West Immunotherapy, Vaccines for Lung Cancer Mage-A3, Stimuvax, and Lucanix

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Information about West Immunotherapy, Vaccines for Lung Cancer Mage-A3, Stimuvax, and Lucanix
Health & Medicine

Published on February 21, 2014

Author: JackWestMD

Source: slideshare.net

Description

Update of results and current clinical trials of vaccines for lung cancer, including MAGE-A3, Stimuvax, and Lucanix for stage I-III non-small cell lung cancer. @JackWestMD, @CancerGRACE cancerGRACE.org

Vaccine Strategies: MAGE-A3, Stimuvax, and Lucanix Howard (Jack) West, MD Swedish Cancer Institute Seattle, WA February, 2014

Disclosures • Consultant: – – – – Genentech/Roche Celgene Novartis Foundation Medicine

MAGE-A3 • Tumor-specific • 30-50% of NSCLC • IHC testing Vansteenkiste, ASCO 2007, JCO 2013

Biomarker Selection in NSCLC: Predictive Gene Signature & DFI

Phase III Study - MAGRIT MAGE-A3 as Adjuvant Non-Small Cell LunG CanceR ImmunoTherapy Resected MAGE-A3 (+) NSCLC Pathological stage IB, II, IIIA No chemo Chemo Randomization Up to 4 cycles of platinum-based chemo MAGE-A3 ASCI Placebo Randomization Powered for efficacy MAGE-A3 ASCI Powered for efficacy >6000 screened for MAGE-A3 to enroll > 2000 Results expected 2H2014 -5- Placebo

Stimuvax (L-BLP25, Tecemotide) Mucinous glycoprotein overexpressed or abnormally glycosylated in epithelial malignancies MUC1 mucin GSTAPPAHGVTSAPDTRPAP S T A P P A H G V T S A P D T R P A P G S T A P P - Lys (PAL) G Antigen = BLP25 lipopeptide The amino acids of the lipopeptide provide antigenic epitopes for T cells Adjuvant = Monophosphoryl lipid A (MPL®) The adjuvant supports T-cell response by inducing pro-inflammatory cytokines (via TLR4 stimulation) Structural lipids = cholesterol, DPPC, and DMPG Further enhancement of antigen delivery/uptake into APCs and immune reaction 6 Presented by: Charles Butts, M.D.

Rand Phase 2 of BLP-25 vs. Placebo N = 171, stage IIIB or IV NSCLC Prior chemo  CR/PR/SD Overall, median OS 17.4 vs. 13 mo, HR .739, p = 0.112 MPE/Stage IV Stage IIIB (no MPE) 7 Butts,Presented by: Charles Butts, M.D. J Clin Oncol, 2005

Study design of EMR 63325-001 (START) Screening Weekly treatment 6-weekly treatment Survival follow-up Day −3 i.v. cyclophosphamide / saline Unresectable NSCLC stage IIIA/B No progression following chemo/RT* L-BLP25 + BSC s.c. administrations L-BLP25/placebo Randomize 2:1 Placebo + BSC Disease progression Randomization strata: • Stage IIIA vs. IIIB at first diagnosis • CR/PR vs. SD to initial chemo/RT • Concurrent vs. sequential chemo/RT • Geographical region The primary analysis (OS) was adjusted for these four variables. Primary endpoint: Overall survival Key secondary endpoints: • Time to symptom progression (TTSP) as measured by the Lung Cancer Symptom Scale (LCSS) • Time to progression (TTP, investigator assessment) • Safety *Chemo/RT ≥2 cycles of platinum-based chemotherapy and radiation ≥50 Gy Presented by: Charles Butts, M.D.

Primary endpoint: Overall survival L-BLP25 (N=829) Placebo (N=410) Median OS 25.6 mo 22.3 mo Adjusted HR 0.88 (95% CI 0.75‒1.03) p=0.123* OS rate (%) Median follow-up 39.9 mo 37.7 mo *Two-sided, strata and multiplicity adjusted At risk (N) Placebo L-BLP25 9 410 829 353 757 285 617 Presented by: Charles Butts, M.D. 188 429 127 301 108 255 88 204 59 128 33 73 18 33 4 8 0 0

Secondary endpoint: Time to progression Placebo (N=410) Median TTP 10.0 mo 8.4 mo Hazard ratio TTP rate (%) L-BLP25 (N=829) 0.87 (95% CI 0.75‒1.00) p=0.053* *Two-sided, adjusted for strata Imaging intervals according to institutional standards At risk (N) Placebo L-BLP25 10 410 829 226 513 144 329 Presented by: Charles Butts, M.D. 90 205 58 144 49 122 42 96 25 60 15 30 9 13 3 5 0 0

OS: Subgroup analyses by randomization strata Median OS (months) L-BLP25 vs. Placebo HR* (95% CI) Stage IIIA (N=487) 23.7 vs. 20.9 0.90 (0.74, 1.09) NA and Aus. (N=321) 34.1 vs. 21.7 0.79 (0.58, 1.09) 24.2 vs. 22.3 0.91 (0.71, 1.17) Rest of world (N=443) Response to chemo/ RT 0.86 (0.67, 1.11) W. Europe (N=475) Region 27.6 vs. 23.1 Stage IIIB (N=752) Stage 21.8 vs. 22.7 0.95 (0.73, 1.22) Stable disease (N=396) 20.4 vs. 17.8 0.85 (0.65, 1.11) Obj. response (N=843) 27.8 vs. 23.9 0.91 (0.75, 1.10) Chemo/ RT Concurrent (N=806) type Sequential (N=433) *Not adjusted for strata 11 Presented by: Charles Butts, M.D. 30.8 vs. 20.6 0.78 (0.64, 0.96) 19.4 vs. 24.6 1.11 (0.86, 1.43) Favors L-BLP25 Favors placebo

Overall survival: Concurrent chemo/RT Placebo (N=268) Median OS 30.8 mo 20.6 mo Hazard ratio 0.78 (95% CI 0.64‒0.95) p=0.016* OS rate (%) L-BLP25 (N=538) *Two-sided, adjusted for strata At risk (N) Placebo L-BLP25 12 268 538 227 499 186 412 Presented by: Charles Butts, M.D. 118 295 73 205 62 176 54 147 40 89 26 51 16 24 4 7 0 0

Overall survival: Sequential chemo/RT Placebo (N=142) Median OS 19.4 mo 24.6 mo Hazard ratio 1.12 (95% CI 0.87‒1.44) p=0.38* OS rate (%) L-BLP25 (N=291) *Two-sided, adjusted for strata At risk (N) Placebo L-BLP25 13 142 291 126 258 99 205 Presented by: Charles Butts, M.D. 70 134 54 96 46 79 34 57 19 39 7 22 2 9 0 1 0 0

Overview of adverse events Preferred term AE L-BLP25 N=1,024 n (%) Placebo N=477 n (%) Any 938 (91.6) 432 (90.6) Any serious 303 (29.6) 151 (31.7) Any grade 3/4 342 (33.4) 171 (35.8) 46 (4.5) 35 (7.3) L-BLP25 (N=1,024) Placebo (N=477) Any 176 (17.3) 56 (11.9) 0 (0) 0 (0) L-BLP25 (N=1,024) Placebo (N=477) 391 (38.2) 8 (1.7) Any Grade 3/4 Flu-like symptoms Any Any Grade 3/4 14 Cough 338 (33.0) 133 (27.9) Dyspnea 238 (23.2) 112 (23.5) Fatigue 197 (19.2) 102 (21.4) 146 (14.3) 53 (11.1) 140 (13.7) 39 (8.2) Chest pain 135 (13.2) 45 (9.4) Nasopharyngitis 128 (12.5) 44 (9.2) Headache 124 (12.1) 54 (11.3) Decreased appetite 109 (10.6) 44 (9.2) Arthralgia 108 (10.5) 34 (7.1) 158 (33.1) 15 (1.5) Placebo N=477 n (%) Nausea Injection site reactions L-BLP25 N=1,024 n (%) Back pain Any leading to death Most frequent adverse events (>10 % in L-BLP25 arm) Presented by: Charles Butts, M.D. Injection-site reactions and flu-like symptoms were identified by MedDRA PT search.

INSPIRE Trial (Asia) • N = 500 Stage III unresectable NSCLC CR/PR/SD after >2 cycles platinum-based doublet chemotherapy with concurrent or sequential RT 15 Presented by: Charles Butts, M.D. 2 R A N D 1 Tecemotide Placebo • Primary endpoint: overall survival

START2 Trial, just being initiated • N = 1002 Stage III unresectable NSCLC CR/PR/SD after >2 cycles platinum-based doublet chemotherapy with concurrent RT 2 R A N D 1 Tecemotide Placebo • Primary endpoint: overall survival 16 Presented by: Charles Butts, M.D.

Belagenpumatucel-L: Allogeneic whole tumor cell vaccine – Four irradiated, cryopreserved NSCLC tumor cell lines – Each gene-modified to block TGF-β2 secretion 1.0 Survival All N Median (months) 1-yr 2-yr 5-yr 75 14.5 55% 35% 20% 1 25 10.4 42% 21% 17% 2 26 21.8 67% 46% 21% 3 24 15.8 57% 39% 0.8 Survival Cohort Cohort 1 Cohort 2 Cohort 3 0.6 22% 2 stage II patients 12 stage IIIA patients 15 stage IIIB patients 46 stage IV patients 0.4 0.2 0.0 0 12/71 patients (17%) alive (Mar, 2009) Survival range: 48 - 76 months 4 lost to follow up 12 24 36 48 60 72 Months Orig data - Nemunaitis, JCO 2006 Data from March 2009

Overall survival of phase III-eligible patients N Median (months) 1-yr 2-yr 5-yr SD, PR, or CR 18 44 65% 59% 50% PD 11 1.0 14 64% 36% 14% BSC-SD, PR, or CR 11 35% 8% <5% BSC-PD 5 0.8 8% <5% <5% Patients received one front-line, combination chemotherapy regimen: • with or without adjuvant chemotherapy • with or without radiation therapy Survival Patients who enrolled with SD/PR/CR 8/16 patients (50%) currently alive Survival range: 51 - 68 months BSC = best standard of care SD = stable disease; PR = partial response; CR = complete response PD = progressive disease 0.6 0.4 Patients who enrolled with PD 0.2 0.0 0 12 24 36 Months Time (Months) 48 60 Orig data - Nemunaitis, JCO 2006 March 2009

STOP trial of Belagenpumatucel vs. Placebo as Maintenance Therapy • N = 532, 42 with stage IIIA, 490 stage IIIB/IV (NOT all “wet” IIIB) Stage IIIA/IIIB/IV NSCLC CR/PR/SD after 4 cycles platinum-based doublet chemotherapy 1 R A N D 1 start Rx 4-17 wks after chemo Belagenpumatucel-L Placebo • Primary endpoint: overall survival

STOP trial of Belagenpumatucel vs. Placebo as Maintenance Therapy • Overall results negative for OS benefit – med OS 20.3 vs. 17.8 mo (HR 0.94) – Minimal toxicity (grade 2 rash at most) • Cox regression analysis (post hoc) – Stage IIIB/IV pts starting within 12 weeks of prior chemo  med OS 20.7 vs. 13.4 mo (HR = 0.75, p = 0.083) – Prior RT: med OS 40.1 vs. 10.3 mo (HR = 0.45, p = 0.014) – Non-adeno, starting within 12 weeks of prior chemo > med OS 19.9 vs. 12.3 mo (HR 0.55, p = 0.036) • FDA notes interest in continued study in subgroups Giaccone, ESMO 2013

Conclusions: Vaccines Have Potential for Efficacy with Excellent Therapeutic Index • MAGE-A3: MAGRIT trial results awaited this year; have potential to change standard of care for MAGE-A3 antigen-positive NSCLC in adjuvant setting • START trial with tecemotide showed promising results for patients who received concurrent chemo/RT – Await results of INSPIRE trial (Asia, START design) – START2 trial of tecemotide after concurrent CT/RT being initiated (N = 1002) • Belagenpumatucel: Subsets identified as beneficiaries – Subsequent study? TBD

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