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Squamous Cell NSCLC Are we making progress?

Squamous Cell NSCLC Are we making progress?. Mark A. Socinski on behalf of Ramaswamy Govindan. Squamous Cell Lung Cancer: An Unmet Need. Clinically challenging population – older, co-morbidities Platinum Doublets remain the standard of care

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Squamous Cell NSCLC Are we making progress?

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  1. Squamous Cell NSCLCAre we making progress? Mark A. Socinski on behalf of RamaswamyGovindan

  2. Squamous Cell Lung Cancer: An Unmet Need Clinically challenging population – older, co-morbidities Platinum Doublets remain the standard of care Gemcitabine- or Taxane-Based Regimens Commonly Used (? Role of nab-paclitaxel) Antiangiogenic strategies are felt to be too toxic Pemetrexed no longer approved for use in this subset Cetuximab + cisplatin-vinorelbine (FLEX study): improved median OS (10.2 vs. 8.9 months) in SQLC– Not FDA-Approved New strategies are needed for this large group of patients 2

  3. Lung Cancer Incidence by Histology1998-2002 Youlden DR et al. J Thorac Oncol 3:819-831, 2008

  4. Lagging Outcomes for Squamous-Cell NSCLC Epidemiological data show recent OS gains more pronounced for patients with adenocarcinoma histology, less for patients with squamous-cell tumors * Comparison uses ADC data as reference Most conspicuous outcome gap for squamous-cell NSCLC coincides with the introduction of targeted therapies ADC=Adenocarcinoma SQCC=Squamous Cell Carcinoma Morgensztern D. J Thor Oncol 2009. vol 4 pp 1524

  5. 1st Line Options

  6. Phase III Study Design Albumin-bound paclitaxel 100 mg/m2 d1, 8, 15 Carboplatin AUC 6 d1 21 Day Cycles No Premedication Chemo-naive PS 0-1 Stage IIIb/IV NSCLC N = 1,050 1:1 Primary Endpoint - ORR Paclitaxel 200 mg/m2 d1 Carboplatin AUC 6 d1 21 Day Cycles With Premedication of Dexamethasone + Antihistamines Stratification factors: • Stage (IIIb vs IV) • Age (<70 vs >70) • Sex • Histology (squame vs nonsquame) • Geographic region

  7. 40% nab-P/C P/C 33% 30% 25% 20% 10% 0% Independent Radiologic Review Primary Endpoint Results Objective Responses – ITT Response Ratio = 1.31 (1.082 – 1.593) P = 0.005 Percent Responses

  8. Independent Radiological Assessment of Overall Response Rate by Histology a 95% CIs for response rate ratios are calculated according to the asymptotic 95% CI of the relative risk of nab-PC to sb-PC. Renschler MF, Okamoto I, Hon JK, et al. Safety and efficacy analysis by histology of weekly nab-paclitaxel in combination with carboplatin as first-line therapy in patients with advanced non-small cell lung cancer [poster 110]. Poster presented at: Chicago Multidisciplinary Symposium in Thoracic Oncology 2012; Sept 6-8; Chicago, IL. ADENO, adenocarcinoma; CI, confidence interval; LC, large cell carcinoma; NOS, not otherwise specified; P/C, paclitaxel + carboplatin; sb, solvent-based; SCC, squamous cell carcinoma.

  9. Conclusions • nab-P/C improves ORR (primary endpoint) vs P/C (P=0.005), particularly in patients with squamous histology (P<0.001) • Secondary endpoints: • No significant difference in PFS or OS between treatment arms, with HRs trending in favor of nab-P/C • Strongest trends in favor of nab-P/C elderly patients and in squamous cell histology • Safety: increased rate of grade 3/4 anemia, reduced rates of grade 3/4 neurotoxicity and myalgias with nab-P/C

  10. R A N D O M I Z E Cisplatin/Vinorelbine + Cetuximab N=550 Stage IIIB or IV EGFR-expressing chemotherapy-naïve NSCLC Cisplatin/Vinorelbine N=550 FLEX Phase III Trial: Cisplatin/Vinorelbine ± Cetuximab in EGFR+ Advanced NSCLC Primary endpoint: OS Secondary endpoints: 1- and 2-year survival rates, 6-month and 12-month PFS rates, response rate, safety, quality of life Pirker R et al. Lancet 373: 1525-31, 2009

  11. 100 75 Overall Survival (%) 50 25 11.3 10.1 0 0 6 12 18 24 30 36 Months At risk CT CT/Erbitux 568 383 225 134 48 0 0 557 383 251 155 53 3 0 Overall Survival Time: ITT

  12. OS by Subgroups: Ethnic Origin and Histology (ITT)

  13. FLEX survival: high EGFR expressionSquamous cell carcinoma (N=144) 100 90 80 70 60 50 Overall survival (%) 40 30 20 10 0 0 6 12 18 24 30 Months Number of patients at risk CT 69 42 17 7 2 0 CT + cetuximab 75 52 32 19 10 0

  14. Necitumumab (IMC-11F8) Fully human IgG1 monoclonal antibody to EGFR Increases antitumor activity when combined with gemcitabine/cisplatin or pemetrexed/cisplatin in NSCLC xenografts First in human study: DLT grade 3 headache associated with nausea, vomiting, and fever (2 pts) RP2D 800 mg weekly or every 2 weeks PR-2 pts; SD-16 pts Kuenen B et al. Clin Cancer Res 15:1915-1923, 2010

  15. SQUIRE: phase III, 1st line NSCLC, squamous PR CR SD Arm A: IMC-11F8 + CIS + GEM IMC-11F8 800 mg (50-min IV), D1, 8 Cisplatin 75 mg/m2 (30-60 min IV), D1 Gemcitabine 1250 mg m2 (30 min IV), D1, 8 IMC-11F8 R A N D O M I Z E 947 patients Stage 4 NSCLC Squamous ECOG PS 0-2 1 PD 1 Arm B: CIS + GEM Cisplatin 75 mg/m2 (30-60 min IV), D1 Gemcitabine 1250 mg/m2 (30 min IV), D1, 8

  16. ECLIPSE Study Overview N= 825 International, Open-label Gemcitabine + Carboplatin • Patient Population: • Advanced squamous cell carcinoma • Patients restaged by CT scans (per RECIST 1.1 version) q 2 cycles (6 wks) • Patients may remain on study regimen after 6 cycles if there is no evidence of PD or the presence of DLTs R Endpoints: Primary: OS Secondary: PFS, TTP, ORR, safety/tolerability, QoL 1:1 Gemcitabine + Carboplatin + iniparib Doses: Gemcitabine 1000 mg/m2 D 1 & 8 q3wk Carboplatin AUC 5 D1 q3wk; Iniparib 5.6 mg/kg IV D 1, 4, 8 & 11 q3wk First Patient Enrolled: March 5, 2010 16

  17. Maintenance

  18. Pemetrexed 15.5 mos Pemetrexed 9.9 mos Placebo 10.3 mos Placebo 10.8 mos Pemetrexed - Overall Survival by Histology Non-squamous (n=481) Squamous (n=182) HR=1.07 (95% CI: 0.49–1.73) P =0.678 HR=0.70 (95% CI: 0.56-0.88) P =0.002 Survival Probability Time (months) Time (months)

  19. SATURN study design Stratification factors: • EGFR IHC (positive vs negative vs indeterminate) • Stage (IIIB vs IV) • ECOG PS (0 vs 1) • CT regimen (cis/gem vs carbo/doc vs others) • Smoking history (current vs former vs never) • Region Erlotinib 150mg/day PD Chemonaïve advanced NSCLC n=1,949 4 cycles of 1st-line platinum-based doublet* Non-PD n=889 1:1 Placebo PD Mandatory tumour sampling Co-primary endpoints: • PFS in all patients • PFS in patients with EGFR IHC+ tumours Secondary endpoints: • Overall survival (OS) in all patients and those with EGFR IHC+ tumours; OS and PFS in EGFR IHC– tumours; biomarker analyses; safety; time to symptom progression; quality of life (QoL) *Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel; cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel; carboplatin/paclitaxel EGFR = epidermal growth factor receptor; IHC = immunohistochemistry

  20. OS*: all patients (ITT) 1.0 0.8 0.6 0.4 0.2 0 HR=0.81 (0.70–0.95) Log-rank p=0.0088 Erlotinib (n=438) Placebo (n=451) OS probability 11.0 12.0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) *OS is measured from time of randomisation into the maintenance phase;ITT = intent-to-treat population

  21. Subgroup analysis of PFS HR (95% CI) n 0.71 (0.62–0.82) 884 0.78 (0.66–0.92) 654 0.56 (0.42–0.76) 230 0.75 (0.64–0.88) 744 0.58 (0.38–0.87) 128 0.60 (0.48–0.75) 401 0.76 (0.60–0.95) 359 0.56 (0.38–0.81) 152 0.66 (0.50–0.88) 242 0.80 (0.67–0.97) 490 All Male Female Caucasian Asian Adenocarcinoma Squamous-cell Never smoker Former smoker Current smoker 0.4 0.6 0.8 1.0 1.2 HR Favoursplacebo Favourserlotinib

  22. SATURN: OS in patients with SD on first-line chemotherapy according to histology Squamous-cell Non-squamous 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 HR=0.67 (0.48–0.92) Log-rank p=0.0116 HR=0.76 (0.59–1.00) Log-rank p=0.0457 Erlotinib (n=155) Placebo (n=142) Erlotinib (n=97) Placebo (n=93) OS probability 8.3 11.3 10.6 13.7 0 3 6 9 12 15 18 21 24 27 30 33 36 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) Time (months) Measured from time of randomisation into the maintenance phase

  23. Squamous NSCLC • Standard remains platinum plus either a taxane or gemcitabine • nab-paclitaxel may be more active • Maintenance options a bit more limited • Avoid bevacizumab and pemetrexed • Cetuximab could be a consideration in selected patients – stay tuned for neci…

  24. New Avenues for theTreatment for Squamous Cell NSCLC Immunotherapy Novel molecular targets

  25. CANCER AND IMMUNE SYSTEM IMMUNOEDITING

  26. Mechanism of Action of Ipilimumab T-cell inhibition T-cell activation T-cell activation and proliferation CTLA-4 T cell T cell T cell CD28 CD28 CTLA-4 CTLA-4 TCR TCR ipilimumab blocks CTLA-4 TCR CD80/ CD86 MHC CD80/ CD86 MHC MHC CD80/ CD86 APC APC APC Adapted from O’Day et al. Plenary session presentation, abstract #4, ASCO 2010.

  27. C C C C C C C C C C C C C C C C C C CA184-041: Study Schema First-line Stage IIIb/IV NSCLC (n=204) ED-SCLC (n=130) Maintenance Phase Treatment Phase IPI IPI Follow-up phase Concurrent IPI + Pac/Carbo 1:1:1 IPI IPI IPI IPI p p IPI IPI Follow-up phase Phased IPI + Pac/Carbo R A N D O M I Z E p p IPI IPI IPI IPI p p Control p + Pac/Carbo Follow-up phase n=130 p p p p p p q3w q12w C: chemotherapy doublet (Pac 175mg/m2)/Carbo (AUC=6); IPI: Ipilimumab (10 mg IV); p: Placebo *Phased : 2 doses of paclitaxel /carboplatin given prior to start of ipilimumab Note: Steroids were given as premedication for chemotherapy

  28. Summary Efficacy Results CA184041 First-line Stage IIIb/IV NSCLC (n=204) ED-SCLC (n=130) *statistically significant Results favouring phased ipilimumab schedule across multiple end-points in both NSCLC and SCLC cohorts Reck M, et al. Presented at the 2011 World Congress of Lung Cancer; July 3-7; Amsterdam, Netherlands. Abstract 1365. Lynch T, et al. Presented at: ESMO Congress, Milan, Italy; October 8-12, 2010; Poster and abstract 375PD.

  29. Activity by Baseline Histology (CA184041, NSCLC) Concurrent-Ipi vs Control Phased-Ipi vs Control Response Patient group All Non-Squamous irPFS Squamous All Non-Squamous mWHO-PFS Squamous All OS Squamous Non-Squamous 0.5 1.5 0.5 1.5 1 1 HR and 95% CI HR and 95% CI Favors Favors Phased Control Control Concurrent Lynch T, et al. Presented at the 2011 World Congress of Lung Cancer; July 3-7, 2011; Amsterdam, Netherlands. Abstract 701.

  30. CA184104 – Study Design in Stage IV Squamous NSCLC PD or AE leading to DC Arm A Screening Induction C C C C C C + + + + I I I I CR PR SD Maintenance I I I… Overall Survival Toxicity Progression Follow-up Randomize Induction C C C C C C + + + + P P P P Maintenance P P P… Stage IV sqNSCLC PS ≤1 No brain mets CR PR SD Arm B PD or AE leading to DC I = ipilimumab P = placebo C = chemotherapy N=920 90% power for HR = 1 during chemotherapy alone period and 0.75 post chemotherapy alone period. Approximately 250sites, 36 countries, 920 subjects treated

  31. PD-1 DIRECTED IMMUNOTHERAPY Ribas A. N Engl J Med 2012;366:2517-2519.

  32. Clinical Activity of BMS-936558 in NSCLC Patients • ORR was assessed using modified RECIST v1.0 • 3 NSCLC patients had a persistent reduction in baseline target lesions in the presence of new lesions but were not classified as responders for the ORR calculation

  33. Clinical Activity by Histology, Efficacy Population *1 patient of unknown histology who received 1mg/kg had an OR.

  34. Phase 3 Study of Anti-PD-1 Compared to Docetaxel in 2nd-Line Advanced/Metastatic Squamous Cell NSCLC (CA209-017/NCT01642004) Phase 3 Trial Stage IIIB/IV or recurrent squamous cell NSCLC N=264 • Primary Endpoints • ORR • OS • Secondary Endpoints • PFS • ORR and OS in PD-L1+vs PD-L1– subgroups • Duration of OR • Time to OR • Proportion of patients exhibiting disease-related symptom progression per Lung Cancer Symptom Scale • Key Eligibility Criteria • ≥ 18 years of age • Stage IIIB/IV squamous cell NSCLC or recurrent disease following RT or surgical resection • Prior Pt-containing chemotherapy • ECOG PS ≤ 1 • Formalin fixed, paraffin-embedded (FFPE) tumor tissue block or unstained slides of tumor sample (archival or recent) must be available for biomarker evaluation Docetaxel 75 mg/m2 IVQ3W Anti-PD-1 3 mg/kg IVQ2W Treat until progression or unacceptable toxicity or withdrawal of consent Co-Primary Objective Response Rate (ORR) & Overall Survival (OS) Start Date: September 2012 Estimated Study Completion Date: August 2014 Estimated Primary Completion Date: August 2014 Status: Recruiting Study Director: BMS ECOG PS, Eastern Cooperative Oncology Group Performance Status; OR, objective response; PFS, progression-free survival; Pt, platinum; RT, radiotherapy

  35. Phase 2 Study of Anti-PD-1 in Subjects With Advanced/ Metastatic Squamous Cell NSCLC Who Have Received At Least Two Prior Systemic Regimens (CA209-063/NCT01721759) Phase 2 Trial Stage IIIB/IV Squamous cell NSCLC N=100 • Primary Endpoints • ORR (investigator assessed) • Secondary Endpoints • ORR (by independent radiology review committee) • Key Eligibility Criteria • ≥ 18 years of age • Stage IIIB/IV squamous cell NSCLC • ECOG PS ≤ 1 • Progression or recurrence after both 1st-line Pt-doublet chemotherapy and ≥1 approved subsequent line of systemic therapy • No active CNS metastases, carcinomatous meningitis, active or suspected autoimmune disease or interstitial lung disease • No prior treatment on either arm of Study CA209-017 or CA184-104 • No prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 or anti-CTLA-4 or other antibody targeting T-cell co-stimulation or checkpoint pathways Anti-PD-1 3 mg/kg IVQ2W Treat until progression or unacceptable toxicity or withdrawal of consent Objective Response Rate (ORR) Start Date: November 2012 Estimated Study Completion Date: February 2014 Estimated Primary Completion Date: February 2014 Status: Recruiting Study Director: BMS ECOG PS, Eastern Cooperative Oncology Group Performance Status; ORR, Objective response rate; PFS, Progression-free survival; Pt, Platinum

  36. Wild type AGTGA Mutant AGAGA Adapted from: Roychowdhury et al. Sci Transl Med; 20122

  37. Therapeutic targets in squamous cell lung carcinoma Nature. 2012 Sep 27;489(7417):519-25

  38. Therapeutic targets in squamous cell lung carcinoma Nature. 2012 Sep 27;489(7417):519-25

  39. Therapeutic targets in squamous cell lung carcinomas, defined by TCGA Nature. 2012 Sep 27;489(7417):519-25

  40. CDKN2A: Loss of Function Through Multiple Mechanisms Three most common mechanisms Homozygous deletion 30% Methylation 21% Mutation 17% Tumor samples

  41. Open clinical trials with targeted agents in SCC- Lung

  42. Chemo-biological Treatment for Squamous Cell NSCLC Platinum based doublet therapy for early stage and locally advanced squamous NSCLC nab-PCb option for advanced disease Role of maintenance chemotherapy limited but erlotinib and docetaxel remain options Immunotherapy holds promise Several novel targets identified

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