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2014 ASCO Annual Meeting Supported by Lilly and Company. Lilly and Company has not influenced the content of this publication Developed in association.

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Presentation on theme: "2014 ASCO Annual Meeting Supported by Lilly and Company. Lilly and Company has not influenced the content of this publication Developed in association."— Presentation transcript:

1 2014 ASCO Annual Meeting Supported by Lilly and Company. Lilly and Company has not influenced the content of this publication Developed in association with the European Thoracic Oncology Platform 30 May – 3 June 2014 Chicago, USA

2 Letter from Prof Rolf Stahel Dear Colleagues It is my pleasure to present this ETOP slide set which has been designed to highlight and summarise key findings in thoracic cancers from the major congresses in This slide set specifically focuses on the American Society of Clinical Oncology 50 th Annual Meeting and is available in 4 languages – English, French, Italian and Japanese. The area of clinical research in oncology is a challenging and ever changing environment. Within this environment we all value access to scientific data and research which helps to educate and inspire further advancements in our roles as scientists, clinicians and educators. I hope you find this review of the latest developments in thoracic cancers of benefit to you in your practice. If you would like to share your thoughts with us we would welcome your comments. Please send any correspondence to I would like to thank our ETOP members Drs Enriqueta Felip, Francoise Mornex, Solange Peters and Martin Reck for their roles as Editors – for prioritising abstracts and reviewing slide content – also Dr Serena Ricciardi for overseeing translation to Italian. The slide set you see before you would not be possible without their commitment and hard work. And finally, we are also very grateful to Lilly Oncology for their financial, administerial and logistical support in the realisation of this complex yet rewarding activity. Yours sincerely, Rolf Stahel President, ETOP Foundation Council

3 ETOP Medical Oncology Slide Deck Editors 2014 Focus: biomarkers (all stages) Dr Enriqueta Felip Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain Focus: biomarkers (all stages) Dr Enriqueta Felip Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain Focus: advanced NSCLC (not radically treatable stage III & stage IV) Dr Solange Peters Multidisciplinary Oncology Center, Lausanne Cancer Center, Lausanne, Switzerland Focus: advanced NSCLC (not radically treatable stage III & stage IV) Dr Solange Peters Multidisciplinary Oncology Center, Lausanne Cancer Center, Lausanne, Switzerland Focus: other malignancies, SCLC, mesothelioma, rare tumours Dr Martin Reck Department of Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, Germany Focus: other malignancies, SCLC, mesothelioma, rare tumours Dr Martin Reck Department of Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, Germany Focus: early and locally advanced NSCLC (stage I–III) Dr Francoise Mornex Department of Radiation Oncology, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France Focus: early and locally advanced NSCLC (stage I–III) Dr Francoise Mornex Department of Radiation Oncology, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France

4 Contents Biomarkers Early stage and locally advanced NSCLC – Stages I, II and III Advanced NSCLC – Not radically treatable stage III and stage IV –1 st line –Maintenance –Later lines Other malignancies –SCLC and mesothelioma –Rare tumours

5 Biomarkers

6 7550: Serum biomarker analysis of WJOG4107: A randomized phase II trial of adjuvant chemotherapy with S-1 versus CDDP+S-1 for resected stage II-IIIA non-small cell lung cancer (NSCLC) – Mitsudomi T et al Study objective –To identify biomarkers associated with outcome to long-term treatment with S-1 or cisplatin+S-1 after resection of stage II–IIIA NSCLC Study design –Serum biomarker analysis of 16 growth factors and 27 cytokines from 197 of 200 patients from the WJOG4107 study –Patients treated with S-1 (80 mg/m 2 /day for consecutive 2 weeks q3w for 1 year) vs cisplatin (60 mg/m 2 d1) + S-1 (80 mg/m 2 for 2 weeks) q3w for 4 cycles Key results –HGF, GCSF and leptin showed moderate association with prognosis (HGF, p=0.0576; GCSF, p=0.0579; leptin, p=0.074) –Patients with lower serum HGF had a significantly favourable prognosis than those with higher HGF levels in postoperative long-term S-1 therapy (p=0.0072) (see next slide) Conclusion –Low serum HGF level may define a patient subset who would benefit from postoperative long-term S-1 therapy Mitsudomi et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7550)

7 7550: Serum biomarker analysis of WJOG4107: A randomized phase II trial of adjuvant chemotherapy with S-1 versus CDDP+S-1 for resected stage II-IIIA non-small cell lung cancer (NSCLC) – Mitsudomi T et al Key results Mitsudomi et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7550) Disease-free survival with S-1 + cisplatin Disease-free survival with S-1 alone HGF=Low HGF=High Time (days) Survival rate p= % 77% HGF=Low HGF=High Time (days) Survival rate p= % 56%

8 8057: Molecular profiling of non-small cell lung cancer by histologic subtype – Peters S et al Study objective –To profile NSCLC by histological subtype Study design –Retrospective analysis of over 6700 NSCLC cases for potential cancer-related genes and pathways through sequencing, protein expression, gene amplification/rearrangement (CISH or FISH) and/or RNA fragment analysis Key results –Patients were grouped into cohorts according to histological subtype: adenocarcinoma (ADC; n=4287), squamous cell carcinoma (SCC; n=1280), adenosquamous carcinoma (ASQ; n=30), lepidic predominant adenocarcinoma (LPA; n=94) and large cell carcinoma (LCC; n=153) –Tumour profiling by histological subtype is shown on the next slide ADC tumours had significantly more cMET overexpression (p<0.0001) and amplification (p=0.0223), more high ER expression (p<0.0001) than SCC tumours ADC tumours also had more ALK fusions (p=0.0051) and ROS1 rearrangements (p=0.0331), higher BRAF (p=0.0218) and EGFR mutations (p<0.0001) prevalence than SCC tumours ADCs (p<0.0001) and LPAs (p=0.0028) had significantly more KRAS mutations than SCCs –Similar significant alterations between ADCs compared with SCCs and LCCs (except for ALK, BRAF and ROS1) were observed Conclusion –These data can help to identify new predictive biomarkers and explore potential innovative treatment strategies Peters et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8057)

9 8057: Molecular profiling of non-small cell lung cancer by histologic subtype – Peters S et al Tumour profiling by histological subtype Peters et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8057) ADC, adenocarcinoma; SCC, squamous cell carcinoma; ASQ, adenosquamous carcinoma; LPA. lepidic predominant adenocarcinoma; LCC, large cell carcinoma

10 8066: PD-L1 expression and survival in patients with non-small cell lung cancer (NSCLC) in Korea – Sun J-M et al Study objective –To investigate the prognostic impact of PD-L1 expression among patients with NSCLC Study design –Correlation of expression of PD-L1 by IHC with OS among 1070 patients with NSCLC Key results –Median (range) age 63 (21–86) years; 67% male; 62% adenocarcinoma; 28% SCC; 10% large cell carcinoma or other; 75% stage I/II; 6.4% strong PD-L1 positivity; 38.3% weak positivity –Higher incidence of PD-L1 positivity was observed in males, older patients, smokers, those with SCC and more advanced stage disease (p<0.001) –PD-L1 positivity was associated with worse OS, for strong positive vs negative, respectively 5-year OS rate overall of 51% (95% CI 39, 63) vs 73% (69, 76) (HR a 1.57; p=0.02) 5-year OS in adenocarcinoma 53% (95% CI 36, 69) vs 77% (72, 82) (HR a 1.86; p=0.02) Conclusion –PD-L1 may be a negative prognostic factor among non-SCC NSCLC, particularly adenocarcinoma Sun et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8066) a Adjusted for age, sex, smoking status, histology, stage, PS with the PD-L1 negative group as the reference; PD-L1, programmed cell death ligand-1; SCC, squamous cell carcinoma

11 8075: Clinicopathologic features of lung cancer patients harboring de novo EGFR T790M mutation – Lee YJ et al Study objective –To evaluate clinico-pathological features of lung cancer with de novo EGFR T790M mutations Study design –Genotyping for EGFR T790M mutation of pretreatment tissue from 124 advanced NSCLC patients with EGFR mutations (exon 19 deletion and exon 21 L858R) Key results –25% (31/124) patients had T790M mutation –TTP after EGFR TKI was shorter among patients with T790M mutation compared with patients without (6.3 vs 11.5 months, respectively; p<0.001) –The T790M mutation frequency at which the risk of progression to EGFR TKI begins to increase was estimated to be 3.2% Conclusion –Lung cancer patients with 3.2% or more of de novo T790M mutation frequency showed decreased efficacy to EGFR TKI Lee et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8075)

12 8081: EGFR mutation status in cerebrospinal fluid of NSCLC patients who developed leptomeningeal metastasis after EGFR-TKI treatment – Zhao J et al Study objective –To investigate EGFR mutation status in CSF of NSCLC patients who developed leptomeningeal metastasis after initial response to EGFR TKI Study design –Droplet digital PCR was used to detect EGFR mutation in CSF samples from 7 patients with NSCLC Key results –EGFR-sensitive mutations were detected in all CSF samples Conclusions –CSF remained positive for EGFR mutations dominant by sensitive mutations only, even though the plasma was either negative for EGFR mutations or carried TKI-resistant T790M mutation –This is supportive of the protection of EGFR mutation-positive tumour cells within leptomeningeal space from the exposure to current EGFR TKIs Zhao et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8081)

13 8082: Clinical significance of TILs subtypes in non-small cell lung cancer – Schalper KA et al Study objective –To investigate the impact of tumour infiltrating lymphocytes (TILs) on clinico-pathological characteristics and survival in patients with NSCLC Study design –Quantitative fluorescence was used to measure levels of CD3, CD8 and CD20 in 552 stage I–IV NSCLC in two tissue microarrays (YTMA79, n=202; YTMA140, n=350) –Multiplexed immunofluorescence was used to simultaneously measure TIL subtypes in different tumour compartments Key results –CD3, CD8 and CD20 signals showed a positive non-linear relationship (R=0.3–0.7; p<0.001) in both NSCLC collections –CD3 levels were not correlated with age, gender, smoking, tumour size, stage and histology –High CD3 and CD8 were significantly associated with longer survival in YTMA79 (p=0.009 for CD3 and p=0.004 for CD8) and YTMA140 (p=0.041 for CD3 and p=0.002 for CD8) Conclusion –Increased CD3 and CD8 positive TILs are independent prognostic factors in NSCLC Schalper et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8082)

14 Early and locally advanced NSCLC Stages I, II and III

15 7514: SELECT: A multicenter phase II trial of adjuvant erlotinib in resected early-stage EGFR mutation-positive NSCLC – Pennell NA et al Study objective –To investigate the efficacy of adjuvant erlotinib in EGFR-mutant NSCLC Study design –Phase II study of patients treated with erlotinib 150 mg/day for 2 years after completion of standard adjuvant CT and/or radiotherapy –Primary endpoint: DFS at 2 years; secondary endpoints: safety/tolerability and OS Key results –100 patients had a median (range) age of 63 (41–84) years; 77% female; 59% never smokers; 45% stage I; 27% stage II; 28% stage IIIA; 62% EGFR exon 19 deletion –69% of patients completed at least 22 months of treatment although 40% required dose reduction –2-year DFS of 89% (96% for stage I, 78% stage II, 91% stage IIIA) significantly higher than historical control (p=0.0047); median DFS not yet reached Conclusions –Treatment with 2 years of adjuvant erlotinib for EGFR-mutant NSCLC is feasible –A randomised trial is planned Pennell et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7514)

16 7572: Phase II study of biomarker guided neoadjuvant treatment strategy for IIIA-N2 non-small cell lung cancer based on EGFR-mutation status – Zhong W et al Study objective –To evaluate the role of biomarker-guided neoadjuvant treatment strategy in patients with IIIA-N2 NSCLC stratified by EGFR mutation status Zhong et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7572) Primary endpoint RR PD Key patient inclusion criteria Resectable histologically documented stage IIIA-N2 NSCLC (n=24) Wild-type EGFR Neoadjuvant gemcitabine/carboplatin for 3 cycles (n=12) EGFR mutation Neoadjuvant erlotinib for 42 days (n=12) Secondary endpoints: PFS and OS

17 7572: Phase II study of biomarker guided neoadjuvant treatment strategy for IIIA-N2 non-small cell lung cancer based on EGFR-mutation status – Zhong W et al Key results –Overall RR was 42%; 58.3% (7/12) for the erlotinib arm with mutant EGFR and 25.0% (4/12) for the gemcitabine/carboplatin arm with wild-type EGFR (p=0.18) Conclusions –In patients with IIIA-N2 NSCLC, a biomarker-guided neoadjuvant treatment strategy is feasible –Erlotinib had a tendency to improve the response, but this did not transfer to a better PFS or OS in this subgroup Zhong et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7572)

18 7557: A randomized phase II trial of concurrent chemoradiation of oral vinorelbine and two doses of radiotherapy, 60 and 66 Gy, in local-regionally advanced non-small cell lung cancer (LA-NSCLC) – Hansen O et al Study objective –To investigate two doses of radiotherapy together with vinorelbine in patients with locally advanced NSCLC Study design –Randomised phase II study of patients treated with navelbine oral 150 mg of vinorelbine (3 weekly doses for 6–6.5 weeks) with concomitant radiotherapy to 60 Gy (2 Gy x 30, 5 F W) in Arm A or to 66 Gy (2 Gy x 33, 5 F W) in Arm B –Primary endpoint: Local PFS 9 months after start of radiotherapy; secondary endpoints: OS and safety –Comparison with data from historical cohort as control Key results –Local PFS at 9 months was 46% (95% CI 40%, 53%) in Arm A and 56% (95% CI 40%, 63%) compared with 78% (95% CI 68%, 88%) for control –OS was similar between all three groups –No haematological grade 4 AEs were observed Conclusions: –Both regimens were well tolerated, but neither met the phase II criteria –OS was comparable to historical control Hansen et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7557)

19 7511^: Phase II study of cetuximab, pemetrexed, cisplatin and concurrent radiotherapy in patients with locally advanced, unresectable, stage III, non- squamous, non-small cell lung cancer (NSCLC): Results of the IFCT-0803 trial – Tredaniel J et al Study objective –To evaluate the benefit of adding cetuximab to radiotherapy+concomitant CT with cisplatin and pemetrexed in patients with stage III non-squamous NSCLC Study design –Interim analysis of a phase II study in which patients treated with thoracic radiation (66 Gy) with four cycles of cisplatin (75 mg/m 2 ) + pemetrexed (500 mg/m 2 ) on day 1 q3w and weekly cetuximab (400 mg/m 2 for first week then 250 mg/m 2 ) –Primary endpoint: disease control rate at week 16 Key results –Patients (n=99) had median age of 57 years; 63% male; 60% PS 0; 6% never smokers; 50% stage IIIA; 77% adenocarcinoma –Disease control rate at 16 weeks was 89.8% (95% CI 83.8, 95.8) Conclusion –This study demonstrated high disease control rate and feasibility of radiation, cisplatin, pemetrexed and cetuximab combination with a tolerable toxicity profile, especially for lung parenchyma Tredaniel et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7511^) ^Abstract granted an exception in accordance with the ASCO Conflict of Interest Policy

20 7545: A randomized phase III trial comparing triple weekly usage with weekly usage of paclitaxel in concurrent chemoradiotherapy for patients with locally advanced non-small cell lung cancer – Zhu G et al Study objective –To compare triple-weekly usage with weekly usage of paclitaxel in concurrent chemoradiotherapy for patients with locally advanced NSCLC Study design –Randomised, controlled phase III trial of 60–70 Gy radiotherapy in combination with paclitaxel (15 mg/m 2 triple weekly) or paclitaxel (45 mg/m 2 once weekly) Key results –Incidence of radiation-related AEs was generally less with the triple-weekly usage –Response rate was significantly higher among the patients who received triple-weekly doses of paclitaxel compared with those who were given once-weekly dosing (87.3% vs 57.7%; p=0.023) –Similarly, median PFS was higher with triple-weekly dosing (11.0 vs 7.4 months; p=0.039) Conclusion –Triple-weekly usage of paclitaxel is associated with improved tolerability and efficacy over a once-weekly regimen Zhu et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7545)

21 7501: A randomized, double-blind phase 3 trial of adjuvant erlotinib (E) versus placebo (P) following complete tumor resection with or without adjuvant chemotherapy in patients (pts) with stage IB-IIIA EGFR positive (IHC/FISH) non- small cell lung cancer (NSCLC): RADIANT results – Kelly K et al Study objective –To evaluate adjuvant erlotinib vs placebo following complete tumour resection in patients with stage IB–IIIA NSCLC and EGFR FISH+ or EGFR IHC+ Kelly et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7501) Primary endpoint Disease-free survival (FAS) Secondary endpoints OS (FAS) Disease-free survival and OS (EGFR M+ subset) R 2:1 Stratification Histology, stage, prior adjuvant CT, EGFR FISH status, smoking status, country Key patient inclusion criteria Complete resected NSCLC Stage IB–IIIA EGFR IHC+/FISH+ ECOG PS 0–2 (n=973) Placebo (n=350) Erlotinib 150 mg/day (n=623) FAS, full analysis set No adjuvant chemotherapy ≤4 cycles of platinum- based doublet

22 Key results –Adjuvant erlotinib did not prolong disease-free survival 7501: A randomized, double-blind phase 3 trial of adjuvant erlotinib (E) versus placebo (P) following complete tumor resection with or without adjuvant chemotherapy in patients (pts) with stage IB-IIIA EGFR positive (IHC/FISH) non- small cell lung cancer (NSCLC): RADIANT results – Kelly K et al Kelly et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7501) † Not significant due to hierarchical testing DFS (overall population) DFS (del19 and L858R) Disease-free survival (probability) Disease-free survival (months) Placebo (156 events) Median: 48.2 months Erlotinib (254 events) Median: 50.5 months Log-rank test: p= HR 0.90 (95% CI 0.74, 1.10) 5466 Erlotinib Placebo Disease-free survival (probability) Disease-free survival (months) Placebo (32 events) Median: 28.5 months Erlotinib (39 events) Median: 46.4 months Log-rank test: p= † HR 0.61 (95% CI 0.384, 0.981) 5466 Erlotinib Placebo

23 Conclusions –Adjuvant erlotinib did not prolong disease-free survival in patients with early stage resected EGFR mutation-positive NSCLC –Survival data immature –In the subset of patients with exon 19 deletions and L858R mutations, survival favoured erlotinib However, this was not statistically significant due to hierarchical testing –No DFS survival found at 4 years of follow-up Further investigation in EGFR mutation-positive patients is warranted in a properly conducted randomised dedicated trial in EGFR mutation-positive NSCLC subpopulation –The safety profile of erlotinib was consistent with that in advanced disease 7501: A randomized, double-blind phase 3 trial of adjuvant erlotinib (E) versus placebo (P) following complete tumor resection with or without adjuvant chemotherapy in patients (pts) with stage IB-IIIA EGFR positive (IHC/FISH) non- small cell lung cancer (NSCLC): RADIANT results – Kelly K et al Kelly et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7501)

24 7513: Adjuvant erlotinib (E) versus placebo (P) in non-small cell lung cancer (NSCLC) patients (pts) with tumors carrying EGFR-sensitizing mutations from the RADIANT trial – Shepherd FA et al Study objective –To evaluate treatment with erlotinib compared with placebo in patients with completely resected stage IB–IIIA NSCLC and EGFR IHC+ and/or FISH+ Shepherd et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7513) Primary endpoint DFS Secondary endpoints OS (FAS), disease-free survival and OS (EGFR M+ subset) Stratification Histology (adenocarcinoma, other) Stage (IB, II, IIIA) Adjuvant chemotherapy (yes, no) Smoking history (never, current/former) EGFR FISH (positive, negative/undermined) Country Key patient inclusion criteria Resected stage IB–IIIA NSCLC EGFR IHC+ or FISH+ (n=973) Placebo (n=59) Erlotinib 150 mg/day (n=102) No adjuvant chemotherapy ≤4 cycles of platinum- based doublet

25 7513: Adjuvant erlotinib (E) versus placebo (P) in non-small cell lung cancer (NSCLC) patients (pts) with tumors carrying EGFR-sensitizing mutations from the RADIANT trial – Shepherd FA et al Key results –EGFR was mutated in 161 patients (55% exon 19 del, 45% exon 21 L858R) –There were imbalances in baseline characteristics between the groups Erlotinib group had less chemotherapy and lower stage, while placebo group had smaller tumour size Shepherd et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7513) ErlotinibPlaceboHR (95% CI)p-value Median DFS, mo (0.38, 0.98)0.041 † Adjusted DFS0.60 (0.36, 0.98)0.041 † Patients relapsed, n (%)35 (34.3)31 (52.5) Brain relapses, %* Bone relapses, %* Median OS, moNR 1.09 (0.56, 2.16)0.815 ‡ *Percentage calculated using number of patients relapsed as the denominator † p-values exploratory (Wald test) and not statistically significant ‡ log-rank test

26 7513: Adjuvant erlotinib (E) versus placebo (P) in non-small cell lung cancer (NSCLC) patients (pts) with tumors carrying EGFR-sensitizing mutations from the RADIANT trial – Shepherd FA et al Key results Conclusion –Although not statistically significant, the findings suggest that adjuvant treatment with erlotinib may prolong DFS in patients with resected NSCLC and EGFR mutations –Interpretation is limited due to imbalances in stage, use of prior adjuvant chemotherapy and tumour size –Small sample size and immature follow-up limit OS interpretation; crossover to EGFR TKI therapy cannot be determined from the data collected Shepherd et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7513) ErlotinibPlacebo Any AEs leading to discontinuation, %305.1 Any drug-related AEs leading to discontinuation, %250 AEs leading to dose interruption, %226.8 AE leading to dose reduction, %221.7 Grade ≥3 rash, %190 Grade ≥3 diarrhoea, %50

27 7510: Phase III study of surgery (S) versus definitive concurrent chemoradiotherapy boost (def ccCRTx-BOx) in patients (pts) with operable (OP+) stage IIIA(N2)/selected IIIb (sel IIIB) non-small cell lung cancer (NSCLC) following induction (IND) chemotherapy (CTx) and concurrent CRTx (ESPATUE) – Eberhardt WEE et al Study objective –To determine whether a concurrent chemoradiotherapy boost or surgery in patients with operable stage III NSCLC following induction chemotherapy improves survival Eberhardt et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7510) R PD Key patient inclusion criteria NSCLC stage IIIA/B Potentially resectable (n=246) Surgery (n=81) Definitive concurrent chemoradiotherapy boost (65/71 Gy) (n=80) Primary endpoint OS Induction chemotherapy Cisplatin/paclitaxel & concurrent chemoradiotherapy to 45 Gy (1.5 Gy bid/cc cisplatin/vinorelbine)

28 7510: Phase III study of surgery (S) versus definitive concurrent chemoradiotherapy boost (def ccCRTx-BOx) in patients (pts) with operable (OP+) stage IIIA(N2)/selected IIIb (sel IIIB) non-small cell lung cancer (NSCLC) following induction (IND) chemotherapy (CTx) and concurrent CRTx (ESPATUE) – Eberhardt WEE et al Eberhardt et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7510) Key results –OS did not differ between treatment regimens Conclusions –Surgery or definitive concurrent chemoradiotherapy following induction CT are both valid treatment options, are equally acceptable and their use will depend on patient preference OS Survival probability Time (months) Arm B: 5-year OS=44.2% Arm A: 5-year OS=40.6% Log-rank: p=0.31 Boost Surgery

29 7551: The effect of institutional clinical trial enrollment volume on survival of patients with stage III non-small cell lung cancer treated with chemoradiation: A report of the Radiation Therapy Oncology Group (RTOG) 0617 – Eaton BR et al Study objective –To examine whether there is an association between institutional clinical trial accrual volume and outcomes in patients with locally advanced NSCLC receiving chemoradiation therapy Patients –Accrual was 1–3 patients in LVC (n=195) and 4–18 patients in HVC (n=300) Eaton et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7551) Primary endpoints OS and PFS R 1:1 PD Stratification Low volume (LVC) vs. high volume (HVC) centres Key patient inclusion criteria Locally advanced stage IIIA/B NSCLC (n=495) CRT 74 Gy + concurrent carboplatin and paclitaxel +/- cetuximab CRT 60 Gy + concurrent carboplatin and paclitaxel +/- cetuximab

30 7551: The effect of institutional clinical trial enrollment volume on survival of patients with stage III non-small cell lung cancer treated with chemoradiation: A report of the Radiation Therapy Oncology Group (RTOG) 0617 – Eaton BR et al Key results –Both OS and PFS were significantly improved for patients receiving treatment at an HVC compared with those at LVC (figures) Conclusion –Better OS and PFS were observed for patients with locally advanced NSCLC treated at institutions with higher volume accrual Median OSMedian PFS Eaton et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7551)

31 7543: Stereotactic body radiotherapy versus lobectomy for operable clinical stage IA pulmonary adenocarcinoma: Comparison of prospective clinical trials with propensity score analysis (JCOG1313-A) – Eba J et al Study objective –A combined analysis of two prospective studies to evaluate the effects of stereotactic body radiotherapy (SBRT) vs lobectomy on survival in patients with operable early stage NSCLC Eba et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7543) Primary endpoint OS (adjusted with propensity score analysis*) PD Key patient inclusion criteria Operable NSCLC cT1N0M0 Adenocarcinoma Lobectomy (n=219) SBRT (n=40) JCOG 0201 (n=811) JCOG 0403 (n=169) *Patient factors included age, sex and 2 CT findings – tumour diameter and consolidation/tumour ratio (CTR)

32 7543: Stereotactic body radiotherapy versus lobectomy for operable clinical stage IA pulmonary adenocarcinoma: Comparison of prospective clinical trials with propensity score analysis (JCOG1313-A) – Eba J et al Key results –Patients in the lobectomy group were younger than in the SBRT group (median age 62 vs 79 years, respectively; p<0.001) –OS was longer with lobectomy among 21 patients from each group matched for the propensity score analysis Conclusion –Lobectomy may provide better outcomes than surgery, but no definite conclusions can be made owing to the small sample size of the SBRT group; further studies are required Eba et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7543)

33 7561: Treatment-related deaths after concurrent chemoradiotherapy in locally advanced non-small cell lung cancer: A meta-analysis of randomized studies – Zhao J et al Study objective –To compare treatment-related death (TRD) rates between patients treated with concurrent chemoradiation therapy (cCRT) and non-cCRT among patients with locally advanced NSCLC Study design –Meta-analysis of randomised controlled trials of any treatment arms of cCRT and non-cCRT (sequential chemoradiotherapy or radiotherapy alone) Key results –Data from 9 trials (n=1831) included both cCRT and non-cCRT arms –TRD rates were similar between the two groups; p=0.47 –Neither CRT regimen nor radiation dose fractionation were significantly correlated with TRDs Conclusions –Compared with sequential chemoradiotherapy or radiotherapy alone, cCRT did not significantly increase the TRD –Neither radiation dose nor chemotherapy regimens increased the treatment mortality Zhao et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7561)

34 7512: Multidisciplinary treatment for stage IIIA non-small cell lung cancer (NSCLC): Does institution matter? – Samson P et al Study objective –To investigate the impact of the institution carrying out surgery on survival in patients with stage IIIA NSCLC Study design –Retrospective analysis of data from the National Cancer Database from patients who had undergone resection at academic centres or community centres Key results –11,492 clinical stage IIIA NSCLC patients were treated at community centres compared with 7743 at academic centres –Academic centre patients were more likely to receive neoadjuvant CT (49.6% vs 40.6%; p<0.001) –30-day mortality was significantly lower at academic centres (OR 0.75, 95% CI 0.60, 0.93, 3.3% vs 4.5%; p<0.001) Conclusion –Stage IIIA NSCLC patients treated with pulmonary resection at academic centres show better survival than those treated in the community Samson et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7512)

35 Advanced NSCLC Not radically treatable stage III and stage IV 1 st line

36 8023: Nivolumab (anti-PD-1; BMS , ONO-4538) and ipilimumab in first-line NSCLC: Interim phase I results – Antonia SJ et al Study objective –To investigate the efficacy and safety of nivolumab in combination with ipilimumab in patients with advanced NSCLC Study design –Interim results from a phase I study in which CT-naïve patients with squamous or non- squamous advanced NSCLC received the following first-line regimen q3w for 4 cycles followed by nivolumab 3 mg/kg q2w: 1) nivolumab 1 mg/kg + ipilimumab 3 mg/kg or 2) nivolumab 3 mg/kg + ipilimumab 1 mg/kg –Primary endpoint: safety and tolerability; secondary endpoints: objective response rate and PFS Key results –Grade 3/4 treatment-related AEs occurred in 24 of 49 patients (49%) –Among patients with squamous NSCLC, objective response rate was better in the higher nivolumab dose group (33% vs 11% with low-dose nivolumab); this was also higher than in the non-squamous groups (both 13%) –Other outcomes were similar between patients with or without PD-L1 expression Conclusion –These interim data suggest that a nivolumab+ipilimumab immunotherapy regimen is feasible and active in patients with advanced NSCLC, regardless of PD-L1 expression status Antonia et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8023)

37 8024: First-line nivolumab (anti-PD-1; BMS , ONO-4538) monotherapy in advanced NSCLC: Safety, efficacy, and correlation of outcomes with PD-L1 status – Gettinger SN et al Study objective –To investigate PD-L1 as a potential biomarker for nivolumab use in the first-line treatment of advanced NSCLC Study design –Interim results of phase I study of nivolumab 3 mg/kg q2w in CT-naïve patients with squamous or non-squamous advanced NSCLC –Primary endpoint: safety and tolerability; secondary endpoints: objective response rate and PFS Key results –Five grade 3/4 treatment-related AEs occurred in 4 patients (20%; AST or ALT elevations, hyperglycaemia, rash and cardiac failure) –Objective response rate was 30% overall Response at first assessment (11 weeks) was observed in 5 of 6 (83%) patients Response was 50% in patients with PD-L1 expression; no responses were observed in patients without PD-L1 expression Conclusion –Nivolumab was associated with early durable responses in patients with advanced and PD-L1 expression Gettinger et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8024)

38 8113: Nivolumab (anti-PD-1; BMS , ONO-4538) in combination with platinum-based doublet chemotherapy (PT-DC) in advanced non-small cell lung cancer (NSCLC) – Antonia SJ et al Antonia et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8113) Study objective –To assess DLT of nivolumab in combination with platinum-based doublet CT in NSCLC Study design –Updated analysis of a phase I study of first-line nivolumab plus PT-DC in CT-naïve patients –Based on histology patients were assigned to 4 cycles of one of four treatment arms: 1) nivolumab 10 mg/kg q3w + gemcitabine 1250 mg/m 2 + cisplatin 75 mg/m 2 (sq) 2) nivolumab 10 mg/kg IV q3w + pemetrexed 500 mg/m 2 + cisplatin 75 mg/m 2 (non-sq) 3) nivolumab 5 mg/kg q3w + paclitaxel 200 mg/m 2 + carboplatin AUC6 (sq + non-sq) 4) nivolumab 10 mg/kg q3w + paclitaxel 200 mg/m 2 + carboplatin AUC6 (sq + non-sq) Key results –Overall 56 patients were treated across 4 arms with median age of 64 years; 54% female; 96% stage IV –No DLTs were seen during the first 6 weeks of treatment –Objective response rate was 33–47% over up to 10 months of follow-up and was similar between treatment arms –Median OS was 51–83 weeks; 1-year OS rates were 50–87% –45% of patients reported grade 3–4 treatment-related AEs Conclusion –Nivolumab plus PT-DC demonstrated anti-tumour activity with encouraging 1-year OS DLT, dose-limiting toxicity; non-sq, non-squamous; PT-DC, platinum-based doublet CT; sq, squamous

39 8001: Efficacy and safety of crizotinib in patients with advanced c-MET- amplified non-small cell lung cancer (NSCLC) – Camidge DR et al Study objective –To assess the efficacy and safety of crizotinib in patients with advanced c-Met- amplified (low, intermediate or high amplification*) NSCLC Camidge et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8001) Crizotinib 250 mg bid c-MET amplification: Low (n=2) Medium (n=6) High (n=6) PD Key patient inclusion criteria c-MET-amplified advanced NSCLC Low, medium or high Adequate organ function Measurable disease Resolution of acute toxic effects of prior therapies or surgery No prior MET- or HGF-targeted therapies (n=14) *According to MET/CEP7 ratio: ≥1.8–≤2.2 (low), >2.2–<5.0 (intermediate) or ≥5.0 (high)

40 8001: Efficacy and safety of crizotinib in patients with advanced c-MET- amplified non-small cell lung cancer (NSCLC) – Camidge DR et al Key results –1 CR and 4 PRs have been observed with crizotinib among 12 patients to date Conclusion –Crizotinib seemed to have anti-tumour activity and was generally well tolerated which warrants further study of crizotinib in advanced c-MET-amplified NSCLC Camidge et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8001) Low MET n=2 Intermediate MET n=6 High MET n= –20 –40 –60 –80 – –20 –40 –60 –80 –100 Disease progression Stable disease Partial response b Complete response b % Change from baseline –20 –40 –60 –80 –100 Threshold for partial response c c a Confirmed objective responses b Based on investigator assessment c Two patients in the intermediate MET group had an unconfirmed PR that was not confirmed in a second assessment

41 8002: First-line crizotinib versus pemetrexed-cisplatin or pemetrexed- carboplatin in patients (pts) with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014) – Mok et al Study objective –To evaluate the efficacy and safety of crizotinib compared with pemetrexed- platinum chemotherapy as first-line treatment in patients with advanced ALK+ NSCLC Mok et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8002) Primary endpoint PFS Secondary endpoints Objective response rate, OS, PROs and safety R 1:1 PD Key patient inclusion criteria Locally advanced, recurrent or metastatic non-squamous NSCLC ALK+ No previous treatment ECOG PS 0–2 (n=343) Pemetrexed-platinum chemotherapy* IV q3w (n=171) Crizotinib 250 mg bid q3w (n=172) *Pemetrexed 500 mg/m 2 + cisplatin 75 mg/m 2 or carboplatin AUC5–6 for ≤6 cycles Crizotinib Stratification ECOG PS, ethnicity, presence/absence of brain metastases

42 8002: First-line crizotinib versus pemetrexed-cisplatin or pemetrexed- carboplatin in patients (pts) with advanced ALK-positive non-squamous non- small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014) – Mok et al Key results –Addition of crizotinib significantly improved PFS but not OS compared with CT alone Mok et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8002) PFS OS probability (%) Time (months) No. at risk Crizotinib CT Crizotinib CT Crizotinib (n=172) CT (n=171) Median, months HR (95% CI)0.454 (0.35, 0.60) p<0.0001

43 8002: First-line crizotinib versus pemetrexed-cisplatin or pemetrexed- carboplatin in patients (pts) with advanced ALK-positive non-squamous non- small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014) – Mok et al Conclusions –First-line treatment with crizotinib compared with standard chemotherapy demonstrated significant improvements in PFS and objective response rate in patients with advanced ALK+ non-squamous NSCLC –The findings suggest that crizotinib should be the standard of care in patients with previously untreated advanced ALK+ non-squamous NSCLC Mok et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8002)

44 8003^: Ceritinib in advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC): Results of the ASCEND-1 trial – Kim D-W et al Study objectives –To investigate the efficacy and safety of ceritinib in patients with crizotinib-resistant advanced ALK-rearranged NSCLC Study design –Expansion phase dose escalation study in which patients were treated with the established minimum therapeutic dose of ceritinib (750 mg/day) –Patients were grouped according to: ALK inhibitor-pretreated NSCLC (n=163) or ALK inhibitor-naïve NSCLC (n=83) Key results –246 patients had ALK-rearranged NSCLC, with a median follow-up of 7.0 months; of these, 43% had received at least 3 prior treatment regimens –Overall response rate: 58.5% all patients; 54.6% ALK inhibitor pretreated; 66.3% ALK inhibitor naïve –PFS at 12 months: 39.1% all patients; 28.4% ALK inhibitor pretreated; 61.3% ALK inhibitor naïve Conclusions –Ceritinib has rapid, durable and high anti-tumour activity in patients with ALK-rearranged NSCLC, regardless of prior treatment with an ALK inhibitor Kim et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8003^)

45 8003^: Ceritinib in advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC): Results of the ASCEND-1 trial – Kim D-W et al Study objectives –To investigate the efficacy and safety of ceritinib in patients with crizotinib-resistant advanced ALK-rearranged NSCLC Study design –Expansion phase dose escalation study in which patients were treated with the established minimum therapeutic dose of ceritinib (750 mg/day) –Patients were grouped according to: ALK inhibitor-pretreated NSCLC (n=163) or ALK inhibitor-naïve NSCLC (n=83) Key results –246 patients had ALK-rearranged NSCLC, with a median follow-up of 7.0 months; of these, 43% had received at least 3 prior treatment regimens –Overall response rate: 58.5% all patients; 54.6% ALK inhibitor pretreated; 66.3% ALK inhibitor naïve –PFS at 12 months: 39.1% all patients; 28.4% ALK inhibitor pretreated; 61.3% ALK inhibitor naïve Conclusions –Ceritinib has rapid, durable and high anti-tumour activity in patients with ALK-rearranged NSCLC, regardless of prior treatment with an ALK inhibitor Kim et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8003^)

46 8004^: Overall survival (OS) in patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations (EGFR mut): Pooled analysis of two large open-label phase III studies (LUX-Lung 3 [LL3] and LUX-Lung 6 [LL6]) comparing afatinib with chemotherapy – Yang JC-H et al Study objective –Pooled analysis of two Phase III studies (LL3 or LL6) comparing afatinib with standard CT* in EGFR-mutated patients with advanced NSCLC Yang et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8004^) *Cisplatin/pemetrexed (Study LL3) or gemcitabine/cisplatin (Study LL6); † 709 patients originally randomised to LL3 and LL6 Primary endpoint PFS Secondary endpoints OS and safety R 2:1 PD Stratification EGFR mutation (Del19, L858R or other) Race (Asian/non-Asian) Key patient inclusion criteria Treatment-naïve NSCLC EGFR mutation (Del19 or L858R) Stage IIIB/IV ECOG PS 0–1 (n=631 † ) Standard CT* (≤6 cycles) (n=212) Afatinib 40 mg/day (n=419)

47 8004^: Overall survival (OS) in patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations (EGFR mut): Pooled analysis of two large open-label phase III studies (LUX-Lung 3 [LL3] and LUX-Lung 6 [LL6]) comparing afatinib with chemotherapy – Yang JC-H et al Key results –Afatinib significantly prolonged survival in overall EGFR-mutant population Yang et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8004^) OS Afatinib (n=419) CT (n=212) Median, months HR (95%CI) p-value 0.81 (0.66, 0.99) Estimated OS probability Time (months) Afatinib CT No of patients

48 8004^: Overall survival (OS) in patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations (EGFR mut): Pooled analysis of two large open-label phase III studies (LUX-Lung 3 [LL3] and LUX-Lung 6 [LL6]) comparing afatinib with chemotherapy – Yang JC-H et al Key results –Afatinib significantly prolonged survival with EGFR Del19, but not L858R mutation Yang et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8004^) OS (Del19) OS (L858R) Estimated OS probability Time (months) Estimated OS probability Time (months) Afatinib CT No of patients Afatinib CT No of patients Afatinib (n=236) CT (n=119) Median, months HR (95%CI) p-value 0.59 (0.45, 0.77) Afatinib (n=183) CT (n=93) Median, months HR (95%CI) p-value 1.25 (0.92, 1.71)

49 8004^: Overall survival (OS) in patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations (EGFR mut): Pooled analysis of two large open-label phase III studies (LUX-Lung 3 [LL3] and LUX-Lung 6 [LL6]) comparing afatinib with chemotherapy – Yang JC-H et al Conclusions –In both trials, first-line afatinib significantly improved OS in patients with EGFR Del19 advanced NSCLC compared with CT –There was no significant difference in OS of patients with L858R mutations, individually or in exploratory combined analysis –This is the first analysis to show that genotype-directed therapy for EGFR- mutant patients can improve survival –These results suggest that first-line afatinib might become a standard of care for EGFR Del19 patients and remains a treatment option for EGFR L858R patients Yang et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8004^)

50 8005: Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced EGFR mutation-positive nonsquamous non-small cell lung cancer (NSCLC): An open-label randomized trial – Kato T et al Study objective –To compare first-line erlotinib+bevacizumab with erlotinib alone in patients with EGFR-mutated NSCLC Kato et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8005) Primary endpoint PFS Secondary endpoints OS, tumour response, safety and QoL R 1:1 PD Key patient inclusion criteria Non-squamous NSCLC Stage IIIB/IV or recurrent EGFR mutation-positive No previous CT ECOG PS 0/1 (n=150) Erlotinib 150 mg/day alone (n=77) Erlotinib 150 mg/day + bevacizumab 15 mg/kg q3w (n=75) Stratification EGFR mutation (Del19 or L858R) Gender, smoking status, stage

51 8005: Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced EGFR mutation-positive nonsquamous non-small cell lung cancer (NSCLC): An open-label randomized trial – Kato T et al Key results –Median PFS was improved with combination treatment Conclusion –Erlotinib+bevacizumab significantly prolonged PFS compared with erlotinib alone in patients with EGFR mutation-positive NSCLC Kato et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8005) PFS PFS probability Time (months) Erlotinib + bevacizumabErlotinib Median (months) HR (95% CI)0.54 (0.36, 0.79) p-value* *log-rank test, two-sided Number at risk EB E

52 8007: Safety and clinical activity of MK-3475 as initial therapy in patients with advanced non-small cell lung cancer (NSCLC) – Rizvi NA et al Study objective –To evaluate the safety, tolerability and clinical activity of MK-3475 as an initial treatment for patients with locally advanced or metastatic NSCLC Rizvi et al. J Clin Oncol 2014; 32 (suppl; abstr 8007) R PD Key patient inclusion criteria Stage IV NSCLC No prior systemic therapy PD-L1 expressing tumours ECOG PS 0–1 EGFR/ALK negative (n=84) MK mg/kg q2w (n=16) MK mg/kg q3w (n=23) Primary endpoint Tumour response PD MK mg/kg q3w (n=6) Secondary endpoint Immune-related response criteria

53 8007: Safety and clinical activity of MK-3475 as initial therapy in patients with advanced non-small cell lung cancer (NSCLC) – Rizvi NA et al Key results –MK-3475 showed ORR of 26% by independent central review and 47% by investigator assessment (table) –Treatment-related AEs (any grade) occurring in >5% of patients were: fatigue (22%), pruritus (13%), hypothyroidism (9%), dermatitis acneiform (7%), diarrhoea (7%), dyspnoea (7%) and rash (7%) Conclusions –MK-3475 provides robust anti-tumour activity as first-line therapy for patients with NSCLC and PD-L1 expressing tumours –MK-3475 has an acceptable and manageable toxicity profile RECIST v1.1 per independent central review Immune-related response criteria per investigator assessment ORR (95% CI), %26 (14, 42)47 (32, 62) Interim median PFS (95% CI), weeks27.0 (13.6, 45.0)37.0 (27.0, NR) Responses ongoing, n/N (%)11/11 (100)19/21 (90) Responders remaining on treatment, n/N (%)7/11 (64)18/21 (86) Rizvi et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8007)

54 8020: Safety and clinical activity of MK-3475 in previously treated patients (pts) with non-small cell lung cancer (NSCLC) – Garon EB et al Study objective –To evaluate the safety, tolerability and clinical activity of MK-3475 in previously treated patients with progressive locally advanced or recurrent NSCLC Study design –A phase I study of previously treated patients (n=217) with PD-L1 expressing tumours were treated with MK mg/kg q2w (n=98) or q3w (n=119), or patients without PD-L1 expression who had received ≥2 prior lines of therapy were treated with MK mg/kg q2w –Primary endpoint: tumour response by RECIST Key results –Incidence of ≥1 drug-related AEs of any grade was 64%; most common AEs (≥5%) overall were: fatigue (20%), decreased appetite (9%), arthralgia (9%), pruritus (8%), diarrhoea (7%), nausea (6%), rash (6%), pyrexia (6%) and hypothyroidism (5%) –Objective response rate was 20% overall, 23% in patients with PD-L1 expression and 9% in those without PD-L1 expression Conclusion –In previously treated patients with progressive locally advanced or recurrent NSCLC expressing PD-L1, treatment with MK-3475 was generally well tolerated and provided robust anti-tumour activity Garon et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8020)

55 8008^: A randomized, multicenter, open-label, phase III study of gemcitabine- cisplatin (GC) chemotherapy plus necitumumab (IMC-11F8/LY ) versus GC alone in the first-line treatment of patients (pts) with stage IV squamous non-small cell lung cancer (sq-NSCLC) – Thatcher N et al Study objective –To compare gemcitabine/cisplatin+necitumumab with gemcitabine/cisplatin alone as first-line treatment in patients with squamous NSCLC Thatcher et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8008^) *Gemcitabine 1250 mg/m² IV days 1 and 8, cisplatin 75 mg/m² IV day 1; † 800 mg IV days 1 and 8 Primary endpoint OS Secondary endpoints PFS, objective response rate and safety R 1:1 PD Key patient inclusion criteria Squamous NSCLC Stage IV ECOG PS 0–2 (n=1093) Gemcitabine/cisplatin* alone (n=548) Gemcitabine/cisplatin* + necitumumab † (n=545)

56 8008^: A randomized, multicenter, open-label, phase III study of gemcitabine- cisplatin (GC) chemotherapy plus necitumumab (IMC-11F8/LY ) versus GC alone in the first-line treatment of patients (pts) with stage IV squamous non-small cell lung cancer (sq-NSCLC) – Thatcher N et al Key results Thatcher et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8008^) OS Time since randomisation (months) Overall survival (%) Median OS (95% CI), months: Gemcitabine/cisplatin+necitumumab:11.5 (10.4, 12.6) Gemcitabine/cisplatin:9.9 (8.9, 11.1) HR (95% CI) 0.84 (0.74, 0.96); p=0.012* Patients/events: Gemcitabine/cisplatin+necitumuab:545 / 418 Gemcitabine/cisplatin: 548 / % 19.9% 42.8% 47.7% 1-year OS 2-year OS Follow-up time (median): Gemcitabine/cisplatin+necitumumab: 25.2 months; gemcitabine/cisplatin: 24.8 months *Log-rank test (stratified)

57 I I I ^: A randomized, multicenter, open-label, phase III study of gemcitabine- cisplatin (GC) chemotherapy plus necitumumab (IMC-11F8/LY ) versus GC alone in the first-line treatment of patients (pts) with stage IV squamous non-small cell lung cancer (sq-NSCLC) – Thatcher N et al Key results Thatcher et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8008^) PFS Progression-free survival as assessed by investigators ITT population (N=1093) <70 years (n=888) ≥70 years (n=205) Female (n=185) Male (n=908) Caucasian (n=913) Non-Caucasian (n=180) Ex-light & non-smoker (n=97) Smoker (n=995) ECOG PS 0 (n=344) ECOG PS 1 (n=652) ECOG PS 2 (n=96) Favours GC Favours GC+necitumumab Hazard ratio Progression-free survival (%) Time since randomisation (months) *Log-rank test (stratified) Median PFS (95% CI), months: Gemcitabine/cisplatin+necitumumab: 5.7 (5.6, 6.0) Gemcitabine/cisplatin: 5.5 (4.8, 5.6) HR (95% CI) 0.85 (0.74, 0.98); p=0.020*

58 8008^: A randomized, multicenter, open-label, phase III study of gemcitabine- cisplatin (GC) chemotherapy plus necitumumab (IMC-11F8/LY ) versus GC alone in the first-line treatment of patients (pts) with stage IV squamous non-small cell lung cancer (sq-NSCLC) – Thatcher N et al Conclusions –SQUIRE is the largest randomised phase III trial of first-line treatment for metastatic squamous NSCLC –The study met its primary endpoint by showing a statistically significant improvement in OS –Results were consistent across endpoints and pre-specified subgroups, including patients with ECOG PS 2 –Necitumumab combined with gemcitabine/cisplatin showed an acceptable safety profile Thatcher et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8008^)

59 7558: The impact of EGFR mutation on definitive concurrent chemoradiation therapy for inoperable stage III lung adenocarcinoma – Tanaka K et al Study objective –To investigate the impact of EGFR mutation on treatment with concurrent chemoradiation therapy (CRT) in unresectable stage III lung adenocarcinoma Study design –Retrospective analysis of clinical outcomes and recurrence patterns according to mutation status among patients treated with first-line platinum-doublet in first-line setting Key results –EGFR mutation was detected in 28.8% of patients (21 of 73 patients) –Survival was significantly shorter in EGFR-mutated patients than wild-type Median recurrence-free survival (RFS; 95% CI) was 8.7 (6.7, 10.8) vs 13.5 (11.0, 18.3) months; p= year RFS rate was 5.6% vs 23.8%; p=0.090 Distant metastases were more frequently identified as the first recurrence site (81.0% vs 38.5%; p<0.001) Conclusion –Concurrent CRT gave shorter RFS in EGFR-mutated stage III lung adenocarcinoma patients compared with wild-type patients, mainly due to distant metastasis relapse, regardless of better local control Tanaka et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7558)

60 Advanced NSCLC Not radically treatable stage III and stage IV Maintenance

61 8016: Randomized phase II study of concurrent gefitinib and chemotherapy versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer (NSCLC) with sensitive EGFR mutations: NEJ005/TCOG0902 – Oizumi S et al Study objective –To identify an effective combined regimen of gefitinib + carboplatin/pemetrexed in EGFR mutation-positive NSCLC for use in a subsequent phase II trial Oizumi et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8016) R 1:1 PD Key patient inclusion criteria Non-squamous stage IIIB/IV/relapse NSCLC Previously untreated EGFR+ Age 20–75 years ECOG PS 0–1 (n=80) Gefitinib (8 weeks daily)  carboplatin+pemetrexed (2 cycles, q3w) (n=39) Gefitinib (daily) + carboplatin+pemetrexed (4–6 cycles, q3w) (n=41) Stratification Gender, stage Primary endpoint PFS Induction Maintenance Gefitinib (8 weeks daily)  pemetrexed (2 cycles, q3w) (n=24) Gefitinib (daily) + pemetrexed (q3w) (n=35) Gefitinib 250 mg/day; carboplatin AUC6; pemetrexed 500 mg/m 2 Repeat up to 3 cycles Concurrent arm Sequential arm Secondary endpoints OS, tumour response and safety

62 8016: Randomized phase II study of concurrent gefitinib and chemotherapy versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer (NSCLC) with sensitive EGFR mutations: NEJ005/TCOG0902 – Oizumi S et al Key results –Concurrent administration of CT was associated with better OS than sequential CT but there was no improvement in PFS Conclusion –Both treatment arms showed promising efficacy with predictable toxicities, although concurrent regimens might provide better OS Oizumi et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8016) OSPFS ConcurrentSequentialConcurrentSequential Median, mo % CI35.1, NR23.2, , , 17.4 HR p-value year rate, % year rate, % year rate, % OS OS probability (%) Time (months) Concurrent Sequential

63 8019^: Continuation of afatinib beyond progression: Results of a randomized, open-label, phase III trial of afatinib plus paclitaxel (P) versus investigator’s choice chemotherapy (CT) in patients (pts) with metastatic non-small cell lung cancer (NSCLC) progressed on erlotinib/gefitinib (E/G) and afatinib—LUX-Lung 5 (LL5) – Schuler MH et al Study objective –To assess the efficacy of continuation of afatinib beyond progression with the addition of paclitaxel in patients the NSCLC who have shown prior benefit from reversible EGFR TKIs and afatinib Schuler et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8019^) Primary endpoint PFS Secondary endpoints ORR, OS and safety R* 2:1 PD Key patient inclusion criteria Stage IIIB/IV NSCLC Failed ≥1 line of chemotherapy and erlotinib/gefitinib ECOG PS 0–2 (n=1302) Single agent investigator’s choice chemotherapy (n=68) Afatinib 40 mg/day + paclitaxel 80 mg/m 2 /week (n=134) *Those progressing who had received ≥12 weeks of benefit from afatinib Stratification Gender Prior duration of EGFR TKI Afatinib 50 mg/day (n=1154)

64 8019^: Continuation of afatinib beyond progression: Results of a randomized, open-label, phase III trial of afatinib plus paclitaxel (P) versus investigator’s choice chemotherapy (CT) in patients (pts) with metastatic non-small cell lung cancer (NSCLC) progressed on erlotinib/gefitinib (E/G) and afatinib—LUX-Lung 5 (LL5) – Schuler MH et al Key results Conclusion –PFS (and ORR) were significantly improved with continued afatinib combined with paclitaxel vs CT alone in heavily pretreated patients with acquired resistance to erlotinib/gefitinib and progression after afatinib monotherapy Schuler et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8019^) PFSOS Afatinib + paclitaxel (n=134) Investigator choice (n=68) PFS event, n (%)105 (78.4)54 (79.4) Median PFS (mo) HR (95% CI)0.60 (0.43, 0.85) p= Time (months) Progression-free survival (probability) Afatinib CT Time (months) Overall survival (probability) Afatinib Chemo Afatinib + paclitaxel (n=134) Investigator choice (n =68) OS event, n (%)100 (74.6)46 (67.6) Median OS (mo)12.2 HR (95% CI)1.00 (0.70, 1.43) p=

65 8040: Sunitinib (S) switch maintenance in advanced non-small cell lung cancer (NSCLC): An ALLIANCE (CALGB 30607), randomized, placebo-controlled phase III trial – Socinski MA et al Study objective –To evaluate the effect on survival of sunitinib maintenance vs placebo in patients with advanced NSCLC who were stable or responding after 4 cycles of first-line platinum- based chemotherapy (with or without bevacizumab) Socinski et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8040) Primary endpoint PFS after randomisation Secondary endpoints OS, safety and QoL R PD Key patient inclusion criteria Stage IIIB/IV ECOG PS 0–1 Stable or responding disease after 4 cycles of platinum-based therapy No symptomatic or untreated brain metastases or cavitary lesions (n=210) Placebo (n=104) Sunitinib 37.5 mg qd (n=106)

66 8040: Sunitinib (S) switch maintenance in advanced non-small cell lung cancer (NSCLC): An ALLIANCE (CALGB 30607), randomized, placebo-controlled phase III trial – Socinski MA et al Key results –Patients had a median (range) age 66 (25–89) years, 55.7% male, 61.0% ECOG PS 1, 87.6% stage IV, 91.7% current/past smokers. 45.7% had adenocarcinoma, 33.2% squamous, 13.5% undifferentiated NSCLC and 4.3% large cell Conclusion –Significant improvement in PFS (but not OS) observed with sunitinib switch maintenance in patients with advanced NSCLC Socinski et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8040)

67 Advanced NSCLC Not radically treatable stage III and stage IV Later lines

68 8009: Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor–resistant non-small cell lung cancer (NSCLC) – Janne PA et al Study objective –To investigate the efficacy of AZD9291 in patients with EGFR-mutant NSCLC Study design –Phase I dose-escalation study of AZD9291 at doses of 20–240 mg qd in patients with EGFR mutation-positive NSCLC and acquired resistance to EGFR TKIs Key results –To date, 31 and 201 patients have been enrolled to the escalation and expansion studies (median age 61/60 years; 65%/62% female; 71%/63% Asian), respectively –Overall response rate (confirmed+unconfirmed) to date are as follows: 53% (95% CI 46%, 60%) among all evaluable patients 64% (95% CI 55%, 73%) in EGFR T790 mutation-positive patients 22% (95% CI 12%, 36%) in EGFR T790 mutation-negative patients –The overall DCR (CR+PR+SD) in EGFR T790 mutation-positive patients was 94% –No dose-limiting toxicities were observed Conclusions –AZD9291 has robust efficacy and is well tolerated in patients with EGFR mutation-positive NSCLC and acquired resistance to EGFR TKIs Janne et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8009)

69 8112^: Nivolumab (anti-PD-1, BMS , ONO-4538) in patients (pts) with advanced non-small-cell lung cancer (NSCLC): Survival and clinical activity by subgroup analysis – Brahmer JR et al Study objective –To investigate the clinical efficacy of the human IgG4 PD1 immune-checkpoint inhibitor antibody, nivolumab, on patients with previously treated advanced NSCLC Study design –Phase Ib study in which patients received nivolumab (1, 3 or 10 mg/kg) q2w for up to 96 weeks –PD-L1 tumour cell membrane expression was measured in archival specimens Key results –Overall, 129 subjects were treated with nivolumab across the three doses –At the 3 mg/kg dose (n=37) median OS was 14.9 months, 1- and 2-year OS rates were 56% and 45%, respectively, objective response rate was 24% –For patients with PD-L1(+) and (–) tumours, median OS was 7.8 (95% CI 5.6, 21.7) and 10.5 (5.2, 21.2) months, respectively –The most common grade 3–4 treatment-related AE was fatigue (3%) Conclusion –Nivolumab continues to demonstrate an encouraging survival profile Brahmer et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8112^)

70 8010: First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M) – Sequist LV et al Study objective –To investigate the efficacy and safety of CO-1686 in patients with EGFR mutation-positive advanced or recurrent NSCLC Study design –Dose-finding study of CO-1686 free-base (up to 900 mg bid) and CO-1686 hydrobromide salt (HBr; 500–1000 mg bid) among patients who had a tumour biopsy in screening for central EGFR genotyping Key results –72 patients with median age of 59 years; 75% female; 14% Asian –PK of the CO-1686 HBr formulation was consistently linear with a half-life suitable for bid dosing –Objective response rate to date of 58% among T790 mutation-positive patients (n=40) –Median PFS has not yet been reached, but current estimate exceeds 12 months –Treatment-related AEs occurring in >10% were: nausea, hyperglycaemia/IGT, diarrhoea, vomiting, decreased appetite, myalgia and QTc prolonged Conclusions –CO-1686 shows promising efficacy in patients with T790 EGFR-mutant NSCLC –CO-1686 HBr delivered higher exposures than free-base and was equally well tolerated Sequist et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8010)

71 8011: Clinical activity and safety of HM61713, an EGFR-mutant selective inhibitor, in advanced non-small cell lung cancer (NSCLC) patients (pts) with EGFR mutations who had received EGFR tyrosine kinase inhibitors (TKIs) – Kim D-W et al Study objective –To evaluate safety, pharmacokinetics and preliminary efficacy of HM61713 in patients with EGFR mutation-positive advanced NSCLC Study design –Phase I dose-escalation study of HM61713 at 300 mg qd (up to 500 mg/day so far) assigned to treatment arm according to time since EGFR TKI (Arm A: <4 weeks; Arm B: ≥4 weeks) Key results –83 patients enrolled to date –Treatment-related AEs were mostly grade 1/2; those occurring in ≥10% were: nausea, skin exfoliation, headache, rash, decreased appetite, diarrhoea, pruritus, constipation, dry skin, vomiting, productive cough, upper abdominal pain, cough, dyspepsia and dyspnoea –Disease control rate was 61.9% and 73.2% in Arm A and B, respectively Conclusions –HM61713 showed good safety profile and promising anti-tumour activity in patients with EGFR-mutated NSCLC who failed to respond to EGFR TKIs, especially in patients with T790M mutation Kim et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8011

72 8021^: Clinical activity and biomarkers of MEDI4736, an anti-PD-L1 antibody, in patients with NSCLC – Brahmer JR et al Study objective –To evaluate the safety and efficacy of MEDI4736 in patients with NSCLC and other solid tumours Study design –Ongoing phase I study of patients with NSCLC who are receiving MEDI4736 IV q2w or q3w using 3+3 dose-escalation followed by expansion cohorts stratified by histology and line of therapy –Primary endpoint: maximum tolerated dose and safety Key results –As of May 2014, 155 patients with NSCLC have been treated with MEDI4736 in the dose- escalation and expansion cohorts, 143 patients were dosed at 10 mg/kg q2w –Most patients have remained on treatment with median duration of 6 weeks –Grade 3/4 treatment-related AEs were seen in 3% of all patients; the most common grade ≥3 AE was arthralgia (1%) –Efficacy of MEDI mg/kg q2w was higher in patients with PD-L1 expression Response (CR + PR) 13% overall; 39% with PD-L1 expression; 5% without Disease control rate 30% overall; 54% with PD-L1 expression; 32% without Conclusions –The findings support the continuing clinical development of MEDI4736 –Response rates were higher in patients with PD-L1 expression Brahmer et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8021^)

73 8047: Updated efficacy and safety of the ALK inhibitor AP26113 in patients (pts) with advanced malignancies, including ALK+ non-small cell lung cancer (NSCLC) – Gettinger SN et al Study objective –To investigate the efficacy and safety of AP26113 in patients with advanced NSCLC (including ALK+) Study design –Ongoing phase II portion of a phase I/II single arm study Key results –125 patients enrolled in phase II to date with median age 57 years; 58% female –Most common treatment-emergent AEs (≥20%) were generally grade 1/2 in severity: nausea (40%), diarrhoea (34%), fatigue (34%), cough (26%), headache (25%) and vomiting (21%) –Among 51 evaluable ALK+ NSCLC patients with prior crizotinib, 35 (69%) responded (23 confirmed response, 7 awaiting confirmation and 5 not confirmed); duration of response was 1.6–14.7 months (ongoing) –Among 49 patients with follow-up scans, median PFS is 10.9 months Conclusion –AP26113 has promising anti-tumour activity in patients with crizotinib-resistant ALK+ NSCLC, including patients with brain metastases Gettinger et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8047)

74 8014: Phase II trial of XL184 (cabozantinib) plus erlotinib in patients (pts) with advanced EGFR-mutant non-small cell lung cancer (NSCLC) with progressive disease (PD) on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy: A California Cancer Consortium phase II trial (NCI 9303) – Reckamp KL et al Study objective –To investigate the efficacy and safety of the dual MET-VEGF inhibitor, cabozantinib, plus erlotinib in pretreated EGFR mutation-positive NSCLC Study design –Single-arm study of cabozantinib 40 mg/day + erlotinib 150 mg/day on a 28-day cycle in patients with progressive disease on an EGFR TKI immediately prior to enrolment –Primary endpoint: response rate (proportion of patients with ≥30% increase in tumour doubling time); secondary endpoints: PFS, OS and safety Key results –37 patients have been treated, median age 64.6 years; 62% female; 51% ECOG PS 0 –Tumour growth rate reduction of ≥30% was achieved in 85% of patients –Diarrhoea (11/37, 30%) was the most common grade 3 AE; 4 patients had grade 4 AEs: 1 increased serum amylase, 2 patients increased lipase and 1 patient nausea/vomiting Conclusion –Combination of erlotinib and cabozantinib demonstrates anti-tumour activity in patients with EGFR mutation-positive NSCLC and progressive disease on EGFR TKI Reckamp et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8014)

75 8015: Phase II study of the AKT inhibitor MK-2206 plus erlotinib (E) in patients (pts) with advanced non-small cell lung cancer (NSCLC) who progressed on prior erlotinib: A California Cancer Consortium Phase II trial (NCI 8698) – Lara P et al Study objective –To investigate the efficacy and safety of the highly selective inhibitor of AKT, MK2206, in combination with erlotinib in patients with advanced NSCLC Study design –Single-arm study of erlotinib 150 mg/day + MK mg/day on a 28-day cycle in patients who had responded previously to erlotinib (response or stable disease >12 weeks) –Accrual into two strata: presence of EGFR-activating mutation; EGFR wild-type –Primary endpoints: response rate >30% and disease control rate >20% at 12 weeks Key results –80 patients have been treated, median (range) age 64 (40–86) years; 58% EGFR mutation-positive; 64% female; 66% PS 90–100% –Disease control rate was higher among patients with EGFR wild-type NSCLC treated with a combination of erlotinib+MK2206 compared with those with EGFR-mutant disease (47% vs 39%); median PFS was similar between groups (4.6 and 4.4 months, respectively) Conclusion –Combination of erlotinib and MK2206 demonstrates anti-tumour activity in patients with EGFR wild-type NSCLC Lara et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8015)

76 8043: E7080 (lenvatinib) in addition to best supportive care (BSC) versus BSC alone in third-line or greater nonsquamous, non-small cell lung cancer (NSCLC) – Havel L et al Study objective –To investigate the efficacy of lenvatinib as a third-line or greater treatment of NSCLC Study design –Randomised, controlled phase II study of lenvatinib 24 mg/day + BSC vs placebo+BSC in patients who had failed ≥2 systemic treatments –Primary endpoint: OS; secondary endpoints: PFS, ORR and DCR Key results –Patients in the lenvatinib/placebo groups (n=89/n=46) had median age of 63/64 years; % male 51/59; % white 70/67; % former smokers 55/63; % ECOG PS1 71/63; % adenocarcinoma 93/98 –There were clinically meaningful improvements (>3 months) in OS and PFS with lenvatinib+BSC vs placebo+BSC: OS 38.4 vs 24.1 weeks (HR 0.7 [95% CI 0.45, 1.03]; p=0.065) PFS 20.9 vs 7.9 weeks (HR 0.4 [95% CI 7.43, 8.14]; p<0.001) –A post-hoc analysis showed similar treatment effect in subjects with wild-type EGFR Conclusion –Lenvatinib showed clinical meaningful improvement in survival in heavily pretreated patients with NSCLC, including those with prior EGFR inhibitors Havel et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8043)

77 8045: Phase 2 HERALD study of patritumab (P) with erlotinib (E) in advanced NSCLC subjects (SBJs) – Von Pawel J et al Study objective –To assess safety and efficacy patritumab+erlotinib vs placebo+erlotinib in erlotinib-naïve patients with advanced NSCLC (second-line or later) Study design –Phase II study in which patients were randomised to erlotinib 150 mg/day and either high-dose patritumab (18 mg/kg q3w) or low-dose patritumab (18 mg/kg loading dose followed by 9 mg/kg q3w) or to erlotinib 150 mg/day plus placebo –Heregulin mRNA was measured using a quantitative polymerase chain reaction assay –Primary endpoints: PFS; secondary endpoints: OS and safety Results –Among 212 subjects in the ITT population, PFS was similar among the treatment groups (1.4, 2.5 and 1.6 months in the high, low and placebo arms, respectively) –PFS was significantly improved in the heregulin high subgroup (3.4, 3.0 and 1.4 months in the high, low and placebo arms, respectively) –Safety was similar with the exception of rash and gastrointestinal effects Conclusions –Patritumab improved PFS in the heregulin high subgroup, but not the ITT population –Heregulin appears to be a predictive biomarker for patritumab Von Pawel et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8045)

78 8026: Clinical activity of LY , a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with non-small cell lung cancer – Goldman JW et al Study objective –To investigate the efficacy and safety of the cell cycle inhibitor, LY (abemaciclib), in patients with advanced NSCLC and other solid tumours Goldman et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8026) Primary endpoint Safety PD Key patient inclusion criteria Advanced NSCLC PD or relapse after standard treatments (n=57) LY mg or 200 mg q12h, days 1–28 Secondary endpoints Anti-tumour activity, pharmacodynamics and predictive biomarkers

79 8026: Clinical activity of LY , a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with non-small cell lung cancer – Goldman JW et al Goldman et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8026) Key results Conclusions –LY demonstrated anti-tumour activity in advanced NSCLC, particularly in KRAS mutation-positive disease –LY had an acceptable safety profile –20 –40 –60 –80 –100 Percentage change from baseline †SQ Disease control rate (CR + PR + SD) All NSCLC (n=57) 49.1% KRAS mutant (n=29) 55.2% KRAS wild-type (n=24) 37.5% Best overall response CR PR SD PD Not evaluable All NSCLC N=57, n (%) 0 (0.0) 2 (3.5) 26 (45.6) 14 (24.6) 15 (26.3) KRAS mutant N=29, n (%) 0 (0.0) 1 (3.4) 15 (51.7) 7 (24.1) 6 (20.7) KRAS wild-type N=24, n (%) 0 (0.0) 1 (4.2) 8 (33.3) 7 (29.2) 8 (33.3) KRAS status: Mutant Wild-type Unknown Each bar represents one evaluable patient † Value truncated

80 8000: Onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIb or IV NSCLC: Results from the pivotal phase III randomized, multicenter, placebo-controlled METLung (OAM4971g) global trial – Spigel DR et al Study objective –To evaluate the efficacy and safety of onartuzumab in combination with erlotinib vs erlotinib alone in patients with stage IIIB/IV NSCLC Spigel et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8000) Primary endpoint OS Secondary endpoints PFS, ORR, QoL, safety and PK R 1:1 PD Stratification EGFR mutant vs wild-type, MET 2+ vs 3+, number of prior treatments, histology Key patient inclusion criteria Stage IIIB/IV NSCLC MET-positive (2+ or 3+) 1 prior platinum-based treatment ECOG PS 0–1 (n=490) Erlotinib 150 mg/day + placebo (n=249) Erlotinib 150 mg/day + onartuzumab 15 mg/kg IV q3w (n=250)

81 8000: Onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIb or IV NSCLC: Results from the pivotal phase III randomized, multicenter, placebo-controlled METLung (OAM4971g) global trial – Spigel DR et al Key results –An independent committee recommended to stop the trial for futility Conclusions –Addition of onartuzumab did not confer any benefit on survival in patients with MET-positive 2/3L NSCLC regardless of MET FISH or EGFR mutation status Spigel et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8000) OS PFS Probability of PFS Time (months) Median 2.6 months (95% CI 1.5, 2.8) HR 0.99 (95% CI 0.81, 1.2) p=0.92 Median 2.7 months (95% CI 2.4, 2.9) Placebo+erlotinib (n=249) Onartuzumab+erlotinib (n=250) Censored ORR 8.8% placebo+erlotinib vs. 6.4% onartzumab+erlotinib

82 8041: Randomized phase III study comparing gefitinib (G) with erlotinib (E) in patients (pts) with previously treated advanced lung adenocarcinoma (LA): WJOG 5108L – Katakami N et al Katakami et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8041) Study objective –Phase III study to demonstrate non-inferiority of gefitinib to erlotinib as second-line therapy in patients with advanced lung adenocarcinoma Patients –Median age of 67/68 years; % female 54.3/54.5; % PS0 50.0/40.1; % PS1 42.5/53.8; % stage IV 69.3/69.2; % 2 nd -line 68.9/71.3; % smokers 49.6/49.5; for erlotinib and gefitinib Primary endpoint PFS Secondary endpoints OS, RR, DCR, safety and time to treatment failure (TTF) R PD Stratification Gender, PS, stage, smoking history, EGFR status, institution, prior regimen Key patient inclusion criteria Lung adenocarcinoma Stage III/IV or recurrence ECOG PS 0–2 ≥1 previous CT regimen Evaluable disease Age ≥20 years (n=561) Gefitinib 250 mg/day (n=279) Erlotinib 150 mg/day (n=280)

83 8041: Randomized phase III study comparing gefitinib (G) with erlotinib (E) in patients (pts) with previously treated advanced lung adenocarcinoma (LA): WJOG 5108L – Katakami N et al Katakami et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8041) Key results –TTF: 5.3 vs 5.6 months (HR 1.032, 95% CI 0.866, 1.231) for erlotinib vs gefitinib –OS: 24.5 vs 22.8 months (HR 1.038, 95% CI 0.833, 1.394) for erlotinib vs gefitinib –Median PFS and OS in patients with activating mutation for erlotinib vs gefitinib were 10.1 vs 8.9 months (p=0.532) and 32.0 vs 26.6 months (p=0.111), respectively Conclusion –Non-inferiority in PFS was not demonstrated between erlotinib and gefitinib, and there were no significant differences in PFS or OS

84 8046: Efficacy and safety results from CurrentS, a double-blind, randomized, phase III study of second-line erlotinib (150 mg versus 300 mg) in current smokers with advanced non-small cell lung cancer (NSCLC) – Smit EF et al Study objective –To investigate the use of a higher than usual dose of erlotinib in smokers with stage IIIB/IV NSCLC Patients –% female 22/22; % Asian 30/31; median pack-years 31/30; % adenocarcinoma 65/60; % squamous cell carcinoma 27/30; % large cell carcinoma 4/4; for standard- and high- dose erlotinib, respectively Smit et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8046) Primary endpoint PFS Secondary endpoints OS, DCR and safety R PD Stratification Disease stage, ECOG PS, geographic region Key patient inclusion criteria Stage IIIB/IV Failed first-line platinum-based CT Current smokers (n=213) Erlotinib 300 mg/day (n=159) Erlotinib 150 mg/day (n=154)

85 8046: Efficacy and safety results from CurrentS, a double-blind, randomized, phase III study of second-line erlotinib (150 mg versus 300 mg) in current smokers with advanced non-small cell lung cancer (NSCLC) – Smit EF et al Key results: –No significant increase observed in PFS when erlotinib given at 300 mg vs 150 mg Conclusions –Increased dose of erlotinib did not improve survival of smokers with NSCLC and was associated with decreased tolerability Smit et al. J Clin Oncol 2014; 32 (suppl; abstr 8046)

86 8103: Antitumor activity of alectinib (CH /RO ) for ALK- rearranged NSCLC with or without prior crizotinib treatment in bioequivalence study – Nakagawa K et al Study objective –To investigate bioequivalence and food effect of a high-dose formulation of the highly selective ALK inhibitor, alectinib, in ALK-rearranged NSCLC Study design –Crossover study of alectinib 300 mg bid with 20/40 mg capsules for 10 days followed by 150 mg capsules for 10 days, followed by 150 mg after meals for last 10 days Key results –Among 35 patients with ALK-rearranged NSCLC exposure was similar between 20/40 mg and 150 mg capsules –Food effect with 150 mg capsules at steady state was negligibly small Conclusions –Exposure was similar between capsule strengths, with no food effects –Alectinib 150 mg capsules were efficacious for ALK-rearranged NSCLC patients regardless of crizotinib treatment history, with quick and high efficacy and a good safety profile Nakagawa et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8103)

87 8018: Randomized, double-blinded study of dacomitinib, an irreversible pan- human epidermal growth factor receptor (HER) inhibitor, versus erlotinib for second-line/third-line therapy of locally advanced/metastatic non-small cell lung cancer (ARCHER 1009) – Ramalingam SS et al Study objective –To compare the efficacy and safety of the irreversible pan-HER kinase inhibitor, dacomitinib, with erlotinib as second-/third-line therapy for locally advanced metastatic NSCLC Study design –Interim analysis of a randomised, placebo-controlled phase III study of dacomitinib 45 mg/day or erlotinib 150 mg/day in patients with advanced NSCLC –Primary endpoint: PFS; secondary endpoints: OS and best overall response Key results –878 patients were enrolled, median age 63 years; 64% male; 76% Caucasian; 90% ECOG PS 0/1; 69% adenocarcinoma; 18% never smokers –Median PFS was 2.6 months in both the dacomitinib and erlotinib groups, with HR (95% CI 0.802, 1.104; p=0.229) across all patient population and HR (95% CI 0.834, 1.253; p=0.587) in KRAS wild-type patients Conclusion –Dacomitinib was not superior to erlotinib in pretreated patients with advanced NSCLC –Data from the EGFR mutation-positive subset will be reported when mature Ramalingam et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8018)

88 8022: Safety and response with nivolumab (anti-PD-1; BMS , ONO-4538) plus erlotinib in patients (pts) with epidermal growth factor receptor mutant (EGFR MT) advanced NSCLC – Rizvi NA et al Study objective –To evaluate the safety and efficacy of nivolumab added to erlotinib in patients with advanced NSCLC and EGFR mutations Rizvi et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8022) Primary endpoint Safety and tolerability Secondary endpoints Objective response rate and PFS at 24 weeks PD Key patient inclusion criteria Stage IIIB/IV NSCLC Non-squamous EGFR+ CT naïve (n=21) Nivolumab 3 mg/kg q2w + erlotinib 150 mg/day

89 8022: Safety and response with nivolumab (anti-PD-1; BMS , ONO-4538) plus erlotinib in patients (pts) with epidermal growth factor receptor mutant (EGFR MT) advanced NSCLC – Rizvi NA et al Key results –Grade 3 treatment-related AEs occurred in 24% of patients (no grade 4 reported) –Objective response rate was 19% (PR in 3 of 20 patients treated previously with erlotinib and 1 of 1 patient with no prior erlotinib) –Survival outcomes among all patients are shown in the table Conclusion –Nivolumab in combination with erlotinib may provide durable clinical benefit in EGFR mutation-positive advanced NSCLC, with evidence of activity at TKI resistance Rizvi et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8022) Nivolumab+erlotinib (n=21) PFS PFS rate (95% CI) at 24 weeks, %51 (28, 70) Median (range) PFS, weeks29.4 (4.6, 81.7+) OS 1-year OS rate (95% CI), %73 (46, 88) Median (range) OS, weeksNR (10.7+, 86.9+)

90 7500: A multinational phase III randomized trial with or without consolidation chemotherapy using docetaxel and cisplatin after concurrent chemoradiation in inoperable stage III non-small cell lung cancer (CCheIN) – Park K et al Study objective –To assess the efficacy of consolidation CT with docetaxel and cisplatin after CCRT with the same agents in patients with inoperable stage III NSCLC Park et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7500) *DP (20 mg/m 2 each per week for 6 weeks, total dose of 66 Gy of thoracic RT as 33 fractions); † Additional DP (35 mg/m 2 each on days 1 + 8, q3w); CCRT, concurrent chemoradiotherapy; D, docetaxel; C, cisplatin Primary endpoint PFS Secondary endpoints OS, RR, pattern of failure and safety R 1:1 PD Key patient inclusion criteria Inoperable stage III NSCLC Locally advanced ECOG PS 0–1 Age >18 years (n=437) CCRT* † alone (n=209) CCRT* + D (20 mg/m 2 ) + P (20 mg/m 2 ) (n=211) Stratification Centre Performance

91 7500: A multinational phase III randomized trial with or without consolidation chemotherapy using docetaxel and cisplatin after concurrent chemoradiation in inoperable stage III non-small cell lung cancer (CCheIN) – Park K et al Key results –Survival was similar between treatment arms during a median follow-up of 50.7 months Park et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7500) PFS PatientsEventsmPFS (95% CI) CCRT alone (7.56, 8.90) CCRT + consolidation (7.92, 10.94) Progression-free survival Time (months) CCRT alone CCRT + consolidation HR (95% CI 0.734, 1.119) p=0.410

92 7500: A multinational phase III randomized trial with or without consolidation chemotherapy using docetaxel and cisplatin after concurrent chemoradiation in inoperable stage III non-small cell lung cancer (CCheIN) – Park K et al Conclusions –The primary endpoint of increased PFS with the addition of weekly docetaxel- cisplatin consolidation therapy was not met in this study –Concurrent chemoradiotherapy alone should remain as the standard of care for inoperable stage III NSCLC Park et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7500)

93 LBA8006^: REVEL: A randomized, double-blind, phase III study of docetaxel (DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the second-line treatment of stage IV non-small cell lung cancer (NSCLC) following disease progression after one prior platinum-based therapy – Pérol M et al Study objective –To compare the efficacy and safety of ramucirumab+docetaxel with placebo+docetaxel in pretreated patients with stage IV non-squamous and squamous NSCLC Pérol et al. J Clin Oncol 2014; 32 (suppl 5; abstr LBA8006^) Primary endpoint OS Secondary endpoints PFS, objective response rate, safety and PROs R 1:1 PD Key patient inclusion criteria Stage IV NSCLC Non-squamous or squamous Previous platinum-based CT ECOG PS 0/1 (n=1253) Placebo + docetaxel 75 mg/m 2 q3w (n=625) Ramucirumab 10 mg/kg + docetaxel 75 mg/m 2 q3w (n=628) Stratification Gender, region (East Asia vs ROW), ECOG PS (0 vs 1), prior maintenance therapy

94 LBA8006^: REVEL: A randomized, double-blind, phase III study of docetaxel (DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the second-line treatment of stage IV non-small cell lung cancer (NSCLC) following disease progression after one prior platinum-based therapy – Perol M et al Key results –Ramucirumab+docetaxel significantly improved survival over placebo+docetaxel Pérol et al. J Clin Oncol 2014; 32 (suppl 5; abstr LBA8006^) OS PFS RAM, ramucirumab; DOC, docetaxel

95 LBA8006^: REVEL: A randomized, double-blind, phase III study of docetaxel (DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the second-line treatment of stage IV non-small cell lung cancer (NSCLC) following disease progression after one prior platinum-based therapy – Perol M et al Conclusions –REVEL met its primary endpoint of OS improvement –Ramucirumab+docetaxel showed statistically significant improvement in PFS and ORR compared with placebo+docetaxel –Benefits were similar in non-squamous and squamous patients –No unexpected AEs were identified –REVEL is the first study showing that the addition of a novel agent to standard chemotherapy improves survival in stage IV NSCLC patients with progression after platinum-based chemotherapy Pérol et al. J Clin Oncol 2014; 32 (suppl 5; abstr LBA8006^)

96 7508: A randomized trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA N2 non-small cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy – Wang S-Y et al Study objective –To evaluate survival benefit of prophylactic cranial irradiation (PCI) in patients with resected stage IIIA-N2 NSCLC and a high risk of cerebral metastases following adjuvant chemotherapy Wang et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7508) Primary endpoint DFS Secondary endpoints Incidence of brain metastases, OS, toxicity and QoL R PD Key patient inclusion criteria Resected stage IIIA-N2 NSCLC High risk for cerebral metastases No recurrence following post- operative adjuvant CT (≥2 cycles) ECOG PS 0–2 (n=156) Observation (n=75) Prophylactic cranial irradiation (30 Gy in 10 fractions) (n=81) Study was terminated due to slow accrual

97 7508: A randomized trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA N2 non-small cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy – Wang S-Y et al Wang et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7508) Key results –Prophylactic cranial irradiation increased disease-free survival compared with control Conclusion –Prophylactic cranial irradiation prolonged disease-free survival and reduced the incidence of brain metastases in patients with fully resected stage IIIA NSCLC who were at high risk of cerebral metastases following adjuvant CT Disease-free survival Time from randomisation (months) Disease-free survival (probability) PCI Control Median (months) HR 0.67 (95% CI 0.46, 0.98), p=0.037 OS Time from randomisation (months) Overall survival (probability) PCI Control Median (months) HR 0.81 (95% CI 0.56, 1.16), p=0.310

98 8036^: NCIC CTG BR.26: A phase III randomized, double blind, placebo controlled trial of dacomitinib versus placebo in patients with advanced/metastatic non-small cell lung cancer (NSCLC) who received prior chemotherapy and an EGFR TKI – Ellis PM et al Study objective –To investigate the efficacy and safety of the irreversible pan-HER inhibitor, dacomitinib, in pretreated patients with advanced NSCLC Study design –Randomised phase III study of dacomitinib 45 mg/day (n=480) vs placebo (n=240) in patients with advanced or metastatic NSCLC after 1–3 lines of CT and an EGFR TKI Key results –Median OS was similar between dacomitinib and placebo (6.8 vs 6.3 months, respectively, HR [95% CI 0.828, 1.212]; p=0.9873) OS in KRAS wild-type HR (95% CI 0.606, 1.034; p=0.0858) and KRAS mutant HR (95% CI 1.05, 4.216; p=0.0330) OS in EGFR wild-type HR (95% CI , 1.208; p=0.5656) and EGFR mutant HR (95% CI 0.669, 1.438; p=0.9218) –PFS was significantly improved with dacomitinib (2.7 vs 1.4 months with placebo; HR [95% CI 0.551, 0.793]; p<0.0001) –Dacomitinib was associated with longer time to deterioration of cough (p=0.0001), dyspnoea (p=0.049) and pain (p=0.049) Conclusion –Dacomitinib showed no activity in patients with pretreated NSCLC, although there was a trend to improved survival in patients with KRAS wild-type Ellis et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8036^)

99 8037: Randomized phase III trial of stereotactic radiosurgery (SRS) versus observation for patients with asymptomatic cerebral oligo-metastases in non- small cell lung cancer (NSCLC) – Lim SH et al Study objective –To determine if early treatment with stereotactic radiosurgery (SRS) can improve OS in NSCLC patients with asymptomatic oligo-brain metastases Lim et al. J Clin Oncol 2014; 32 (suppl; abstr 8037) Primary endpoint OS Secondary endpoints CNS disease progression and salvage brain treatment R 1:1 PD Key patient inclusion criteria NSCLC Synchronous asymptomatic brain metastases (<3 cm) >18 years (n=105) Systemic CT alone (n=52) SRS then systemic CT (n=53)

100 8037: Randomized phase III trial of stereotactic radiosurgery (SRS) versus observation for patients with asymptomatic cerebral oligo-metastases in non- small cell lung cancer (NSCLC) – Lim SH et al Key results –Median OS (95% CI): 15.8 (8.1, 23.5) months with SRS+CT vs 17.6 (12.4, 22.8) months with CT alone (p=0.346) –CNS disease progression: 9.4 vs 8.7 months for SRS+CT vs CT (p=0.579) –Salvage treatment for progression of CNS disease was more frequent with CT alone (52.8% vs 47.2% with SRS+CT), but was not significant (p=0.201) –Independent risk factors associated with poor OS were: Higher extra-cranial disease activity, number of brain metastases (≥2), age older than 65 years and non-adenocarcinoma histology Conclusion –SRS followed by systemic CT did not improve OS in asymptomatic oligo-brain metastases NSCLC patients compared with upfront CT alone Lim et al. J Clin Oncol 2014; 32 (suppl; abstr 8037)

101 7509: Postoperative radiotherapy (PORT) for pathologic N2 non-small cell lung cancer (NSCLC) treated with adjuvant chemotherapy: A review of the National Cancer Database – Robinson CG et al Study objectives –To investigate the impact on survival of modern postoperative radiotherapy (PORT) on OS in N2 NSCLC after surgery and adjuvant CT Study design –Retrospective analysis of data from the National Cancer Database from 4483 patients who had undergone complete resection (R0) and adjuvant CT between 2006 and 2010, of whom 1850 (41.3%) received PORT –Stratified by use of PORT (≥45 Gy) Robinson et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7509)

102 7509: Postoperative radiotherapy (PORT) for pathologic N2 non-small cell lung cancer (NSCLC) treated with adjuvant chemotherapy: A review of the National Cancer Database – Robinson CG et al Key results –In multivariate analysis, younger age, treatment at an academic facility, higher income, lower Charlson score, smaller tumour, ≥ lobectomy, and use of PORT (HR for PORT 0.89 [95% CI 0.80, 0.99]; p=0.029) were predictive of improved OS for the entire group –Use of PORT was associated with a significant increase in median OS (figure) Robinson et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7509) Conclusion –Modern PORT may confer an additional 5% survival advantage in NSCLC patients after complete resection beyond that achieved with adjuvant CT alone OS Survival (probability) Time (months) Standard treatment PORT Median OS: 45.0 vs 40.9 months p=0.029

103 Other malignancies SCLC and mesothelioma

104 8034: Targeting FGFR1-amplified lung squamous cell carcinoma with the selective pan-FGFR inhibitor BGJ398 – Nogova L et al Study objective –To investigate the potent, selective pan-FGFR inhibitor, BGJ398, in patients with FGFR1- amplified lung squamous cell carcinoma Study design –Subgroup analysis of phase I dose-escalation study of patients with FGFR1-amplified advanced or metastatic lung squamous cell carcinoma treated with BGJ398 5–150 mg/day in 28-day cycles who had progressed following at least one line of therapy Key results –26 patients were treated at the maximum tolerated dose of 150 mg/day (n=3), 125 mg/day (n=21) or 100 mg/day (n=2) –Of the 26 patients receiving ≥100 mg/day, 4 patients achieved PR; 9 patients had SD, 6 patients had PD and status was unknown in 7 patients –AEs were manageable and reversible Conclusion –This molecular targeted therapy shows evidence of activity supporting further development of BGJ398 in FGFR1-amplified lung squamous cell carcinoma Nogova et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8034)FGFR, fibroblast growth factor receptors

105 8035: A phase 1b open-label multicenter study of AZD4547 in patients with advanced squamous cell lung cancers: Preliminary antitumor activity and pharmacodynamic data – Paik PK et al Study objective –To investigate the safety and efficacy of the FGFR1-3 inhibitor, AZD4547, in squamous cell lung cancer Study design –Phase I expansion study of AZD mg bid q3w in patients with previously treated stage IV FGFR1-amplified squamous cell lung cancer stratified by high and low levels –Primary endpoint: safety; secondary endpoint: preliminary anti-tumour activity Key results –15 patients were treated with a median (range) age of 66 (48–72) years; 40% female; 67% WHO PS restricted activity –Grade ≥3 treatment-related AEs occurred in 20% with 3 patients discontinuing due to AEs (asthenia, retinal oedema and deterioration) –14 patients had evaluable tumour response (1 PR, 4 SD, 9 PD) Conclusions –AZD4547 was well tolerated in patients with FGFR1-amplified squamous cell lung cancer –Prespecified primary efficacy endpoint was not met Paik et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8035)FGFR, fibroblast growth factor receptors

106 7506: A randomized double-blind phase II trial of platinum (P) plus etoposide (E) with or without concurrent ZD6474 (Z) in patients (pts) with previously untreated extensive stage (ES) small cell lung cancer (SCLC): Hoosier Oncology Group LUN – Sanborn RE et al Study objective –To evaluate the efficacy and tolerability of concurrent ZD6474 added to standard platinum+etoposide treatment in patients with extensive-stage SCLC Sanborn et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7506) Primary endpoint Time to disease progression Secondary endpoints Safety, RR, DCR and OS R 1:1 PD Key patient inclusion criteria Untreated extensive-stage SCLC or high grade poorly differentiated neuroendocrine tumours ECOG PS 0–1 (n=74) Placebo + CT* (cisplatin/carboplatin, etoposide) (n=33) ZD6474 (100 mg qd) + CT* (cisplatin/carboplatin, etoposide) (n=41) *Cisplatin 60 mg/m 2 day 1/etoposide 120 mg/m 2 days 1–3 OR Carboplatin AUC5 day 1/etoposide 100 mg/m 2 days 1–3 q3w for 4 cycles

107 7506: A randomized double-blind phase II trial of platinum (P) plus etoposide (E) with or without concurrent ZD6474 (Z) in patients (pts) with previously untreated extensive stage (ES) small cell lung cancer (SCLC): Hoosier Oncology Group LUN – Sanborn RE et al Key results –Higher incidence of grade 3/4 toxicities observed with ZD6474 vs placebo (69% vs 37%) –Survival was not improved by ZD6474 Conclusions –ZD6474 in combination with CT did not improve outcomes for patients with newly- diagnosed extensive stage SCLC –Toxicity was increased with the combination compared with CT alone –Therefore, ZD6474 is not recommended for unselected patients with extensive SCLC Sanborn et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7506) *PE, platinum+etoposide Time to progression 5.6 vs 5.5 months with ZD6474 vs placebo (HR 1.13; p=0.66) Probability of survival Time to disease progression (months) 25 Placebo ZD Censored Log-rank p=0.9518

108 7505: Randomized phase II-III study of bevacizumab in combination with chemotherapy in previously untreated extensive small-cell lung cancer: Results from the IFCT-0802 trial – Pujol J-L et al Study objective –Phase II study to assess the efficacy and safety of adding bevacizumab to first-line standard CT in extensive disease SCLC Patients – Median number of CT cycles was 6 in both treatment arms Pujol et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7505) Primary endpoint Response rate 2 cycles after randomisation R 1:1 PD Stratification ECOG PS, liver metastases, gender, induction CT, centre Key patient inclusion criteria Extensive disease SCLC ECOG PS 0–2 Age ≤75 years Weight loss <10% (n=147) 4 x cycles of CT + bevacizumab 7.5 mg/kg q3w (n=37) 4 x cycles of CT (n=37) 2 x induction cycles of CT (cisplatin+ etoposide) or (cisplatin+ cyclophosphamide +epidoxorubicin+ etoposide) Secondary endpoints PFS, OS, biomarkers, safety and QoL

109 7505: Randomized phase II-III study of bevacizumab in combination with chemotherapy in previously untreated extensive small-cell lung cancer: Results from the IFCT-0802 trial – Pujol J-L et al Key results –Survival was unchanged by the addition of bevacizumab Conclusions –The addition of bevacizumab to CT did not improve survival in patients with extensive- stage SCLC –Phase III study has been cancelled Pujol et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7505) OS Probability of survival Months after randomisation CT alone (n=37) mOS = 13.3 (95% CI 9.8, 16.6) CT plus bevacizumab (n=37) mOS = 11.1 (95% CI 8.7, 14.0) HR for CT alone = 0.80 (95% CI 0.50, 1.28)

110 7519: Randomized phase III trial in extensive-disease small cell lung cancer comparing first-line etoposide to topotecan in combination with platinum – Mau-Soerensen M et al Study objective –To compare first-line treatment with etoposide to topotecan in combination with platinum in patients with extensive disease SCLC Study design –Interim analysis of a randomised phase III study of 6 cycles of topotecan 2.0 mg/m 2 days 1–3 + cisplatin 50 mg/m 2 day 3, or etoposide 120 mg/m 2 days 1–3 + carboplatin AUC5 day 1, q3w in previously untreated patients with extensive disease SCLC –Primary endpoint: OS; secondary endpoints: response, PFS and safety Key results –Trial stopped prematurely due to poor accrual (281 patients recruited out of 380 planned) –Survival was similar between arms (OS: 10.9 vs 9.8 months with topotecan and etoposide [HR 0.87, 95% CI 0.67, 1.17, p=0.26; PFS: 6.9 vs 6.6 months [HR 0.93, 95% CI 0.72, 1.19], p=0.55) Conclusions –No differences in survival observed between first-line treatment with etoposide and topotecan in patients with extensive disease SCLC –Significantly more haemtological toxicity was observed in the etoposide group Mau-Soerensen et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7519)

111 7502: Randomized trial on thoracic radiotherapy (TRT) in extensive-stage small cell lung cancer – Slotman BJ et al Study objective –To assess the role of thoracic radiotherapy (TRT) in extensive-stage SCLC patients receiving prophylactic cranial irradiation (PCI) following 4–6 cycles of standard CT Slotman et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7502) Primary endpoint OS Secondary endpoints Local control, failure pattern and toxicity R 1:1 PD Key patient inclusion criteria Extensive-stage SCLC WHO PS 0–2 Any response to 4–6 cycles of platinum-based CT (n=495) PCI (n=248) TRT (30 Gy/10 fractions) + PCI (n=247) Stratification Institute Presence of intrathoracic disease

112 Key results –Addition of TRT to PCI improved 2-year survival Conclusion –Although TRT did not influence the median OS (primary endpoint) or the risk of death after 1 year (data not shown), it significantly increased 2-year survival and is an option in extensive-stage SCLC patients with a response to initial CT 7502: Randomized trial on thoracic radiotherapy (TRT) in extensive-stage small cell lung cancer – Slotman BJ et al Slotman et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7502) Time (months) OS OS Probability Thoracic RT No thoracic RT Thoracic RT No thoracic RT Survival difference at: 18 months: p= months: p= months (95% CI), % Thoracic RT : 13 (8.8, 18.7) No thoracic RT : 3 (1.5, 7.6) PFS PFS Probability Thoracic RT No thoracic RT Time (months) Thoracic RT No thoracic RT HR (95% CI) 0.73 (0.61, 0.87) p=0.001

113 7503: Prophylactic cranial irradiation (PCI) has a detrimental effect on the overall survival (OS) of patients (pts) with extensive disease small cell lung cancer (ED-SCLC): Results of a Japanese randomized phase III trial – Seto T et al Study objective –To investigate impact of prophylactic cranial irradiation on survival of patients with extensive-disease SCLC Patients –Patients in Arms A/B had median age 69/68 years; % male 81/89; % ECOG PS 0–1 95/97; % PR+MR response to CT 88/85 Seto et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7503) Primary endpoint OS Secondary endpoints Time to BM, PFS, safety, MMSE R PD Stratification Age, ECOG PS, response, institution Key patient inclusion criteria Extensive-disease SCLC Any response to first-line platinum doublet CT No BM by MRI assessment ECOG PS 0–2 (n=163) Observation alone (n=79) Prophylactic cranial irradiation (n=84) BM, brain metastases; MMSE, Mini-Mental State Examination Arm A Arm B

114 7503: Prophylactic cranial irradiation (PCI) has a detrimental effect on the overall survival (OS) of patients (pts) with extensive disease small cell lung cancer (ED-SCLC): Results of a Japanese randomized phase III trial – Seto T et al Key results –Study was terminated because of futility –Prophylactic cranial irradiation had no positive impact on OS (figure) but reduced the risk of brain metastases (32.4% vs 58.0% at 12 months; Gray’s test, p<0.001) Conclusion –Prophylactic cranial irradiation had no positive impact on OS in patients with extensive- disease SCLC with a confirmed absence of brain metastases Seto et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7503) Stratified log-rank test: p=0.091 (2-sided) Arm B: No PCI Arm A: PCI n=84 Arm B: no PCI n=79 No. of OS events6150 Hazard ratio (95% CI)1.38 (0.95, 2.02) Median OS (95% CI), mo10.1 (8.5, 13.2)15.1 (10.2, 18.7)

115 7504: A randomized phase III study of cisplatin (CDDP), etoposide (ETOP) and irinotecan versus topotecan as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer (SCLC): Japan Clinical Oncology Group study JCOG0605 – Goto K et al Study objective –To confirm the superiority of cisplatin+etoposide+irinotecan over topotecan as second-line treatment in patients with sensitive relapsed SCLC Patients –180 patients with a median (range) age of 64 (44–75) years; 86% male; 75% extensive disease; 97% ECOG PS 0–1 Goto et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7504) Primary endpoint OS Secondary endpoints PFS, response rate and safety R PD Stratification PS, localised/extensive disease, institution Key patient inclusion criteria SCLC Responded to first-line treatment Relapse/PD ≥90 days after treatment ECOG PS 0–2 (n=180) 4 cycles of topotecan (1.0 mg/m 2 d1–5, q3w) (n=90) 5 cycles of cisplatin (25 mg/m 2 d1/8) + etoposide (60 mg/m 2 d1–3) + irinotecan (90 mg/m 2 d8) (n=90) Arm A Arm B

116 7504: A randomized phase III study of cisplatin (CDDP), etoposide (ETOP) and irinotecan versus topotecan as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer (SCLC): Japan Clinical Oncology Group study JCOG0605 – Goto K et al Key results –OS was significantly longer with cisplatin+etoposide+irinotecan vs topotecan –Cisplatin+etoposide+irinotecan had a higher incidence of grade 3/4 AEs than topotecan for the following: leukopenia (80.0% vs 51.1%), anaemia (84.4% vs 27.8%), thrombocytopenia (41.1% vs 27.8%), hyponatremia (16.7% vs 11.1%), diarrhoea (7.8% vs 0%) and febrile neutropenia (31.1% vs 6.7%) Conclusion –Combination CT with cisplatin, etoposide and irinotecan is a good option for second-line CT for sensitive relapsed SCLC Goto et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7504) OS Topotecan (n=90) PEI (n=90) Events8272 MST (95% CI) 12.5 months (10.8, 14.9) 18.2 months (15.7, 20.6) One-sided p HR (90% CI)0.67 (0.51, 0.88) Proportion of OS Months after randomisation PEI Topotecan PEI, cisplatin+etoposide+irinotecan

117 7596: Comparison of cisplatin- versus carboplatin-based concurrent chemoradiation for limited-stage small cell lung cancer using SEER-Medicare data – Kim E et al Study objective –To compare impact on survival of cisplatin vs carboplatin as concurrent chemoradiation therapy (cCRT) in patients with limited-stage SCLC Study design –Retrospective study of 1603 cases from the population-based SEER-Medicare lung cancer database who had been treated with radiation within 60 days of starting cCRT –Endpoints: OS and cause-specific survival (CSS) Key results –Median age 72 years; 50% male; 85% stage III; 37% received cisplatin and this group was younger (p=0.0039) –Survival was not different between the cisplatin and carboplatin groups, respectively Median survival (months) was OS: 13.3 and 13.8 (p=0.59), CSS: 15.0 and 16.0 (p=0.86) 5-year survival was OS: 10.1% and 10.5% (p=0.16) and CSS: 25.2% and 22.3% (p=0.68) Conclusions –Cisplatin and carboplatin had comparable survival even though the cisplatin group was younger –Therefore, carboplatin is preferable for patients with limited-stage SCLC providing that it can be tolerated Kim et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7596)

118 7532: Antimesothelin vaccine CRS-207 plus chemotherapy as front-line treatment for malignant pleural mesothelioma (MPM) – Hassan R et al Study objective –To investigate the impact of adding the anti-mesothelin vaccine, CRS-207, to CT in patients with malignant pleural mesothelioma Study design –Phase Ib study in which CT-naïve patients with unresectable malignant pleural mesothelioma received two prime vaccinations with CRS-207 (1 x 10 9 CFU; 250 mL IV over 2 hours) 2 weeks apart, followed by up to 6 cycles of pemetrexed (500 mg/m 2 ) and cisplatin (75 mg/m 2 ) 3 weeks apart, and two CRS-207 boost vaccinations 3 weeks apart Key results –16 patients with median age 68 years; 88% male; 50% ECOG PS 0 –Of 16 subjects evaluable for response, 69% (11/16) had confirmed PR post CRS-207 and CT and 25% (4/16) had stable disease Conclusions –CRS-207 combined with CT shows encouraging anti-tumour activity better than those expected with CT alone Hassan et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7532)

119 7507: Randomized trial of arginine deprivation with pegylated arginine deiminase in patients with malignant pleural mesothelioma – Sziosarek PW et al Study objective –To examine the efficacy and safety of the arginine-lowering agent ADI-PEG20 Primary endpoint PFS Secondary endpoints Response rate, OS and toxicity R PD Key patient inclusion criteria Inoperable mesothelioma Measurable disease by CT CT naïve or prior platinum- doublet ASS1-deficient ECOG PS 0–1 (n=68) Best supportive care (n=24) Best supportive care + ADI-PEG IU/m 2 IM injection/week (36.8 mg/m 2 ) (n=44) Arm A Arm B Sziosarek et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7507) ADI-PEG20, pegylated arginine deiminase; ASS1, argininosuccinate synthetase 1; FDG-PET [18F]Fluorodeoxyglucose Positron Emission Tomography FDG-PET was used to measure plasma arginine, citrulline, ADI-PEG20 antibody, ASS1 methylation status and metabolic response

120 7507: Randomized trial of arginine deprivation with pegylated arginine deiminase in patients with malignant pleural mesothelioma – Sziosarek PW et al Key results –Survival was improved by ADI-PEG20 Conclusion –Arginine deprivation using ADI-PEG20 in patients with ASS1-deficient malignant pleural mesothelioma almost halved the risk of progression Sziosarek et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7507) ADI-PEG20, pegylated arginine deiminase; ASS1, argininosuccinate synthetase 1; BSC, best supportive care; FDG- PET, [18F]Fluorodeoxyglucose Positron Emission Tomography PFS % alive and progression-free Time since randomisation (days) HR (95% CI) 0.51 (0.30, 0.86), p=0.012 Median PFS (67 events*) BSC1.9 months BSC + ADI-PEG203.2 months BSC BSC + ADI-PEG20 *One patient remains progression-free and alive: 12 months (BSC + ADI+PEG20)

121 7589: T-cell inflamed phenotype and PDL1 expression in malignant mesothelioma – Kindler HL et al Study objective –To investigate markers of an anti-tumour immune response in malignant mesothelioma Study design –Data from a 44 malignant mesothelioma gene expression dataset that were retrospectively analysed using a melanoma-derived signature of T-cell inflammation and evaluated for other immune response-related genes; results were validated by IHC (CD68 staining, CD8, PD-L1) Key results –32% (14/44) of malignant mesothelioma had high CD8 gene expression –11% had a T-cell inflamed phenotype similar to melanoma –Two patterns of PD-L1 expression were observed Conclusions –Malignant mesothelioma is an inflammatory tumour with prominent infiltration with CD68+ cells (macrophages) –A fraction of malignant mesothelioma showed CD8+ tumour infiltrating lymphocytes and T-cell inflamed expression pattern similar to other tumours that benefit from immune checkpoint blockade –PD-L1 may be an appropriate target for future research in this cancer Kindler et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7589) IHC, immunohistochemistry

122 Other malignancies Rare tumours

123 7525: Phase II trial of sunitinib in patients with thymic epithelial tumors (TET) – Thomas A et al Study objective –To evaluate the efficacy of sunitinib in patients with thymic epithelial tumours who have failed prior platinum-based chemotherapy Study design –Non-randomised, phase II study of sunitinib 50 mg qd in 6-week cycles for 4 weeks followed by 2 weeks off until PD –Primary endpoint: objective response rate in two parallel cohorts (thymoma and thymic carcinoma) Key results –24 patients with thymic carcinoma (median age 58 years, 63% male) and 16 patients with thymoma (median age 54 years, 44% male) –Objective response and disease control rates were 26% (95% CI 10.2, 48.4) and 91% (72.0, 98.9) for thymic carcinoma and 6% (0.2, 30.2) and 81% (54.4, 96.0) for thymoma, respectively Conclusions –Sunitinib demonstrated anti-tumour activity unprecedented for a targeted agent in previously treated patients with thymic carcinoma –Activity was modest in thymoma Thomas et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7525)

124 7526: A phase II study of milciclib (PHA AC) in patients (pts) with thymic carcinoma (TC) – Besse B et al Study objective –To investigate the efficacy and safety of milciclib in patients with advanced thymic carcinoma or B3 thymoma Study design –Single arm phase II study of milciclib 150 mg qd 7 days on/7 days off in 2-week cycles in patients with thymic carcinoma or B3 thymoma who have received only one prior systemic therapy –Primary endpoint: PFS rate at 3 months Key results –49 patients have been treated to date with median (range) age of 55 (21–80) years; 55% female –Successful treatment achieved with 14 of 28 evaluable patients with an overall 3-month PFS rate of 50.0% (95% CI 30.6, 69.3) –Toxicity was generally moderate with asthenia (10.3%) and nausea (7.7%) the most common grade 3/4 AEs Conclusion –The study has already met its predefined endpoint and supports the full investigation of milciclib as a new therapeutic agent to treat thymic carcinoma and B3 thymoma Besse et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7526)

125 7528: Capecitabine plus gemcitabine in thymic epithelial tumors: Final analysis of a phase II trial – Buonerba C et al Study objective –To investigate the efficacy and safety of capecitabine+gemcitabine in patients with thymic epithelial tumours Study design –Phase II study of capecitabine (650 mg/mq bid, days 1–14) + gemcitabine (1000 mg/mq, days 1 and 8) q3w in patients with thymic epithelial tumours who have PD after at least one prior systemic therapy –Primary endpoint: radiographic response rate Key results –30 patients with median (range) age 57 (48–61) years; 60% male; 73% thymoma; 63% disease progression within 2 months from last dose of previous systemic CT –Overall, there was a response rate of 40% (3 CR, 8 PR) –PFS for patients with thymoma and thymic carcinoma was 11 (95% CI 6, 17) months and 6 (95% CI 3, 11) months, respectively Conclusion –Capecitabine and gemcitabine is an active combination therapy in thymic epithelial tumours and might deserve further prospective evaluation Buonerba et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7528)

126 2014 ASCO Annual Meeting Supported by Lilly and Company. Lilly and Company has not influenced the content of this publication Developed in association with the European Thoracic Oncology Platform 30 May – 3 June 2014 Chicago, USA


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