SQUIRE: Improved Survival With Necitumumab + Gemcitabine/Cisplatin vs Gemcitabine/Cisplatin as First-line Treatment in Patients With Squamous NSCLC Slideset on: Thatcher N, Hirsch FR, Luft AV, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomized, controlled phase 3 trial. Lancet Oncol. 2015;16:763-774. NSCLC, non-small-cell lung cancer. This activity is supported by educational grants from Genentech, Lilly, and Novartis Pharmaceuticals Corporation.

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Background: Necitumumab in Advanced Squamous NSCLC Platinum-based doublet chemotherapy longtime standard first- line treatment option for the ~ 30% of pts with squamous NSCLC[1] Necitumumab: fully human IgG1 anti–EGFR mAb Addition to gemcitabine/cisplatin increased antitumor activity in mouse xenograft models of NSCLC[2] Failed to improve OS when added to pemetrexed/cisplatin in pts with advanced nonsquamous NSCLC in phase III INSPIRE trial[3] Phase III SQUIRE trial evaluated safety, efficacy of necitumumab + gemcitabine/cisplatin vs gemcitabine/cisplatin in chemotherapy-naive pts with stage IV squamous NSCLC[1] mAb, monoclonal antibody; NSCLC, non-small-cell lung cancer. 1. Thatcher N, et al. Lancet Oncol. 2015;16:763-774. 2. Samakoglu S, et al. Cancer Genomic Proteomics. 2012;9:77-92. 3. Paz-Ares L, et al. Lancet Oncol. 2015;16:328-337. Slide credit: clinicaloptions.com

SQUIRE: Phase III Study Schema Stratified by ECOG PS (0-1 vs 2) and geographic region (North America/Europe/Australia vs South America/South Africa/India vs eastern Asia) Maximum 6 cycles Pts without PD receiving necitumumab could continue on single-agent necitumumab until PD or unacceptable toxicity Necitumumab 800 mg IV on Days 1, 8 + Gemcitabine 1250 mg/m2 IV on Days 1, 8 + Cisplatin 75 mg/m2 IV on Day 1 Q3W (n = 545) (n = 548) Chemotherapy-naive pts with stage IV squamous NSCLC, ECOG PS 0-2, adequate organ function (N = 1093) PD ECOG, Eastern Cooperative Oncology Group; ITT, intention to treat; NSCLC, non-small-cell lung cancer; PD, progressive disease; PS, performance status; TTF, time to treatment failure. Primary endpoint: OS (ITT) Secondary endpoints: PFS, ORR, TTF, safety Slide credit: clinicaloptions.com Thatcher N, et al. Lancet Oncol. 2015;16:763-774.

Median OS, Mos (95% CI) 11.5 (10.4-12.6) 9.9 (8.9-11.1) SQUIRE: OS OS significantly improved with necitumumab + gemcitabine/cisplatin vs gemcitabine/cisplatin alone 20 40 60 80 100 2 4 6 8 10 12 14 16 18 22 24 26 28 30 32 34 36 38 Mos OS (%) N + G/C Censored pts G/C N + G/C (n = 545) G/C (n = 548) HR: 0.84 (95% CI: 0.74-0.96; P = .01) Median OS, Mos (95% CI) 11.5 (10.4-12.6) 9.9 (8.9-11.1) 1-Yr OS, % (95% CI) 48 (43-52) 43 (39-47) 2-Yr OS, % (95% CI) 20 (16-24) 17 (13-20) G/C, gemcitabine/cisplatin; N, necitumumab. Slide credit: clinicaloptions.com Thatcher N, et al. Lancet Oncol. 2015;16:763-774.

SQUIRE: OS by Subgroup Necitumumab + Gemcitabine/ Cisplatin, n/Events Gemcitabine/ Cisplatin, n/Events HR (95% CI) Age group, yrs < 65 ≥ 65 to < 70 ≥ 70 332/258 105/79 108/81 340/277 111/94 97/71 0.88 (0.74-1.04) 0.63 (0.46-0.85) 1.03 (0.75-1.42) Sex Women Men 95/77 450/341 90/72 458/370 0.88 (0.64-1.21) 0.84 (0.73-0.98) Race White Non-white 457/355 88/63 456/369 92/73 0.86 (0.75-1.00) 0.78 (0.55-1.09) Smoking status Never/light exsmoker Current smoker 44/34 500/383 53/44 495/398 0.82 (0.52-1.29) 0.85 (0.74-0.98) ECOG PS 1 2 164/117 332/260 49/41 180/139 320/261 47/42 0.82 (0.64-1.05) 0.85 (0.72-1.01) 0.78 (0.51-1.21) Overall ITT population 545/418 548/442 0.84 (0.74-0.96) ECOG, Easter Cooperative Oncology Group; ITT, intent to treat; PS, performance status. 0.45 1 1.5 Favors necitumumab plus gem/cisplatin Favors gem/cisplatin Slide credit: clinicaloptions.com Thatcher N, et al. Lancet Oncol. 2015;16:763-774.

Median PFS, Mos (95% CI) 5.7 (5.6-6.0) SQUIRE: PFS PFS significantly improved with necitumumab + gemcitabine/cisplatin vs gemcitabine/cisplatin alone Median TTF: 4.3 vs 3.6 mos, respectively (P = .006) 20 40 60 80 100 2 4 6 8 10 12 14 16 18 22 24 26 28 30 32 34 Mos PFS (%) N + G/C Censored pts G/C Median PFS, Mos (95% CI) 5.7 (5.6-6.0) 5.5 (4.8-5.6) 3-Mo PFS, % (95% CI) 79 (76-83) 73 (68-76) 6-Mo PFS, % (95% CI) 45 (40-49) 37 (33-42) N + G/C (n = 545) G/C (n = 548) HR: 0.85 (95% CI: 0.74-0.98; P = .02) G/C, gemcitabine/cisplatin; N, necitumumab; TTF, time to treatment failure. Slide credit: clinicaloptions.com Thatcher N, et al. Lancet Oncol. 2015;16:763-774.

Gemcitabine/Cisplatin SQUIRE: Responses ORR similar between 2 groups, but disease control was more common with the addition of necitumumab (P = .043) Response, % Necitumumab + Gemcitabine/Cisplatin (n = 545) (n = 548) ORR, % (95% CI) CR PR 31 (27-35) 31 29 (25-33) < 1 28 SD 51 48 PD 8 10 DCR, % (95% CI) 82 (78-85) 77 (73-80) Not evaluable 2 Not assessed 11 DCR, disease control rate; PD, progressive disease; SD, stable disease. Slide credit: clinicaloptions.com Thatcher N, et al. Lancet Oncol. 2015;16:763-774.

SQUIRE: Efficacy by EGFR Expression EGFR expression not predictive or prognostic of survival benefit Trend toward improved OS with high EGFR expression Outcome, HR (95% CI) High EGFR Expression* (n = 374) Low EGFR Expression* (n = 608) Interaction P Value OS 0.75 (0.60-0.94) 0.90 (0.75-1.07) .24 PFS 0.88 (0.70-1.11) 0.83 (0.69-0.99) .68 ORR 0.97 (0.62-1.50) 1.27 (0.90-1.79) .34 NSCLC, non-small-cell lung cancer; ORR, objective response rate. *EGFR expression determined in 982 pts with evaluable samples via IHC assay with EGFR PharmDx Kit (Dako) and independently scored by 2 pathologists. High: H-score ≥ 200; low: H-score < 200. Slide credit: clinicaloptions.com Thatcher N, et al. Lancet Oncol. 2015;16:763-774.

SQUIRE: Most Common AEs Treatment-Related AEs of Interest, % Necitumumab + Gemcitabine/Cisplatin (n = 538) Gemcitabine/Cisplatin (n = 541) Any Grade Grade ≥ 3 Any 99 72 98 62 Skin reactions Rash 79 76 8 7 12 10 < 1 Neutropenia Febrile neutropenia 44 1 24 46 2 28 Fatigue 43 Anemia 42 11 Hypomagnesemia 31 9 16 Thrombocytopenia 22 27 Diarrhea Venous thromboembolic events 5 3 Conjunctivitis Arterial thromboembolic events 4 Hypersensitivity/infusion rxn Interstitial Lung disease AE, adverse event; rxn, reaction. Slide credit: clinicaloptions.com Thatcher N, et al. Lancet Oncol. 2015;16:763-774.

Conclusions and Faculty Assessment Necitumumab addition to gemcitabine/cisplatin conferred significant survival benefit to chemotherapy-naive pts with stage IV squamous NSCLC vs gemcitabine/cisplatin alone Median OS: 11.5 vs 9.9 mos (P = .01) Median PFS: 5.7 vs 5.5 mos (P = .02) Grade ≥ 3 and serious AEs more common with necitumumab + gemcitabine/cisplatin vs gemcitabine/cisplatin (72% vs 62% and 48% vs 38%, respectively) Necitumumab plus gemcitabine/cisplatin approved by FDA for firstline treatment of patients with metastatic squamous NSCLC AE, adverse event; NSCLC, non-small-cell lung cancer. Slide credit: clinicaloptions.com Thatcher N, et al. Lancet Oncol. 2015;16:763-774.

Conclusions and Faculty Assessment EGFR expression not predictive/prognostic of necitumumab benefit Weaknesses of this study: Dichotomous categorization of EGFR expression into high vs low groups may have reduced ability to detect efficacy differences Interpretation of subgroup analyses limited by size of subgroups Future directions: Explore benefit of continued necitumumab use following treatment with necitumumab + platinum-based doublet chemotherapy in squamous NSCLC NSCLC, non-small-cell lung cancer. Slide credit: clinicaloptions.com Thatcher N, et al. Lancet Oncol. 2015;16:763-774.

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