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Individualized Tx in NSCLC: How Do We Tackle Advanced Squamous Cell Ca of the Lung

Individualized Tx in NSCLC: How Do We Tackle Advanced Squamous Cell Ca of the Lung. Corey J Langer MD, FACP Professor of Medicine Director of Thoracic Oncology Abramson Cancer Center University of Pennsylvania Philadelphia, PA 19104 Corey.langer@uphs.upenn.edu. Disclosures.

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Individualized Tx in NSCLC: How Do We Tackle Advanced Squamous Cell Ca of the Lung

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  1. Individualized Tx in NSCLC:How Do We Tackle Advanced Squamous Cell Ca of the Lung Corey J Langer MD, FACP Professor of Medicine Director of Thoracic Oncology Abramson Cancer Center University of Pennsylvania Philadelphia, PA 19104 Corey.langer@uphs.upenn.edu

  2. Disclosures • Grant/Research Support: • Bristol Myers Squibb, Pfizer, Imclone, Lilly, Schering-Plough Research Institute, Sanofi-Aventis, Amgen, Cell Therapeutics Inc., OrthoBiotech, Celgene, Vertex, Genentech, OSI, AstraZeneca, Pfizer, Active Biothech, Medimmune • Scientific Advisor: • Bristol Myers Squibb, Imclone, Sanofi-Aventis, Pfizer-Pharmacia, Intrabiotics, GlaxoSmithKline, Pharmacyclics, Amgen, AstraZeneca, Novartis, Genentech, OSI, Savient, Bayer/Onyx, Abraxis, Clarient, Synta • Speakers Bureau: curtailed as of 12/10 • Bristol Myers Squibb, Imclone, Sanofi- Aventis, Lilly, OrthoBiotech, Genentech, OSI

  3. Lung Cancer • In 2010, ~213,380 new cases and ~160,390 deaths are predicted in the United States • Second most common cancer in men and women and leading cause of cancer deaths • Accounts for more deaths than breast, colon and prostate cancer combined • Unfavorable stage distribution at the time of diagnosis • Types of lung cancer • Non–small cell lung cancer (NSCLC): 87% • 1/2 to 2/3 adenoca • 1/3+ squamous and other histologies • Small cell lung cancer (SCLC): 13% Cancer Facts and Figures 2007. Atlanta, GA: American Cancer Society; 2007.

  4. Adenocarcinoma Glandular pattern Mucin positivity (50%) CK7+/CK20- TTF-1+ (75%) Squamous cell carcinoma Cellular keratinization Intercellular bridges Keratin “pearl” formation CK7-/CK20- TTF-1 neg P63or p40+ or CK5/6+ Non-small Cell Lung cancer WHO Common, but not 100% WHO Common, but not 100%

  5. Histologic Distinctions in NSCLC • Squamous: • More central presentation • Higher incidence of locoregional recurrence • Decreased incidence of metastatic spread • Relatively more common in men, Eastern Europe, smokers • Declining incidence overall • Adenocarcinoma: • More often peripheral • Higher incidence of metastatic spread • Less profound link with tobacco use • Increasing incidence; relatively more common in women

  6. Therapeutic ImplicationsHistologic Prism • Tendency until 2005 to “lump” NSCLC histologies • Little difference in Tx outcome • Therapeutic Empiricism • Increasing NOS designation • Insufficient tissue • Pathologic “laziness”

  7. ECOG 1594:Overall Survival by Treatment Group 1207 patients, stage IIIB/IV :(15/85%), PS 0–2; Median age 63, M/F (64/36%) Schiller JH et al. NEJM. 2002;346(2):92-98.

  8. Therapeutic ImplicationsHistologic Prism • Tendency until 2005 to “lump” NSCLC histologies • Little difference in Tx outcome • Therapeutic Empiricism • Increasing NOS designation • Insufficient tissue • Pathologic “laziness” • Since 2004, histology and molecular fingerprints have become ascendant • Tx restrictions and risk: bevacizumab • Histologic Variations in outcome • Adenocarcinoma: better outcome with EGFr TKI, pemetrexed • Province of Actionable molecular markers [EGFR; ALK; ROS-1, etc

  9. Therapeutic ImplicationsHistologic Prism • Tendency until 2005 to “lump” NSCLC histologies • Little difference in Tx outcome • Therapeutic Empiricism • Increasing NOS designation • Insufficient tissue • Pathologic “laziness” • Since 2004, histology and molecular fingerprints have become ascendant • Tx restrictions and risk: bevacizumab • Histologic Variations in outcome • Adenocarcinoma: better outcome with EGFr TKI, pemetrexed • Province of Actionable molecular markers [EGFR; ALK; ROS-1, etc • Squamous ca: tendency for better outcome • gemcitabinevspemetrexed • Nab-paclitaxelvs standard paclitaxel (RR%) • Immunologic Tx: Ipilimumab; PD1 • FGFR and PI3K as targets: still investigational

  10. An Evolving View of AdenocarcinomaEmergence of “Actionable” Molecular Markers 2014 2000 KRAS Pending EGFR BRAF PIK3CA ROS1 HER2 EML4-ALK

  11. An Evolving View of Squamous Cell CaEmergence of “Actionable” Molecular Markers 2014 2000

  12. An Evolving View of Squamous Cell CaEmergence of “Actionable” Molecular Markers 2014 2000

  13. Squamous Cell Ca: Wallflower at the Dance • Safety Signals: Bevacizumab • Lack of Efficacy: Pemetrexed • Lack of Actionable Molecular Markers:

  14. Paclitaxel 200 mg/m2 carboplatin AUC 6 (PC) q3w × 6 Progression of disease* * Crossover to 15 mg/kg q3w bevacizumab allowed PC × 6+ bevacizumab 7.5 mg/kg q3w Previously untreated metastatic NSCLC(N=98) Bevacizumab 7.5 mg/kg q3w to PD or unacceptable toxicity PC × 6 + bevacizumab 15 mg/kg q3w Bevacizumab 15 mg/kg q3w to PD or unacceptable toxicity Rand Phase II: Bevacizumab +Paclitaxel/Carboplatin in Advanced NSCLC Excluded: CNS metastasis On therapeutic anticoagulation Objectives = time to progression, response, survival, and safety 1. Johnson et al. J Clin Oncol. 2004;22:2184–2191.

  15. Randomized Phase II Trial: Pulmonary Bleeding • 6 cases of severe or fatal pulmonary hemorrhage • 4 (31%) of 13 bevacizumab-treated patients with squamous cell histology • 2 (4%) of 53 bevacizumab-treated patients with histology other than squamous cell • Patients receiving chemotherapy alone (N=32) had no pulmonary hemorrhages • On the basis of this analysis, squamous cell histology and bevacizumab therapy were identified as risk factors for pulmonary hemorrhage • These phase II data were used to design the phase III trial exclusion criteria [squamous histology has been excluded ever since] 1. Johnson et al. J Clin Oncol. 2004;22:2184–2191.

  16. R Study Design Pemetrexed 500 mg/m2+ Cisplatin 75 mg/m2 day 1 • Stage IIIB/IV NSCLC • PS 0 - 1 • No prior chemo • Randomization: gender, PS, stage, histo vs cyto dx, brain mets Primary objective: Overall Survival 15% Non-inferiority margin (HR 1.17) N = 1700 Patients , Power 80% Gemcitabine 1250 mg/m2 days 1 + 8 Cisplatin 75 mg/m2 day 1; B12, folate, and dexamethasone given in both arms Scagliotti GV et al. JCO 2008; 26:3543

  17. TS Expression Levels Are Higher in Squamous Versus Adenocarcinoma “May be useful in selecting patients with NSCLC who should receive treatment with TS-inhibiting agents” Ceppi, P et al. Cancer 107:1589, 2006

  18. Phase III Trial: Cisplatin/PemetrexedvsCisplatin/Gemcitabine - Overall Survival in Patients with Adenocarcinoma or Large Cell Ca -

  19. Second -Line Study of Pemetrexed vs. Docetaxel : Efficacy by Histology Treatment by Histology Interaction: Survival Adjusted for Cofactors (p=0.001) Peterson P. et al. 12th World Conference on Lung Cancer 2007

  20. Progression-free Survival by Histology JMEN Switch Maintenance Trial Pemetrexed 4.4 mos Pemetrexed 2.4 mos Placebo 1.8 mos Placebo 2.5 mos Non-squamous Squamous HR=1.03 (95% CI: 0.77-1.5) P =0.896 HR=0.47 (95% CI: 0.37-0.6) P <0.00001 Progression-free Probability Time (months) Time (months)

  21. Overall Survival by Histology JMEN Switch Maintenance Trial Pemetrexed 15.5 mos Pemetrexed 9.9 mos Placebo 10.3 mos Placebo 10.8 mos Non-squamous (n=481) Squamous (n=182) HR=1.07 (95% CI: 0.49–0.73) P =0.678 HR=0.70 (95% CI: 0.56-0.88) P =0.002 Survival Probability Time (months) Time (months)

  22. Advanced NSCLC with Squamous Histology Disappointments to date have not prevented us from targeting this group of pts in ongoing, empiric trials

  23. ECOG 4508: RP2Non-Bev Eligible • CTEP E4508 • All histology • NSCLC • 1st line 1 Carboplatin / Paclitaxel / Cetuximab Cetux Carboplatin / Paclitaxel / A12 A12 1 1 Carboplatin / Paclitaxel / Cetuximab / A12 Cetux / A12 PFS N=225 PI: N. Hanna (ECOG)

  24. ECOG 4508: RP2Non-Bev Eligible • CTEP E4508 • All histology • NSCLC • 1st line 1 Carboplatin / Paclitaxel / Cetuximab Cetux Carboplatin / Paclitaxel / A12 A12 1 1 Carboplatin / Paclitaxel / Cetuximab / A12 Cetux / A12 PFS N=225 PI: N. Hanna (ECOG) Suspended because of untoward toxicity in both Cetuximab arms, including an increased rate of grade 5 toxicity

  25. ESCAPE - Phase III Trial Comparing Carboplatin and Paclitaxel +/- Sorafenib in NSCLC Maintenance phase Chemotherapy phase n=900 Carboplatin AUC 6 d1 + Paclitaxel 200 mg/m2 d1 +Sorafenib 400 mg bid d2-19, q3w (CPS) Sorafenib400 mg bid R A N D O M I Z E Stratification: • Geographic region • ECOG PS 0 vs 1 • Squamous vsnon-squamous cell • Stage IIIb (with effusion) vs Stage IV Carboplatin AUC 6 d1 + Paclitaxel 200 mg/m2 d1 +Placebo d2-19, q3w (CPP) Placebo Scagliotti GV et al. Proc ESMO/IASLC 2008

  26. CPSMedian: 8.9 months 95% CI: 6.1, 13.9 CPP Median: 13.6 months 95% CI: 9.6, — CPP 112 97 41 12 3 CPP 350 280 168 22 2 CPS 107 73 24 9 2 CPS 357 281 173 38 5 Overall Survival by Histology Squamous Cell Non-Squamous Cell 1.00 1.00 CPSMedian: 11.5 months 95% CI: 9.7, 14.8 CPP Median: 10.3 months 95% CI: 9.3, 11.5 0.75 0.75 Survival Probability Survival Probability 0.50 0.50 0.25 0.25 HR = 0.98 95% CI: 0.78, 1.24 HR = 1.81 95% CI: 1.19, 2.74 0 0 0 4 8 12 16 20 0 4 8 12 16 20 Months Months Patients at Risk Patients at Risk Scagliotti GV et al. Proc ESMO/IASLC 2008

  27. Study A1016: Phase III Study of Carboplatin + Paclitaxel +/- Figitumumab in 1st Line NSCLC of non-adenocarcinoma histology RANDOMIZE Figitumumab (20 mg/kg) Paclitaxel Carboplatin Key Entry Criteria • Other than Adenoca • Brain mets allowed • Adjuvant > 12 month prior N = 410 Paclitaxel Carboplatin N = 410 N=820

  28. Overall Survival PC mOS = 10.3 mo % Probability of Survival PCF mOS = 8.5 mo HR (95%CI):1.23 (1.0,1.5), p=0.051 Months

  29. 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 29

  30. ECLIPSE Study Overview N= 825 International, Open-label Gemcitabine + Carboplatin Negative • 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 30

  31. Is there any hope for patients with squamous cell histology?

  32. Pemetrexed Plus Cisplatin in 1st-line: Survival with Gemcitabine/Cisplatin for Patients with Squamous Cell Carcinoma 1.0 0.9 0.8 0.7 0.6 0.5 Survival probability 0.4 0.3 0.2 0.1 0 6 12 18 24 30 Survival time (months) Scagliotti GV et al: J Clin Oncol. 26 (21), 2008: 3543-3551.

  33. Second -Line Study of Pemetrexed vs. Docetaxel : Efficacy by Histology Treatment by Histology Interaction: Survival Adjusted for Cofactors (p=0.001) Peterson P. et al. 12th World Conference on Lung Cancer 2007

  34. Phase III nab-P/C vs P/C Study Design nab-Paclitaxel 100 mg/m2 d1, 8 15 Carboplatin AUC 6 d1 No Premedication n = 525 Chemo-naive PS 0-1 Stage IIIb/IV NSCLC N = 1,050 1:1 Paclitaxel 200 mg/m2 d1 Carboplatin AUC 6 d1 With Premedication of Dexamethasone + Antihistamines n = 525 Stratification factors: • Stage (IIIb vs IV) • Age (<70 vs >70) • Sex • Histology (squamous vs nonsquamous) • Geographic region Socinski et al 2010, ASCO

  35. 50% Ab-P/C P/C 40% 41% 30% 26% 25% 24% 20% 10% 0% Objective Responses by Histology* P < 0.001 RR =1.680 P = 0.808 RR=1.034 Response Rate (%) Interaction p-Value for Histology: 0.036 Squamous Histology Non-Squamous Histology n = 228 n = 221 n = 292 n = 310 * Not a pre-specified subgroup analysis

  36. PFS – ITT Population 1.00 Ab-P/carboplatin (N=521)paclitaxel/carboplatin (N=531) 0.75 * PFS based on Independent assessment 0.50 Proportion Not Progressed 0.25 0.00 33 24 6 9 12 15 18 21 27 30 3 0 Pt at risk Ab-PP 0 0 23 19 10 10 0 2 0 1 521 531 330 321 167 162 86 75 38 48 4 4 Months

  37. Overall Survival – ITT Population 1.00 Ab-P/carboplatin (N=521)Paclitaxel/carboplatin (N=531) 0.75 0.50 Probability of Survival 0.25 0.00 33 24 6 9 12 15 18 21 27 30 3 0 Pt at risk Ab-PPac 0 0 0 1 200 191 163 148 23 24 0 5 521 531 469 470 381 389 313 308 246 243 98 89 Months

  38. Secondary Endpoint: OS Favors ab-P/C

  39. Secondary Endpoint: OS Favors ab-P/C

  40. Chinese Trial: RP2NCI CTG 01236716; PI: Wu Yilong R A N D O M I Z E Gemcitabine Carboplatin Nab-Paclitaxel Carboplatin • Restricted to Tx-naïve advanced NSCLC with squamous histology • N= 120; started 11/10

  41. Ipilimumab and NSCLC histology, WCLC 2011, Abstr 701 Efficacy in Total NSCLC Population *Statistically significant per protocol-stipulated one-sided  = 0.1; P values not adjusted for multiple comparisons irPFS, PFS by immune-related response criteria (irRC); irBORR, best overall response rate by irRC; mWHO-PFS, PFS by modified WHO criteria (mWHO); mWHO-BORR, best overall response rate by mWHO

  42. Ipilimumab and NSCLC histology, WCLC 2011, Abstr 701 Activity of Phased-Ipilimumab by Baseline Histology Phased vs. Control Response Patient group Events/Patients HR (95% CI) All 54/68 vs 56/66 0.72 (0.50-1.06) Non-Squamous irPFS 36/47 vs 41/51 0.82 (0.52-1.28) Squamous 18/21 vs 15/15 0.55 (0.27-1.12) All 56/68 vs 61/66 0.69 (0.48-1.00) mWHO-PFS Non-Squamous 37/47 vs 46/51 0.81 (0.53-1.26) Squamous 19/21 vs 15/15 0.40 (0.18-0.87) All 51/68 vs 51/66 0.87 (0.59-1.28) OS Non-Squamous 38/47 vs 37/51 1.17 (0.74-1.86) Squamous 13/21 vs 14/15 0.48 (0.22-1.03) 1 1.5 0.5 HR and 95% CI Favors Phased-Ipi Control • In the Phased-Ipilimumab arm, improvements in irPFS, mWHO-PFS and OS vs. Control appeared greater for squamous histology than for non-squamous • Small sample size warrants caution in interpretation

  43. Ipilimumab and NSCLC histology, WCLC 2011, Abstr 701 Activity of Phased-Ipilimumab by Baseline Histology Phased vs. Control Response Patient group Events/Patients HR (95% CI) All 54/68 vs 56/66 0.72 (0.50-1.06) Non-Squamous irPFS 36/47 vs 41/51 0.82 (0.52-1.28) Squamous 18/21 vs 15/15 0.55 (0.27-1.12) All 56/68 vs 61/66 0.69 (0.48-1.00) mWHO-PFS Non-Squamous 37/47 vs 46/51 0.81 (0.53-1.26) Squamous 19/21 vs 15/15 0.40 (0.18-0.87) All 51/68 vs 51/66 0.87 (0.59-1.28) OS Non-Squamous 38/47 vs 37/51 1.17 (0.74-1.86) Squamous 13/21 vs 14/15 0.48 (0.22-1.03) 1 1.5 0.5 HR and 95% CI Favors Phased-Ipi Control • In the Phased-Ipilimumab arm, improvements in irPFS, mWHO-PFS and OS vs. Control appeared greater for squamous histology than for non-squamous • Small sample size warrants caution in interpretation

  44. Ipilimumab and NSCLC histology, WCLC 2011, Abstr 701 1.0 0.8 0.6 0.4 0.2 0.0 0 3 6 9 12 15 18 21 24 27 21 13 11 6 4 3 3 2 0 0 21 19 15 12 9 9 8 5 3 0 15 11 10 7 4 1 1 1 0 0 OS: Squamous NSCLC Subset Proportion Alive Months Patients at risk Concurrent Phased Control

  45. Phase 3 Trial Comparing Ipilimumab Plus Paclitaxel and Carboplatin Versus Placebo Plus Paclitaxel and Carboplatin in Squamous NSCLC (CA184-104/NCT01285609) Phase 3 Trial Squamous cell NSCLC or Stage IV or recurrent NSCLC N=920 Primary Endpoint • OS Secondary Endpoints • OS in pts that receive one dose of blinded therapy • PFS • BORR Key Eligibility Criteria • ≥ 18 years of age • Squamous cell NSCLC • Stage IV or recurrent NSCLC • ECOG PS ≤ 1 • No brain metastases or autoimmune disease IPI 10 mg/kg IV Q3W x 4 dosesQ12W from W24 PAC 175 mg/m² IV Q3W x 6 doses CARB AUC 6 IV Q3W x 6 doses PBO IV Q3W x 4 doses Q12W from W24 PAC 175 mg/m² IV Q3 W x 6 doses CARB AUC 6 IVQ3W x 6 doses Treat until progression or unacceptable toxicity Start Date: August 2011 Estimated Study Completion Date: June 2016 Estimated Primary Completion Date: September 2014 Status: Recruiting Study Director: BMS Overall Survival (OS) BORR, Best overall response rate; CARB, Carboplatin; ECOG PS, Eastern Cooperative Oncology Group Performance Status; IPI, ipilimumab; OS, Overall survival; PAC, Paclitaxel; PFS, Progression-free survival; PBO, Placebo; W, Week

  46. Actionable Targets in Lung Adenocarcinomas 2004 2005-2014 1999 Unknown 75% Unknown 60% EGFR Kris M et al. IASLC 2012 Targeted Therapies Conference

  47. Actionable Targets ? in Squamous Cell Lung Cancers 2004-2010 2014 1999 FGFR1 amplification Unknown 100% Unknown 100% PIK3CA mutation PTEN mutation PTEN loss DDR2 mutation Okudela et al. Cancer Res 2008 Yamamoto et al. Pathol Int 2007 Weiss et al. Sci Transl Med 2010 Hammerman et al. Cancer Discovery 2011 TCGA Nature 2012

  48. 2002-2012 – Changes in the therapeuticlandscapeof stage IV lungcancer Paik et al. J Clin Oncol 30: 2012 (suppl; abstr 7505)

  49. Novel Therapeutic Targets • FGFR1 amplification • NFE2L2 oxidative stress pathway • DDR2 mutations • PI3K pathway • EGFR

  50. FGFR1 amplification

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