Riyaz Shah Kent Oncology Centre Maidstone, UK ErbB family blockade in squamous cell carcinoma (SCC): Latest clinical understanding

Background SCC of the lung remains a disease with high unmet medical need ErbB pathway dysregulation is frequently observed in SCC 1-3 Erlotinib, a reversible EGFR TKI, is an approved second- line therapy for these patients  Although no direct head-to-head trials, erlotinib has improved tolerability over docetaxel 4 yet similar survival in second-line unselected and EGFR WT NSCLC 5 Afatinib could confer additional benefit over erlotinib  Irreversible inhibition of signaling from ErbB1(EGFR), HER2 to HER4 6 *Afatinib is approved in a number of markets, including the EU, Japan, Taiwan and Canada under the brand name GIOTRIF ® and in the USA under the brand name GILOTRIF ® for use in patients with distinct types of EGFR mutation-positive NSCLC. Registration conditions differ internationally, please refer to locally approved prescribing information. Afatinib is under regulatory review by health authorities in other countries worldwide. Afatinib is not approved in other indications. 1. Heinmöller P, et al. Clin Cancer Res 2003;9:5238–43; 2. Ugocsai K, et al. Anticancer Res 2005;25:3061–6. 3. Cancer Genome Atlas Research Network. Nature 2012;489:519–25; 4. Lee C, et al. J Natl Cancer Inst 2013;105:595–605; 5. Li N, et al. PLoS One 2014;9:e102777; 6. Solca F, et al. J Pharmacol Exp Ther 2012;343:342–50

Question: What is your current standard-of-care in treatment of second-line SCC? 1.Erlotinib 2.Chemotherapy (e.g. docetaxel) 3.Nivolumab 4.Other TKIs 5.Other

Question: In what SCC patients do you typically prescribe erlotinib? 1.All patients 2.Older patients 3.Younger, more active patients 4.PS>2 5.PS≤2 6.As ≥third-line treatment only

Question: In what SCC patients do you typically prescribe docetaxel? 1.All patients 2.Older patients 3.Younger, more active patients 4.PS>2 5.PS≤2

Question: In what setting do you prescribe a TKI to SCC patients? 1.Second-line only 2.Second- or third-line in patients unfit for chemotherapy (BR.21) 3.Combination of 2 and 3 4.As maintenance in patients with stable disease post-first-line 5.I don’t prescribe TKIs to squamous cell cancer patients

Is erlotinib the right TKI comparator? BR.21 trial in patients not eligible for further chemotherapy Shepherd F, et al. N Engl J Med 2005;352:123–32; Clark G, et al. Clin Lung Cancer 2006;7:389–94; Bezjak A, et al. J Clin Oncol 2006;24:3831–7 Patient characteristics Erlotinib (n=488) Placebo (n=243) Squamous-cell carcinoma 29.5%32.1% PS225.8%23% PS38.6% ≥2 lines prior therapy 49.4%49.8% Survival time (months) Erlotinib (n=488) Placebo (n=243) Patients HR 0.70 (95% CI 0.58–0.85) p<0.001 by stratified log-rank test Survival by histologyHR (95% CI) Squamous-cell carcinoma0.67 (0.50–0.90) Adenocarcinoma 0.71 (0.56–0.92) TTD of symptoms better regardless of histology QoL better regardless of histology

Is erlotinib the right TKI comparator? 1. Shepherd F, et al, J Clin Oncol 2000;18:2095–103; 2. Thatcher N, et al. Lancet 2005;366:1527–37; 3. Kim E, et al. Lancet 2008;372:1809–18;4. Shepherd N, et al. N Engl J Med 2005;352:123–32; 5. Cappuzzo F, et al. Lancet Oncol 2010;11:521–9 Study Treatment line Outcome TAX ≥2 nd Docetaxel > BSC ISEL 2 2 nd /3 rd Gefitinib = BSC INTEREST 3 ≥2 nd Docetaxel = Gefitinib BR nd /3 rd Erlotinib > Placebo SATURN 5 Maintenance (SD) Erlotinib > Placebo

LUX-Lung 8: Study design Soria J, et al. Lancet Oncol 2015;16:897–907 Advanced NSCLC (Stage IIIB/IV) Squamous histology ≥4 cycles of a first-line platinum doublet ECOG PS 0–1 Adequate organ function Afatinib 40 mg qd Erlotinib 150 mg qd Treatment until disease progression or unacceptable AEs Randomisation 1:1 Excluded: Patients without PD Prior EGFR TKI or antibody Active brain metastases, interstitial lung disease Stratification: East Asian vs non-East Asian Tumour tissue collected for correlative science Radiographic tumour assessment at baseline; Weeks 8, 12, 16; every 8 weeks thereafter Primary endpoint – progression-free survival by central independent radiology review (RECIST 1.1) Key secondary endpoint – overall survival Other secondary endpoints – ORR, DCR, RR, PRO, safety

Afatinib*** (n=398) Erlotinib*** (n=397) Median age, years6564 Male, %8483 Ethnic origin Non-eastern Asian78 East Asian22 Smoking history, % Never smoker 7 5 Light ex-smoker §§ 3 3 Current and other ex-smoker ¶¶ 9192 ECOG,* % 0/132/6834/66 Clinical stage, § % IIIB/IV12/8812/87 Median time since diagnosis, years (range) 0.8 (0.2–9.3)0.7 (0.2–13.5) Histology, ¶ % Squamous96 Mixed 4 4 Best response to first-line chemotherapy, % CR/PR47 SD4042 Unknown1211 Demographics and baseline characteristics * 1 year before diagnosis; ¶¶ 71 (17.8%) and 85 (21.4%) patients were current smokers, respectively; ***Percentages may not total 100 due to rounding. Soria J, et al. Lancet Oncol 2015;16:897–907

Progression-free survival (primary endpoint independent review) CI, confidence interval; HR, hazard ratio. Soria J, et al. Lancet Oncol 2015;16:897–907 No. of patients Afatinib Erlotinib Afatinib (n=335) Erlotinib (n=334) Patients progressed or died, n (%) 202 (60)212 (64) Median PFS (months) HR 0.82 (95% CI 0.676–0.998); p= Probability of PFS (%) Time (months)

Primary analysis of overall survival (n=795) CI, confidence interval; HR, hazard ratio. Median follow-up time: 18.4 months. Soria J, et al. Lancet Oncol 2015;16:897–907 Afatinib (n=398) Erlotinib (n=397) Median OS (months) HR 0.81 (95% CI 0.69–0.95); p= Probability of OS (%) No. at risk Afatinib Erlotinib % 28.2% 22.0% 14.4% Time (months)

FactorsNo. of patientsHR (95% CI) Overall (0.69–0.95) Age <65 years (0.55–0.85) ≥65 years (0.76–1.19) Gender Male (0.69–0.97) Female (0.51–1.14) Race Non-East Asian (0.73–1.03) East Asian (0.44–0.88) ECOG at baseline (0.58–1.01) (0.66–0.97) Smoking history Never smoker (0.37–1.57) Light ex-smoker (0.16–1.12) Current and other ex-smoker (0.69–0.96) Histology Squamous (0.70–0.96) Mixed (0.26–1.17) Best response to first-line chemotherapy CR/PR (0.72–1.15) SD (0.56–0.90) Unknown (0.44–1.17) Overall survival subgroup analysis Favours afatinibFavours erlotinib CI, confidence interval; HR, hazard ratio. Soria J, et al. Lancet Oncol 2015;16:897–907

Objective response and tumour shrinkage Soria J, et al. Lancet Oncol 2015;16:897–907 Afatinib Erlotinib Patient index sorted by maximum decrease (%) Maximum decrease from baseline SLD (%) –100 –80 –60 –40 – ≥20% increase (n=62) 0–<20% increase (n=90) >0–<30% decrease (n=81) ≥30% decrease (n=22) Patient index sorted by maximum decrease (%) –100 –80 –60 –40 – ≥20% increase (n=74) 0–<20% increase (n=101) >0–<30% decrease (n=77) ≥30% decrease (n=13) Maximum decrease from baseline SLD (%) p=0.055 p=0.002 Per cent Duration of response was 7.3 months for afatinib and 3.7 months for erlotinib Objective responseTumour shrinkage

No. of patientsHR (95% Cl) Coughing (Q1 from QLQ-LC13) (0.72–1.09) Dyspnoea (Q3–Q5 from QLQ-LC13) (0.66–0.94) Pain (Q9, Q19 from QLQ-C30) (0.82–1.18) GHS/QoL (Q29–Q30 from QLQ-C30) (0.78–1.12) Patient-reported outcomes GHS, global health status. Gadgeel S, et al. ASCO Poster 425 1/41/2124 Symptom improvementTime to deterioration Patients with improvement in symptoms (%) Dyspnoea (Q3–Q5 from QLQ-LC13) p=0.04 p=0.78 p=0.06 p=0.03 Favours afatinibFavours erlotinib Adverse events as expected based on the mechanism of action

Summary and conclusion LUX-Lung 8 is the largest Phase III trial in the second-line treatment for SCC of the lung Afatinib significantly improved PFS when compared with erlotinib – Independent and investigator reviews were consistent In this head-to-head trial, afatinib showed a significant reduction in the risk of death and disease progression by 19% when compared with erlotinib –~8% more patients alive at 12 and 18 months with afatinib treatment Consistent advantage across most endpoints and subgroups Overall symptom relief and QoL measures favouring afatinib Afatinib should be the TKI of choice in patients with advanced SCC progressing after treatment with first-line chemotherapy

Questions and discussion