Optimizing the Care of Patients With Squamous Non-Small Cell Lung Cancer This activity is supported by educational grants from Boehringer Ingelheim Pharmaceuticals, Inc. and Lilly.

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Faculty Leora Horn, MD, MSc, FRCPC Associate Professor of Medicine Clinical Director, Thoracic Oncology Research Program Assistant Director, Education Development Program Vanderbilt Ingram Cancer Center Nashville, Tennessee Leora Horn, MD, MSc, FRCPC, has disclosed that she has received consulting fees from Genentech and Merck, has consulted without personal honorarium for Bayer, Bristol- Myers Squibb, Boehringer Ingelheim, and Xcovery, received fees for non-CME/CE services received directly from a commercial interest or their agents (eg, speakers’ bureaus) from Biodesix, and funds for research support from AstraZeneca. This slide lists the faculty who were involved in the production of these slides.

Agenda Lung Cancer: Overview Therapeutic Options in Squamous NSCLC: Chemotherapy Therapeutic Options in Squamous NSCLC: Targeted Therapy Therapeutic Options in Squamous NSCLC: Checkpoint Inhibitors NSCLC, non-small-cell lung cancer. Slide credit: clinicaloptions.com

Lung Cancer Remains Major Global Health Burden One of the most common cancers and leading cause of cancer deaths in US and worldwide[1,2] New cases, 2015 (estimated): US, 221,200; global, 2M Deaths, 2015 (estimated): US, 158,040; global, 1.5M 5-yr US survival rates[3] Overall: 18% Metastatic: 4% 1. GLOBOSCAN Cancer Fact Sheets. 2012. 2. Siegel RL, et al. CA Cancer. 2015; 65:5-29. 3. Surveillance, Epidemiology, and End Results (SEER) Program. Slide credit: clinicaloptions.com

Traditional View of Lung Cancer 40% 45 20% 40 10% to 15% 35 30 25 25% to 30% Cancer Incidence (%) 20 15 10 Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Other or not otherwise specified 5 NSCLC, non-small-cell lung cancer. 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 Yr of Diagnosis (3-Yr Moving Average) Adenocarcinoma Squamous cell Large cell 85% of lung cancers are NSCLC American Cancer Society database. Wahbah M, et al. Ann Diagn Pathol. 2007;11:89-96. Slide credit: clinicaloptions.com

Histology-Based Subtyping Evolution of NSCLC Subtyping to a Multitude of Molecular-Defined Subsets NSCLC as one disease Histology-Based Subtyping Squamous 34% Other 11% Adenoca 55% Adenocarcinoma Squamous Cell Cancer ALK HER2 BRAF PIK3CA AKT1 MAP2K1 NRAS ROS1 RET EGFR KRAS Unknown EGFRvIII PI3KCA DDR2 FGFR1 Amp First-targeted tx NSCLC, non-small-cell lung cancer; tx, treatment Slide credit: clinicaloptions.com Li T, et al. J Clin Oncol. 2013;31:1039-1049.

Biopsy: Establish Diagnosis, Determine Histologic Subtype, Molecular Testing Adequate tissue for histologic subtyping, molecular analysis critical Histologic subtyping: squamous or nonsquamous? Determination of EGFR mutation, ALK, and ROS1 translocations indicated in all nonsquamous cancers Should other genes be evaluated? KRAS, BRAF, HER2, RET, others? Should these genes be evaluated in squamous NSCLC? Rebiopsy at time of progression Helps in determining resistance in EGFR-mutated and ALK+ cases Bone biopsy (for molecular testing) contraindicated due to decalcification and degradation of DNA Liquid biopsies (cell-free DNA in plasma) increasingly used NSCLC, non-small-cell lung cancer. Slide credit: clinicaloptions.com

Therapeutic Options in Squamous NSCLC: Chemotherapy NSCLC, non-small-cell lung cancer.

Therapeutic Plateau in Metastatic NSCLC ECOG 1594 1.0 Cisplatin/paclitaxel Cisplatin/gemcitabine Cisplatin/docetaxel Carboplatin/paclitaxel 0.8 0.6 Overall Survival (%) 0.4 NSCLC, non-small-cell lung cancer. 0.2 5 10 15 20 25 30 Mos Slide credit: clinicaloptions.com Schiller JH, et al. N Engl J Med. 2002;346:92-98.

Cisplatin + Pemetrexed vs Cisplatin + Gemcitabine in Advanced NSCLC Randomized, noninferiority phase III study Stratified by stage, PS, history of brain metastasis, sex, pathologic diagnosis, center Cisplatin 75 mg/m2 on Day 1 + Pemetrexed 500 mg/m2 on Day 1 (n = 862) Chemotherapy naive stage IIIB-IV NSCLC, ECOG PS 0-1 (N = 1725) ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small cell lung cancer; PS, performance status. Cisplatin 75 mg/m2 on Day 1 + Gemcitabine 1250 mg/m2 on Days 1 and 8 (n = 863) Vitamin B12, folate, and dexamethasone administered in both arms Slide credit: clinicaloptions.com Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551. 11 11

Cisplatin + Pemetrexed vs Cisplatin + Gemcitabine: OS by Histology 8832 Post-IASLC Program Cisplatin + Pemetrexed vs Cisplatin + Gemcitabine: OS by Histology Nonsquamous Squamous C/P C/G C/P vs C/G Median Survival, Mos 11.8 10.4 Adjusted HR: 0.81 (95% CI: 0.70-0.94) Median Survival, Mos 1.0 1.0 C/P C/G C/P vs C/G 9.4 10.8 0.8 0.8 Adjusted HR: 1.23 (95% CI: 1.00-1.51) 0.6 0.6 Survival Probability Survival Probability 0.4 0.4 0.2 0.2 C/G, cisplatin/gemcitabine; C/P, cisplatin/pemetrexed; NSCLC, non-small-cell lung cancer. 6 12 18 24 30 6 12 18 24 30 Mos Mos No difference in overall group between study arms: C/P 10.3 mos vs C/G 10.3 mos; adjusted HR: 0.94 (95% CI: 0.84-1.05) Slide credit: clinicaloptions.com Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551. 12

Carboplatin/Albumin-Bound Paclitaxel vs Carboplatin/Paclitaxel in Advanced NSCLC Stratified by stage (IIIb vs IV), age (< 70 yrs vs > 70 yrs), sex, histology (squamous vs nonsquamous), geographic region 21-day cycles Albumin-bound Paclitaxel 100 mg/m2 on Days 1, 8, 15 + Carboplatin AUC 6 on Day 1 No premedication Pts with stage IIIb/IV NSCLC, ECOG PS 0-1, no previous chemotherapy for metastatic disease (N = 1050) Paclitaxel 200 mg/m2 on Day 1 + Carboplatin AUC 6 on Day 1 Premedication: dexamethasone, antihistamines AUC, area under the curve; ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PS, performance status. Phase III Primary endpoint: ORR Secondary endpoints: PFS, OS, safety Slide credit: clinicaloptions.com Socinski MA, et al. J Clin Oncol. 2012;30:2055-2062.

Carboplatin/Albumin-Bound Paclitaxel vs Carboplatin/Paclitaxel: Response Carboplatin/albumin-bound paclitaxel Carboplatin/paclitaxel P < .001 RRR: 1.680 50 Response Rate (%) P = .005 RRR: 1.31 41% 40 P = .808 RRR: 1.034 33% 30 26% 25% 24% 25% 20 RRR, response rate ratio. 10 n = 521 531 229 221 292 310 Intent to Treat Squamous* Nonsquamous* *Not a prespecified endpoint. Interaction P value for histology = .036 Slide credit: clinicaloptions.com Socinski MA, et al. J Clin Oncol. 2012;30:2055-2062.

Carboplatin/Albumin-Bound Paclitaxel vs Carboplatin/Paclitaxel: OS ITT nab-P/ Carbo Paclitaxel/ Carbo HR P Value N/events 521/360 531/384 Median OS, mos (95% CI) 12.1 (10.8-12.9) 11.2 (10.3-12.6) 0.922 (0.797-1.066) .271 Squamous Cell nab-P/ Carbo Paclitaxel/ Carbo HR P Value N/events 229/170 221/173 Median OS, mos (95% CI) 10.7 (9.4-12.5) 9.5 (8.6-11.6) 0.890 (0.719-1.101) .284 nab-P/carbo (n = 521) Paclitaxel/carbo (n = 531) 1.00 1.00 nab-P/carbo (n = 229) Paclitaxel/carbo (n = 221) 0.75 0.75 Probability of Survival 0.50 Carbo, carboplatin; ITT, intent to treat; nab-paclitaxel, albumin-bound paclitaxel. Probability of Survival 0.50 0.25 0.25 3 6 9 12 15 18 21 24 27 30 33 3 6 9 12 15 18 21 24 27 30 33 Mos Mos Slide credit: clinicaloptions.com Socinski MA, et al. J Clin Oncol. 2012;30:2055-2062.

Therapeutic Options in Squamous NSCLC: Targeted Therapy NSCLC, non-small-cell lung cancer.

SQUIRE: Gemcitabine/Cis + Necitumumab vs Gemcitabine/Cis in Stage IV NSCLC 21-day cycles; maximum of 6 cycles Necitumumab 800 mg Days 1, 8 Gemcitabine 1250 mg/m² Days 1, 8 Cisplatin 75 mg/m² Day 1 (N = 545) Necitumumab 800 mg Days 1, 8 Stage IV squamous NSCLC ECOG PS 0-2 (N = 1093) Treatment continued until PD or intolerable AEs Gemcitabine 1250 mg/m² Days 1, 8 Cisplatin 75 mg/m² Day 1 (N = 548) Radiographic tumor assessment (investigator read): at baseline and every 6 wks until PD Mandatory tissue collection AE, adverse event; Cis, cisplatin; ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PD, progressive disease; PS, performance status Phase III Primary endpoint: OS Slide credit: clinicaloptions.com Thatcher N, et al. Lancet Oncol. 2015;16:763-774.

SQUIRE: Progression-Free Survival HR: 0.85 (95% CI: 0.74-0.98; P = .020) HR (95% CI) 100 0.85 0.82 1.07 0.63 0.90 0.88 0.70 0.84 0.86 0.79 ITT population (N = 1093) < 70 yrs of age (n = 888) ≥ 70 yrs of age (n = 205) Female (n = 185) Male (n = 908) White (n = 913) Nonwhite (n = 180) Ex-light & nonsmoker (n = 97) Smoker (n = 995) PS 0 (n = 344) PS 1 (n = 652) PS 2 (n = 96) 32 28 24 20 16 12 8 4 Mos Since Randomization PFS (%) Median PFS, Mos (95% CI) 80 Gem/Cis + Neci: Gem/Cis: 5.7 (5.6-6.0) 5.5 (4.8-5.6) 60 40 20 Cis, cisplatin, Gem, gemcitabine; ITT, intent to treat; Neci, necitumumab; PS, performance status. 0.5 1.0 1.5 Favors Gem/Cis + Neci Favors Gem/Cis Slide credit: clinicaloptions.com Thatcher N, et al. Lancet Oncol. 2015;16:763-774.

SQUIRE: Overall Survival Gemcitabine/ Cisplatin + Necitumumab (n = 545) 100 Gemcitabine/ Cisplatin (n = 548) Pts censored, n (%) Median OS, mos (95% CI) Stratified P value (log rank) Stratified HR (95% CI) 127 (23) 11.5 (10.4-12.6) .01 0.84 (0.74-0.96) 106 (19) 9.9 (8.9-11.1) 80 60 OS (%) 40 20 Gemcitabine/cisplatin + necitumumab Censored pts Gemcitabine/cisplatin 4 8 12 16 20 24 28 32 36 40 Mos Slide credit: clinicaloptions.com Thatcher N, et al. Lancet Oncol. 2015;16:763-774.

SQUIRE: Adverse Events AEs, % Gem/Cis + Neci Overall (N = 538) Gem/Cis Overall (N = 541) Any AEs 99.1 97.8 Grade ≥ 3 AEs 72.1 61.6 Serious AEs 47.8 37.5 AEs leading to discontin. of any study drug 31.2 24.6 AEs with outcome of death* 12.3 10.5 Treatment related death† 2.8 1.8 AE, adverse event; Cis, cisplatin, Gem, gemcitabine; Neci, necitumumab; PD, progressive disease. *Including death due to PD. †As assessed by investigators; missing relationship was counted as related. Thatcher N, et al. Lancet Oncol. 2015;16:763-774. Thatcher N, et al. ASCO 2014. Abstract 8008. Slide credit: clinicaloptions.com

SWOG S089: Carbo/Pac ± Bevacizumab ± Cetuximab in Advanced NSCLC Randomized phase III trial Primary endpoints: OS (total); PFS in EGFR-positive pts Secondary endpoints: OS and PFS by bevacizumab use, safety Exploratory endpoint: OS in EGFR+ and squamous pts Stratified by appropriate for bevacizumab treatment (yes/no), smoking status, stage (M1a vs M1b) Paclitaxel Carboplatin Bevacizumab* (n = 657) Bevacizumab* Advanced NSCLC (N = 1313) Paclitaxel Carboplatin Cetuximab Bevacizumab* (n = 656) Cetuximab Bevacizumab* Carbo, carboplatin; NSCLC, non-small-cell lung cancer; Pac, paclitaxel. *In appropriate pts. Slide credit: clinicaloptions.com Herbst RS, et al. WCLC 2015. Abstract 3612.

SWOG S089: Carbo/Pac ± Bevacizumab ± Cetuximab: OS 100 Median OS, Mos 10.9 9.4 95% CI 9.6-12.0 8.7-10.3 Cetuximab arm Control arm N 656 657 Events, n 536 558 80 HR: 0.94 (95% CI: 0.84-1.06; P = .34) 60 OS (%) 40 Carbo, carboplatin; NSCLC, non-small-cell lung cancer; Pac, paclitaxel. 20 12 24 36 48 60 Mos After Registration Slide credit: clinicaloptions.com Herbst RS, et al. WCLC 2015. Abstract 3612.

SWOG S089: OS in EGFR-Positive Squamous NSCLC Events, n Median OS, Mos 95% CI Cetuximab arm 55 50 11.8 8.6-13.5 Control arm 56 52 6.4 4.2-8.7 100 80 HR: 0.56 (95% CI: 0.37-0.84; P = .006) 60 OS (%) 40 NSCLC, non-small-cell lung cancer. 20 12 24 36 48 60 Mos Slide credit: clinicaloptions.com Herbst RS, et al. WCLC 2015. Abstract 3612.

SWOG S089: OS in EGFR-Positive Pts and by Bevacizumab Use OS, Mos (95% CI) Cetuximab (n = 199) Control (n = 201) EGFR positive 13.4 (11.7-14.8) 9.8 (8.7-12.1) HR: 0.83 (0.67-1.04; P = .10) Bevacizumab appropriate* Yes (all) 12.7 (10.9-13.4) 11.6 (10.5-13.8) n = 279/275 HR: 1.04 (0.86-1.25; P = .70) No (all) 9.2 (8.2-10.9) 8.2 (7.3-8.7) n = 377/382 HR: 0.88 (0.76-1.03; P = .12) Yes (EGFR+) 15.5 (13.4-18.4) 13.2 (11.2-19.1) n = NR HR: 0.97 (0.69-1.38; P = .88) No (EGFR+) 11.2 (8.6-12.9) 8.7 (5.9-9.7) n = 113/121 HR: 0.75 (0.57-1.00; P = .05) *Patients with squamous-cell NSCLC were not eligible for bevacizumab therapy. Slide credit: clinicaloptions.com Herbst RS, et al. WCLC 2015. Abstract 3612.

SWOG S089: Adverse Events AEs, % Cetuximab Arm Control Arm No Bev (n = 365) Bev (n = 262) No Bev (n = 367) Bev (n = 265) Grade 3/4 Grade 5 Grade 3/4 5 Blood/bone marrow 44 33 37 Metabolic/laboratory 18 20 12 14 Gastrointestinal 16 1 10 Infection 9 11 Pulmonary/upper respiratory 7 8 3 Dermatology/skin 17 0.3 0.4 Allergy/immunology 6 2 Renal/genitourinary Total 66 4 77 54 69 AE, adverse event; Bev, bevacizumab. Slide credit: clinicaloptions.com Herbst RS, et al. WCLC 2015. Abstract 3612.

REVEL: Docetaxel ± Ramucirumab in Second-line NSCLC: Study Design Stratified by ECOG PS 0 vs 1, sex, prior maintenance, East Asia vs ROW Phase III study Ramucirumab 10 mg/kg + Docetaxel 75 mg/m2 q3w (n = 628) Stage IV NSCLC after 1 platinum- based chemo ± maintenance, prior Bev allowed, all histologies, ECOG PS 0 or 1 (N = 1253) Treatment until disease progression or unacceptable toxicity Placebo + Docetaxel 75 mg/m2 q3w (n = 625) Bev, bevacizumab; ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PS, performance status; ROW, rest of world Ramucirumab: VEGFR2 antibody Primary endpoint: OS Secondary endpoints: PFS, ORR, safety, pt-reported outcomes Slide credit: clinicaloptions.com Garon EB, et al. Lancet. 2014;384:665-673.

REVEL: Docetaxel ± Ramucirumab in Second-line NSCLC: Response Phase III Study Ram + Doc Pl + Doc HR P Value ORR, % (95% CI) 22.9 (19.7-26.4) 13.6 (11.0-16.5) < .001 Median PFS, mos 4.5 (4.2-5.4) 3.0 (2.8-3.9) 0.72 < .0001 Median OS, mos 10.5 (9.5-11.2) 9.1 (8.4-10.0) 0.86 .0235 100 80 60 40 20 OS (%) Ram + Doc Pl + Doc 3 6 9 12 15 18 21 24 27 30 33 36 Doc, docetaxel; NSCLC, non-small-cell lung cancer; Pl, placebo; Ram, ramucirumab. Survival Time (Mos) First study in the second-line setting to show an OS advantage for the addition of a “targeted” agent to docetaxel compared with docetaxel alone First and only study of angiogenesis inhibition in advanced NSCLC to show a benefit in a squamous cell cancer cohort Slide credit: clinicaloptions.com Perol M, et al. ASCO 2014. Abstract LBA8006^.

REVEL: Tumor Response by RECIST v1.1 Response, n (%) Ramucirumab + Docetaxel (n = 628) Placebo + Docetaxel (n = 625) P Value CR 3 (0.5) 2 (0.3) PR 141 (22.5) 83 (13.3) SD 258 (41.1) 244 (39.0) PD 128 (20.4) 206 (33.0) NE/NA 98 (15.6) 90 (14.4) ORR (CR + PR), % (95% CI) 22.9 (19.7-26.4) 13.6 (11.0-16.5) < .001 DCR (CR + PR + SD), % (95% CI) 64.0 (60.1-67.8) 52.6 (48.6-56.6 ) DCR, disease control rate; NE, not evaluable; NA, not available; PD, progressive disease; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease. Garon EB, et al. Lancet. 2014;384:665-673. Perol M, et al. ASCO 2014. Abstract LBA8006. Slide credit: clinicaloptions.com

REVEL: Progression-Free Survival Censoring Rate, % 20 40 60 80 100 Median (95% CI) Ram + Doc Pbo + Doc Ram + Doc vs Pbo + Doc: HR: 0.762 (95% CI: 0.677-0.859; P < .0001) 4.5 (4.2-5.4) 3.0 (2.8-3.9) 11.1 6.7 PFS (%) Ram + Doc Pbo + Doc Censored Doc, docetaxel; Pbo, placebo; Ram, ramucirumab. 3 6 9 12 15 18 21 24 27 30 33 36 Mos Slide credit: clinicaloptions.com Garon EB, et al. Lancet. 2014;384:665-673.

REVEL: Overall Survival Censoring Rate, % 20 40 60 80 100 Median (95% CI) Ram + Doc Pbo + Doc Ram + Doc vs Pbo + Doc: HR: 0.857 (95% CI: 0.759-0.979; P = .0235) 10.5 (9.5-11.2) 9.1 (8.4-10.0) 31.8 27.0 OS (%) Doc, docetaxel; Pbo, placebo; Ram, ramucirumab. Ram + Doc Pbo + Doc Censored 3 6 9 12 15 18 21 24 27 30 33 36 Mos Slide credit: clinicaloptions.com Garon EB, et al. Lancet. 2014;384:665-673.

LUX-Lung 8: Afatinib vs Erlotinib Study Design Stratified by East Asian vs non-East Asian Afatinib 40 mg* QD (n = 398) SCC of the lung (stage IIIB/IV);; progressed after ≥ 4 cycles of a first-line platinum doublet; ECOG PS 0-1; adequate organ function (N = 795) Erlotinib 150 mg† QD (n = 397) *Dose escalation to 50 mg and dose reduction to 30 or 20 mg permitted. †Dose reduction to 100 or 50 mg permitted. Tumor assessment at baseline, Wks 8, 12, 16; every 8 wks thereafter. DCR, disease control rate; ECOG, Eastern Cooperative Oncology Group; PRO, patient-reported outcomes; PS, performance status; SCC, squamous cell carcinoma. Primary endpoint: PFS by independent review Secondary endpoints: OS, ORR, DCR, tumor shrinkage, PRO, safety Slide credit: clinicaloptions.com Soria JC, et al. Lancet Oncol. 2015;16:897-907.

Objective Response Rate LUX-Lung 8: Response P = .002 60 Afatinib Erlotinib 50.5 50 p=0.002 39.5 40 30 Patients (%) 20 P = .055 10 5.5 2.8 Disease Control Rate Objective Response Rate Duration of response was 7.29 mos for afatinib and 3.71 mos for erlotinib Slide credit: clinicaloptions.com Soria JC, et al. Lancet Oncol. 2015;16:897-907.

LUX-Lung 8: Progression-Free Survival Afatinib (n = 398) Erlotinib (n = 397) 1.0 Pts progressed/died, n (%) Median PFS, mos 299 (75.1) 2.6 306 (77.1) 1.9 0.8 HR (95% CI) = 0.81 (0.69-0.96; P = .010) 0.6 PFS (%) 0.4 0.2 3 6 9 12 15 18 21 24 27 Mos Pts at Risk, n Afatinib Erlotinib 398 397 139 99 50 34 30 17 14 10 10 2 5 1 2 1 2 1 Slide credit: clinicaloptions.com Soria JC, et al. Lancet Oncol. 2015;16:897-907.

LUX-Lung 8: Overall Survival Afatinib (n = 398) Erlotinib (n = 397) 1.0 Median OS, mos 7.9 6.8 HR (95% CI) = 0.81 (0.69-0.95; P = .008) 0.8 0.6 OS (%) 0.4 36.4% 22.0% 0.2 28.2% Afatinib Erlotinib 14.4% 3 6 9 12 15 18 21 24 27 30 Mos Median follow-up: 18.4 mos Slide credit: clinicaloptions.com Soria JC, et al. Lancet Oncol. 2015;16:897-907.

LUX-Lung 8: Drug-Related AEs (> 10%) Events, % Afatinib (n = 392) Erlotinib (n = 395) Grade 1 Grade 2 Grade 3 Diarrhea 42 17 10 24 7 2 Rash or acne 40 21 6 36 Stomatitis 8 4 5 3 Fatigue Nausea 9 1 < 1 Decreased appetite Paronychia Dry skin Pruritus Vomiting Dehydration AE, adverse event. Grade 4 AEs: afatinib, diarrhea < 1%, dehydration 1%; erlotinib, diarrhea < 1. Slide credit: clinicaloptions.com Soria JC, et al. Lancet Oncol. 2015;16:897-907.

Therapeutic Options in Squamous NSCLC: Checkpoint Inhibitors NSCLC, non-small-cell lung cancer.

PD-1 as a Target in Cancer Therapy Exhausted T cell Persistent antigen stimulation Tumor or APC Tumor or APC Activated T cell Initial immune response CD80 CD86 CD28 Cytokines Proliferation Activation APC, antigen-presenting cell. CD80 CD86 CD28 PD-L1 PD-1 Atezolizumab Durvalumab MSB0010718C Nivolumab Pembrolizumab Pidilizumab Slide credit: clinicaloptions.com McDermott DF, et al. Cancer Med. 2013;2:662-673.

Treatment continued until progressive disease or unacceptable toxicity CheckMate-063: Nivolumab in Previously Treated Squamous NSCLC: Study Design Stage IIIB/IV squamous NSCLC; ≥ 2 previous systemic therapies; ECOG PS 0-1 (N = 140) Treatment continued until progressive disease or unacceptable toxicity Nivolumab 3 mg/kg IV Q2W (n = 117) Planned to treat approximately 100 pts Expected ORR of 10% to 50%, with 20% maximum width of exact 2-sided 95% CI Assessments (RECIST v1.1) performed at Wk 8 and every 6 wks Primary endpoint: ORR and DoR by IRC (July 2014 database lock) Secondary endpoint: ORR and DoR by investigator (March 2014 database lock) Exploratory: safety and tolerability, PFS/OS, PD-L1 expression and efficacy DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; IRC, independent review committee; NSCLC; nonsmall cell lung cancer; RECIST, Response Evaluation Criteria in Solid Tumors; PS, performance status. Slide credit: clinicaloptions.com Rizvi NA, et al. Lancet Oncol. 2015;16:257-265.

Best Reduction From Baseline in Target Lesion ( by IRC) (%) CheckMate-063: Response and Survival Status by Best Reduction in Target Lesion Outcome IRC Assessment (n = 95) ORR, % (95% CI) 15 (9-22) Median DoR, mos (95% CI) NR (8.3-NR) Ongoing response, n/N (%) 13/17 (77) Median time to response, mos (range) 3.3 (2.2-4.8) Median OS, 8.2 (6-11) 1-yr OS, % (95% CI) 41 (32-50) 18-mo OS, % (95% CI) 27 (19-35) 100 75 50 -100 25 -25 -50 -75 Alive Deceased Confirmed responders n = 95 response evaluable Best Reduction From Baseline in Target Lesion ( by IRC) (%) DoR, duration of response; IRC, independent radiology review committee; NR, not reached Pts Rizvi NA, et al. Lancet Oncol. 2015;16:257-265. Horn L, et al. WCLC 2015. Abstract 828. Slide credit: clinicaloptions.com

CheckMate-063: Overall Survival Median Follow-up, Mos (Range) Median OS, Mos (95% CI) 1-Yr OS Rate, % (95% CI) 18-Mo OS Rate, % (95% CI) Events, n/N July 2014 8.0 (0-17.3) 8.2 (6.1-10.9) 41 (32-50) – 72/117 June 2015 8.0 (0-26.8) 8.1 (6.1-10.9) 39 (30-48) 27 (19-35) 90/117 20 40 60 80 100 8.1 mos OS (%) 39% 8.2 mos 41% 27% 6 12 18 24 3 9 15 21 27 Mos Rizvi NA, et al. Lancet Oncol. 2015;16:257-265. Horn L, et al. WCLC 2015. Abstract 828. Slide credit: clinicaloptions.com

CheckMate-063: Exploratory Analysis of ORR by PD-L1 Expression Subgroups ORR, % (n/N) Overall 15 (17/117) PD-L1 ≥ 1% 20 (9/45) < 1% 13 (4/31) ≥ 5% 24 (6/25) < 5% 14 (7/51) Indeterminate/not evaluable 30 (3/10) 86 available samples (76 evaluable) Slide credit: clinicaloptions.com Rizvi NA, et al. Lancet Oncol. 2015;16:257-265.

CheckMate-063: OS by PD-L1 Expression Median OS, Mos (95% CI) Events, n/N PD-L1 < 1% 8.3 (5.6-15.6) 23/31 PD-L1 ≥ 1% 10.1 (5.5-16.8) 32/45 Not evaluable 13.0 (1.1-20.8) 8/10 100 80 60 OS (%) 40 < 1% ≥ 1% Not evaluable 20 3 6 9 12 15 18 21 24 27 Mos Slide credit: clinicaloptions.com Horn L et al. WCLC 2015. Abstract 828.

CheckMate-063: Treatment-Related AEs AEs, % (≥ 10% Pts) Nivolumab 3 mg/kg (N = 117) Any Grade Grade 3/4 Total pts with an AE 74 17 Fatigue 33 4 Decreased appetite 19 Nausea 15 Asthenia 12 Rash 11 1 Diarrhea 10 3 85% of pts received at least 90% of planned dose intensity 12% discontinued treatment due to study drug toxicity (4% pneumonitis) Grade 3 treatment-related pneumonitis reported in 4 pts (3%); 1 additional grade 3 occurred between 30-100 days after last nivolumab dose 62% had died at time of analysis (including 54% PD and 2% study drug toxicity) 2 treatment-related deaths (1 hypoxic pneumonia and 1 ischemic stroke) occurred in pts with multiple comorbidities and concurrent PD AE, adverse event; PD, progressive disease. Slide credit: clinicaloptions.com Rizvi NA, et al. Lancet Oncol. 2015;16:257-265.

CheckMate-017: Nivolumab vs Docetaxel in Previously Treated Squamous NSCLC Open-label, randomized phase III trial Primary endpoint: OS Secondary endpoint: ORR, PFS, associations with PD-L1 expression, QoL Nivolumab 3 mg/kg IV q2w (n = 135) Stage IIIB/IV squamous NSCLC; after failure of 1 previous platinum-based tx; ECOG PS 0-1 (N = 272) Docetaxel 75 mg/m2 IV q3w (n = 137) ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PS, performance status; QoL, quality of life; tx, treatment. Slide credit: clinicaloptions.com Brahmer J, et al. N Engl J Med. 2015;373:123-135.

CheckMate-017: Overall Survival 100 80 60 40 20 Median OS, Mos (95% CI) 9.2 (7.3-13.3) 6.0 (5.1-7.3) 1-Yr OS, % 42 24 18-Mo OS, % 28 13 Nivolumab Docetaxel HR: 0.59 (95% CI: 0.44-0.79; P < .001) OS (%) 3 6 9 12 15 18 21 24 Mos Slide credit: clinicaloptions.com Brahmer J, et al. N Engl J Med. 2015;373:123-135.

CheckMate-017: ORR by PD-L1 Expression PD-L1 Expression Level* ORR,† % < 1% ≥ 1% < 5% ≥ 5% < 10% ≥ 10% NE Nivolumab 17 15 21 16 19 39 Docetaxel 10 11 12 8 9 3 Interaction P value .94 .29 .64 *Percent membranous staining in ≥100 tumor cells. †CR + PR per RECIST v1.1 criteria confirmation of response required (investigator assessment). NE, not evaluable; RECIST, Response Evaluation Criteria in Solid Tumors. Slide credit: clinicaloptions.com Brahmer J, et al. N Engl J Med. 2015;373:123-135.

CheckMate-017: OS by PD-L1 Expression 1% PD-L1 Expression Level 5% PD-L1 Expression Level 10% PD-L1 Expression Level Median OS, Mos Median OS, Mos Median OS, Mos PD-L1 ≥ 1% PD-L1 < 1% Nivolumab 9.3 8.7 Docetaxel 7.2 5.9 PD-L1 ≥ 5% PD-L1 < 5% Nivolumab 10.0 8.5 Docetaxel 6.4 6.1 PD-L1 ≥ 10% PD-L1 < 10% Nivolumab 11.0 8.2 Docetaxel 7.1 6.1 100 80 60 OS (%) 40 20 6 12 18 24 6 12 18 24 6 12 18 24 Mos Mos Mos Nivolumab PD-L1+ Nivolumab PD-L1- Docetaxel PD-L1+ Docetaxel PD-L1- Slide credit: clinicaloptions.com Brahmer J, et al. N Engl J Med. 2015;373:123-135.

CheckMate-017: Safety Treatment-related AEs in ≥ 5% of pts AE, % Nivolumab (n = 131) DocetaxeL (n = 129) Any Grade Grade 3/4 Total pts with an AE 58 7 86 55 Fatigue 16 1 33 8 Asthenia 10 14 4 Decreased appetite 11 19 Nausea 9 23 2 Diarrhea 20 Vomiting 3 Anemia 22 Myalgia Neutropenia 30 Peripheral neuropathy 12 Alopecia Febrile neutropenia AE, adverse event. Slide credit: clinicaloptions.com Brahmer J, et al. N Engl J Med. 2015;373:123-135.

KEYNOTE-001: Pembrolizumab in NSCLC: Subanalysis of Phase I Trial Mandatory tumor biopsy Pembrolizumab IV 2 mg/kg q3w (n = 6) Continue dosing and assessments every 9 wks CR, PR, SD Treatment-naive or previously treated advanced NSCLC (N = 495) Pembrolizumab IV 10 mg/kg q3w (n = 287) PD, unacceptable AE, or investigator decision Off study Pembrolizumab IV 10 mg/kg q2w (n = 202) Administered tumor assessment: imaging every 9 wks Primary: Response rate (RECIST) Secondary: immune-related response criteria (irRC) Tumor biopsy Tumor biopsy within 60 days prior to first dose of pembrolizumab required Tumor PD-L1 expression determined by prototype assay to inform enrollment; samples were independently reanalyzed using clinical trial IHC assay AE, adverse event; irRC, immune-related response criteria; NSCLC, non-small-cell lung cancer; PD, progressive disease; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; Slide credit: clinicaloptions.com Garon EB, et al. N Engl J Med. 2015;372:2018-2028.

KEYNOTE-001: Pembrolizumab Efficacy in Overall Population ORR Pts, n All Cohorts, % (95% CI) Total 495 19.4 (16.0-23.2) Treatment naive 101 24.8 (16.7-34.4) Previously treated 394 18.0 (14.4-22.2) Nonsquamous 401 18.7 (15.0-22.9) Squamous 85 23.5 (15.0-34.0) Slide credit: clinicaloptions.com Garon EB, et al. N Engl J Med. 2015;372:2018-2028.

KEYNOTE-001: Pembrolizumab Efficacy by PD-L1 Expression ORR Pts, n All Cohorts, % (95% CI) Percent PD-L1 staining ≥ 50% 73 45.2 (33.5-57.3) 1% to 49% 103 16.5 (9.9-25.1) < 1% 28 10.7 (2.3-28.2) 100 PFS 100 OS 80 80 PS ≥ 50% (n = 119) 60 60 PFS (%) OS (%) PS, proportion score. PS ≥ 50% (n = 119) 40 40 PS 1 - 49% (n = 161) PS < 1% (n = 76) 20 PS < 1% (n = 76) 20 PS 1 - 49% (n = 161) 2 4 6 8 10 12 14 16 18 20 22 24 26 4 8 12 16 20 24 28 Mos Mos Slide credit: clinicaloptions.com Garon EB, et al. N Engl J Med. 2015;372:2018-2028.

KEYNOTE-001: Antitumor Activity by Histology TPS ≥ 50% TPS 1-49% TPS < 1% Total n ORR, % (95% CI) N Overall 144 38.2 (30.2-46.7) 185 11.9 (7.6-17.4) 80 10.0 (4.4-18.8) 550 20.2 (16.9-23.8) Squamous 24 50.0 (29.1-70.9) 29 17.2 (5.8-35.8) 13 0.0 (0.0-24.7) 95 26.3 (17.8-36.4) Non-squamous 117 35.9 (27.2-45.3) 153 11.1 (6.6-17.2) 65 12.3 (5.5-22.8) 446 19.1 (15.5-23.0) TPS, tumor proportion score. Patients with squamous histology represent 17% of the total population 17% of the TPS ≥50% group 16% of the TPS 1-49% group 16% of the TPS <1% group Histology is not associated with response after adjusting for smoking status or smoking status and PD-L1 TPS PD-L1 score is strongly associated with response after adjusting for histology and smoking status There is no strong evidence of an interactive effect on ORR between histology and PD-L1 TPS (P = 0.81) Slide credit: clinicaloptions.com Hellman MD, et al. WCLC 2015. Abstract 3057.

KEYNOTE-001: PFS by Histology Squamous Nonsquamous Median PFS, Mos (95% CI) Median PFS, Mos (95% CI) 4 8 12 16 20 24 28 32 40 60 80 100 Mos PFS (%) 6 4 8 12 16 20 24 28 32 40 60 80 100 Mos PFS (%) 6 TPS ≥ 50% TPS 1-49% TPS < 1% 10.3 (1.9-15.7) 6.0 (4.1-8.2) 3.5 (2.0-6.2) TPS ≥ 50% TPS 1-49% TPS < 1% 4.3 (2.3-10.2) 2.3 (2.1-3.3) 2.2 (2.0-3.7) TPS, tumor proportion score. Median (range) duration of follow-up Squamous: 14.6 mo (6.4-32.1) Nonsquamous: 15.3 mo (6.5-32.3) TPS ≥ 50% TPS 1-49% TPS < 1% 24 29 13 17 21 6 11 8 3 6 3 2 1 117 153 65 62 57 23 46 20 7 29 8 4 7 2 5 4 2 Slide credit: clinicaloptions.com Hellman MD, et al. WCLC 2015. Abstract 3057.

KEYNOTE-001: OS by Histology Squamous Nonsquamous Median OS, Mos (95% CI) Median OS, Mos (95% CI) 100 100 TPS ≥ 50% TPS 1-49% TPS < 1% 14.0 (8.3-15.7) 9.2 (6.0-NR) 15.8 (3.4-NR) TPS ≥ 50% TPS 1-49% TPS < 1% 18.5 (11.3-NR) 9.0 (6.2-16.2) 8.8 (5.5-12.0) 80 80 60 60 OS (%) OS (%) 40 40 20 20 NR, not reached; TPS, tumor proportion score. 4 8 12 16 20 24 28 32 4 8 12 16 20 24 28 32 Mos Mos TPS ≥ 50% TPS 1-49% TPS < 1% 24 29 13 20 24 10 16 15 7 8 12 5 2 117 153 65 91 109 47 70 69 32 49 47 19 22 13 9 9 6 4 3 3 1 Slide credit: clinicaloptions.com Hellman MD, et al. WCLC 2015. Abstract 3057.

KEYNOTE-010: Pembrolizumab vs Doc in Previously Treated PD-L1+ NSCLC Phase II Study Stratified by ECOG PS (0 vs 1); region (East Asia vs non-East Asia); PD-L1 status (TPS ≥50% vs 1%-49%) Pembrolizumab 2 mg/kg IV q3w/24 mos (n = 345) Advanced NSCLC; confirmed PD after ≥ 1 line of chemotherapy; no active brain metastases; ECOG PS 0-1; PD-L1 TPS ≥ 1%; no serious autoimmune disease; no ILD or pneumonitis requiring systemic steroids (N = 1034) Pembrolizumab 10 mg/kg IV q3w/24 mos (n = 346) Docetaxel 75 mg/m2 IV q3w (n = 343) Doc, docetaxel; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; ILD, interstitial lung disease; NSCLC, non-small-cell lung cancer; PD, progressive disease; PS, performance status; TPS, tumor proportion score. End points in the TPS ≥ 50% stratum and TPS ≥ 1% population Primary: PFS and OS Secondary: ORR, DoR, safety Slide credit: clinicaloptions.com Herbst RS, et al. Lancet. 2015;[Epub ahead of print].

KEYNOTE-010: Overall Survival Total Pt Population Pts With PD-L1 TPS ≥ 50%* Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Docetaxel Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Docetaxel 100 100 80 80 60 60 OS (%) OS (%) 40 40 20 20 TPS, tumor proportion score. 5 10 15 20 25 5 10 15 20 25 Mos Mos *Treatment Arm Median, mo (95% CI) HR (95% CI) P Pembro 2 mg/kg 14.9 (10.4-NR) 0.54 (0.38-0.77) .0002 Pembro 10 mg/kg 17.3 (11.8-NR) 0.50 (0.36-0.70) < .0001 Docetaxel 8.2 (6.4-10.7) — Slide credit: clinicaloptions.com Herbst RS, et al. Lancet. 2015;[Epub ahead of print].

KEYNOTE-010: OS Subgroup Analysis Events/Pts, n HR (95% CI) Sex Male Female < 65 ≥ 65 1 ≥ 50% 1-49% Archival New Squamous Adenocarcinoma Mutant Wild type 332/634 189/399 317/604 204/429 149/348 367/678 204/442 317/591 266/455 255/578 128/222 333/708 46/86 447/875 521/1033 0.65 (0.52-0.81) 0.69 (0.51-0.94) 0.63 (0.50-0.79) 0.76 (0.57-1.02) 0.73 (0.52-1.02) 0.63 (0.51-0.78) 0.53 (0.40-0.70) 0.76 (0.60-0.96) 0.70 (0.54-0.89) 0.64 (0.50-0.83) 0.74 (0.50-1.09) 0.88 (0.45-1.70) 0.66 (0.55-0.80) 0.67 (0.56-0.80) Age, yrs ECOG PS PD-L1 TPS Tumor sample Histology ECOG, Eastern Cooperative Oncology Group; PS, performance status; TPS, tumor proportion score. EGFR status Overall 0.1 1 10 Favors pembrolizumab Favors docetaxel Slide credit: clinicaloptions.com Herbst RS, et al. Lancet. 2015;[Epub ahead of print].

KEYNOTE-010: Progression-Free Survival Total Pt Population Pts With PD-L1 TPS ≥ 50% 100 Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Docetaxel 100 Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Docetaxel 80 80 60 60 PFS (%) PFS (%) 40 40 20 20 TPS, tumor proportion score. 5 10 15 20 25 5 10 15 20 25 Mos Mos Slide credit: clinicaloptions.com Herbst RS, et al. Lancet. 2015;[Epub ahead of print].

KEYNOTE-010: Adverse Events AE, % Pembrolizumab 2 mg/kg (n = 339) Pembrolizumab 10 mg/kg (n = 343) Docetaxel (n = 309) Any Grade Grades 3-5 Related to treatment Any 63 13 66 16 81 35 Occurring in ≥ 10% of pts in any group Decreased appetite 14 1 10 < 1 Fatigue 2 25 4 Nausea 11 9 15 Rash 5 Diarrhea 7 6 18 Asthenia Stomatitis Anaemia 3 Alopecia 33 Neutropenia 12 Slide credit: clinicaloptions.com Herbst RS, et al. Lancet. 2015;[Epub ahead of print].

POPLAR: Atezolizumab vs Docetaxel in Previously Treated NSCLC Phase II Study Pts with locally advanced or metastatic NSCLC and ECOG PS 0-1 who failed prior platinum-containing chemotherapy (N = 287) Atezolizumab 1200 mg IV q3w (n = 144) Docetaxel 75 mg/m2 IV q3w (n = 143) Stratified by PD-L1 immune cell expression (0 vs 1 vs 2 vs 3), histology (squamous vs nonsquamous), and line of therapy (second vs third line) DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; ITT, intent to treat; NSCLC, non-small-cell lung cancer; PS, performance status. Primary endpoint: OS in PD-L1–selected and ITT populations Secondary endpoints: overall safety as well as PFS, ORR, DoR in PD-L1– selected and ITT populations Slide credit: clinicaloptions.com Spira AI, et al. ASCO 2015. Abstract 8010.

POPLAR : Overall Response Rates and Overall Survival 50 Atezolizumab (n = 144) 38 Docetaxel (n = 143) 40 30 ORR (%) 22 20 18 18 15 15 15 13 10 10 8 TC3 or IC3 TC1/2/3 or IC1/2/3 TC0 and IC0 TC2/3 or IC2/3 ITT Median OS, Mos (Range) TC3 or IC3 (n = 47) TC2/3 or IC2/3 (n = 105) TC or IC1/2/3 (n = 195) TC0 or IC0 (n = 92) Atezolizumab 15.5 (9.8-NE) 15.1 (8.4-NE) 11.5 (11.0-NE) 9.7 (8.6-12.0) Docetaxel 11.1 (6.4-14) 7.4 ( 6.0-12.5) 9.2 (7.3-12.8) 9.7 (6.7-11.4) HR (95% CI) P value 0.49 (0.22-1.07) .068 0.54 (0.33-0.89) .014 0.63 (0.40-0.85) .005 1.12 (0.64-1.93) .871 IC, tumor-infiltrating immune cells; ITT, intent to treat; NE, not estimable; TC, tumor cells. Spira AI, et al. ASCO 2015. Abstract 8010. Vansteenkiste J, et al. ESMO 2015. Abstract LBA14. Slide credit: clinicaloptions.com

POPLAR: OS by Histology Median OS, Mos (95% CI) Subgroup n (%) 0.80 Atezolizumab Docetaxel Squamous 97 (34) 10.1 (6.7-14.5) 8.6 (5.4-11.6) 0.69 Nonsquamous 190 (66) 15.5 (9.8-NE) 10.9 (8.8-13.6) 0.73 ITT N = 287 12.6 (9.7-16.4) 9.7 (8.6-12.0) 0.2 1 2 HR* ITT, intent to treat; NE, not estimable. Favors atezolizumab Favors docetaxel *Unstratified HR for subgroups and stratified HR for ITT. Data cutoff May 8, 2015. Event/pt ratio: Squamous 69% (63% for atezolizumab, 75% for docetaxel) Nonsquamous 56% (49% for atezolizumab, 62% for docetaxel) Slide credit: clinicaloptions.com Vansteenkiste J, et al. ESMO 2015. Abstract LBA14.

POPLAR: All-Cause AEs (≥ 5% Difference Between Arms) Myalgia Decreased appetite Dyspnea Arthralgia Insomnia Musculoskeletal pain Pneumonia Hypothyroidism Alopecia Nausea Diarrhea Asthenia Neutropenia Febrile neutropenia Peripheral sensory neuropathy Peripheral neuropathy Anemia AEs more frequent with docetaxel AEs more frequent with atezolizumab AE, adverse event. More respiratory events were reported for atezolizumab. When adjusted for exposure, there was no difference between study arms Grade 1/2 AEs Grades 3-5 AEs Grade 1/2 AEs Grades 3-5 AEs 40 30 20 10 Docetaxel Atezolizumab Dry skin, stomatitis, and nail disorder were additional AEs with ≥ 5% higher frequency in docetaxel Safety population includes pts who received any amount of either study treatment Slide credit: clinicaloptions.com Spira AI, et al. ASCO 2015. Abstract 8010.

Conclusions First line platinum-based therapy remains standard of care in pts with squamous cell NSCLC Immune checkpoint inhibitors are approved as second-line therapy: nivolumab in unselected pts, pembrolizumab in pts with tumors positive for PD-L1 expression Docetaxel combined with ramucirumab is a reasonable second-line option EGFR TKIs have a limited role in this pt population Novel targets are still needed Slide credit: clinicaloptions.com

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