Slide 1. Slide 2. Slide 3. Immunotherapy in Lung Cancer. Disclosures. Objectives. No disclosures relevant to this talk

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1 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

2 Slide 4 Evolution of L. Bazhenova, MD V V V adenocarcinoma SCC Large cell carcinoma NOS Chemotherapist Vocabulary: NSCLC Visual aid: 5% 5% NSCLC Unkn, 42% Histopathologist Vocabulary: 30% CK 7, CK 20, TTF-1, CK 5/6, p63 Visual aid: Molecular biologist EGFR, 15% Vocabulary: EGFR, KRAS, ALK, BRAF, C-MET, PI3K, HER2, MAPK 21, MEK, AKT, FISH, PCR.. Visual aid: 100% MEK, V 4.0 1% Budding Immunologist In the Vocabulary: PIK3CA, 1% THL, CTLA4, MHC, B7, Antigen, TGF, IL-2 works Visual aid: FGFR4, 2% HER EML4-ALK, 5% BRAF, 2% 2, 2% KRAS, 30% 60% 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 Talactoferrin Toll like receptor agonists Cadi-05 (TRL2 agonist) Anti CTL4 antibodies. Ipilimumab Monoclonal antibodies to tumor antigens Vaccines Dendritic cell vaccines Tumor cell vaccines GM-CSF modified tumor cell vaccine Belagenpumatucel-L Protein/peptide vaccines IDM MAGE A3 vaccine L-BLP25

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

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

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

6 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

7 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 mwho Criteria irresponse criteria CR PR SD PD All lesions gone SPD of index lesions decreases 50% SPD of index lesions of neither CR, PR or PD New lesions not allowed ircr irpr irsd irpd All lesions gone SPD of index and any new lesions decreases 50% New lesions are allowed SPD of index and any new lesions neither ircr, irpr or irpd New lesions allowed SPD of index lesions increases 25% and/or new lesions develop SPD of index and any new lesions increase 25% Wolchok, Clin CancerRes 2009; 15

8 Slide 22 Summary of irrc Appearance of new lesions no longer automatically signifies progression as in WHO. unless they add to a tumor burden by at least 25% If patient is classified as irpd confirmation of progression is required. Confirmation is done at the discretion of investigator in the context of tumor type, patient overall clinical status The new response patterns appear to be clinically meaningful as they correlate with improved outcomes. Further confirmation of irrc is needed in the prospective clinical trials They are not ready for wide acceptance AND they are not accepted by FDA on immune studies. Slide 23 Slide 24 Ipilimumab (Ipi) Fully human monoclonal anti CTLA4 antibody CTLA4 inhibits anti-tumor immunity. Blocking CTLA4 potentiates T cells Improves survival in metastatic melanoma Serious, potentially life threatening immune toxicities Colitis, dermatitis, hepatitis, neuritis. Early diagnosis and prompt treatment of those management is required.

9 [TITLE] Slide 25 Slide courtesy of Raffit Hassan. MD Slide 26 Study design Objectives: To evaluate safety and efficacy of ipilimumab in combination with chemotherapy Primary endpoint irpfs Evaluate 2 different schedules Tumor antigen present before Ipi started (aka give chemotherapy first for 2 cycles) Ipi started at the same time as chemotherapy. Key inclusion criteria Chemotherapy naïve patients with ECOG 0-1 without brain metastases or autoimmune disease Response evaluated by both WHO and irrc Lynch et al, abs #7531 ASCO 2011 Slide 27 Trial CA Study Design Treatment Phase Maintenance Phase (N=203) C C C C C C IPI IPI Followup Arm A IPI + Chemo IPI IPI IPI IPI p p phase Concurrent R A N C C C C C C IPI IPI D 1:1:1 Arm B Followup O IPI + Chemo n=204 M Phased* p p IPI IPI IPI IPI phase I Z E C C C C C C p p Arm C Followup Chemo only Placebo p p p p p p phase Chemo: Paclitaxel (175 mg/m 2 )/Carboplatin (AUC=6) IV C: chemotherapy doublet q3w q12w IPI: Ipilimumab (10 mg IV) p: Placebo Note: Steroids were given as premedication. * The term sequential, which was listed in the abstract, is now referred to as phased to more accurately reflect the schedule.

10 Slide 28 Kaplan-Meier Plots of irpfs per irrc Concurrent Schedule Phased Schedule Slide 29 Kaplan-Meier Plot of Interim Overall Survival Concurrent Schedule Phased Schedule Slide 30 Results Concurrent Phased Placebo ir BORR 21% 32% 18% irdcr 70% 86.8% 81.8% irpfs 5.5m OS HR P= m HR P= m HR 0.69 P= m HR P= m 10m

11 Slide 31 Key Immune-Related Adverse Events Arm A Concurrent IPI + Chemo (N=71) Arm B Phased IPI + Chemo (N=67) Arm C Placebo Chemo Only (N=65) N(%) Total Gr 3 Gr 4 Total Gr 3 Gr 4 Total Gr 3 Gr 4 Any irae 46 (64.8) 13 (18.3) 1 (1.4) 44 (65.7) 7 (10.4) 3 (4.5) 34 (52.3) 4 (6.2) 0 Dermatologic 40 (56.3) 3 (4.2) 0 35 (52.2) 2 (3.0) 0 31 (47.7) 1 (1.5) 0 Pruritus 12 (16.9) (7.5) (6.2) 1 (1.5) 0 Rash 20 (28.2) 2 (2.8) 0 9 (13.4) 2 (3.0) 0 6 (9.2) 1 (1.5) 0 Gastrointestinal 21 (29.6) 5 (7.0) 0 16 (23.9) 4 (6.0) 0 11 (16.9) 2 (3.1) 0 Diarrhea 21 (29.6) 5 (7.0) 0 15 (22.4) 3 (4.5) 0 10 (15.4) 2 (3.1) 0 Colitis (3.0) 2 (3.0) AST* 4 (5.6) 2 (2.8) 0 4.(6.0) (3.1) 0 0 ALT* 4 (5.6) 2 (2.8) 0 5 (7.5) 1 (1.5) 0 2 (3.1) 0 0 No grade 4 dermatologic or gastrointestinal iraes were observed Fatal (grade 5) toxic epidermal necrolysis (TEN) was observed in 1 patient in Arm A Hypopituitarism and adrenal Insufficiency were not observed 2 patients experienced grade 1-2 hypothyroidism (1 each in Arm A and B, respectively) Slide 32 Slide 33 Cancer Vaccines Cell Based Antigen/peptide based Dendritic cells Tumor cells

12 Slide 34 Vaccines Dendritic cell vaccines Tumor cell vaccines GM-CSF modified tumor cell vaccines Belagenpumatucel-L Protein/peptide vaccines IDM-2101 MAGE A3 vaccine L-BLP25 Slide 35 Slide 36 Belagenpumatucel-L Belagenpumatucel-L is a nonviral therapeutic vaccine comprised of 4 TGF-β2 antisense gene-modified allogeneic NSCLC cell lines. 2 adenocarcinoma, 1 Squamous cell carcinoma, 1 large cell carcinoma. TGF-β2 production is blocked Irradiated and cryopreserved

13 Slide 37 Phase II study design R 1:1:1 Cohort x10 7 Cells/injection Cohort 2 2.5x10 7 Cells/injection Key inclusion criteria: Histologically confirmed NSCLC PS 2, stages II-IV (AJCC 6.0) tumor burden of < 125mL Stage breakdown: 2 stage II 12 stage IIIA 14 stage IIIB 47 stage IV Cohort 3 5 x 10 7 Cells/injection Intradermal injections administered monthly at 3 clinical sites. Nemunaitis J et al. JCO 2006 Slide 38 Safety and Tolerability of Belagenpumatucel-L Adverse events: Injection site reactions Flu-like symptoms All are transient All are grade 2 Slide courtesy of Dan Shawler, PhD Slide 39 Overall Survival by Cohort, All Patients Survival Cohort Median N (months) 1-yr 2-yr 5-yr 7-yr % 21% 17% 20% % 46% 21% 9% % 39% 22% 23% Cohort 1 Cohort 2 Cohort 3 N = 75

14 Slide 40 Overall Survival by Cohort, Stage IIIB/IV Survival Cohort Median N (months) 1-yr 2-yr 5-yr 7-yr % 20% 20% 20% % 40% 17% 7% % 43% 20% 22% Cohort 1 Cohort 2 Cohort 3 N = 61 Slide 41 Overall Survival Median N (months) 1-yr 2-yr 5-yr 7-yr 44 65% 59% 50% 50% SD, PR, or CR 18 PD % 36% 14% 0% N = 29 Slide 42 STOP trial Phase III. Double blind. N=506 Started: October 2008 Expected completion June 2012 R 1:1 Arm A 2.5x10 7 Cells/injection +BSC Arm B Placebo +BSC Key inclusion criteria: Histologically confirmed NSCLC IIIA (T3N2) IIIB IV Maintenance therapy for patients with SD or better following frontline chemotherapy Primary Objective Overall Survival Secondary Objectives: Adverse events Tumor progression Quality of life

15 Slide 43 Slide 44 L-BLP 25 MUC 1 (mucin1) glycoprotein antigen Commonly overexpressed in lung cancer and aberrantly glycosylated. L-BLP 25 is a liposomal vaccine containing peptides of the extracellular domain of MUC1 + adjuvant. Slide 45 Phase IIB study design R 1:1 Arm A L-BLP25* Arm B BSC * Patients randomized to vaccine arm received cyclophosphamide 300mg/m2 3 days before vaccine injection N=171 Key inclusion criteria: Histologically confirmed NSCLC Stage IIIB or IV Maintenance therapy for patients with SD or better following frontline chemotherapy Stage breakdown: IIIB Locoregional N=65 IIIB MPE/IV N=106 Injections intradermal, weekly x 8 weeks, followed by q6 weeks till progression C. Butts, J Cancer Res Clin Onc, epub

16 Survival distribution function Survival distribution function Slide 46 Safety Well tolerated. Most common side effects attributable to vaccine Flu like symptoms Injection site reactions Slide Overall survival, all patients. L-BLP25 (n=88) BSC (n=83) 0.75 HR = 0.745, 95% CI 0.533, Censored observation 0.50 Cohort Median N (months) 3yr BLP % BSC % p Survival time (months) Slide courtesy of Charles Butts 70 Slide Overall survival, IIIB (effusion), IV L-BLP25 (n=53) BSC (n=53) 0.75 HR = 0.878, 95% CI 0.587, Censored observation 0.50 Cohort Median N (months) 3yr BLP % BSC % p Survival time (months) Slide courtesy of Charles Butts 70

17 Survival distribution function Slide Overall survival, IIIB L-BLP25 (n=35) BSC (n=30) 0.75 HR = 0.548, 95% CI 0.301, Censored observation Cohort Median N (months) 3yr BLP % BSC % p Survival time (months) Slide courtesy of Charles Butts 70 Slide 50 START trial Phase III. Double blind. N=1500 Started: December 2006 Completed accrual. R 1:1 Arm A L-BLP 25 +BSC* Arm B Placebo +BSC * Patients randomized to vaccine arm received cyclophosphamide 300mg/m2 3 days before vaccine injection Key inclusion criteria: Histologically confirmed NSCLC Unresectable IIIB Maintenance therapy following curative chemoxrt Primary Objective Overall Survival Secondary Objectives: TTSF TTP Adverse events Slide 51

18 Slide 52 MAGE-A3 Vaccine MAGE melanoma associated antigen Expressed in 35-40% of lung cancers Expression increases with stage and associated with poor prognosis MAGE A3 is a recombinant protein vaccine combined with proprietary immunological adjuvant ASO2B Slide 53 Phase II MAGE A3 study design R 2:1 Arm A MAGE A3 vaccine +BSC Arm B BSC Key inclusion criteria Tumor expresses MAGE Ag Stages IB-II surgically resected 1089 surgical specimens evaluated 363 positive for MAGE 182 entered the trial IB 123 IIA 8 IIB 35 IIIA 16 IM q 3 weeks x 5, followed q3m x 8 Primary endpoint DFI Slide 54 Safety Well tolerated Grade 1 and 2 local or systemic reactions

19 DFS Distribution DFS Distribution Slide 55 Randomized Phase II Trial of MAGE-A3 Vaccine in MAGE-A3+ NSCLC DFI Time From Surgery (Months) HR=0.73 P= % reduction in relative risk of cancer recurrence following surgery Vansteenkiste. ASCO (abstr 7554)). MAGE-A3 Placebo DFS MAGE-A3 Placebo HR=0.73 P= Time From Surgery (Months) Slide 56 MAGRIT Phase III double blind. N=2270 Started October 2007 Estimated completion December 2022 R 2:1 Arm A MAGE A3 vaccine +BSC Arm B BSC Stage IB of BSC closed Stage IIIA of chemotherapy closed Key inclusion criteria Tumor expresses MAGE Ag Stages I-III surgically resected Stratified by adjuvant therapy received or not Primary objectives Disease free survival Secondary objective Prospective validation of a predictive gene signature Slide 57 What have we learned over the years Developing immunotherapies is not the same as developing cytotoxics Responses take longer resist RECIST Lower bulk tumors could derive more benefit Generally not toxic Stay tuned for results of phase III trials MAGRIT Resected I-III START and INSPIRE unresectable treated IIIB (locoregional) STOP Treated advanced IIIA Unresectable treated IIIB Controlled IV

20 Slide 58 Immunotherapy agents that I did not cover. GVAX An adenoviral gene-based autologous vaccine TG Vaccinia virus coding for MUC1 and IL2 IDM 2101 Talactoferrin Cadi-05 (TRL2 agonist) Slide 59 Evolution of L. Bazhenova, MD V 1.0 V 2.0 V3.0 V 4.0 V 5.0???????? Chemotherapist Vocabulary: NSCLC Visual aid: Histopathologist Vocabulary: CK 7, CK 20, TTF-1, CK 5/6, p63 Visual aid: Molecular biologist Vocabulary: EGFR, KRAS, ALK, BRAF, C-MET, PI3K, HER2, MAPK 21, MEK, AKT, FISH, PCR.. Visual aid: Budding Immunologist Vocabulary: THL, CTLA4, MHC, B7, Antigen, TGF, IL-2 Visual aid: