NSCLC with squamous histology: Current treatment and new options on horizon

NSCLC with squamous histology: Current treatment and new options on horizon Prof. Yasser A.Kader Professor of Oncology Faculty of Medicine, Cairo University 2015

Lung Cancer: Incidence and Mortality New cases in 2013: 228,190 40% with stage IV disease at presentation (~ 90,000) ~ 160,000 deaths in 2012, comparable to prostate, pancreas, breast, and colon cancer combined 5-yr relative survival rate: 15.7 % overall; 3.7% for patients with distant-stage disease 180,000 160,000 140,000 120,000 100,000 80,000 60,000 40,000 20,000 0 Estimated Cancer Deaths by Site, 2012 Prostate Pancreas Breast Colon Other Cancers Lung cancer Lung Cancer NCI. Non-small-cell lung cancer treatment (PDQ ). ACS. Cancer facts & figures: 2012. CDC. Lung cancer rates by race and ethnicity. Howlader N, et al. SEER cancer statistics review.

Cancer Incidence, % Histologic Subtypes of NSCLC Decreasing Incidence of Squamous Cell Subtype Over Time 10%-15% 20% Adenocarcinoma 25%-30% Squamous cell carcinoma Large cell carcinoma Other or not otherwise specified 40% 85% of lung cancers are NSCLC. American Cancer Society database. Available at: www.cancer.org. Accessed March 24, 2014. Incidence of Histologic Types: Males and Females 45 40 35 30 25 20 15 10 5 0 Yr of Diagnosis (3-Yr Moving Average) Adenocarcinoma Squamous cell Large cell Wahbah M et al. Ann Diagn Pathol. 2007;11:89-96.

Histology in Management of Advanced- Stage Non Oncogene-Driven NSCLC What is the current treatment algorithm in the absence of a known and targetable oncogenic driver? Is NSCLC histologic subtype prognostic (ie, portends patient outcome independent of therapeutic intervention)? Is NSCLC histologic subtype predictive of differential benefit from available therapies? Adenocarcinoma Squamous Large Cell

Outcomes for Advanced Adenocarcinoma vs Squamous Cell NSCLC Recent OS gains more pronounced for patients with adenocarcinoma histology, less for patients with squamous cell tumors Period Overall Survival, 1 Yr vs 2 Yr, % HR*, P Value 1998-2001 2002-2005 All (N = 129,337) 1 yr 17.2 1 yr 19.3 2 yr 6.5 2 yr 7.8 Adenocarcinoma (n = 53,300) 1 yr 20.4 1 yr 23.3 2 yr 7.9 2 yr 9.9 *Comparison uses adenocarcinoma data as reference. Squamous Cell (n = 22,944) 1 yr 17.1 1 yr 19.9 2 yr 6.4 2 yr 7.2 0.997; P =.85 1.033; P =.02 Adapted from Morgensztern D, et al. J Thor Oncol. 2009;4:1524-1529.

Retrospective Analysis of ECOG 1594 by Histology Squamous (n=224) Adenocarcinoma (n=647) Large Cell (n=74) Other (n=194) Regimen Median 95% C1 Median 95% C1 Median 95% C1 Median 95% C1 p- value CP 6.9 (5.3, 9.4) 9.1 (7.9, 10.9) 6.1 (2.9, inf) 6 (3.9, 9.1) 0.09 CG 9.4 (5.7, 15.5) 8.1 (6.8, 9.8) 9.7 (4.5, 17.1) 7.9 (6.3, 11.3) 0.63 OS (mo) CD 8.1 (5.5, 11.2) 7.7 (6.5, 9.4) 6.8 54.9, 11.7 8.2 (5.6, 12.4) 0.01 CbP 9.3 (7.3, 12.1) 7.6 (6.6, 9.8) 8.3 (3.6, 16.7) 6.9 (4.9, 11.6) 0.37 p-value 0.18 0.39 0.37 0.82 CP 2.6 (1.7, 4.2) 3.7 (3.1, 4.3) 3.5 (1.4, inf) 2.8 (1.8, 4.0) 0.43 CG 4.1 (3.3, 6.6) 4.4 (3.8, 5.4) 4.5 (2.0, 11.5) 3.4 (2.8, 5.1) 0.43 PFS (mo) CD 3.1 (2.4, 5.0) 3.7 (2.6, 4.6) 4.2 (2.0, 6.6) 3.6 (2.7, 5.6) 0.54 CbP 3.7 (3.0, 5.0) 3.5 (2.9, 4.2) 3.9 1.9, 7.8) 2.2 1.7, 3.9) 0.25 p-value 0.2 0.19 0.56 0.68 Histological subtypes did not influence overall survival and progression free survival in chemonaïve patients treated with platinum-based doublets involving paclitaxel, docetaxel or gemcitabine Tien H et al. J Thorac Oncol 4:S493, 2009

Phase III nab-p/c vs P/C Study Design Socinski MA et al. ASCO 2010, LBA# 7511 Chemo-naive PS 0-1 Stage IIIb/IV NSCLC N = 1,050 Stratification factors: Stage (IIIb vs IV) Age (<70 vs >70) Sex Histology (squamous vs nonsquamous) Geographic region 1:1 nab-paclitaxel 100 mg/m 2 d1, 8, 15 Carboplatin AUC 6 d1 No Premedication n = 525 Paclitaxel 200 mg/m 2 d1 Carboplatin AUC 6 d1 With Premedication of Dexamethasone + Antihistamines n = 525

Results: Baseline Demographics nab-p/c (n = 521) P/C (n = 531) All Patients (N = 1052) Age, median (range) years 60 (28, 81) 60 (24, 84) 60 (24, 84) <70 years, n (%) 70 years, n (%) 448 (86) 73 (14) 449 (85) 82 (15) 897 (85) 155 (15) Female, n (%) 129 (25) 134 (25) 263 (25) ECOG, n (%) 0 133 (26) 113 (21) 246 (23) 1 385 (74) 416 (78) 801 (76) Histology of Primary Diagnosis, n (%)* Adenocarcinoma 254 (49) 264 (50) 518 (49) Squamous Cell Carcinoma 228 (44) 221 (42) 449 (43) Large Cell Carcinoma 9 (2) 13 (2) 22 (2) Other 29 (6) 33 (6) 62 (6) Stage at Current Diagnosis, n (%)* Stage III 99 (19) 107 (20) 206 (20) Stage IV 421 (81) 424 (80) 845 (80) Prior Chemotherapy, n (%) 12 (2) 8 (2) 20 (2) Smoking Status, n (%) 513 521 1034 Never Smoked 138 (27) 144 (28) 282 (27) Smoked and Quit 165 (32) 146 (28) 311 (30) Smoked and Still Smokes 210 (41) 231 (44) 441 (43) *Data was missing for 1 pt at the time of this analysis

Percent Responses Objective Responses by Histology Squamous Nonsquamous P < 0.001 P = 0.060 P = 0.808 P = 0.069 50% nab-p/c 40% 30% 20% 41% 24% 37% 29% 26% 25% 37% 30% P/C 10% 0% Independent Radiologic Review Investigator Assessment Independent Radiologic Review Investigator Assessment n = 228 n = 221 n = 292 n = 310 Socinski MA et al. ASCO 2010 #7511

Exploratory Overall Survival Analysis in Selected Strata Carboplatin/ paclitaxel Carboplatin/ nab paclitaxel Hazard ratio p-value Squamous (n = 221, 229) 9.5 months 10.7 months 0.890 0.284* Age 70 years (n = 82, 74) 10.4 months 19.9 months 0.583 0.009* * Subgroup analyses exploratory in nature

Targeted Agents in Squamous cell Carcinoma

Trial Outcome with Targeted Agents in Squamous Cell CA Agent Trial Results Bevacizumab Phase II Associated with increased risk of severe pulmonary hemorrhage (4/13 pts) Sorafenib Phase III ESCAPE Increased risk of death Motesanib Phase III MONET Increased risk of hemoptysis Cediranib Phase II BR24 No increased toxicity or efficacy Figitumumab Phase III No histology specific findings but ADVIGO (2) increased toxicity and no benefit Cetuximab Phase III FLEX No histology specific findings

FLEX: Phase III Evaluation of Cetuximab Plus Chemotherapy Advanced-stage, previously untreated NSCLC patients with EGFR+ in 1 tumor cell and no brain metastases (N = 1125) Cisplatin 80 mg/m 2 on Day 1 Vinorelbine 25 mg/m 2 on Days 1 and 8 Six 3-wk cycles Cetuximab 400 mg/m 2 over 2 hrs on Day 1 250 mg/m 2 over 1 hr wkly from Day 8 Continued until disease progression Cisplatin 80 mg/m 2 on Day 1 Vinorelbine 25 mg/m 2 on Days 1 and 8 Six 3-wk cycles Primary endpoint: OS Secondary endpoints: PFS, RR, QoL, safety Pirker R, et al. Lancet. 2009;373:1525-1531.

FLEX: Efficacy Outcomes Outcome Cisplatin/ Vinorelbine + Cetuximab (n = 557) Cisplatin/ Vinorelbine (n = 568) HR (95% CI) Median OS, mos 11.3 10.1 0.871 (0.762-0.996) Median PFS, mos 4.8 4.8 0.943 (0.825-1.077) Median TTF, mos 4.2 3.7 0.860 (0.761-0.971) P Value.044.39.015 Response rate, % 36 29.010 Pirker R, et al. Lancet. 2009;373:1525-1531.

OS (%) FLEX: Cetuximab + Chemotherapy vs Chemotherapy in Advanced NSCLC Significant OS benefit for addition of cetuximab to cisplatin/vinorelbine 100 Chemotherapy + cetuximab 80 Chemotherapy 60 40 20 HR: 0.871 (95% CI: 0.762-0.996; P =.044) 0 0 6 12 18 24 30 Mos Patients at Risk, n Chemotherapy+ 557 383 251 155 53 3 cetuximab 568 383 225 134 48 0 Chemotherapy Pirker R, et al. Lancet. 2009;373:1525-1531.

OS (%) OS (%) FLEX Study: OS by Histology in Patients with High EGFR Expression 100 Adenocarcinoma (N = 135) Squamous (N = 144) Survival Survival Median, Mos 1 Yr, % Median, Mos 1 Yr, % CT + cetuximab 20.2 65 CT + cetuximab 11.2 44 100 CT 13.6 52 CT 8.9 25 80 HR: 0.74 (95% CI: 0.48-1.14) 80 HR: 0.62 (95% CI: 0.43-0.88) 60 60 40 40 20 20 0 0 6 12 18 24 30 Time (Mos) 0 0 6 12 18 24 30 Time (Mos) Pirker R, et al. IASLC 2011. Abstract 1557.

SQUIRE: Chemotherapy +/- Necitumumab for First Line Adv. Squamous NSCLC Necitumumab (Neci) (IMC-11F8) is a human IgG1 anti-egfr monoclonal antibody Adv. squamous NSCLC Treatment-naïve N = 1093 Primary endpoint: OS R A N D O M I Z E Cisplatin/Gemcitabine + Necitumumab up to 6 cycles Cisplatin/Gemcitabine up to 6 cycles Cisplatin 75 mg/m2 IV day 1 q21 days Gemcitabine 1250 mg/m2 IV days 1, 8 q21 days Necitumumab 800 mg/kg IV days 1, 8 q21 days Maintenance neci until progression Thatcher, A#8008

SQUIRE: Efficacy of Necitumumab Chemo/Neci (N = 545) Chemo alone (N = 548) ORR (CR + PR) 31.2% 28.8% 0.400 DCR (CR + PR +SD) 81.8% 77.0% 0.043* P Progression-Free Survival (ITT) *Cochran-Mantel-Haenszel test (stratified) Overall Survival (ITT) Thatcher, A#8008

SQUIRE: Toxicity of Necitumumab Thatcher, A#8008

SQUIRE: FLEX Redux? (Re-FLEX?) SQUIRE FLEX Thatcher, A#8008 Pirker, Lancet 2009 Extremely similar agent; extremely similar results. Cetuximab has had negligible impact on NSCLC management Highlights distinction between statistical & clinical significance

Place of Maintenance in S.C.C.? SATURN (old) ABOUND (new)

SATURN study design Chemonaïve advanced NSCLC n=1,949 Mandatory tumour sampling 4 cycles of firstline platinum doublet chemotherapy* Non-PD n=889 Erlotinib 150mg/day Placebo PD PD 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 Co-primary endpoints: PFS in all patients PFS in patients with EGFR IHC+ tumours Secondary endpoints: OS in all patients and those with EGFR IHC+ tumours, OS and PFS in EGFR IHC tumours; biomarker analyses; safety; time to symptom progression; QoL *Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxel Future Oncology, December 2010, Vol. 6, No. 12, Pages 1827-1832

PFS according to histology Adenocarcinoma Squamous-cell carcinoma PFS probability PFS probability 1.0 HR=0.60 (0.48 0.75) 1.0 HR=0.76 (0.60 0.95) 0.8 Log-rank p<0.0001 0.8 Log-rank p=0.0148 0.6 0.6 0.4 Erlotinib (n=204) Placebo (n=197) 0.4 Erlotinib (n=166) Placebo (n=193) 0.2 0.2 0 88 80 72 64 56 48 40 32 24 16 8 0 0 88 80 72 64 56 48 40 32 24 16 8 0 Time (weeks) Time (weeks) Future Oncology, December 2010, Vol. 6, No. 12, Pages 1827-1832

NEW COMER Ramucirumab

Breakthrough of the year Couzin-Frankel. Science 2013 Hanahan & Weinberg. Cell 2011

PD-L1 is expressed in many solid tumours PD-L1 is broadly expressed by tumour cells and tumour-infiltrating immune cells PD-L1 prevalence 1 3 Tumour type Non-trial study 1,2 * (immune cell), % Phase I study3 Immune Tumour cell cell* NSCLC 45% 26% 24% RCC 20% 25% 10% PD-L1+ immune cells (NSCLC) 1 Melanoma 40% 36% 5% Bladder 4 N/A 27% 11% HNSCC 33% 28% 19% Gastric cancer N/A 18% 5% CRC 45% 35% 1% Pancreatic cancer N/A 12% 4% PD-L1+ tumour cells (melanoma) 1 PD-L1 expression assessed with proprietary Genentech/Roche IHC reagent *PD-L1+ defined as patients with 5% tumour infiltrating immune cells positive for PD-L1 Surgical tumour specimens; PD-L1-positive defined as patients with 5% tumour cells positive for PD-1 1. Kohrt, et al. 2013; 2. Roche/Genentech data; 3. Herbst, et al. 2014; 4. Powles, et al. 2014

Overview of several anti-pdl1/pd1 therapies currently in development Therapies are currently in development that target both PD-L1 and PD-1 Therapeutic Lead company Antibody type Affinity/K 2 * Reference Anti-PDL1 MPDL3280A MEDI-4736 BMS-936559 Anti-PD1 Nivolumab MK3475 (pembrolizumab) AMP-224 Roche AstraZeneca Bristol-Myers Squibb Bristol-Myers Squibb Engineered IgG1 (no ADCC) Modified IgG1 (no ADCC) IgG4 IgG4 0.4nM Not available Not available 2.6nM Merck & Co IgG4 (humanised) 29pM GlaxoSmithKline PD-L2 IgG1 Fc fusion Not available Herbst, et al. ASCO 2013 Stewart, et al. Cancer Res 2011 Brahmer, et al. NEJM 2012 Brahmer, et al. J Clin Oncol 2010 Patnaik, et al. J Clin Oncol 2012 Smothers, et al. Ann Oncol 2013 *Affinity/K 2 describes the strength of binding of an antibody to PD-L1 or PD-1; the lower the value, the higher the affinity

Current Players OPDIVO Atezolizumab KEYTRUDA

NIVOLUMAB Story in 2014-2015 Checkmate-017 Checkmate-063 (label trial) Checkmate-057

*July 2014 database lock Ramalingam, et al. 2014

*July 2014 database lock Ramalingam, et al. 2014

CheckMate 017: study design Stage IIIB/IV NSCLC Squamous histology Nivolumab 3mg/kg IV q2w (n=135) 1 prior line of platinum doubletbased chemotherapy Pre-treatment (archival or fresh) tumour samples required for PD-L1 analysis R 1:1 PD ECOG PS 0 1 (n=272) Docetaxel 75mg/m 2 IV q3w (n=137) Primary endpoint OS Secondary endpoints Investigator assessed ORR Investigator assessed PFS Correlation between PD-L1 expression and efficacy Safety Quality of life (LCSS) NCT01642004 Spigel, et al. ASCO 2015 (updated data from congress presentation)

CheckMate 017: baseline characteristics Nivolumab (n=135) Docetaxel (n=137) Median age (range), years 62 (39 85) 64 (42 84) Age category: 75 years, % 8 13 Male, % 82 71 Disease stage: IIIB / IV, % 21 / 78 18 / 82 PS 0 / 1, % 20 / 79 27 / 73 CNS metastasis, % 7 6 Prior paclitaxel, % 34 34 Current or former smoker, % 90 94 PD-L1 expression:* 1% / 5% / 10% / not quantifiable 47 / 31 / 27 / 13 41 / 29 / 24 / 21 83% (225/272) of patients had quantifiable PD-L1 expression *Percentage of all randomised patients NCT01642004 Spigel, et al. ASCO 2015 (updated data from congress presentation)

OS estimate CheckMate 017: OS (updated) 1.0 0.8 0.6 mos, months (95% CI) Nivolumab (n=135) 9.2 (7.33 12.62) Docetaxel (n=137) 6.0 (5.29 7.39) Number of events 103 122 HR 0.62 (0.48 0.81) p=0.0004 0.4 12-month OS rate = 42% 18-month OS rate = 28% Nivolumab Docetaxel 0.2 12-month OS rate = 24% 18-month OS rate = 13% 0 0 Minimal follow-up for survival: 18 months Based on August 2015 database lock Symbols refer to censored observations HR = hazard ratio 3 6 9 12 15 18 21 24 27 30 33 Time (months) NCT01642004 Reckamp, et al WCLC 2015; Reck, et al. ECC 2015; Gralla, et al. WCLC 2015 (updated data from congress presentation)

PFS estimate CheckMate 017: PFS (updated) 1.0 0.8 0.6 0.4 mpfs, months (95% CI) Nivolumab (n=135) 3.5 (2.14 5.06) Docetaxel (n=137) 2.8 (2.14 3.52) Number of events 105 122 HR 0.63 (0.48 0.83) p=0.0008 Nivolumab Docetaxel 0.2 12-month PFS rate = 21% 18-month PFS rate = 17% 0 0 Minimal follow-up for survival: 18 months Based on August 2015 database lock Symbols refer to censored observations 12-month PFS rate = 6.4% 3 6 9 12 15 18 21 24 27 30 Time (months) 18-month PFS rate = 2.7% NCT01642004 Reckamp, et al WCLC 2015 (updated data from congress presentation)

CheckMate 017: survival benefit by PD-L1 expression PD-L1 expression OS PFS <1% 1% <5% 5% <10% 10% Nivo n 54 63 75 42 81 36 Doc n 52 56 69 39 75 33 HR (95% CI) 0.58 (0.37 0.92) 0.69 (0.45 1.05) 0.70 (0.47 1.02) 0.53 (0.31 0.89) 0.70 (0.48 1.01) 0.50 (0.28 0.89) Not quantifiable 18 29 0.39 (0.19 0.82) <1% 1% <5% 5% <10% 10% 54 63 75 42 81 36 52 56 69 39 75 33 0.66 (0.43 1.00) 0.67 (0.44 1.01) 0.75 (0.52 1.08) 0.54 (0.32 0.90) 0.70 (0.49 0.99) 0.58 (0.33 1.02) Not quantifiable 18 29 0.45 (0.23 0.89) Interaction p-value 0.56 0.47 0.41 0.70 0.16 0.35 Favours nivolumab Favours docetaxel Nivolumab benefit was independent of PD-L1 expression 0 0.5 1.0 1.5 2.0 PD-L1 positive expression HR PD-L1 negative expression Not quantifiable 83% of patients (225/272) had quantifiable PD-L1 expression Based on December 2014 database lock CI = confidence intervals NCT01642004 Reckamp, et al WCLC 2015 (updated data from congress presentation)

CheckMate 017: Conclusions With longer follow-up, nivolumab continues to demonstrate OS and PFS benefit compared with docetaxel in previously treated patients with advanced squamous cell NSCL 41% reduction in risk of death (HR=0.59; p=0.00025) 1-yr OS: 42% vs 24% 18-month OS (28% vs 13%) and PFS (17% vs 2.7%) mos: 9.2 vs 6.0 months (HR=0.62; p=0.0004) Nivolumab demonstrated superiority over docetaxel across all secondary efficacy endpoints ORR: 20% vs 9% (p=0.0083) 1-yr PFS: 21% vs 6.4%; mpfs 3.5 vs 2.8 months (HR=0.62; p=0.0004) Nivolumab benefit was independent of PD-L1 expression NCT01642004 Reck, et al. ECC 2015; Gralla, et al. WCLC 2015; Reckamp, et al WCLC 2015 (updated data from congress presentation) NCT01642004 Spigel, et al. ASCO 2015 (updated data from congress presentation)

PEMBROLIZUMAB(KEYTRUDA) Keynote-001 Keynote-010 Keynote-024 Keynote-042

KEYNOTE-001: study design Locally-advanced or metastatic disease Carcinoma, melanoma, NSCLC Pembrolizumab in chemo-naïve patients with PD-L1+ NSCLC (n=101) 2mg/kg q3w 10mg/kg q2w 10mg/kg q3w NSCLC: EGFR Mut+ or ALK+ permitted in previously-treated patients (with PD on relevant TKI) but not for treatment-naïve patients ECOG PS 0 1 (n=1,137 all tumour types) Pembrolizumab in previously treated NSCLC (n=449) 18%SCC 2L 3L 10mg/kg q2w; PD-L1 (n=43) 2mg/kg q3w; PD-L1+ (n=55) randomized 3:2 to 10mg/kg q2w or q3w; PD-L1+ (n=280) 10mg/kg q3w; PD-L1+ or PD- L1 (n=38) 10mg/kg q3w; PD-L1+ (n=33) Primary endpoint DLTs AEs Response rate Biomarker expression Secondary endpoints Pharmacokinetics PFS OS DoR *PD-L1+ defined as 1% tumour PD-L1 expression by central IHC assay using the 22C3 antibody AEs = adverse events; DLTs = dose-limiting toxicities; DoR = duration of response ECOG PS = Eastern Cooperative Oncology Group performance status EGFR = epidermal growth factor receptor; OS = overall survival; PD = progressive disease PD-L1 = programmed death-ligand 1; PFS = progression-free survival; TKI = tyrosine kinase inhibitor NCT01295827 Soria, et al. ECC 2015 (updated data from congress presentation)

KEYNOTE-001: Conclusions Efficacy and safety were similar across 2 mg/kg and 10 mg/kg doses of pembrolizumab, supporting 2 mg/kg q3w as an effective dose in NSCLC PD-L1 TPS(Tissue polyppteptide specificic antigen) 50% identifies patients with greatest likelihood of clinical benefit patients with higher PD-L1 expression may have a faster time to response Additional data will be provided by the ongoing randomised KEYNOTE-010 study (NCT01905657) of pembrolizumab at 2mg/kg or 10mg/kg versus docetaxel NCT01295827 Soria, et al. ECC 2015 (updated data from congress presentation)

Atezolizumab POPLAR BIRCH

POPLAR summary The POPLAR Phase II randomized study demonstrated significant improvements in OS for unselected NSCLC patients receiving atezolizumab vs docetaxel ITT: OS HR = 0.73 (P =.040) Higher PD-L1 expression associated with improved overall survival with atezolizumab Activity was observed in both squamous and non-squamous NSCLC patients treated with atezolizumab Atezolizumab was well tolerated with a safety profile consistent with previous studies,distinct from chemotherapy

(28%SCC)

Cancer immunotherapy: induction of longterm survival future Direction...Combination??!! Overall survival Combinations Checkpoint inhibitors Chemotherapy 60

Pembrolizumab

Where to go and How to Follow in Advanced NSCLC(Sq.Cell Ca) 2015?

Current Treatment Guidelines for Metastatic NSCLC (2015)

Current Treatment Guidelines for Metastatic NSCLC (2015)

Take Home Messages

We are rapidly moving from Clinical to Biological Predictors in NSCLC Treatment Algorithms in 2015.