INTRODUCTION

Lung cancer• Among all cancers, lung cancer is the leading cause of death in the United States

and globally, with non-small cell lung cancer (NSCLC) accounting for >85% of all lung-cancer cases1,2

• The majority of patients with NSCLC present with metastatic disease; the 5-year survival rate in these patients is <2%3,4

• Platinum-based doublet chemotherapy is a 1st-line treatment for metastatic NSCLC that results in 1-year overall survival (OS) rates of approximately 30% to 43%5

– In the 2nd-line, the addition of a biologic agent to docetaxel provides modest gains in OS6

• In a small subset of patients, targeted therapy with oral tyrosine kinase inhibitors has demonstrated clinical efficacy, but resistance eventually develops7

• New approaches are needed to improve OS beyond what is currently achievable with standard-of-care or newer targeted therapies

Immune-based therapies in cancer: PD-1/PD-L1 pathway8

• Increased progression-free survival (PFS) and OS have been demonstrated in NSCLC and melanoma with immune checkpoint inhibitors9,10

– Durable antitumor responses and manageable safety profiles have been reported in a growing list of tumor types

• The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers

Avelumab* (MSB0010718C)• Key attributes (Figure 1)11

– Fully human anti-PD-L1 IgG1 antibody – Binds PD-L1

• Inhibits PD-1/PD-L1 interactions• Leaves PD-1/PD-L2 pathway intact

– Half-life of ~3.5-4.8 days; >95% target occupancy over the whole dosing period – Antibody-dependent cell-mediated cytotoxicity (ADCC) may contribute to

activity, as shown in preclinical models12

– Preliminary (n=28) safety, pharmacokinetic (PK), and efficacy data from a phase I dose-escalation trial (JAVELIN Solid Tumor; NCT01772004) have been previously reported• Doses up to 20 mg/kg once every 2 weeks were safely administered• Antitumor activity in lung, gastric, bladder, and other malignancies

• In this prespecified analysis performed 6 months after start of treatment of the last patient, we report safety and clinical activity of avelumab in a cohort with advanced NSCLC progressing after platinum-based doublet chemotherapy

Figure 1. Mechanism of action of avelumab

Immunemediators

T-cell mediatedimmune response

PD-1

PD-1PD-L1

PD-L1

AvelumabAvelumab

FcγRTumorCell

T Cell

NK Cell

Potential ADCCactivity

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

OBJECTIVES

• Primary objective of this phase Ib, dose-expansion study: – Assess safety and tolerability of avelumab in patients with NSCLC, post-platinum

doublet chemotherapy• Select secondary objectives include:

– Assess best overall response (BOR), PFS, and OS of patients treated with avelumab

– Evaluate association between tumor PD-L1 expression and BOR

METHODS

• Patients with histologically confirmed stage IIIB or stage IV NSCLC and ECOG performance status of 0 or 1 received avelumab at 10 mg/kg intravenously (IV) every 2 weeks (Q2W) until progression, unacceptable toxicity, or any criterion for withdrawal occurred (Figure 2) – Other eligibility criteria included:

• Disease that had progressed after 1 line of platinum-containing doublet chemotherapy

• ≥1 measurable lesion• Availability of tumor archival material or fresh biopsies for analysis of PD-L1

expression• Patients with active or history of central nervous system metastases were

excluded• Efficacy was assessed every 6 weeks according to Response Evaluation Criteria

In Solid Tumors (RECIST) version 1.1 and modified immune-related response criteria (irRC); time-to-event endpoints were estimated using the Kaplan-Meier method

• Subgroup analysis of efficacy parameters was performed according to tumor PD-L1 expression status (positive or negative) of any intensity by immunohistochemistry using 1% cutoff level

• Adverse events (AEs) were monitored throughout the study and evaluated according to NCI-CTCAE v4.0 – AEs that were potentially immune-related were indicated by investigators

Figure 2. Study design

Patients with histologically

confirmed stageIIIB or stage IV

NSCLC post-platinum-doublet

Treatment withavelumab

10 mg/kg IV Q2W

Selectassessments:

safety, ORR, PFS,OS, PD-L1 status

RESULTS

• In total, 184 patients with stage IIIB and stage IV NSCLC were treated with avelumab 10 mg/kg Q2W for a median duration of 12.2 weeks (range, 2.0-64.0) and followed for ≥6 months

• 41 patients were still on treatment at the time of data analysis (15 Jan 2015)

• Patient demographics and disease characteristics are shown in Table 1

Table 1. Patient demographics and disease characteristics

Characteristics n=184

Median age, years (range) 65.0 (31.0-83.0)

Gender, n (%) Male Female

100 (54.3)84 (45.7)

ECOG PS, n (%) 0 1 >1

55 (29.9)128 (69.6)

1 (0.5)

Histology, n (%) Adenocarcinoma Squamous cell carcinoma Other

114 (62.0)53 (28.8)17 (9.2)

Number of prior anticancer therapies for LA/M disease, n (%) 0 1 2 3 ≥4 Median (range)

1 (0.5)122 (66.3)44 (23.9)8 (4.3)9 (4.9)1 (0-5)

LA/M, locally advanced/metastatic

PD-L1 expression status• The majority of tumors were positive for PD-L1 (122; 66.3%) based on a cutoff of

≥1% of tumor cells showing staining of any intensity; 20 (10.9%) were assessed as PD-L1-negative and 42 (22.8%) were not evaluable for analysis of PD-L1 expression

Safety• Treatment-related treatment-emergent AEs (TEAEs; all grades) occurred in

142 patients (77.2%; Table 2)

Table 2: Treatment-related TEAEs

Events, n (%)Most common (>5%) treatment-related TEAEs,

all grades (n=184)Fatigue 46 (25.0)

Infusion-related reaction* 38 (20.7)

Nausea 24 (13.0)

Chills 12 (6.5)

Decreased appetite 13 (7.1)

Diarrhea 13 (7.1)

Hypothyroidism 12 (6.5)

* On Jan 29 2014, a mandatory premedication regimen of diphenhydramine and acetaminophen was implemented for all patients. According to protocol, other treatment modifications were permitted for patients experiencing infusion-related reactions, including a reduction of the infusion rate. 37.5% of patients in this cohort received ≥1 of the first 4 infusions without premedication.

• 12.5% (23/184) of patients experienced treatment-related grade ≥3 TEAEs, including 4 infusion-related reactions (Table 3)

• All grade treatment-related/immune-related AEs occurred in 23 (12.5%) patients

– Those occurring >1% included hypothyroidism (12; 6.5%), adrenal insufficiency (2; 1.1%), and radiation pneumonitis (2; 1.1%)

• Treatment-related TEAE leading to death was reported in 2 patients (radiation pneumonitis [1], acute respiratory failure [1])

Table 3. Grade 3/4 treatment-related TEAEs

Events, n (%)Grade 3/4 treatment-related TEAEs

occurring >1%, (n=184)Infusion-related reaction 4 (2.2)

Lipase increased 3 (1.6)

Dyspnea 2 (1.1)

Constipation 2 (1.1)

Clinical activity of avelumab• Objective responses to avelumab monotherapy observed in 13.6% (25/184) of patients,

including 1 complete response (CR) and 24 partial responses (PR), as shown in Table 4 and Figure 3

Table 4. Antitumor activity

Best Overall Response* n (%)

CR 1 (0.5)

PR 24 (13.0)

Stable disease (SD) 68 (37.0)

Progressive disease (PD) 68 (37.0)

Non-evaluable (NE) 23 (12.5)

Objective Response Rate (ORR) 25 (13.6) [95% CI: 9.0, 19.4]

Disease control rate (DCR)† 93 (50.5%)

* Includes confirmed and unconfirmed responses as assessed by RECIST 1.1 in patients with measurable disease at baseline

† DCR is defined by CR + PR + SD

Figure 3. Percent change from baseline

180

160

140

120

100

80

60

40

20

-20

-40

-60

-80

-100

0

0

Cha

nge

in ta

rge

t le

sio

ns fr

om

ba

selin

e (

%)

Weeks since treatment initiation

10 20 30 40 50 60 70

Patients with NSCLC (n=158)

Complete responsePartial responseStable diseaseProgressive diseaseNot evaluableFirst occurrence of new lesionPatient off treatment

* Number of patients with baseline tumor assessment and ≥1 treatment-related tumor assessment.

• Tumor shrinkage by ≥30% was observed in 25 (13.6%) patients, as shown in Figure 4

Figure 4. Change in target lesions from baseline

80706050403020100

-10-20

-40-50-60-70-80-90

-100

-30

Cha

nge

fro

m b

ase

line

in s

um o

f lo

nge

st d

iam

ete

r (%

) Patients with NSCLC (n=158)

Complete responsePartial response

• Responses were observed early in the treatment cycle and appear to be durable based on 6-month follow-up data

– 1st response assessment (6 wks): 40.0% (10/25)

– 2nd response assessment (12 wks): 9 additional patients had a response

• Among the 25 patients who responded to treatment with avelumab, the response was ongoing in 19 (76.0%) of them at the time of analysis, including in 2 patients who continued to respond off-treatment (Figure 5)

Figure 5. Time to and duration of response

0

Ind

ivid

ual p

atie

nts

Weeks since treatment initiation

10 15 20 25 30 40 50 60 65554535 70

Complete responsePartial responseProgressive diseaseOngoing responseEnd of treatment

5

• Median PFS: 11.6 weeks (95% CI: 8.4, 13.7) based on 139 events (Figure 6)

• Proportion of patients alive and progression-free at 24 weeks and 48 weeks was 26.2% (95% CI: 19.9, 33.0) and 18.1% (12.0, 25.2), respectively

Figure 6. PFS

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Kapl

an-M

eier

est

imat

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PFS time (weeks)

0 10 15 20 25 30 40 50 60 65554535 705

184At risk 99 70 52 33 23 14 6 2 141020 0156

• Median OS was 8.4 months (95% CI: 7.3, 10.7; Figure 7)• Proportion of patients alive at 12 months was 37.0% (95% CI: 27.1, 46.9)

Figure 7. OS

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Kapl

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OS time (months)

0 2 3 4 5 6 7 9 11 12 14 1513

5

108 161

184 155 144 129 118 100 73 31 18 13 4 22654 0170At risk

Clinical activity and PD-L1 expression• Trend indicating improved PFS in the PD-L1+ population compared with the

PD-L1– population (Table 5 and Figures 8 and 9)

Table 5: Clinical activity by PD-L1 expression status*

Evaluable population, n=142

PD-L1+(n=122)

PD-L1–(n=20)

Between-group comparison

ORR†, n (%)[95% CI] 19 (15.6) [9.6, 23.2]

2 (10.0)[1.2, 31.7] p=0.738‡

Median PFS, weeks (95% CI) 12.0(10.9, 17.7)

5.9(5.6, 7.1)

HR 0.449 (0.271, 0.746)

Median OS, months (95% CI) 8.9(8.0, NE)

4.6(2.8, NE)

HR 0.630 (0.336, 1.180)

NE, not estimable* Based on a cutoff of ≥1% tumor cells with staining of any intensity† Includes confirmed and unconfirmed responses as assessed by RECIST 1.1.‡ Fisher’s exact test

Figure 8. PFS by PD-L1 expression status*

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

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0.0

Ka

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PFS time (weeks)

0 10 15 20 25 30 40 50 60 65554535 705

122At riskPD-L1+PD-L1–

71 51 38 26 20 12 5 2 13818 010520 4 2 1 1 1 1 1 0 0111 017

Patients with NSCLC evaluable for PD-L1 expression (n=142)

PD-L1+PD-L1–

* Based on a cutoff of ≥1% tumor cells with staining of any intensity

Figure 9. OS by PD-L1 expression status*

1.0

0.9

0.8

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0.6

0.5

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0.3

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122At riskPD-L1+PD-L1–

106 99 88 71 54 25 14 4 252140 011520 17 15 11

859 9 8 3 2 0 00

10237 018

Patients with NSCLC evaluable for PD-L1 expression (n=142)

PD-L1+PD-L1–

0 2 3 4 5 6 7 9 11 12 14 1513108 161

OS time (months)

* Based on a cutoff of ≥1% tumor cells with staining of any intensity

CONCLUSIONS

• Treatment with avelumab was associated with a manageable safety profile

• Avelumab monotherapy showed early and sustained responses as a 2nd-line treatment for patients with metastatic or recurrent NSCLC progressing after platinum-doublet chemotherapy– 13.6% ORR, with 1 CR and 24 PRs– 76% of responses were ongoing at the time of analysis– Stable disease was achieved in 37% of patients; 50.5% DCR

• PD-L1 expression by tumor cells was associated with improved ORR and PFS

• JAVELIN Solid Tumor is ongoing with recruitment of 150 additional patients to a 1st-line NSCLC cohort

• A phase III head-to-head trial of avelumab vs docetaxel in patients with recurrent NSCLC (JAVELIN Lung 200) is also underway

REFERENCES1. Siegel RL, et al. CA Cancer J Clin. 2015;65(1):5-29.

2. International Agency for Research on Cancer. GLOBOCAN 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed 2 April 2015.

3. Molina JR, et al. Mayo Clin Proc. 2008;83(5):584-94.

4. National Cancer Institute Fact Sheet. 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 2 April 2015.

5. Zhu J, et al. Cancer. 2013;119(11):2048-60.

6. Garon EB, et al. Lancet. 2014;384(9944):665-73.

7. Jackman D, et al. J Clin Oncol. 2010;28(2):357-60.

8. Hamid O, Carvajal RD. Expert Opin Biol Ther. 2013;13(6):847-61.

9. Robert C, et al. N Engl J Med. 2015;372(4):320-30.

10. Rizvi NA, et al. Lancet Oncol. 2015;16(3):257-65.

11. Heery CR, et al. J Clin Oncol. 2014;32(Suppl 15): Abstract 3064.

12. Lepone LM, et al. AACR Annual Meeting. 2015:Abstract 1316.

ACKNOWLEDGMENTS

This trial was sponsored by Merck KGaA, Darmstadt, Germany and is part of an alliance between Merck KGaA and Pfizer. The authors would like to thank the patients, 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*. Medical writing support was provided by ClinicalThinking, Hamilton, NJ and funded by Merck KGaA, Darmstadt, Germany.

* A US subsidiary of Merck KGaA, Darmstadt, Germany

DISCLOSURES

HJG and AvH are employees of Merck KGaA, Darmstadt, Germany; AvH is a stockholder of Merck KGaA, Darmstadt, Germany; KC is an employee of EMD Serono, Inc.*, Billerica, Massachusetts. These authors disclose the following relationships with Merck KGaA: KK, DJLW, and JL have received research funding; DJLW and JG have received travel/accommodation funding. All other authors have nothing to declare in relation to Merck KGaA.

* EMD Serono, Inc. is a subsidiary of Merck KGaA, Darmstadt, Germany

Correspondence: J. L. Gulley, gulleyj@mail.nih.gov

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Avelumab (MSB0010718C), an anti-PD-L1 antibody, in advanced NSCLC patients: a phase Ib, open-label expansion trial in patients progressing after platinum-based chemotherapy J. L. Gulley,1,2 D. R. Spigel,3 K. Kelly,4 J. Chandler,5 A. Rajan,6 R. Hassan,6 D. J. L. Wong,7 J. Leach,8 W. J. Edenfield,9 D. Wang,10 N. Vrindavanam,11 G. J. Weiss,12 J. Gurtler,13 H. J. Grote,14 A. von Heydebreck,14 K. Chin,15 N. Iannotti16

1Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; 2Genitourinary Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; 3Sarah Cannon Research Institute/Tennessee Oncology, North Nashville, Tennessee, USA; 4University of California-Davis Comprehensive Cancer Center, Sacramento, California, USA; 5The West Clinic, Memphis, Tennessee, USA; 6Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; 7Division of Hematology-Oncology, UCLA Medical Center, Los Angeles, California, USA; 8Virginia Piper Cancer Institute, Minneapolis, Minnesota, USA; 9Institute for Translational Oncology Research, Greenville, South Carolina, USA; 10Henry Ford Hospital, Detroit, Michigan, USA; 11Signal Point Clinical Research Center, Middletown, Ohio, USA; 12Western Regional Medical Center, Cancer Treatment Centers of America, Goodyear, Arizona, USA; 13Metairie Oncologists, Metairie, Louisiana, USA; 14Merck KGaA, Darmstadt, Germany; 15EMD Serono, Billerica, Massachusetts, USA; 16Hematology Oncology Associates of the Treasure Coast, Port St. Lucie, Florida, USA

Poster Presentation at the 51st ASCO Annual Meeting, May 29-June 2, 2015; Chicago, Illinois. Abstract No. 8034.