Immune therapy-continuum of biological events ___________________________________ ___________________________________ ___________________________________ Slide 15 ___________________________________ Continuum of biological events ___________________________________ Immune activation and T- Early cell proliferation Clinically measurable Weeks to ___________________________________ antitumor effects mediated months by activated immune cells Months Potential delayed effect on survival to years ___________________________________ Hoos, JNCI, vol 102, Sep 2010 ___________________________________ ___________________________________ ___________________________________

Slide 16 ___________________________________ Measuring response – a holy grail of clinical trials ___________________________________ • WHO, RECIST, RECIST 1.1 assume that decrease in the tumor size is an evidence of activity of anticancer agent. • Immunotherapy agents do not obey those rules. ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 17 ___________________________________ Response patterns in melanoma patients treated with anti CTLA-4 antibody ipilimumab Immediate response “Stable disease” with slow, steady decline in total tumor burden ___________________________________ ___________________________________ Response after initial progression Initial mixed response ___________________________________ Wolchok, Clin CancerRes 2009; 15 ___________________________________ ___________________________________ ___________________________________ Slide 18 ___________________________________ Resected progressing metastatic melanoma lesion in a patient treated with ipilimumab ___________________________________ ___________________________________ ___________________________________ Wolchok, Clin CancerRes 2009; 15 ___________________________________ ___________________________________ ___________________________________

Slide 19 ___________________________________ Cancer Vaccine Clinical Trial Working Group (CVCTWG) ___________________________________  Appearance of measurable clinical activity may take longer for immunotherapeutics  Responses can occur after conventional RECIST defined progression  Discontinuation of vaccine therapy might not be ___________________________________ appropriate for some progressive patients unless the progression is confirmed.  Durable stable disease may represent clinical benefit ___________________________________ Hoss, J Immunother, 2007, vol 30 ___________________________________ ___________________________________ ___________________________________ Slide 20 ___________________________________ Immune related response criteria (irRC) Tumor burden= ___________________________________ SPD index lesions + SPD new measurable lesions ___________________________________ ___________________________________ Index lesion New measurable lesion Total sum ___________________________________ ___________________________________ ___________________________________ Slide 21 ___________________________________ mWHO vs. irRC CR PR SD PD ___________________________________ mWHO All lesions SPD of index SPD of index SPD of index Criteria gone lesions lesions of lesions decreases neither CR, increases ≥50% PR or PD ≥25% and/or new lesions develop New lesions not allowed ___________________________________ irCR irPR irSD irPD irResponse All lesions SPD of index SPD of index SPD of index criteria gone and any new and any new and any new lesions lesions lesions decreases neither irCR, increase ___________________________________ ≥50% irPR or irPD ≥25% New lesions New lesions are allowed allowed Wolchok, Clin CancerRes 2009; 15 ___________________________________ ___________________________________ ___________________________________