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

2014 ASCO Annual Meeting

Supported by Lilly and Company.Lilly and Company has not influenced the content of this publication

Developed in association with theEuropean Thoracic Oncology Platform

30 May – 3 June 2014Chicago, USA

Letter from Prof Rolf StahelDear 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 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 [email protected].

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

mailto:[email protected]

ETOP Medical Oncology Slide Deck Editors 2014

Focus: biomarkers (all stages)Dr Enriqueta FelipOncology Department, Vall d'Hebron University Hospital, Barcelona, Spain

Focus: advanced NSCLC (not radically treatable stage III & stage IV)Dr Solange PetersMultidisciplinary Oncology Center, Lausanne Cancer Center, Lausanne, Switzerland

Focus: other malignancies, SCLC, mesothelioma, rare tumours Dr Martin ReckDepartment of Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, Germany

Focus: early and locally advanced NSCLC (stage I–III) Dr Francoise MornexDepartment of Radiation Oncology, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France

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

Biomarkers

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 Clin Oncol 2014; 32 (suppl 5; abstr 7550)

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

1.0

0.8

0.6

0.4

0.2

0

Time (days)

0 200 400 600 800 1000 1200 1400

Su

rviv

al r

ate

p=0.0072

56%

77%HGF=Low

HGF=High

1.0

0.8

0.6

0.4

0.2

0

Time (days)

0 200 400 600 800 1000 1200 1400S

urv

iva

l ra

te

p=0.981

61%

56%

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)

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

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) vs 77% (72, 82) (HRa 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)

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

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)

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)

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)

Early and locally advanced NSCLCStages I, II and III

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)

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

PD

Key patient inclusion criteria• Resectable histologically

documented stage IIIA-N2 NSCLC

(n=24) Wild-type EGFRNeoadjuvant

gemcitabine/carboplatin for 3 cycles

(n=12)

EGFR mutationNeoadjuvant erlotinib

for 42 days(n=12)

Secondary endpoints:

• PFS and OS

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)

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 controlHansen et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7557)

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

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

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/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 Clin Oncol 2014; 32 (suppl 5; abstr 7545)

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)

R2:1

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

• Key results– Adjuvant erlotinib did not prolong disease-free survival


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)

Dis

ea

se-f

ree

su

rviv

al

(p

rob

ab

ility

)

1.0

0.8

0.6

0.4

0.2

0.00 6 12 18 24 30 36 42 48 60

Disease-free survival (months)

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)

54 66

Erlotinib

Placebo

Dis

ea

se-f

ree

su

rviv

al

(p

rob

ab

ility

)

1.0

0.8

0.6

0.4

0.2

0.00 6 12 18 24 30 36 42 48 60

Disease-free survival (months)

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)

54 66

Erlotinib

Placebo

• 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 Clin Oncol 2014; 32 (suppl 5; abstr 7501)

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)


No adjuvant chemotherapy

≤4 cycles of platinum-

based doublet


• 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


Erlotinib Placebo HR (95% CI) p-value

Median DFS, mo 46.4 28.5 0.61 (0.38, 0.98) 0.041†

Adjusted DFS 0.60 (0.36, 0.98) 0.041†

Patients relapsed, n (%) 35 (34.3) 31 (52.5)

Brain relapses, %* 40.0 12.9

Bone relapses, %* 14.3 29.0

Median OS, mo NR NR 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


• 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


Erlotinib Placebo

Any AEs leading to discontinuation, % 30 5.1

Any drug-related AEs leading to discontinuation, % 25 0

AEs leading to dose interruption, % 22 6.8

AE leading to dose reduction, % 22 1.7

Grade ≥3 rash, % 19 0

Grade ≥3 diarrhoea, % 5 0

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

PDKey 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)

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

OSS

urvi

val p

rob

abili

ty1.0

0.8

0.6

0.4

0.2

0.0

Time (months)0 12 24 36 48 60 72 84 96 108 120

Arm B: 5-year OS=44.2%Arm A: 5-year OS=40.6%Log-rank: p=0.31

BoostSurgery

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

R1:1

PD

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

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 Clin Oncol 2014; 32 (suppl 5; abstr 7551)

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

PDKey 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)

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)

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)

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)

Advanced NSCLCNot radically treatable stage III and stage IV

1st line

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 Clin Oncol 2014; 32 (suppl 5; abstr 8023)

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 Clin Oncol 2014; 32 (suppl 5; abstr 8024)

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

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/m2 + cisplatin 75 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

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 bidc-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)

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 METn=2

Intermediate METn=6

High METn=6

100

80

60

40

20

0

–20

–40

–60

–80

–100

100

80

60

40

20

0

–20

–40

–60

–80

–100

Disease progressionStable diseasePartial responseb

Complete responseb

% C

han

ge

fro

m b

asel

ine

100

80

60

40

20

0

–20

–40

–60

–80

–100

Threshold for partial responsec

c

aConfirmed objective responsesbBased on investigator assessmentcTwo patients in the intermediate MET group had an unconfirmed PR that was not confirmed in a second assessment

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

R1:1

PD

PDKey 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/m2 + cisplatin 75 mg/m2 or carboplatin AUC5–6 for ≤6 cycles

Crizotinib

Stratification

• ECOG PS, ethnicity, presence/absence of brain metastases

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

OS

pro

babi

lity

(%)

100

80

60

40

20

00 5 10 15 20 25 30 35

Time (months)No. at riskCrizotinibCT

172171

120105

6536

3812

192

71

10

00

CrizotinibCT

Crizotinib (n=172)

CT (n=171)

Median, months 10.9 7.0

HR (95% CI) 0.454 (0.35, 0.60)

p<0.0001

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


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 inhibitorKim et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8003^)

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 inhibitorKim et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8003^)

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

R2:1

PD

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)


• 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)


HR (95%CI) p-value

0.81 (0.66, 0.99) 0.0374

1.0

0.8

0.6

0.4

0.2

0

Est

ima

ted

OS

pro

babi

lity

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51Time (months)

419 411 390 371 343 320 284 251 225 201 181 141 77 58 33 9 1 0

212 199 185 173 162 141 124 110 101 83 70 52 34 23 10 5 1 0

Afatinib

CT

No of patients


• Key results– Afatinib significantly prolonged survival with EGFR Del19, but not L858R mutation


OS (Del19) OS (L858R)1.0

0.8

0.6

0.4

0.2

0

Est

imat

ed O

S p

roba

bilit

y

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Time (months)

1.0

0.8

0.6

0.4

0.2

0

Est

imat

ed O

S p

roba

bilit

y

Time (months)

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

236 230 223 217 202 192 173 160 145 131 117 90 50 38 22 6 1 0

119 113 103 95 87 72 63 55 51 43 38 27 14 9 1 1 0 0

Afatinib

CT

No of patients

183 181 167 154 141 128 111 91 80 70 64 51 27 20 11 3 0 0

93 86 82 78 75 69 61 55 50 40 32 25 20 14 9 4 1 0

Afatinib

CT

No of patients

Afatinib (n=236)

CT(n=119)


HR (95%CI)p-value

0.59 (0.45, 0.77) 0.0001

Afatinib (n=183)

CT(n=93)

Median,months 22.1 26.9

HR (95%CI) p-value

1.25 (0.92, 1.71) 0.1600


• 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


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

R1:1

PD

PDKey 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

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)

PFSP

FS

pro

ba

bili

ty

100

80

60

40

20

00 2 4 6 8 10 12 14 16 18

Time (months)

20 22 24 26 28

Erlotinib + bevacizumab Erlotinib

Median (months) 16.0 9.7

HR (95% CI) 0.54 (0.36, 0.79)

p-value* 0.0015

*log-rank test, two-sided

Number at risk

EBE

7577

7266

6957

6444

6039

5329

4924

3821

3018

2012

1310

85

42

41

00

9.7 16.0

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

PDKey patient inclusion criteria• Stage IV NSCLC• No prior systemic therapy• PD-L1 expressing tumours• ECOG PS 0–1 • EGFR/ALK negative

(n=84) MK-3475 10 mg/kg q2w(n=16)

MK-3475 10 mg/kg q3w(n=23)

Primary endpoint

• Tumour response

PDMK-3475 2 mg/kg q3w

(n=6)

Secondary endpoint

• Immune-related response criteria

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), weeks 27.0 (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)

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-3475 10 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-3475 10 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)

8008^: A randomized, multicenter, open-label, phase III study of gemcitabine-cisplatin (GC) chemotherapy plus necitumumab (IMC-11F8/LY3012211) 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

R1:1

PD

PDKey patient inclusion criteria• Squamous NSCLC• Stage IV• ECOG PS 0–2

(n=1093) Gemcitabine/cisplatin* alone

(n=548)

Gemcitabine/cisplatin* + necitumumab†

(n=545)


• Key results

Thatcher et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8008^)

OS

Time since randomisation (months)

Ove

rall

surv

ival

(%

)

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 / 418Gemcitabine/cisplatin: 548 / 442

16.5%

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

100

80

60

40

20

0

0 4 8 12 16 20 24 28 32 36 40

*Log-rank test (stratified)

I I I

0.5 1.0 1.5


• Key results


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

Pro

gre

ssio

n-f

ree

su

rviv

al (

%)

Time since randomisation (months)

0.85

0.821.07

0.630.90

0.880.70

0.880.85

0.840.860.79

20 24 28 320 4 8 12 16

0

100

80

60

40

20

*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*


• 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


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=0.022

• 2-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)


Maintenance

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)

R1:1

PD

PD


• 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/m2

Repeat up to 3 cycles

Concurrent arm

Sequential arm

Secondary endpoints

• OS, tumour response and safety

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)

OS PFS

Concurrent Sequential Concurrent Sequential

Median, mo 41.9 30.7 18.3 15.3

95% CI 35.1, NR 23.2, 40.5 9.7, 21.9 11.3, 17.4

HR 0.55 0.80

p-value 0.042 0.20

1-year rate, % 87.8 87.2 61.0 61.2

2-year rate, % 80.5 64.0 29.1 25.2

3-year rate, % 58.9 39.8 20.6 18.9

OS

OS

pro

babi

lity

(%)

100

80

60

40

20

00 12 24 36 48 60

Time (months)

ConcurrentSequential

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

PDKey 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/m2/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)

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^)

PFS OSAfatinib + paclitaxel (n=134)

Investigator choice (n=68)

PFS event, n (%) 105 (78.4) 54 (79.4)

Median PFS (mo) 5.6 2.8

HR (95% CI) 0.60 (0.43, 0.85)

p=0.0031

Time (months)

Pro

gre

ssio

n-fr

ee s

urvi

val

(pro

babi

lity)

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27

AfatinibCT

Time (months)

Ove

rall

surv

ival

(p

roba

bilit

y)

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27

AfatinibChemo

Afatinib + paclitaxel (n=134)

Investigator choice

(n =68)

OS event, n (%) 100 (74.6) 46 (67.6)

Median OS (mo) 12.2 12.2

HR (95% CI) 1.00 (0.70, 1.43)

p=0.99

33 36 3930

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

PDKey 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)

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)


Later lines

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)

8112^: Nivolumab (anti-PD-1, BMS-936558, 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^)

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)

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

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 MEDI4736 10 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^)

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)

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)

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-2206 45 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)

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)

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)

8026: Clinical activity of LY2835219, 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, LY2835219 (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)

LY2835219 150 mg or 200 mg q12h,

days 1–28

Secondary endpoints• Anti-tumour activity, pharmacodynamics

and predictive biomarkers

8026: Clinical activity of LY2835219, 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– LY2835219 demonstrated anti-tumour activity in advanced NSCLC, particularly in KRAS

mutation-positive disease– LY2835219 had an acceptable safety profile

80

60

40

20

0

–20

–40

–60

–80

–100

Per

cen

tag

e ch

ang

e fr

om b

asel

ine

† SQ SQ SQ

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

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

R1:1

PD

PD

Stratification

• EGFR mutant vs wild-type, MET 2+ vs 3+, number of prior treatments, histology


• 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)

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

Pro

ba

bili

ty o

f P

FS

1.0

0.8

0.6

0.4

0.2

0.00 3 6 9 12 15

Time (months)

Median 2.6 months(95% CI 1.5, 2.8)

HR 0.99 (95% CI 0.81, 1.2)p=0.92


HR 1.27 (95% CI 0.98, 1.65)p=0.07

Pro

ba

bili

ty o

f O

S

1.0

0.8

0.6

0.4

0.2

0.00 3 6 9 12 15 18 21

Time (months)



Placebo+erlotinib (n=249)

Onartuzumab+erlotinib (n=250)

Censored Placebo+erlotinib (n=249)

Onartuzumab+erlotinib (n=250)

Censored

ORR 8.8% placebo+erlotinib vs. 6.4% onartzumab+erlotinib

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; % 2nd-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

PD

Stratification

• Gender, PS, stage, smoking history, EGFR status, institution, prior regimen


• 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)


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

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)


Secondary endpoints• OS, DCR and safety

R

PD

PD

Stratification

• Disease stage, ECOG PS, geographic region


• Stage IIIB/IV

• Failed first-line platinum-based CT

• Current smokers

(n=213) Erlotinib 300 mg/day(n=159)


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)

8103: Antitumor activity of alectinib (CH5424802/RO5424802) 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)

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 0.941 (95% CI 0.802, 1.104; p=0.229) across all patient population and HR 1.022 (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 matureRamalingam et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8018)

8022: Safety and response with nivolumab (anti-PD-1; BMS-936558, 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


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

8022: Safety and response with nivolumab (anti-PD-1; BMS-936558, 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


Nivolumab+erlotinib (n=21)

PFS

PFS rate (95% CI) at 24 weeks, % 51 (28, 70)

Median (range) PFS, weeks 29.4 (4.6, 81.7+)

OS

1-year OS rate (95% CI), % 73 (46, 88)

Median (range) OS, weeks NR (10.7+, 86.9+)

7500: A multinational phase III randomized trial with or without consolidation chemotherapy using docetaxel and cisplatin after concurrent chemoradiationin 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/m2 each per week for 6 weeks, total dose of 66 Gy of thoracic RT as 33 fractions); †Additional DP (35 mg/m2 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

R1:1

PD

PDKey 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/m2) + P (20 mg/m2)

(n=211)

Stratification

• Centre

• Performance


• Key results

– Survival was similar between treatment arms during a median follow-up of 50.7 months


PFS

Patients Events mPFS (95% CI)

CCRT alone 209 180 8.05 (7.56, 8.90)

CCRT + consolidation 211 169 9.10 (7.92, 10.94)

Pro

gre

ssio

n-fr

ee s

urvi

val

1.0

0.8

0.6

0.4

0.2

0.0

Time (months)0 12 24 36 48 60 72 84

CCRT alone

CCRT + consolidation

HR 0.906(95% CI 0.734, 1.119)p=0.410


• 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


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

R1:1

PD

PDKey patient inclusion criteria• Stage IV NSCLC• Non-squamous or squamous• Previous platinum-based CT• ECOG PS 0/1

(n=1253) Placebo + docetaxel 75 mg/m2 q3w

(n=625)

Ramucirumab 10 mg/kg + docetaxel 75 mg/m2 q3w

(n=628)

Stratification

• Gender, region (East Asia vs ROW), ECOG PS (0 vs 1), prior maintenance therapy

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


Median (95% CI) Censoring rate

RAM+DOC

RAM+DOC vs PL+DOC:

10.5 (9.5, 11.2) 31.8%

PL+DOC 9.1 (8.4, 10.0) 27.0%

Stratified HR (95% CI) 0.857 (0.751, 0.979)

Stratified log-rank p=0.0235

0

20

40

60

80

100

Ove

rall

surv

ival

(%

)

RAM+DOCPL+DOC

Number at risk

0 3 6 9 12 15 18 21 24 27 30 33

527501

415386

329306

231197

156129

10386

7056

4536

2323

119

20

36

Survival time (months)

628625

00

RAM+DOCPL+DOCCensored

OS PFS

Median (95% CI) Censoring Rate

RAM+DOC vs PL+DOC:

4.5 (4.2, 5.4) 11.1%3.0 (2.8, 3.9) 6.7%

Stratified HR (95% CI) 0.762 (0.677, 0.859)Stratified log-rank p<0.0001

RAM+DOCPL+DOC

Pro

gre

ssio

n-f

ree

surv

ival

(%

)

RAM+DOCPL+DOC

Number at risk

RAM+DOCPL+DOCCensored

0 3 6 9 12 15 18 21 24 27 30 33

383301

204172

12095

5937

3817

119

74

33

32

00

00

36

Survival time (months)

628625

00

0

20

40

60

80

100

RAM, ramucirumab; DOC, docetaxel

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


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

PDKey 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

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)

Dis

ea

se-f

ree

su

rviv

al

(pro

ba

bili

ty)

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 36 42 48 54 60

PCIControl

28.521.2

Median (months)

HR 0.67 (95% CI 0.46, 0.98), p=0.037

OS

Time from randomisation (months)

Ove

rall

surv

iva

l (p

rob

ab

ility

)

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 36 42 48 54 60

PCIControl

31.227.4

Median (months)

HR 0.81 (95% CI 0.56, 1.16), p=0.310

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 1.002 [95% CI 0.828, 1.212]; p=0.9873)• OS in KRAS wild-type HR 0.792 (95% CI 0.606, 1.034; p=0.0858) and KRAS mutant

HR 2.104 (95% CI 1.05, 4.216; p=0.0330)• OS in EGFR wild-type HR 0.925 (95% CI 0.7008, 1.208; p=0.5656) and EGFR mutant

HR 0.981 (95% CI 0.669, 1.438; p=0.9218)– PFS was significantly improved with dacomitinib (2.7 vs 1.4 months with placebo; HR 0.661

[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^)

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

R1:1

PD

PDKey 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)

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)

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)

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

Su

rviv

al (

pro

ba

bili

ty)

1.00

0.75

0.50

0.25

0.00

Time (months)0 12 24 36 48 60 72

Standard treatmentPORT

Median OS: 45.0 vs 40.9 monthsp=0.029

Other malignanciesSCLC and mesothelioma

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

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 AZD4547 80 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

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 LUN06-113 – 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

R1:1

PD

PDKey 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/m2 day 1/etoposide 120 mg/m2 days 1–3 ORCarboplatin AUC5 day 1/etoposide 100 mg/m2 days 1–3 q3w for 4 cycles

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 LUN06-113 – 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)

Pro

ba

bili

ty o

f su

rviv

al

1.0

0.8

0.6

0.4

0.2

0.00 5 10 15 20 30

Time to disease progression (months)

25

PlaceboZD6474

3131

1616

12

11

10

1 0

CensoredLog-rank p=0.9518

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

R1:1

PD

PD

Stratification

• ECOG PS, liver metastases, gender,induction CT, centre


• 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

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

Pro

bab

ility

of

surv

ival

1.0

0.8

0.6

0.4

0.2

0.00 6 12 18 24 30

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)

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/m2 days 1–3 + cisplatin 50 mg/m2 day 3, or etoposide 120 mg/m2 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)

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

R1:1

PD

PDKey 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

• 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)

0 6 12 18 24Time (months)

OS

OS

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0

247 147 67 26 14Thoracic RT

248 160 61 17 5 No thoracic RT

Thoracic RTNo

thoracic RT

Survival difference at:18 months: p=0.0324 months: p=0.004

24 months (95% CI), %Thoracic RT : 13 (8.8, 18.7)No thoracic RT : 3 (1.5, 7.6)

PFS

PF

S P

roba

bilit

y

0 3 6 9 12 15 18 21 24

Thoracic RT

No thoracic RT

0.0

0.2

0.4

0.6

0.8

1.0

Time (months)

247 163 59 31 15 10 9 9 7 Thoracic RT

248 126 48 15 8 3 3 3 3 No thoracic RT

HR (95% CI) 0.73 (0.61, 0.87)p=0.001

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

PD

Stratification

• Age, ECOG PS, response, institution


• 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

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)

0 3 6 9 12 15 18 21 24 27 30 33 36 390

20

40

60

80

100

months

Stratified log-rank test: p=0.091 (2-sided)

Arm B: No PCI

Arm A: PCI

Arm A: PCIn=84

Arm B: no PCIn=79

No. of OS events 61 50

Hazard ratio (95% CI) 1.38 (0.95, 2.02)

Median OS (95% CI), mo 10.1 (8.5, 13.2) 15.1 (10.2, 18.7)

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

PD

Stratification

• PS, localised/extensive disease, institution


• 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/m2 d1–5, q3w)

(n=90)

5 cycles of cisplatin (25 mg/m2 d1/8) +

etoposide (60 mg/m2 d1–3) + irinotecan (90 mg/m2 d8)

(n=90)

Arm A

Arm B

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)

Events 82 72

MST (95% CI)12.5 months (10.8, 14.9)

18.2 months (15.7, 20.6)

One-sided p 0.0079

HR (90% CI) 0.67 (0.51, 0.88)Pro

por

tion

of O

S

1.0

0.8

0.6

0.4

0.2

0.00 6 12 18 24 30 36 42 48 54 60 66

Months after randomisation

PEI

Topotecan

PEI, cisplatin+etoposide+irinotecan

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)

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 109 CFU; 250 mL IV over 2 hours) 2 weeks apart, followed by up to 6 cycles of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) 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)

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


Secondary endpoints• Response rate, OS and toxicity

R

PD

PDKey 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-PEG20 320 IU/m2 IM

injection/week (36.8 mg/m2)(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 PositronEmission Tomography

FDG-PET was used to measure plasma arginine, citrulline, ADI-PEG20 antibody, ASS1 methylation status and metabolic response

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%

aliv

e a

nd

pro

gre

ssio

n-f

ree 100

80

60

40

20

00 50 100 150 200 250 300 350 400 450

Time since randomisation (days)

HR (95% CI) 0.51 (0.30, 0.86), p=0.012

Median PFS (67 events*)BSC 1.9 monthsBSC + ADI-PEG20 3.2 months

BSCBSC + ADI-PEG20

*One patient remains progression-free and alive: 12 months (BSC + ADI+PEG20)

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 cancerKindler et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7589) IHC, immunohistochemistry

Other malignanciesRare tumours

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)

7526: A phase II study of milciclib (PHA-848125AC) 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 thymomaBesse et al. J Clin Oncol 2014; 32 (suppl 5; abstr 7526)

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)

2014 ASCO Annual Meeting

Supported by Lilly and Company.Lilly and Company has not influenced the content of this publication

Developed in association with theEuropean Thoracic Oncology Platform

30 May – 3 June 2014Chicago, USA

Documents

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