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Immunotherapy in Lung Cancer

Lyudmila Bazhenova, MD Associate Clinical Professor, Moores UCSD Cancer Center

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Disclosures

• No disclosures relevant to this talk

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Objectives

• Review immune pathways

▫ Immunology 101

• Review pitfalls of immunotherapeutic agents

▫ irRC ▫ Flair phenomenon.

• Review several agents in development

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Evolution of L. Bazhenova, MD

V 1.0 2002

• Chemotherapist
• Vocabulary: NSCLC
• Visual aid:

V 2.0 2008

• Histopathologist
• Vocabulary: CK 7, CK 20, TTF-1, CK 5/6, p63
• Visual aid:

V3.0 2010

• Molecular biologist
• Vocabulary: EGFR, KRAS, ALK, BRAF, C-MET, PI3K, HER2, MAPK

21, MEK, AKT, FISH, PCR…..

• Visual aid:

V 4.0 In the works

• Budding Immunologist
• Vocabulary: THL, CTLA4, MHC, B7, Antigen, TGF, IL-2
• Visual aid:

100%

NSCLC

60% 30% 5% 5% adenocarcinoma SCC Large cell carcinoma NOS KRAS, 30% EGFR, 15% EML4-ALK, 5% HER 2, 2% BRAF, 2% FGFR4, 2% PIK3CA, 1% MEK, 1% Unkn, 42%

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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

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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 -2101  MAGE A3 vaccine  L-BLP25

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[TITLE]

Slide courtesy of Raffit Hassan. MD

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[TITLE]

Slide courtesy of Raffit Hassan. MD

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Nov 2009 Feb 17 2010 Started on Phase III Belagenpumatucel-L trial December 2009

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Tissue biopsy

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Pseudoprogression

Nov 2009 Feb 17 2010 Mar 12 2010

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Paradigm shift

Traditional chemotherapy- cytotoxic Targeted therapy-cytostatic for unselected patients Immune therapy-continuum of biological events

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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

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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.

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Response patterns in melanoma patients treated with anti CTLA-4 antibody ipilimumab

Wolchok, Clin CancerRes 2009; 15

Immediate response “Stable disease” with slow, steady decline in total tumor burden Response after initial progression Initial mixed response

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Resected progressing metastatic melanoma lesion in a patient treated with ipilimumab

Wolchok, Clin CancerRes 2009; 15

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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

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Index lesion New measurable lesion Total sum

Immune related response criteria (irRC)

Tumor burden= SPDindex lesions + SPDnew measurable lesions

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mWHO vs. irRC

CR PR SD PD mWHO Criteria All lesions gone SPD of index lesions decreases ≥50% SPD of index lesions of neither CR, PR or PD SPD of index lesions increases ≥25% and/or new lesions develop New lesions not allowed irCR irPR irSD irPD irResponse criteria 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 and any new lesions increase ≥25% Wolchok, Clin CancerRes 2009; 15

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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

• f 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.

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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.

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[TITLE]

Slide courtesy of Raffit Hassan. MD

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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

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Trial CA184-041 Study Design

Arm A IPI + Chemo Concurrent Arm B IPI + Chemo Phased* Arm C Chemo only Placebo Treatment Phase Maintenance Phase Follow- up phase C C C C C C C C C C C C C C C C C C p p p p p p p p IPI IPI IPI IPI p p

q3w q12w

Follow- up phase Follow- up phase

Chemo: Paclitaxel (175 mg/m2)/Carboplatin (AUC=6) IV C: chemotherapy doublet IPI: Ipilimumab (10 mg IV) p: Placebo

p p IPI IPI IPI IPI IPI IPI IPI IPI R A N D O M I Z E 1:1:1 n=204 (N=203)

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.

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Kaplan-Meier Plots of irPFS per irRC

Concurrent Schedule Phased Schedule

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Kaplan-Meier Plot of Interim Overall Survival

Concurrent Schedule Phased Schedule

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Results

Concurrent Phased Placebo ir BORR 21% 32% 18% irDCR 70% 86.8% 81.8% irPFS 5.5m HR 0.775 P= 0.094 5.7m HR 0.69 P=0.026 4.6m OS 11m HR 0.962 P=0.429 11.6m HR 0.748 P=0.104 10m

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Key Immune-Related Adverse Events

• 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)

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) Dermatologic 40 (56.3) 3 (4.2) 35 (52.2) 2 (3.0) 31 (47.7) 1 (1.5) Pruritus 12 (16.9) 5 (7.5) 4 (6.2) 1 (1.5) Rash 20 (28.2) 2 (2.8) 9 (13.4) 2 (3.0) 6 (9.2) 1 (1.5) Gastrointestinal 21 (29.6) 5 (7.0) 16 (23.9) 4 (6.0) 11 (16.9) 2 (3.1) Diarrhea 21 (29.6) 5 (7.0) 15 (22.4) 3 (4.5) 10 (15.4) 2 (3.1) Colitis 2 (3.0) 2 (3.0) AST* 4 (5.6) 2 (2.8) 4 .(6.0) 2 (3.1) ALT* 4 (5.6) 2 (2.8) 5 (7.5) 1 (1.5) 2 (3.1)

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Cancer Vaccines Cell Based Dendritic cells Tumor cells Antigen/peptide based

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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

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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

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1:1:1 Cohort 1 1.25x107 Cells/injection Cohort 2 2.5x107 Cells/injection Cohort 3 5 x 107 Cells/injection

Phase II study design

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 Intradermal injections administered monthly at 3 clinical sites. Nemunaitis J et al. JCO 2006

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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

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Overall Survival by Cohort, All Patients

N = 75 Survival Cohort N Median (months) 1-yr 2-yr 5-yr 7-yr 1 25 10.4 42% 21% 17% 20% 2 26 21.8 67% 46% 21% 9% 3 24 15.8 57% 39% 22% 23% Cohort 1 Cohort 2 Cohort 3

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Overall Survival by Cohort, Stage IIIB/IV

N = 61 Cohort 1 Cohort 2 Cohort 3 Survival Cohort N Median (months) 1-yr 2-yr 5-yr 7-yr 1 20 6.9 45% 20% 20% 20% 2 20 14.9 60% 40% 17% 7% 3 20 15.9 62% 43% 20% 22%

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Overall Survival

N = 29 N Median (months) 1-yr 2-yr 5-yr 7-yr SD, PR, or CR 18 44 65% 59% 50% 50% PD 11 14 64% 36% 14% 0%

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1:1

Arm A 2.5x107 Cells/injection +BSC Arm B Placebo +BSC

STOP trial

Phase III. Double blind. N=506 Started: October 2008 Expected completion June 2012 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

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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.

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1:1

Arm A L-BLP25* Arm B BSC

Phase IIB study design

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 * Patients randomized to vaccine arm received cyclophosphamide 300mg/m2 3 days before vaccine injection

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• C. Butts, J Cancer Res Clin Onc, epub

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Safety

• Well tolerated.
• Most common side effects attributable to vaccine

▫ Flu like symptoms ▫ Injection site reactions

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Survival distribution function Survival time (months) 1.00 70 0.75 0.50 0.25 0.00 10 20 30 40 50 60 HR = 0.745, 95% CI 0.533, 1.042 L-BLP25 (n=88) BSC (n=83) Censored observation Slide courtesy of Charles Butts Cohort N Median (months) 3yr BLP25 88 17.2 31% BSC 83 13.0 17% p 0.035

Overall survival, all patients.

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Survival distribution function Survival time (months) 1.00 70 0.75 0.50 0.25 0.00 10 20 30 40 50 60 HR = 0.878, 95% CI 0.587, 1.313 L-BLP25 (n=53) BSC (n=53) Censored observation Cohort N Median (months) 3yr BLP25 53 15.1 19% BSC 53 12.9 11% p 0.278

Overall survival, IIIB (effusion), IV

Slide courtesy of Charles Butts

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Survival distribution function Survival time (months) 1.00 70 0.75 0.50 0.25 0.00 10 20 30 40 50 60 HR = 0.548, 95% CI 0.301, 0.999 L-BLP25 (n=35) BSC (n=30) Censored observation Cohort N Median (months) 3yr BLP25 35 30.6 49% BSC 30 13.3 27% p 0.07

Overall survival, IIIB

Slide courtesy of Charles Butts

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1:1

Arm A L-BLP 25 +BSC* Arm B Placebo +BSC

START trial

Phase III. Double blind. N=1500

• Started: December 2006
• Completed accrual.

Key inclusion criteria:

• Histologically confirmed NSCLC
• Unresectable IIIB
• Maintenance therapy following

curative chemoXRT Primary Objective Overall Survival Secondary Objectives: TTSF TTP Adverse events * Patients randomized to vaccine arm received cyclophosphamide 300mg/m2 3 days before vaccine injection

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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

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R

2:1

Arm A MAGE A3 vaccine +BSC Arm B BSC

Phase II MAGE A3 study design

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

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Safety

• Well tolerated

▫ Grade 1 and 2 local or systemic reactions

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• Vansteenkiste. ASCO. 2007 (abstr 7554)).

27% reduction in relative risk of cancer recurrence following surgery

Randomized Phase II Trial of MAGE-A3 Vaccine in MAGE-A3+ NSCLC

Time From Surgery (Months)

DFS

HR=0.73 P=0.093 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 DFS Distribution 6 12 18 24 30 36 42 48 54 MAGE-A3 Placebo

DFI

Time From Surgery (Months) HR=0.73 P=0.107 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 DFS Distribution 6 12 18 24 30 36 42 48 54 MAGE-A3 Placebo

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R 2:1

Arm A MAGE A3 vaccine +BSC Arm B BSC

MAGRIT

Phase III double blind. N=2270 Started October 2007 Estimated completion December 2022 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 Stage IB of BSC closed Stage IIIA of chemotherapy closed

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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

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Immunotherapy agents that I did not cover.

• GVAX

▫ An adenoviral gene-based autologous vaccine

• TG4010.05

▫ Vaccinia virus coding for MUC1 and IL2

• IDM 2101
• Talactoferrin
• Cadi-05

▫ (TRL2 agonist)

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Evolution of L. Bazhenova, MD

V 1.0

• Chemotherapist
• Vocabulary: NSCLC
• Visual aid:

V 2.0

• Histopathologist
• Vocabulary: CK 7, CK 20, TTF-1, CK 5/6, p63
• Visual aid:

V3.0

• Molecular biologist
• Vocabulary: EGFR, KRAS, ALK, BRAF, C-MET, PI3K, HER2, MAPK 21, MEK, AKT, FISH, PCR…..
• Visual aid:

V 4.0

• Budding Immunologist
• Vocabulary: THL, CTLA4, MHC, B7, Antigen, TGF, IL-2
• Visual aid:

V 5.0

• ????????

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