Immunotherapies in Lung Cancer: Can We Deliver on the Promise? (Part 2) with Drs. Ramaswamy Govindan & Julie Brahmer

Transcription

1 Immunotherapies in Lung Cancer: Can We Deliver on the Promise? (Part 2) with Drs. Ramaswamy Govindan & Julie Brahmer

2 Cancer Immunotherapy

3 Disclosure of Financial Relationships Consulting: Bristol Meyers Squibb (uncompensated)

4 Immune Checkpoints!

5 T Cell Activation: THWARTED By CTLA-4! Signal 2 B7.1/2 CD28 CTLA-4 HLA Signal 1 antigen T Cell Receptor Tumor Cell or Antigen Presenting Cell T cell

6 Blocking the Immune Checkpoint CTLA-4 Signal 2 B7.1/2 CD28 CTLA-4 HLA Signal 1 antigen T Cell Receptor T cell

7 Ipilimumab in Lung Cancer

8 Ipilimumab Blocks Negative Signaling From CTLA-4 Co-stimulation via CD28: T-cell activation CTLA-4 blocks co-stimulation: No T-cell activation Ipilimumab blocks CTLA-4: T-cell activation T cell T cell T cell TCR MHC B7 CD28 TCR MHC CD28 B7 CTLA4 TCR MHC CD28 B7 CTLA4 ipilimumab APC APC APC Adapted from Lebbé et al. ESMO 2008 APC, antigen-presenting cell; CTLA-4, cytotoxic T-lymphocyte antigen-4; MHC, major histocompatibility complex; TCR, T-cell receptor.

9 Ipilimumab - Background Evidence of activity in a broad range of other tumors, 1 including: Melanoma: first-line, second-line, and adjuvant therapy 2-3 Brain metastases 4 Prostate, lung, renal and pancreatic cancers, NHL, and other tumors 5-7 Safety profile in melanoma is well-characterized and mechanismbased The key drug-related side effects are immune-related Skin rash, diarrhea, endocrine dysfunction, transaminitis 1. Gabriel EM, Lattime EC. Clin Cancer Res. 2007;13: Hodi FS, et al. N Engl J Med Aug;363(8): O Day 9 SJ, et al. Ann Oncol Feb Urba WJ et al. J Clin Oncol. 26:2008 (May 20 suppl; abstr 3018). 5. Slovin SF et al. J Clin Oncol. 27:15s (suppl; abstr 5138). 6. Yang JC et al. J Immunother Nov-Dec; 30(8): Royal RE et al. GI Canc Symp. 2009, Abstr 153.

10 Ipilimumab in Melanoma Phase III trial: 676 patients with chemoresistant metastatic melanoma Randomized to ipilimumab + gp100, or either treatment alone Median overall survival of ipilimumab group 10 months, vs 6.4 months for gp100 Immune-related adverse events in 60% of patients (skin, GI, endocrine, liver) FDA decision March, 2011 Hodi et al, NEJM :711

11 Ipilimumab in Lung Cancer: Randomized Phase II Study Design Chemo: Paclitaxel (175 mg/m 2 )/Carboplatin (AUC=6) IV C: chemotherapy doublet IPI: Ipilimumab (10 mg IV) p: Placebo 11 Note: Steroids were given as premedication with paclitaxel

12 Ipilimumab in Lung Cancer: Conclusions PFS was extended with phased ipilimumab in combination with paclitaxel/ carboplatin A numerical improvement in OS was observed in the phased schedule but was not significant in this randomized phase II study Safety profile consistent with other ipilimumab studies Analysis of SCLC arm is awaited Phase III study in development (NCT ): 800 patients with squamous NSCLC, randomized to: Carboplatin/paclitaxel/ipilimumab vs Carboplatin/paclitaxel 12

13 It Takes a Village to Control a T Cell? Tumor Cell or Antigen Presenting Cell Signal 2 T cell B7.1/2 CD28 B7-H1 (PD-L1) HLA Class II MHC Signal 1 antigen CTLA-4 T Cell Receptor LAG-3 PD-1 Others: ICOS, GITR, Tim-3

14 PD-1 / PD-L1 Role in T Cell Activation What is PD-1? Involved in T cell regulation Expressed by activated memory and regulatory T cell Down regulates T cell by binding to PD-L1/L2

15 Tumor PD-L1 / B7-H1 Expression Potential way tumor cells evade immune system (self-defense) Poor prognosis in multiple tumor types including NSCLC 1 Seen in both Adeno and Squamous 1 NSCLC- membranous staining B7H1 (5h1 clone) 1 Mu CY et al Med Oncol 2010, Taube J personal communication

16 Multidose Phase Ib Trial of Anti-PD-1 (BMS /MDX 1106) 16

17 BMS Multi-dose Phase I Study Once every two week schedule (n=106) Doses tested - 1, 3, 10 mg/kg Dose escalation Standard 3+3 design, MTD not achieved Cohort expansion Melanoma and NSCLC (1, 3, 10 mg/kg) RCC, Prostate and Colorectal Ca 10 mg/kg Sznol, M et al ASCO 2010

18 BMS Drug-Related AEs by Dose Cohort (frequency >5%) 1 mg/kg Dose (n = 21) 3 mg/kg Dose (n = 16) 10 mg/kg Dose (n = 69) Total (n = 106) AE Any Grade (%) Grade 3/4 (%) Any Grade (%) Grade 3/4 (%) Any Grade (%) Grade 3/4 (%) Any Grade (%) Grade 3/4 (%) Total Subjects with AE Fatigue Rash Pruritus Investigations (lab/vitals) Diarrhea Nausea Sznol, M et al ASCO

19 BMS (Anti-PD-1): Preliminary Clinical Activity in NSCLC Dose PR SD PD 3 mg/kg (1) 1 10 mg/kg (16) 5 5 Pt with PR at 3 mg/kg has been on study for 14+ months Sznol M et al, ASCO 2010

20 BMS (Anti-PD-1): Expansion Cohorts for NSCLC Eligible NSCLC Pts Randomized between 3 dose levels 1 mg/kg IV q 2 wks N=32 3 mg kg IV q 2 wks N=32 10 mg/kg IV q 2 wks N=32 Recently completed accrual

21 Phase I of BMS Combination Chemotherapy -Advanced NSCLC -Nonsquamous Pemetrexed + Cisplatin IV q 3 wk + PD-1 Ab 10 mg/kg IV q 3 wk x 4 cycles -Advanced NSCLC -Squamous Enrollment ongoing Paclitaxel+ Carboplatin IV q 3 wk + PD-1 Ab IV 10 mg/kg q 3 wk x 4 cycles Gemcitabine D1, D8+ Cisplatin IV q 3 wk + PD-1 Ab IV q 3 wk x 4 cycles SD or PR PD-1 Ab IV q 3wk Until PD or 2 yrs

22 Potential Differences in PD-1 vs. PD- L1 Blockade Topalian S et al Curr Opin Immunol 2012

23 BMS (Anti-PD-L1) Phase I Study Design Screening 6 wk Treatment Cycle Worsened PD or Deterioration Off Study i.v. 15 i.v. 29 i.v. SCANS Response Assessment Confirmed CR or SD/PR + Unacceptable Toxicity Stable Disease/ Partial Response/ ucr/pd & clinically-stable Expanded cohort of NSCLC assessing dose levels 1, 3, 10 mg/kg ongoing Follow up every 6 wks (~52 wks total) Treat to Unacceptable Toxicity, wpd, ccr or 16 cycles (max=96 wks)

24 Fighting biology with biology: anti-cancer viruses Reolysin SVV-001

25 The mammalian reovirus Naturally occurring, unmodified oncolytic virus Non-enveloped Genome of 10 dsrna segments

26 Phase I/II: Reolysin with carbo/taxol in NSCLC Miguel Villalona et al., IASLC 2011 Paclitaxel 175 mg/m 2 Carboplatin AUC 5 Reolysin 3!10 10 TCID 50 Day 1 22 KRAS- or EGFR- activated NSCLC, metastatic or recurrent Primary endpoint: Response Rate note: PR means RECIST response OR 40% decrease in FDG-avidity by PET N = 36

27 Current study: phase II in squamous cell CA Alain Mita MD (Cedars-Sinai) Paclitaxel 200 mg/m 2 Carboplatin AUC 6 Reolysin 3!10 10 TCID 50 Day 1 22 Squamous cell NSCLC, first line metastatic or recurrent Primary endpoint: Response Rate N = 36

28 Study update: M. Villalona Response to date (carbo/paclitaxel/reolysin) KRAS mutant patients Pt. Mutation Cycles Response 1 KRAS 3 PR 2 KRAS 4 SD 4 KRAS, EGFR Amp 6 SD 6 KRAS, EGFR Amp 6 SD 7 KRAS 1 N/A* 13 KRAS 4 SD 14 KRAS 4 SD 17 KRAS 3 SD 20 KRAS, EGFR Amp 4 SD 23 KRAS, EGFR Amp 2 PD 25 KRAS 1 N/A* 26 KRAS, EGFR Amp (6) SD, active 27 KRAS, EGFR Amp (1) (active in cycle 2) 28 KRAS (0) (active in cycle 1) 14 Patients: 1 PR 8 SD 1 PD 2 N/A, 3 active * Withdrew after cycle 1 KRAS wildtype patients Pt. Mutation Cycles Response 3 EGFR Amp 3 PR 5 EGFR Mut, Amp 6 PR 8 EGFR Amp 8 SD 9 EGFR Amp 6 SD 10 EGFR Amp 2 PD 11 EGFR Mut, Amp 1 PD 12 EGFR Amp 4 PR 15 EGFR Amp 4 SD 16 EGFR Amp 8 PR 18 EGFR Mut 5 SD 19 EGFR Amp 10 PR 21 EGFR Amp 8 PR 22 EGFR Amp 6 SD 24 EGFR Amp 6 SD 14 Patients: 6 PR 6 SD 2 PD TOTAL 28 patients to date: 7 PR, 14 SD, 3 PD, 2 N/A, 3 active

29 SVV-001: a replication-competent picornavirus AUG UAG 5 3 VPg L 1A 1B 1C 1D 2A 2B 2C VPg Pro Pol PolyA Discovered serendipitously as a contaminant of an adenoviral vector preparation total genome size 7309bp Selective tropism for tumors with neuroendocrine features Reddy et al., J Natl Cancer Inst 2007 Venkataraman et al., Structure 2008

30 SVV-001 phase I in patients with neuroendocrine tumors Tumors with neuroendocrine differentiation 3+3 dose escalation in log increments Intensive monitoring of viral kinetics/clearance Nasal swabs, sputum, blood, urine, stool Viral titer and PCR analyses Cohort SVV-001 (vp/kg) N 1* 10 7! 1 dose only ! 1 dose only ! 1 dose only ! 1 dose only ! 1 dose only 6 * the only SCLC patients enrolled were in cohort 1 Rudin et al., Clin Cancer Res 2011

31 Phase II study of SVV-001 in SCLC Intergroup Alliance and ECOG Julian Molina (PI; Mayo Clinic) Primary endpoint: Progression-free survival Tumor material required for entry Correlative analyses: markers of permissivity ES-SCLC 4 cycles platinum based chemorx SD or better SVV vp/kg N = 90; randomized 1:1 PD (placebo) Stratified by response and PS

32 SVV-001: persistent intratumoral infection and activity Liver metastasis Adjacent normal liver Viral IHC Pre-treatment 6 weeks post Rudin et al., CCR 2011

33 Talactoferrin Alfa (TLF) Human lactoferrin is an important immunomodulatory protein It is expressed throughout the body in immune cells and on all body surfaces exposed to the external environment Found in the highest concentrations in milk and colostrum Plays a central role in helping establish the immune system, including the gut associated lymphoid tissue (GALT), in infants TLF is a unique recombinant human lactoferrin 80 kd protein produced in Aspergillus niger (A. niger) Ward PP et al. Cell Mol Life Sci 2005; 62:

34 Talactoferrin is an oral Dendritic Cell Mediated Immunotherapy (DCMI) Postulated role for DCs in activating both Innate and Adaptive Immunity Talactoferrin, taken orally, acts on the GI epithelium to release key chemokines (e.g. CCL20) Immature dendritic cells (idcs) are recruited to the GALT by chemokines and undergo maturation/activation Activated dendritic cells initiate tumoricidal response of NK-T cells (Innate immunity) and cross present tumor antigens to CD8+ lymphocytes (Adaptive immunity) Immune cells seek out, infiltrate and kill tumor cells 34

35 LF-0201: Phase II Study of Talactoferrin vs. Best Supportive Care (BSC) in Refractory NSCLC Intent to Treat Evaluable* 100 patients Stage IIIB/IV NSCLC who have failed 1 st line platinumbased or 2 nd line chemotherapy ECOG PS 0-1 R A N D O M I Z E 1:1 TLF 1.5g BID 12 wks on, 2 wks off, up to 3 cycles (n=47) Placebo BID 12 wks on, 2 wks off, up to 3 cycles (n=53) At least one TLF dose 7-Week CT Scan (n=38) At least one PBO dose 7-Week CT Scan (n=43) Primary Endpoint: Overall Survival (OS) (ITT population) Secondary Endpoints: 6-month & 1-year OS, PFS, Tumor Response, Time to Progression, Toxicity & QoL (ITT & Evaluable populations) *Prospectively defined as patients who had at least one CT scan after start of therapy (~7 weeks) Parikh PM et al. J Clin Oncol. 2011;31:

36 LF-0201: Primary Endpoint Overall Survival ITT Population (N=100) 1 Evaluable Population (N=81) 2 Proportion Event Free (%) HR: 0.68 (0.47, 0.98)* P = * Talactoferrin Placebo HR: 0.59 (CI: 0.42, 0.82)* P = * Talactoferrin Placebo Months Months Evaluable group was a prespecified analysis of patients receiving at least one dose of TLF and at least one post-treatment CT * One-tailed p-value using log-rank test; 90% CI as pre-specified in the protocol. 1. Parikh PM et al. J Clin Oncol. 2011;31: Agennix Inc: Data on File. 36

37 LF-0201: Secondary Endpoint - Disease Control Rate Placebo Disease Control Rate (DCR) TLF (n=100) (n=81) Relative Improvement 57% 61% P-value** Disease Control = CR + PR + SD. There were no CRs and 2 PRs in TLF group. There were no CRs and 1 PR in placebo group. * Evaluable group was a prespecified analysis of patients receiving at least one dose of TLF and at least one post-treatment CT ** One-tailed p-value obtained using Fisher s Exact test. Parikh PM et al. J Clin Oncol. 2011;31:

38 LF-0201: Survival by Histology Non-Squamous Talactoferrin Placebo Squamous Talactoferrin Placebo Survival Probability Survival Probability Time (Months) TLF Placebo Pts Median (Mo) Time (Months) TLF Placebo Pts 6 15 Median (Mo) Parikh PM et al. J Clin Oncol. 29: 2011 (suppl; abstr 7569) 38

39 LF-0206: Phase II Study of TLF in Combination with Carboplatin/Paclitaxel (C/P) in 1st Line NSCLC Intent to Treat Evaluable 110 patients Stage IIIB/IV measurable & unresectable NSCLC ECOG PS 0-1 R A N D O M I Z E 1:1 TLF 1.5 g BID* + Carboplatin (AUC 5) + Paclitaxel (175 mg/m 2 ) q3 weeks for 6 cycles (n=55) Placebo BID* + Carboplatin (AUC 5) + Paclitaxel (175 mg/m 2 ) q3 weeks for 6 cycles (n=55) At least one TLF dose 6-Week CT Scan (n=49) At least one PBO dose 6-Week CT Scan (n=51) Primary Endpoint: Confirmed Response Rate in Evaluable Patient Population Secondary Endpoints: PFS, Overall Survival, 1-Year Survival and QoL * Placebo or TLF administered in 42-day cycles for up to three cycles or until radiological progression, starting the day after C/P dosing in chemo-cycles 1, 3 and 5 Digumarti R et al. J Thorac Oncol. 2011;6:

40 LF-0206: Primary Endpoint - Confirmed Response Rate in Evaluable Population Confirmed Response Rate (%) Placebo + C/P TLF + C/P (n=110) (n=100) Relative Improvement 56% 62% P-value* * P-values are one-tailed by Fisher s exact test. The trial protocol prospectively targeted a one-tailed p-value in the evaluable population of 0.05 ** Defined as any patient who received at least one dose of TLF/placebo, one dose of C/P and at least one post treatment CT Digumarti R et al. J Thorac Oncol. 2011;6:

41 LF-0206: Secondary Endpoint - OS ITT Population (N=110) Evaluable Population (N=100) HR = 0.87 HR = 0.75 Survival Probability (%) P = Survival Probability (%) TLF + C/P Placebo + C/P 11.3 P = 0.11 TLF + C/P Placebo + C/P Months Months The median OS in the ITT population increased from 8.5 Mo in the placebo arm to 10.4 months in the TLF arm (HR 0.87; p = 0.26) The median OS in the evaluable patients increased from 8.5 Mo in the placebo arm to 11.3 Mo in the TLF arm (HR 0.75; p = 0.11) Digumarti R et al. J Thorac Oncol. 2011;6:

42 FORTIS-M (LF-0207): A Randomized, Double-blind, Placebocontrolled Study of Oral TLF in Addition to Best Supportive Care in Patients with NSCLC Who Have Failed Two or More Prior Regimens 742 patients enrolled Stage IIIB/IV NSCLC who have failed two or more prior regimens ECOG PS 0-2 R A N D O M I Z E 2:1 TLF 1.5 g BID 12 wks on, 2 wks off up to 5 cycles + BSC Placebo BID 12 wks on, 2 wks off up to 5 cycles + BSC Primary Endpoint: Overall Survival Secondary Endpoints: 6-month & 1-year survival rate, PFS, ORR, Disease Stabilization Rate (PR+CR+SD), TLF safety and tolerability Stratifications: Prior regimens (2 vs!3), ECOG PS, Geographical region U.S. National Institutes of Health. Clinicaltrials.gov. Accessed 05/25/11 at: 42

43 FORTIS-C (LF-0208): A Randomized, Double-blind, Placebo-controlled Study of Oral TLF in Combination with Carboplatin & Paclitaxel as First-line Therapy in Patients with Locally Advanced or Metastatic NSCLC 1,100 patients previously untreated Stage IIIB/IV NSCLC ECOG PS 0-1 R A N D O M I Z E 1:1 TLF 1.5g BID + Carboplatin (AUC 6) + Paclitaxel (200mg/m 2 ) q3 weeks for 6 cycles Placebo BID + Carboplatin (AUC 6) + Paclitaxel (200mg/m 2 ) q3 weeks for 6 cycles TLF until disease progression (up to 18 months) Placebo until disease progression (up to 18 months) Co-Primary Endpoints: PFS & OS Secondary Endpoints: Objective Response Rate, Duration of Response, Safety Stratifications: gender; disease stage; geographical region U.S. National Institutes of Health. Clinicaltrials.gov. Accessed 05/25/11 at: 43

44 Conclusions Immune checkpoint inhibitors Viruses Talactoferrin

45