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2014 ASCO Annual Meeting

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

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2014 ASCO Annual Meeting

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

  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 2014. This slide set specifically focuses on the American Society of Clinical Oncology 50th 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 etop@etop.eu-org. 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 EnriquetaFelip Oncology Department, Valld'Hebron University Hospital, Barcelona, Spain Focus: early and locally advanced NSCLC (stage I–III) Dr Francoise Mornex Department of Radiation Oncology, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France Focus: advanced NSCLC (not radically treatable stage III & stage IV) Dr SolangePeters 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

  4. Contents • Biomarkers • Early stage and locally advanced NSCLC – Stages I, II and III • Advanced NSCLC – Not radically treatable stage III and stage IV • 1st 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/m2/day for consecutive 2 weeks q3w for 1 year) vs cisplatin (60 mg/m2 d1) + S-1 (80 mg/m2 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 ClinOncol 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 Disease-free survival with S-1 + cisplatin Disease-free survival with S-1 alone 1.0 1.0 HGF=Low HGF=Low 77% 56% 0.8 0.8 0.6 0.6 Survival rate Survival rate 0.4 0.4 HGF=High HGF=High 56% 61% 0.2 0.2 p=0.0072 p=0.981 0 0 0 200 400 600 800 1000 1200 1400 0 200 400 600 800 1000 1200 1400 Time (days) Time (days) Mitsudomi et al. J ClinOncol 2014; 32 (suppl 5; abstr 7550)

  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 ClinOncol 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 ADC, adenocarcinoma; SCC, squamous cell carcinoma; ASQ, adenosquamouscarcinoma; LPA. lepidicpredominant adenocarcinoma; LCC, large cell carcinoma Peters et al. J ClinOncol 2014; 32 (suppl 5; abstr 8057)

  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) (HRa 1.57; p=0.02) • 5-year OS in adenocarcinoma 53% (95% CI 36, 69) vs77% (72, 82) (HRa1.86; p=0.02) • Conclusion • PD-L1 may be a negative prognostic factor among non-SCC NSCLC, particularly adenocarcinoma aAdjusted 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 Sun et al. J ClinOncol 2014; 32 (suppl 5; abstr 8066)

  11. 8075: Clinicopathologicfeatures 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 EGFRT790M 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 ClinOncol 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 ClinOncol 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 ClinOncol 2014; 32 (suppl 5; abstr 8082)

  14. Early and locally advanced NSCLCStages 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 ClinOncol 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 NSCLCstratified by EGFR mutation status EGFR mutation Neoadjuvant erlotinib for 42 days(n=12) PD • Key patient inclusion criteria • Resectable histologically documented stage IIIA-N2 NSCLC (n=24) Wild-type EGFRNeoadjuvant gemcitabine/carboplatin for 3 cycles(n=12) PD Primary endpoint • RR Secondary endpoints: • PFS and OS Zhong et al. J ClinOncol 2014; 32 (suppl 5; abstr 7572)

  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 erlotinibarm with mutant EGFR and 25.0% (4/12) for the gemcitabine/carboplatinarm 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 ClinOncol 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 ClinOncol 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/m2) + pemetrexed (500 mg/m2) on day 1 q3w and weekly cetuximab (400 mg/m2 for first week then 250 mg/m2) • 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 ^Abstract granted an exception in accordance with the ASCO Conflict of Interest Policy Tredaniel et al. J ClinOncol 2014; 32 (suppl 5; abstr 7511^)

  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 Gyradiotherapy in combination with paclitaxel (15 mg/m2 triple weekly) or paclitaxel (45 mg/m2 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 ClinOncol 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 erlotinibvs placebo following complete tumour resection in patients with stage IB–IIIA NSCLC and EGFR FISH+ or EGFR IHC+ • Key patient inclusion criteria • Complete resected NSCLC • Stage IB–IIIA • EGFRIHC+/FISH+ • ECOG PS 0–2 • (n=973) Erlotinib 150 mg/day (n=623) No adjuvant chemotherapy • Stratification • Histology, stage, prior adjuvant CT, EGFR FISHstatus, smoking status, country R 2:1 ≤4 cycles of platinum-based doublet Placebo (n=350) Primary endpoint • Disease-free survival (FAS) Secondary endpoints • OS (FAS) • Disease-free survival and OS (EGFR M+subset) FAS, full analysis set Kelly et al. J ClinOncol 2014; 32 (suppl 5; abstr 7501)

  22. 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 • Key results • Adjuvant erlotinib did not prolong disease-free survival DFS (overall population) DFS (del19 and L858R) 1.0 1.0 Erlotinib Erlotinib 0.8 0.8 Placebo Placebo 0.6 0.6 Disease-free survival (probability) Disease-free survival (probability) Placebo (156 events) Median: 48.2 months Erlotinib (254 events) Median: 50.5 months Log-rank test: p=0.3235 HR 0.90 (95% CI 0.74, 1.10) Placebo (32 events) Median: 28.5 months Erlotinib (39 events) Median: 46.4 months Log-rank test: p=0.0391† HR 0.61 (95% CI 0.384, 0.981) 0.4 0.4 0.2 0.2 0.0 0.0 0 6 12 18 24 30 36 42 48 54 60 66 0 6 12 18 24 30 36 42 48 54 60 66 Disease-free survival (months) Disease-free survival (months) †Not significant due to hierarchical testing Kelly et al. J ClinOncol 2014; 32 (suppl 5; abstr 7501)

  23. 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 • 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 Kelly et al. J ClinOncol 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+ Erlotinib 150 mg/day (n=102) • Key patient inclusion criteria • Resected stage IB–IIIA NSCLC • EGFR IHC+ or FISH+ (n=973) No adjuvant chemotherapy • Stratification • Histology (adenocarcinoma, other) • Stage (IB, II, IIIA) • Adjuvant chemotherapy (yes, no) • Smoking history (never, current/former) • EGFR FISH (positive, negative/undermined) • Country ≤4 cycles of platinum-based doublet Placebo (n=59) Primary endpoint • DFS Secondary endpoints • OS (FAS), disease-free survival and OS (EGFR M+subset) Shepherd et al. J ClinOncol 2014; 32 (suppl 5; abstr 7513)

  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 *Percentage calculated using number of patients relapsed as the denominator †p-values exploratory (Wald test) and not statistically significant ‡log-rank test Shepherd et al. J ClinOncol 2014; 32 (suppl 5; abstr 7513)

  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 ClinOncol 2014; 32 (suppl 5; abstr 7513)

  27. 7510: Phase III study of surgery (S) versus definitive concurrent chemoradiotherapy boost (defccCRTx-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 Definitive concurrent chemoradiotherapy boost (65/71 Gy) (n=80) Induction chemotherapy Cisplatin/paclitaxel & concurrent chemoradiotherapy to 45 Gy (1.5 Gy bid/cc cisplatin/vinorelbine) PD • Key patient inclusion criteria • NSCLC stage IIIA/B • Potentially resectable • (n=246) R Surgery (n=81) PD Primary endpoint • OS Eberhardt et al. J ClinOncol 2014; 32 (suppl 5; abstr 7510)

  28. 7510: Phase III study of surgery (S) versus definitive concurrent chemoradiotherapy boost (defccCRTx-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 • 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 1.0 OS Boost Surgery 0.8 0.6 Survival probability 0.4 Arm B: 5-year OS=44.2% Arm A: 5-year OS=40.6% Log-rank: p=0.31 0.2 0.0 0 12 24 36 48 60 72 84 96 108 120 Time (months) Eberhardt et al. J ClinOncol 2014; 32 (suppl 5; abstr 7510)

  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) CRT 60 Gy + concurrent carboplatin and paclitaxel +/- cetuximab PD • Key patient inclusion criteria • Locally advanced stage IIIA/B NSCLC (n=495) • Stratification • Low volume (LVC) vs. high volume (HVC) centres R 1:1 CRT 74 Gy + concurrent carboplatin and paclitaxel +/- cetuximab PD Primary endpoints • OS and PFS Eaton et al. J ClinOncol 2014; 32 (suppl 5; abstr 7551)

  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 OS Median PFS Eaton et al. J ClinOncol 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 SBRT (n=40) JCOG 0403 (n=169) • Key patient inclusion criteria • Operable NSCLC • cT1N0M0 • Adenocarcinoma PD Lobectomy (n=219) JCOG 0201 (n=811) PD Primary endpoint • OS (adjusted with propensity score analysis*) *Patient factors included age, sex and 2 CT findings – tumour diameter and consolidation/tumour ratio (CTR) Eba et al. J ClinOncol 2014; 32 (suppl 5; abstr 7543)

  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 ClinOncol 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 ClinOncol 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 ClinOncol 2014; 32 (suppl 5; abstr 7512)

  35. Advanced NSCLCNot radically treatable stage III and stage IV 1st line

  36. 8023: Nivolumab (anti-PD-1; BMS-936558, 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 ClinOncol 2014; 32 (suppl 5; abstr 8023)

  37. 8024: First-line nivolumab (anti-PD-1; BMS-936558, 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 ClinOncol 2014; 32 (suppl 5; abstr 8024)

  38. 8113: Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with platinum-based doublet chemotherapy (PT-DC) in advanced non-small cell lung cancer (NSCLC) – Antonia SJ et al • 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/m2+ cisplatin75 mg/m2(sq) 2) nivolumab 10 mg/kg IV q3w + pemetrexed 500 mg/m2+ cisplatin 75 mg/m2(non-sq) 3) nivolumab 5 mg/kg q3w + paclitaxel 200 mg/m2 + carboplatin AUC6 (sq+ non-sq) 4) nivolumab 10 mg/kg q3w + paclitaxel 200 mg/m2 + 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 Antonia et al. J ClinOncol 2014; 32 (suppl 5; abstr 8113)

  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 crizotinibin patients with advanced c-Met-amplified (low, intermediate or high amplification*) NSCLC • 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) • Crizotinib 250 mg bid • c-MET amplification: • Low (n=2) • Medium (n=6) • High (n=6) PD *According to MET/CEP7 ratio: ≥1.8–≤2.2 (low), >2.2–<5.0 (intermediate) or ≥5.0 (high) Camidge et al. J ClinOncol 2014; 32 (suppl 5; abstr 8001)

  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 100 100 100 Disease progression Stable disease 80 80 80 Low METn=2 Intermediate METn=6 High METn=6 Partial responseb Complete responseb 60 60 60 40 40 40 20 20 20 % Change from baseline 0 0 0 –20 –20 –20 –40 –40 –40 Threshold for partial response –60 –60 –60 –80 –80 –80 c c –100 –100 –100 aConfirmed objective responses bBased on investigator assessment cTwo patients in the intermediate MET group had an unconfirmed PR that was not confirmed in a second assessment Camidge et al. J ClinOncol 2014; 32 (suppl 5; abstr 8001)

  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 • Key patient inclusion criteria • Locally advanced, recurrent or metastatic non-squamous NSCLC • ALK+ • No previous treatment • ECOG PS 0–2 (n=343) Crizotinib 250 mg bid q3w (n=172) PD • Stratification • ECOG PS, ethnicity, presence/absence of brain metastases R1:1 Crizotinib Pemetrexed-platinum chemotherapy* IV q3w (n=171) PD Primary endpoint • PFS Secondary endpoints • Objective response rate, OS, PROs and safety *Pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC5–6 for ≤6 cycles Mok et al. J ClinOncol 2014; 32 (suppl 5; abstr 8002)

  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 PFS 100 80 60 OS probability (%) Crizotinib CT 40 20 0 0 5 10 15 20 25 30 35 Time (months) No. at risk Crizotinib CT 172 171 120 105 65 36 38 12 19 2 7 1 1 0 0 0 Mok et al. J ClinOncol 2014; 32 (suppl 5; abstr 8002)

  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 ClinOncol 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 hadALK-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 ClinOncol 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 hadALK-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 ClinOncol 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 Afatinib 40 mg/day (n=419) • Key patient inclusion criteria • Treatment-naïve NSCLC • EGFR mutation (Del19 or L858R) • Stage IIIB/IV • ECOG PS 0–1 • (n=631†) PD • Stratification • EGFR mutation (Del19, L858R or other) • Race (Asian/non-Asian) R 2:1 Standard CT* (≤6 cycles) (n=212) PD Primary endpoint • PFS Secondary endpoints • OS and safety *Cisplatin/pemetrexed (Study LL3) or gemcitabine/cisplatin (Study LL6); †709 patients originally randomised to LL3 and LL6 Yang et al. J ClinOncol 2014; 32 (suppl 5; abstr 8004^)

  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 OS 1.0 0.8 0.6 Estimated OS probability 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time (months) No of patients Afatinib 419 411 390 371 343 320 284 251 225 201 181 141 77 58 33 9 1 0 CT 212 199 185 173 162 141 124 110 101 83 70 52 34 23 10 5 1 0 Yang et al. J ClinOncol 2014; 32 (suppl 5; abstr 8004^)

  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 OS (L858R) OS (Del19) 1.0 1.0 0.8 0.8 0.6 0.6 Estimated OS probability Estimated OS probability 0.4 0.4 0.2 0.2 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time (months) Time (months) No of patients No of patients Afatinib 183 181 167 154 141 128 111 91 80 70 64 51 27 20 11 3 0 0 Afatinib 236 230 223 217 202 192 173 160 145 131 117 90 50 38 22 6 1 0 CT 93 86 82 78 75 69 61 55 50 40 32 25 20 14 9 4 1 0 CT 119 113 103 95 87 72 63 55 51 43 38 27 14 9 1 1 0 0 Yang et al. J ClinOncol 2014; 32 (suppl 5; abstr 8004^)

  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 ClinOncol 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 Erlotinib 150 mg/day + bevacizumab 15 mg/kg q3w (n=75) • Key patient inclusion criteria • Non-squamous NSCLC • Stage IIIB/IV or recurrent • EGFR mutation-positive • No previous CT • ECOG PS 0/1 (n=150) PD • Stratification • EGFR mutation (Del19 or L858R) • Gender, smoking status, stage R 1:1 Erlotinib 150 mg/day alone (n=77) PD Primary endpoint • PFS Secondary endpoints • OS, tumour response, safety and QoL Kato et al. J ClinOncol 2014; 32 (suppl 5; abstr 8005)

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