BACKGROUNDLung Cancer• Lung cancer is the leading cause of cancer-related death in the United States and worldwide,

and non-small-cell lung cancer (NSCLC) accounts for ≈85% of cases1,2 • Patients with metastatic NSCLC who have good performance status may benefit from first-line

chemotherapy, typically with a platinum-based regimen3 – Commonly used first-line regimens for nonsquamous NSCLC include cisplatin (or carboplatin)/

pemetrexed or carboplatin/pacitaxel with or without bevacizumab(anti-VEGF targeted agent); gemcitabine/cisplatin is used for squamous NSCLC

– Patients with epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations may be treated with tyrosine kinase inhibitors targeting EGFR and ALK

• Despite improvements in chemotherapy options and supportive care, 1-year survival rates with platinum-based regimens are only ≈30%-40% and median survival is 8-10 months3; the 5-year survival rate for patients who present with metastatic disease is <2%4

• There is significant medical need for new therapeutic strategies to overcome limitations of currently used first-line therapies for NSCLC

Immune-based therapies in cancer: PD-1/PD-L1 pathway• Programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the

reactivation of the immune response against multiple cancers5,6

• Clinical data in a growing list of tumor types suggest that anti-PD-(L)1 antibodies are well-tolerated and provide durable antitumor responses – PD-1 blockade with nivolumab or pembrolizumab has been associated with improved

responses and longer survival compared with docetaxel in patients with advanced NSCLC in the second-line setting, leading to regulatory approval7-9

• PD-L1, a marker of immune activation, is expressed in up to 60% of NSCLC specimens and is associated with poor prognosis10,11

Avelumab* (MSB0010718C)• Fully human IgG1 anti-PD-L1 monoclonal antibody12

• Binds PD-L1 (Figure 1)12 – Inhibits PD-1/PD-L1 interactions – Leaves PD-1/PD-L2 pathway intact

• Antibody-dependent cell-mediated cytotoxicity (ADCC) may contribute to activity, as shown in preclinical models13

• Safety, pharmacokinetic (PK), and clinical activity of avelumab have been investigated in phase 1 trials in advanced solid tumors (JAVELIN Solid Tumor and JAVELIN Solid Tumor JPN)12,14-16

– Half-life ≈4-5 days; >95% target occupancy dosing every 2 weeks (Q2W) at 10 mg/kg dose – Doses up to 20 mg/kg Q2W were safely administered during dose-escalation studies

• Objective responses and disease stabilization with avelumab have been reported in several tumor types, including NSCLC, ovarian cancer, urothelial carcinoma, gastric cancer, mesothelioma, and breast cancer17-24

– In NSCLC, avelumab has shown efficacy in patients progressing after platinum-based chemotherapy, including a trend toward greater activity in patients with PD-L1+ tumors17,18

*Avelumab is the proposed nonproprietary name for the anti-PD-L1 monoclonal antibody (MSB0010718C).

Figure 1. Mechanism of action of avelumab

OBJECTIVES• Primary objective of the JAVELIN Solid Tumor (NCT01772004) phase 1b trial:

– Assess safety and tolerability of avelumab• Secondary objectives include:

– Assess best overall response (BOR), progression-free survival (PFS), and OS – Evaluate the association between PD-L1 expression on tumor cells and tumor-infiltrating

immune cells and clinical activity of avelumab

METHODSSelect patient eligibility criteria• Eligible patients were adults with histologically or cytologically confirmed metastatic or recurrent

NSCLC negative for EGFR mutation or ALK translocations, who had not received prior treatment for metastatic or recurrent disease (Figure 2) – Patients with non-squamous NSCLC whose tumors had unknown EGFR and ALK status were

tested and were excluded if found to be positive• Other eligibility criteria included ECOG performance status score of 0 or 1, estimated life

expectancy ≥3 months, measurable disease per RECIST v1.1, and availability of fresh biopsy or tumor archival material for analysis of PD-L1 expression – Patients were not preselected based on PD-L1 expression

PD-L1 expression• PD-L1 expression (positive or negative) in tumor samples was assessed using a proprietary

immunohistochemistry assay (Dako; clone 73-10) at various cut-off levels based on quantity and intensity of staining (Table 1)

Table 1: Cut-off levels for analysis of PD-L1 expression

Cut-off levels for PD-L1+ Site of staining Intensity of staining

≥1% cut-off Tumor cells Any intensity (≥1+)

≥5% cut-off Tumor cells Any intensity (≥1+)

≥25% cut-off Tumor cells Moderate-to-high (≥2+)

≥10% cut-off Tumor-infiltrating immune cells Any intensity (≥1+)

Treatment and assessments• Patients received avelumab 10 mg/kg as a 1-hour intravenous (IV) infusion Q2W• Treatment continued until confirmed disease progression, unacceptable toxicity, or other criteria

for withdrawal were met• Efficacy was assessed every 6 weeks according to RECIST v1.1; time-to-event endpoints were

analyzed using Kaplan-Meier methodology• Adverse events (AEs) were assessed throughout the trial period and graded by NCI-CTCAE v4.0

Figure 2. JAVELIN Solid Tumor first-line NSCLC cohort study design

Patients with histologically confirmedstage IV or recurrent NSCLC,

not previously treated inthe advanced setting

No EGFR mutation or ALK translocation

Unselected for PD-L1 expression

Avelumab10 mg/kg IV Q2W

Select assessments:– Safety– BOR– PFS– OS– PD-L1 expression

RESULTS• As of data cut-off on October 23, 2015, 145 patients with advanced NSCLC were treated with

avelumab as first-line therapy (Table 2 and Figure 3)• Median duration of treatment was 10.0 weeks (range, 2-30), and patients received a median of

5 doses (range, 1-15)• Median follow-up was 13 weeks (range, 0-31; Figure 3)• 91 patients (62.8%) were still on treatment at the cut-off date• Specimens from 79 patients (54.5%) were evaluable for PD-L1 expression by different cut-off levels

(Table 3)

Figure 3. Safety analysis set and follow-up time for efficacy analyses

Safety analysis setN=145

≥6 weeks follow-upn=124

≥13 weeks follow-upn=75

≥6 weeks follow-up and≥1 post-baseline tumor assessment

n=105

≥13 weeks follow-up andevaluable for PD-L1 expression

n=45

Table 2. Patient and disease characteristicsCharacteristics N=145Median age, years (range) 70 (41-90)Sex, n (%)

MaleFemale

74 (51.0)71 (49.0)

ECOG PS, n (%)01

45 (31.0)100 (69.0)

Histology, n (%)AdenocarcinomaSquamous cell carcinomaBronchoalveolarLarge cellOtherUnknown

92 (63.4)39 (26.9)1 (0.7)1 (0.7)3 (2.1)9 (6.2)

Smoking status, n (%)Ever smoked*Never smokedUnknown

126 (86.9)17 (11.7)2 (1.4)

Median time since first diagnosis, months (range)† 1.9 (0.2, 99.4)Median time since diagnosis metastatic disease, months (range)‡ 1.6 (0.3, 92.0)

* Includes regular (25), occasional (2), and former (99). † Data available for 137 patients at cut-off. ‡ Data available for 97 patients at cut-off.

Table 3. PD-L1 expression statusStaining cut-off level(N=79)*

PD-L1+n (%)

PD-L1−n (%)

≥1% tumor cells 62 (78.5) 17 (21.5)≥5% tumor cells 52 (65.8) 27 (34.2)≥25% tumor cells† 29 (36.3) 51 (63.8)≥10% tumor-infiltrating immune cells 9 (11.4) 70 (88.6)

* Non-evaluable specimens (n=66) included those that were missing, of poor quality, or otherwise not available to provide results.† 80 specimens were evaluable for assessment based on ≥25% tumor cells cut-off.

Safety• Treatment-related adverse events (TRAEs) of any grade occurred in 82 patients (56.6%) and were

mostly grade 1 or 2 (Table 4)• 13 patients (9.0%) had a grade 3 or 4 TRAE

– Only infusion-related reaction and fatigue occurred at grade ≥3 in >1 patient (n=3 each; 2.1%) • Potential immune-mediated TRAEs occurred in 4 patients (2.8%) and were all grade 1 or 2

(pneumonitis [n=3; 2.1%] and hypothyroidism [n=1; 0.7%]) – Only 1 patient had a serious immune-mediated TRAE (pneumonitis)

• 7 patients (5.6%) discontinued treatment following a TRAE• There were no deaths related to trial treatment

Table 4. Incidence of TRAEs*

N=145 Any graden (%)

Grade 1-2n (%)

Grade 3-4†

n (%)Any TRAE 82 (56.6) 69 (47.6) 13 (9.0)Infusion-related reaction‡ 24 (16.6) 21 (14.5) 3 (2.1)Fatigue 21 (14.5) 18 (12.4) 3 (2.1)Nausea 11 (7.6) 11 (7.6) 0Diarrhea 9 (6.2) 9 (6.2) 0Chills 9 (6.2) 9 (6.2) 0Decreased appetite 8 (5.5) 7 (4.8) 1 (0.7)Anthralgia 7 (4.8) 6 (4.1) 1 (0.7)Hypoxia 2 (1.4) 1 (0.7) 1 (0.7)Hypertension 1 (0.7) 0 1 (0.7)Pneumothorax 1 (0.7) 0 1 (0.7)Hyponatremia 1 (0.7) 0 1 (0.7)Hyperkalemia 1 (0.7) 0 1 (0.7)Musculoskeletal chest pain 1 (0.7) 0 1 (0.7)

* Any grade in ≥5% or any grade ≥3 based on worst grade per patient. † 1 patient (0.7%) had a grade 4 infusion-related reaction; all other TRAEs were grade 3. ‡ Signs and symptoms of a potential infusion-related reaction (eg, fever, chills, or rigors) reported on the day of infusion were queried with investigators to ascertain whether an AE of “infusion-related reaction” should be recorded.

Clinical activity• In 75 patients with ≥13 weeks follow-up, responses by RECIST included 1 complete response and

13 partial responses (Table 5 and Figure 4) – The objective response rate (ORR) was 18.7% (14/75) – Disease control rate (DCR) was 64.0% based on 14 responses and 34 patients with stable disease

• Early and durable responses were observed (Figure 4) – 7/14 patients (50.0%) responded by the first assessment at 6 weeks – Median duration of response was not reached, and 85.7% of responses (12/14) were ongoing

at time of data cut-off, including 1 patient with a complete response

• Tumor regression of ≥30% occurred in 14/67 evaluable patients with ≥13 weeks of follow-up (Figure 5)• PFS rate at 24 weeks in all patients was 35.6% (95% CI: 23.2, 48.1), and median PFS was 11.6 weeks

(95% CI: 6.7, 17.9) – OS data are immature at this time

Table 5. Summary of clinical activity in patients with ≥13 weeks of follow-upClinical activity endpoint* n=75Complete response, n (%) 1 (1.3)Partial response, n (%) 13 (17.3)Stable disease, n (%) 34 (45.3)Progressive disease, n (%) 19 (25.3)Non-evaluable, n (%)† 8 (10.7)ORR, % (95% CI) 18.7 (10.6, 29.3)DCR, % 64.0

CI, confidence interval; DCR, disease control rate (defined as responses + stable disease); ORR, objective response rate.* Clinical activity of BOR based on unconfirmed and confirmed responses. Lack of response confirmation was due to no further tumor assessments at the time of cut-off or no confirmation in subsequent assessments (stable disease or progressive disease observed). Stable disease at the first post-baseline tumor assessment after 6 weeks was required to qualify for a BOR of stable disease. † Missing and/or not assessable information.

Figure 4. Time to and duration of response in patients with ≥13 weeks of follow-up

0 5 10 15 20Weeks since treatment initiation

PD-L1+

PD-L1 ne

PD-L1 ne

PD-L1+

PD-L1 ne

PD-L1+

PD-L1+

PD-L1+

PD-L1 ne

PD-L1+

PD-L1 ne

PD-L1+

PD-L1 ne

PD-L1 ne

Complete responsePartial responseProgressive diseaseOngoing responseEnd of treatment

Indi

vidu

al p

atie

nts

25 30 35

ne, not evaluable

Figure 5. Best change in target lesions

0

Perc

ent c

hang

e fro

m b

asel

ine

in su

m o

f tar

get l

esio

n di

amet

ers (

%)

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100

10

20

30

40

50

60

70 Complete response (n=1)Partial response (n=13)Stable disease (n=34)Progressive disease (n=17)Not evaluable (n=2)

80

* Evaluable patients (n=67) were those with ≥13 weeks follow-up, baseline tumor assessment, and ≥1 post-baseline assessment.

Clinical activity associated with PD-L1 expression level• Among patients with ≥13 weeks of follow-up and based on a ≥1% threshold in tumor cells,

ORR was 20.0% in PD-L1+ tumors (7/35) and 0% (0/10) in PD-L1– tumors (Table 6)• PFS associated with levels of expression are shown in Figure 6

Table 6: Unconfirmed ORR according to PD-L1 expression level in patients evaluable for PD-L1 expression and with ≥13 weeks of follow-up

Staining cut-off level(n=45)

PD-L1+, n/N1* (%)[95% CI]

PD-L1−, n/N1* (%)[95% CI]

≥1% tumor cells 7/35 (20.0)[8.4, 36.9]

0/10[0.0, 30.8]

≥5% tumor cells† 6/28 (21.4)[8.3, 41.0]

1/16 (6.3)[0.2, 30.2]

≥25% tumor cells 2/13 (15.4)[1.9, 45.4]

5/32 (15.6)[5.3, 32.8]

≥10% tumor-infiltrating immune cells 2/4 (50.0)[6.8, 93.2]

5/41 (12.2)[4.1, 26.2]

* N1=number of patients with evaluable PD-L1 expression and ≥13 weeks follow-up.† 44 patients were evaluable for response based on a ≥5% threshold in tumor cells.

Figure 6. PFS by PD-L1 expression status*

PFS

(%)

0

10

20

30

40

50

60

70

80

90

100

Time (weeks)

PD-L1+PD-L1–

Median PFSPD-L1+: 11.6 wks (6.3, ne)PD-L1–: 6.0 wks (3.3, 6.1)

0 5 10 15 20 25

62 51 21 12 3 117 11 2 1 1 1

PD-L1+PD-L1–

At risk

ne, not estimable. * Based on a ≥1% threshold for tumor cells (N=79 evaluable).

CONCLUSIONS• Avelumab showed clinical efficacy, including 1 complete response

(ORR, 18.7%; DCR, 64.0%), in patients with NSCLC treated in the first-line setting• PD-L1 expression in tumor cells was associated with a potential trend for higher

response and prolonged PFS with avelumab – Further evaluation of PD-L1 expression as a predictive biomarker for

avelumab is ongoing to determine the optimal PD-L1 staining threshold • First-line avelumab therapy for NSCLC was well-tolerated, with a low rate of

grade 3-4 toxicities and no deaths related to trial treatment• Two randomized phase 3 trials in NSCLC of single-agent avelumab vs

chemotherapy are in progress: – Avelumab vs standard of care chemotherapy as first-line treatment of

patients with NSCLC (Reck et al. ASCO 2016 abstract #TPS9105 [JAVELIN Lung 100; NCT02576574])

– Avelumab vs docetaxel in patients with NSCLC, post-platinum doublet chemotherapy (JAVELIN Lung 200; NCT02395172)

REFERENCES1. Siegel RL, et al. CA Cancer J Clin. 2016;66(1):7-30.2. Torre LA, et al. CA Cancer J Clin. 2015;65(2):87-108.3. National Comprehensive Cancer Network. NCCN Guidelines,

Non-Small Cell Lung Cancer. V4.2016.4. American Cancer Society. Non-small cell lung cancer survival rates

by stage. Available at: http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-survival-rates. Accessed 8 April 2016.

5. Postow MA, et al. J Clin Oncol 2015;33(17):1974-82.6. Anagnostou VK, Brahmer JR. Clin Cancer Res. 2015:21(5):976-84.7. Borghaei H, et al. N Engl J Med. 2015;373(17):1627-39.8. Brahmer J, et al. N Engl J Med. 2015;373(2):123-35.9. Herbst RS, et al. Lancet. 2016;387(10027):1540-50.10. Pan ZK, et al. J Thorac Dis 2015;7(3):462-70.11. Zhou ZJ, et al. Transl Lung Cancer Res 2015;4(2):203-8.

12. Heery CR, et al. J Clin Oncol. 2014;32(Suppl):Abstract 3064.13. Boyerinas B, et al. Cancer Immunol Res. 2015;3(10):1148-57.14. Heery CR, et al. J Clin Oncol. 2015;33(Suppl):Abstract 3055.15. Kelly K, et al. J Clin Oncol. 2015;33(Suppl):Abstract 3044.16. Shitara K, et al. J Clin Oncol. 2015;33(Suppl):Abstract 3023.17. Gulley JL, et al. J Clin Oncol. 2015;33(Suppl):Abstract 8034.18. Gulley JL, et al. Eur J Cancer. 2015;51(Suppl):Abstract 3090.19. Apolo A, et al. Eur J Cancer. 2015;51(Suppl S3):Abstract 2630.20. Disis ML, et al. J Clin Oncol. 2015;33(Suppl):Abstract 5509.21. Yamada Y, et al. J Clin Oncol. 2015;33(Suppl):Abstract 4047.22. Chung HC, et al. Eur J Cancer. 2015;51(Suppl S3):Abstract 2364.23. Hassan R, et al. Eur J Cancer. 2015;51(Suppl S3):Abstract 3110.24. Dirix LY, et al. Cancer Res. 2016;76(4 Suppl):Abstract S1-04.

ACKNOWLEDGMENTSThe authors would like to thank the patients and their families, investigators, co-investigators, and the study teams at each of the participating centers and at Merck KGaA, Darmstadt, Germany and EMD Serono, Billerica, MA, USA*. This trial was sponsored by Merck KGaA, Darmstadt, Germany and is part of an alliance between Merck KGaA and Pfizer Inc. Medical writing support was provided by ClinicalThinking, Hamilton, NJ and funded by Merck KGaA, Darmstadt, Germany and Pfizer Inc.

* A US-subsidiary of Merck KGaA, Darmstadt, Germany

DISCLOSURESFLC has participated in speakers’ bureaus for Onyx and Celgene. EMM has participated in speakers’ bureaus for Genentech, Merck and Bristol-Myers Squibb. EMM has also received honoraria from Genentech and Bristol-Myers Squibb. CHR holds stock in Pfizer. JB has provided consulting/advisory role and received honoraria from Roche, Boehringer Ingelheim, Novartis and Pierre Fabre Medicament. MT has provided consulting/advisory role to Eisai, Onyx and PDX Pharmacy. MT’s institution has received research funding from Merck KGaA, AstraZeneca, Eisai, Novartis, Celldex and Bristol-Myers Squibb. HK has provided consulting/advisory role to Alkermes, Amgen, Merck, Merck Serono and Prometheus, and has participated in a speakers’ bureau for Merck. HK has also received honoraria from Alkermes, Amgen, EMD Serono, Merck, Prometheus and Sanofi Pasteur, and has been reimbursed for travel, accommodations, or expenses from Alkermes, EMD Serono and Sanofi. HK has also received research funding from Bristol-Myers Squibb/Medarex. KK has provided consulting/advisory role to Clovis Oncology, Eli Lilly, Synta and AstraZeneca. KK has also received honoraria from Roche and Bristol-Myers Squibb, and has been reimbursed for travel, accommodations, or expenses from Clovis Oncology, Eli Lilly, Synta, AstraZeneca, Roche and Bristol-Myers Squibb. KK also holds author royalties for UpToDate, and KK’s institution has received research funding from Millennium, Novartis, Synta, EMD Serono, Eli Lilly, Genentech, Gilead Sciences and Celgene. MB and JMC are employees of EMD Serono, Inc., Billerica, Massachusetts. AVH is an employee of Merck KGaA, Darmstadt, Germany, and holds stock in Merck KGaA. GJ has provided consulting/advisory role to Novartis, Celgene, Roche, Amgen and Pfizer. GJ has also received honoraria from Novartis, Celgene and Roche, and has been reimbursed for travel, accommodations, or expenses from Novartis, Roche and GlaxoSmithKline. GJ also has received research funding from Novartis, MSD and Roche. All other authors have nothing to declare.

Correspondence: C. Verschraegen, Claire.Verschraegen@uvmhealth.org

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Avelumab (MSB0010718C; anti-PD-L1) as a first-line treatment for patients with advanced NSCLC from the JAVELIN Solid Tumor phase 1b trial: safety, clinical activity, and PD-L1 expression C. Verschraegen1, F. L. Chen2, D. R. Spigel3, N. Iannotti4, E. M. McClay5, C. H. Redfern6, J. Bennouna7, M. Taylor8, H. Kaufman9, K. Kelly10, M. Bajars11, A. von Heydebreck12, J.-M. Cuillerot11, G. Jerusalem13

1University of Vermont Cancer Center, Burlington, Vermont, USA; 2Novant Health Oncology Specialists, Winston-Salem, North Carolina, USA; 3Sarah Cannon Research Institute Tennessee Oncology, North Nashville, Tennessee, USA; 4Hematology Oncology Associates of the Treasure Coast, Port St. Lucie, Florida, USA; 5California Cancer Associates for Research & Excellence, Encinitas, California, USA; 6Sharp Healthcare, San Diego, California, USA; 7ICO René Gauducheau Recruiting, St. Herblain, France; 8Oregon Health & Science University, Knight Cancer Institute, Portland, Oregon, USA; 9Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA; 10University of California-Davis, Comprehensive Cancer Center, Sacramento, California, USA; 11EMD Serono, Inc., Billerica, Massachusetts, USA; 12Merck KGaA, Darmstadt, Germany; 13CHU Sart Tilman Liege and Liege University, Liege, Belgium

Abstract No. 9036. Presented at the 52nd ASCO Annual Meeting; June 3-7, 2016, Chicago, IL, USA.