Evidence-Based Strategies for Challenging Squamous NSCLC Cases Suresh S. Ramalingam, MD Professor of Hematology and Medical Oncology Director, Division of Medical Oncology Assistant Dean for Cancer Research Emory University School of Medicine Deputy Director, Winship Cancer Institute Atlanta, Georgia NSCLC, non-small-cell lung cancer.

Case 1: Newly Diagnosed Squamous NSCLC 68-yr-old man, former smoker with 30 pack-yr history, presented with chest pain on his right side PMH: HTN and COPD Imaging studies identified 5-cm lesion in upper right lobe and mediastinal LN enlargement PET scan identified lesions in bones and adrenal gland Brain MRI negative Biopsy identified squamous NSCLC ECOG PS 1 COPD, chronic obstructive pulmonary disease; ECOG, Eastern Cooperative Oncology Group; HTN, hypertension; LN, lymph node; NSCLC, non-small-cell lung cancer; PMH, past medical history; PS, performance status.

Case 1: Expert Recommendations 68-yr-old man diagnosed with metastatic squamous NSCLC; former heavy smoker, ECOG PS 1 ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PS, performance status.

Recommended First-line Chemotherapy Regimens for Squamous NSCLC PS 0/1 PS 2 Carboplatin/nab-paclitaxel Carboplatin/docetaxel Carboplatin/etoposide Carboplatin/gemcitabine Carboplatin/paclitaxel Carboplatin/vinorelbine Cisplatin/docetaxel Cisplatin/etoposide Cisplatin/gemcitabine Cisplatin/gemcitabine/necitumumab Cisplatin/paclitaxel Cisplatin/vinorelbine Gemcitabine/docetaxel Gemcitabine/vinorelbine Nab-paclitaxel Docetaxel Etoposide Gemcitabine Irinotecan Paclitaxel NSCLC, non-small-cell lung cancer; PS, performance status. NCCN. Clinical practice guidelines in oncology: non-small-cell lung cancer. v4.2016. Slide credit: clinicaloptions.com

Therapeutic Plateau in Metastatic NSCLC ECOG 1594 100 Cisplatin/paclitaxel Cisplatin/gemcitabine Cisplatin/docetaxel Carboplatin/paclitaxel 80 60 OS (%) 40 20 NSCLC, non-small-cell lung cancer. 10 20 30 40 Mos Slide credit: clinicaloptions.com Schiller JH, et al. N Engl J Med. 2002;346:92-98.

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. 6

SQUIRE: Overall Survival Cisplatin/ Gemcitabine + Necitumumab (n = 545) 100 Cisplatin/ Gemcitabine (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 Cisplatin/gemcitabine + necitumumab Censored pts Cisplatin/gemcitabine 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: Progression-Free Survival Cisplatin/ Gemcitabine Necitumumab, n/Events Cisplatin/ Gemcitabine, 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 Nonwhite 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 cisplatin/gemcitabine Favors cisplatin/gemcitabine Slide credit: clinicaloptions.com Thatcher N, et al. Lancet Oncol. 2015;16:763-774.

SQUIRE: Adverse Events Possibly Related to Necitumumab Cisplatin/Gemcitabine + Necitumumab Overall (N = 538) Cisplatin/Gemcitabine Overall (N = 541) Grade 1/2 Grade ≥ 3 Skin reactions 71 8 11 < 1 Rash 69 7 10 Hypomagnesemia 22 9 15 1 Venous thromboembolic events 4 5 3 Slide credit: clinicaloptions.com Thatcher N, et al. Lancet Oncol. 2015;16:763-774.

Carboplatin/Nab-Paclitaxel vs Carboplatin/ Paclitaxel in Advanced NSCLC: Responses Carboplatin/nab-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 ITT, intent to treat; NSCLC, non-small-cell lung cancer; RRR, response rate ratio. 10 n = 521 531 229 221 292 310 ITT Squamous Nonsquamous Less neuropathy reported with nab-paclitaxel vs paclitaxel Slide credit: clinicaloptions.com Socinski MA, et al. J Clin Oncol. 2012;30:2055-2062.

Doublet vs Single-Agent Chemotherapy in Pts With Advanced NSCLC and PS 2 CALGB 9730 trial compared carboplatin/paclitaxel vs single- agent paclitaxel 18% of pts with a PS of 2 40% reduction for risk of death with doublet (P = .016) IFCT-0501 trial compared carboplatin/paclitaxel vs gemcitabine or vinorelbine 37% reduction for risk of death with doublet in PS 2 pts (n = 123) Regimen Pts With PS 2, n Median OS, Mos 1-Yr Survival Rate, % Carboplatin/paclitaxel 49 4.7 18 Paclitaxel 50 2.4 10 NSCLC, non-small-cell cancer; PS, performance status. Lilenbaum RC, et al. J Clin Oncol. 2005;23:190-196. Quoix E, et al. Lancet. 2011;378:1079-1088. Slide credit: clinicaloptions.com

Case 2: Progressive Squamous NSCLC 72-yr-old man diagnosed with squamous NSCLC 6 mos ago ECOG PS 1 Treated with carboplatin/paclitaxel for 4 cycles; achieved stable disease Recent follow-up identified disease progression in lungs, adrenal gland, and bones Biopsy tissue testing revealed PD-L1 positive with 63% staining of tumor cells ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell cancer; PS, performance status.

Case 2: Expert Recommendations 72-yr-old man with progressive metastatic squamous NSCLC, ECOG PS 1, previous carboplatin/paclitaxel, PD-L1 positive ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell cancer; PS, performance status.

CheckMate-017: OS 100 80 60 40 20 OS (%) 3 6 9 12 15 18 21 24 Mos 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: 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.

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 (%) 40 PS, proportion score. PS ≥ 50% (n = 119) 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-010: OS All pts experienced OS benefit from pembrolizumab PD-L1 TPS ≥ 1% PD-L1 TPS ≥ 50% 100 80 60 40 20 Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Docetaxel 100 80 60 40 20 OS (%) OS (%) 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. 2016;387:1540-1550.

POPLAR: Atezolizumab vs Docetaxel in NSCLC Updated OS, Biomarker Analyses HR (95% CI) P Value n Median OS, Mos ITT 144 12.6 143 9.7 0.69 (0.52-0.92) .011 TC3 or IC3 24 Not estimable 23 11.1 0.45 (0.22-0.95) .033 TC2/3 or IC2/3 50 15.1 55 7.4 0.50 (0.31-0.80) .003 TC1/2/3 or IC1/2/3 93 102 9.2 0.59 (0.41-0.83) TC0 and IC0 51 9.7 41 0.88 (0.55-1.42) .601 IC, immune cell; ITT, intent to treat; NSCLC, non-small-cell lung cancer; TC, tumor cell. Squamous 49 10.1 48 8.6 0.66 (0.41-1.05) .075 Nonsquamous 95 14.8 10.9 0.69 (0.49-0.98) .039 Slide credit: clinicaloptions.com Smith DA, et al. ASCO 2016. Abstract 9028.

REVEL: Ramucirumab + Docetaxel vs Docetaxel in Pts With PD After Chemo: OS FDA approved ramucirumab (12/14) in combination with docetaxel in metastatic NSCLC with disease progression on or after platinum-based chemotherapy 20 40 60 80 100 Median OS, Mos (95% CI) Ram + doc Pbo + doc Ram + doc vs pbo + doc HR: 0.86 (95% CI: 0.75-0.98; P = .023) 10.5 (9.5-11.2) 9.1 (8.4-10.0) OS (%) Doc, docetaxel; Pbo, placebo; PD, progressive disease; 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.

Docetaxel + Ramucirumab Overall (N = 627) Docetaxel Overall (N = 618) REVEL: Adverse Events AEs, % Docetaxel + Ramucirumab Overall (N = 627) Docetaxel Overall (N = 618) Any AEs 98 95 Grade ≥ 3 AEs Fatigue Neutropenia Febrile neutropenia 79 14 49 16 71 10 39 Serious AEs 43 42 AEs of special interest Bleeding/hemorrhage Hypertension Any grade 29 11 Grade ≥ 3 2 6 15 5 AE, adverse event. Slide credit: clinicaloptions.com Garon EB, et al. Lancet. 2014;384:665-673.

Case 3: Suspected Pneumonitis 68-yr-old man diagnosed with stage IV squamous NSCLC Experienced disease progression following platinum- based doublet chemotherapy Started pembrolizumab After 4 mos, experienced progressive dyspnea No fever, no hemoptysis Examination revealed hypoxia with oxygen saturation of 86% to 88% on rom air Chest x-ray identified hazy infiltrates in both lungs NSCLC, non-small-cell lung cancer.

Immune-Related Pneumonitis: Signs and Symptoms Shortness of breath Dry cough New or increasing oxygen requirements May be detected just on imaging Decreasing oxygen saturation on room air 11/15/2013: Prepneumonitis 1/21/14: Pneumonitis 2/21/14: Improved with steroids; taper completed 3/7/14 Slide credit: clinicaloptions.com

Summary of PD-1/PD-L1 Blockade Immune-Mediated Toxicities Onset: average is 6-12 wks after initiation of therapy Can occur within days of the first dose, after several mos of treatment, and after discontinuation of therapy Occasional (5% to 20%) Fatigue, headache, arthralgia, fevers, chills, lethargy Rash: maculopapular, pruritus, vitiligo Topical treatments Diarrhea/colitis Initiate steroids early, taper slowly Hepatitis, liver/pancreatic enzyme abnormalities Infusion reactions Endocrinopathies: thyroid, adrenal, hypophysitis Rare (< 5%) Pneumonitis Grade 3/4 toxicities uncommon Low grade reversible with steroids and discontinuation Anemia Villadolid J, et al. Transl Lung Cancer Res. 2015;4:560-575. Weber JS, et al. J Clin Oncol. 2015;33:2092-2099. Slide credit: clinicaloptions.com

General Principles of Immune-Related Toxicity Management Management generally based on severity of symptoms Grade 1: supportive care; ± withhold drug Grade 2: withhold drug, consider restarting if toxicity resolves to grade ≤ 1; low-dose corticosteroids (prednisone 0.5 mg/kg/day or equivalent) if symptoms do not resolve within 1 wk Grade 3/4: discontinue drug; high-dose corticosteroids (prednisone 1-2 mg/kg/day or equivalent) tapered over ≥ 1 mo once toxicity resolves to grade ≤ 1 Ipilimumab adverse reaction management guide. Nivolumab adverse reaction management guide. Pembrolizumab adverse reaction management guide. Slide credit: clinicaloptions.com

Conclusions The therapeutic landscape in advanced squamous NSCLC has changed dramatically over the last few yrs In first-line therapy, cisplatin/gemcitabine + necitumumab improves OS without significantly increasing adverse events In second-line therapy, immune checkpoint inhibitors including nivolumab and pembrolizumab are now a standard of care Vigilance is important for the management of uncommon but potentially serious complications associated with these agents