Avelumab (anti–PD-L1) in combination with crizotinib or lorlatinib in patients with previously treated advanced NSCLC: phase 1b results from JAVELIN Lung 101Alice T. Shaw,1 Se-Hoon Lee,2 Suresh S. Ramalingham,3 Todd M. Bauer,4 Michael J. Boyer,5

Enric Carcereny Costa,6 Enriqueta Felip,7 Ji-Youn Han,8 Toyoaki Hida,9 Brett G. M. Hughes,10

Sang-We Kim,11 Makoto Nishio,12 Takashi Seto,13 Patrick I. Ezeh,14 Debasis Chakrabarti,15

Jing Wang,16 Andrew Chang,16 Luca Fumagalli,17 Benjamin J. Solomon18

1Alice T. Shaw, MD, PhD

1Massachusetts General Hospital Cancer Center, Boston, MA, USA; 2Samsung Medical Center, Seoul, South Korea; 3Winship Cancer Institute, Emory University, Atlanta, GA, USA; 4Tennessee Oncology, Nashville, TN, USA; 5Chris O'Brien Lifehouse, Camperdown, NSW, Australia; 6Institut Catalad'Oncologia de Badalona, Servicio de Oncologia Medica, Badalona, Spain; 7Hospital Universitari Vall d'Hebron, Barcelona, Spain; 8Center for Lung Cancer, National Cancer Center, Goyang-si, South Korea; 9Aichi Cancer Center Central Hospital, Nagoya, Japan; 10The Prince Charles Hospital, Cancer Care Services, Chermside, QLD, Australia; 11Asan Medical Center, Seoul, South Korea; 12The Cancer Institute Hospital of JFCR, Tokyo, Japan; 13National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan; 14Pfizer Inc, Cambridge, MA, USA; 15Pfizer Inc, Collegeville, PA, USA; 16Pfizer Inc, San Diego, CA, USA; 17Pfizer Inc, Milan, Italy; 18Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

Abstract No. 9008

Disclosures

I have the following financial relationships to disclose:

– Consultancy/advisory board member: ARIAD, Blueprint Medicines, Daiichi Sankyo, Genentech, Ignyta, KSQ Therapeutics, Loxo, Merck KGaA/EMD Serono, Natera, Novartis, Pfizer, Roche, Taiho Pharmaceutical, TP Therapeutics, and Takeda

– Research funding or other research support: Pfizer, Novartis, and Roche/Genentech

– Honoraria: Foundation Medicine, Guardant, Pfizer, Novartis, and Roche/Genentech

2Alice T. Shaw, MD, PhD

Background

• ALK tyrosine kinase inhibitors (TKIs) are standard of care for patients with advanced ALK+ NSCLC1

– Patients can have intrinsic resistance or develop acquired resistance to ALK TKIs

– ALK mutations are responsible for 20% to 25% of cases of crizotinib resistance and approximately 50% of cases of resistance to 2nd-generation ALK TKIs2

– Lorlatinib is a 3rd-generation, CNS–penetrant ALK TKI with potent activity against ALK resistance mutations3

• Checkpoint inhibitors (CPIs) have clinical activity in metastatic NSCLC and prolong overall survival1

– Across multiple clinical trials, CPIs have shown minimal benefit in never-smoking patients4,5

– Retrospective studies have shown minimal activity of CPIs in never-smoking patients, including those with ALK+ NSCLC6

– In the phase 2 ATLANTIC study of durvalumab, no responses were observed among 15 patients with ALK+ NSCLC7

3Alice T. Shaw, MD, PhD

1. NCCN Clinical Practice Guidelines in Oncology. NSCLC V3.2018; 2. Gainor JF, et al. Cancer Discov. 2016; 6:1118-33; 3. Shaw AT, et al. Lancet Oncol. 2017;18:1590-9; 4. Borghaei H,

et al. N Engl J Med. 2015;373:1627-39; 5. Reck M, et al. N Engl J Med. 2016;375:1823-33; 6. Gainor JF, et al. Clin Cancer Res. 2016;22:4584-93; 7. Garassino MC, et al. Lancet Oncol.

2018;19:521-36.

Avelumab

• Avelumab is a human anti–PD-L1 IgG1 antibody with a

wild-type Fc region1

• Preclinical studies suggest that avelumab can

induce antitumor activity by activating both

adaptive and innate immune effector cells2,3

• Avelumab has been approved in various countries

for the treatment of metastatic Merkel cell carcinoma

and in the United States and Canada for advanced urothelial

carcinoma progressing after platinum-based chemotherapy4

• Avelumab has shown antitumor activity and manageable safety in

various other tumors, including single-agent activity in NSCLC5–8

4

T-cell–mediated

immune response

Innate

effector

function

1. Heery CR, et al. Lancet Oncol. 2017;18:587-98; 2. Boyerinas B, et al. Cancer Immunol Res. 2015;3:1148-57; 3. Vandeveer AJ, et al. Cancer Immunol Res. 2016;4:452-62; 4. Bavencio

(avelumab) prescribing information. Rockland, MA, USA: EMD Serono, Inc.; October 2017; 5. Gulley JL, et al. Lancet Oncol. 2017;18:599-610; 6. Choueiri TK, et al. Lancet Oncol.

2018;19: 451-60; 7. Chin K, et al. Ann Oncol. 2017;28:1658-66; 8. Kelly K, et al. Cancer. 2018 Feb 22 (Epub ahead of print).

Alice T. Shaw, MD, PhD

Immune

mediators

Avelumab

PD-1

PD-L1

FcγR

Role of ALK in modulating the immune response

5Alice T. Shaw, MD, PhD

PCR, polymerase chain reaction; shRNA, short hairpin RNA

Figures taken from Zhou P, et al. Nature. 2014;506:52-57.

A B

* p≤.05; ** p≤.01.

Hypotheses for combination treatment

6Alice T. Shaw, MD, PhD

• ALK inhibitors and checkpoint inhibitors may have synergistic activity in non–ALK-driven NSCLC

• Combining ALK inhibitors and checkpoint inhibitors may lead to enhanced efficacy in previously treated ALK+ NSCLC

Avelumab + crizotinib

Avelumab + lorlatinib

Study design: JAVELIN Lung 101Phase 1b/2, open-label, multicenter, dose-finding trial

Key eligibility criteria

Group A

• ALK-negative NSCLC

• No known ROS1 gene rearrangement, c-MET gene

amplification, or c-MET exon 14 skipping

• ≥1 prior regimen of systemic therapy

• No prior antibody/drug targeting a T-cell

coregulatory protein (eg, anti-PD-1/PD-L1)

Group B

• ALK-positive NSCLC

• Any number of prior regimens, including zero

• No prior antibody/drug targeting a T-cell

coregulatory protein (eg, anti-PD-1/PD-L1)

• Asymptomatic untreated brain metastases allowed

7

Initial dose level

Group A

Avelumab 10 mg/kg

(1h IV) Q2W

+ crizotinib

250 mg PO BID

Group B

Avelumab 10 mg/kg

(1h IV) Q2W

+ lorlatinib

100 mg PO QD

Key assessments

Maximum tolerated

dose (MTD) and

recommended

phase 2 dose

Dose-limiting

toxicities

Safety and tolerability

Antitumor activity

Alice T. Shaw, MD, PhD

Data cutoff, October 27, 2017.BID, twice a day; IV, intravenous; PO, by mouth; Q2W, every 2 weeks

Patient characteristicsAvelumab +

Crizotinib

ALK− (n=12)

Median age (range),

years

59.5

(43.0-76.0)

Sex, n (%)

Male

Female

6 (50.0)

6 (50.0)

ECOG PS, n (%)

0

1

2

3 (25.0)

9 (75.0)

0

Brain metastases at

baseline, n (%)

Yes

No

0

12 (100.0)

8Alice T. Shaw, MD, PhD

Avelumab +

Crizotinib

ALK− (n=12)

Prior regimens for metastatic/

advanced disease*

0

1

2

3

≥4

Not reported

2 (16.7)

2 (16.7)

4 (33.3)

4 (33.3)

0

0

Prior ALK TKIs*

0

1

≥2

Not reported

Median (range)

12 (100)

0

0

0

-

* Excludes neoadjuvant

Avelumab +

Lorlatinib

ALK+ (n=28)

54.0

(30.0-77.0)

12 (42.9)

16 (57.1)

10 (35.7)

15 (53.6)

3 (10.7)

4 (14.3)

24 (85.7)

Avelumab +

Lorlatinib

ALK+ (n=28)

1 (3.6)

7 (25.0)

5 (17.9)

4 (14.3)

10 (35.7)

1 (3.6)

0

7 (25.0)

20 (71.4)

1 (3.6)

2 (1-3)

Dose-limiting toxicities (DLTs)

9Alice T. Shaw, MD, PhD

Avelumab

+ Crizotinib

ALK− (n=12)

Any DLT, n (%) 5 (41.7)*

ALT increased 2 (16.7)

AST increased 2 (16.7)

Febrile neutropenia 1 (8.3)

Hepatitis 1 (8.3)

QT prolongation 1 (8.3)

Rash 1 (8.3)

ALT, alanine aminotransferase; AST, aspartate aminotransferase

*3 patients had ≥1 DLT

• The DLT period was defined as the first 2 cycles of treatment (28 days)

• In both groups, all patients were treated at the initial dose level

Avelumab

+ Lorlatinib

ALK+ (n=25)

0

0

0

0

0

0

0

Adverse events (any causality)Avelumab + Crizotinib

ALK− (n=12)

Any grade Grade ≥3

Any AE, n (%) 12 (100) 7 (58.3)

Nausea 7 (58.3) 0

Vomiting 6 (50.0) 0

Decreased appetite 5 (41.7) 0

ALT increased 4 (33.3) 2 (16.7)

Rash 4 (33.3) 1 (8.3)

Anemia 3 (25.0) 1 (8.3)

AST increased 3 (25.0) 1 (8.3)

Chills 3 (25.0) 0

Diarrhea 3 (25.0) 0

Myalgia 3 (25.0) 0

Pyrexia 3 (25.0) 0

10Alice T. Shaw, MD, PhD

Avelumab + Lorlatinib

ALK+ (n=28)

Any grade Grade ≥3

Any AE, n (%) 27 (96.4) 15 (53.6)

Blood cholesterol increased 16 (57.1) 2 (7.1)

Hypertriglyceridemia 16 (57.1) 4 (14.3)

Edema peripheral 8 (28.6) 0

Arthralgia 7 (25.0) 0

Anemia 6 (21.4) 2 (7.1)

Hypothyroidism 6 (21.4) 0

Infusion-related reaction 6 (21.4) 0

Peripheral neuropathy 6 (21.4) 0

Pyrexia 6 (21.4) 1 (3.6)

GGT increased 3 (10.7) 3 (10.7)

Tables show individual adverse events (AEs) that occurred at any grade in ≥20% or at grade ≥3 in ≥10% GGT, γ-glutamyltransferase

Serious adverse events (any causality)

11Alice T. Shaw, MD, PhD

Avelumab + Crizotinib

ALK− (n=12)

Any SAE, n (%) 5 (41.7)

Dyspnea 1 (8.3)

Febrile neutropenia 1 (8.3)

Hepatitis 1 (8.3)

Pneumonitis 1 (8.3)

Pneumothorax 1 (8.3)

Rash 1 (8.3)

Avelumab + Lorlatinib

ALK+ (n=28)

Any SAE, n (%) 11 (39.3)

Pneumonitis 2 (7.1)

AST increased 1 (3.6)

Cerebral hemorrhage* 1 (3.6)

Confusional state 1 (3.6)

Delirium 1 (3.6)

Dyspnea† 1 (3.6)

Femoral neck fracture 1 (3.6)

Femur fracture 1 (3.6)

Lung infection 1 (3.6)

NSCLC* 1 (3.6)

Pericardial effusion 1 (3.6)

Pulmonary embolism 1 (3.6)

Pyrexia 1 (3.6)

Seizure 1 (3.6)

Superior vena cava occlusion 1 (3.6)*Grade 5, not treatment related

†Grade 5, treatment relatedSAE, serious adverse event

Avelumab + crizotinib (ALK−): tumor responses

12Alice T. Shaw, MD, PhD

n=12

Confirmed best overall response, n (%)

Complete response

Partial response

Stable disease

Progressive disease

Not evaluable

0

2 (16.7)

5 (41.7)

5 (41.7)

0

Objective response rate, %

(95% CI)

16.7

(2.1–48.4)

Median time to response, months

(range)

1.4

(1.4-1.4)

Median duration of response, months

(95% CI)

4.1

(3.7–4.6)

Disease control rate, %

(95% CI)

58.3

(27.7–84.8)

Change in target lesions from baseline

• 6/11 evaluable patients (54.5%) had a reduction in tumor size

• 3/11 (27.3%) had tumor shrinkage ≥30%

Avelumab + crizotinib (ALK−): change in target lesions over time

13Alice T. Shaw, MD, PhD

Avelumab + lorlatinib (ALK+): tumor responses

14Alice T. Shaw, MD, PhD

n=28

Confirmed best overall response, n (%)

Complete response

Partial response

Stable disease

Progressive disease

Not evaluable

1 (3.6)

12 (42.9)

6 (21.4)

7 (25.0)

2 (7.1)

Objective response rate, %

(95% CI)

46.4

(27.5–66.1)

Median time to response, months

(range)

1.9

(1.4-3.7)

Median duration of response, months

(95% CI)

7.4

(3.7–NE)

Disease control rate, %

(95% CI)

67.9

(47.6–84.1)

Change in target lesions from baseline

• 16/25 evaluable patients (64.0%) had a reduction in tumor size

• 13/25 (52.0%) had tumor shrinkage ≥30%

Avelumab + lorlatinib (ALK+): responses over time

15Alice T. Shaw, MD, PhD

Time to and duration of response Change in target lesions over time

Conclusions

• Avelumab + lorlatinib treatment in heavily pretreated patients with ALK+ NSCLC showed an acceptable safety profile, with no DLTs

– Antitumor activity was promising, including an ORR of 46% consistent with a prior study of lorlatinib alone1

– Median duration of response was 7.4 months; however, the 95% CI is wide (3.7–not estimable) because the data are still maturing and the number of patients is small

– This arm is currently enrolling treatment-naive, ALK+ NSCLC patients

• Avelumab + crizotinib treatment was not well tolerated, and no further development of this combination is planned

16Alice T. Shaw, MD, PhD

1. Shaw AT, et al. Lancet Oncol. 2017;18:1590-9

Acknowledgments• The authors would like to thank the patients and their families

• The authors would also like to thank the investigators, coinvestigators, and study teams at each of the participating centers and at Pfizer, Inc, New York, NY, USA

• Participating centers:

• This trial was sponsored by Pfizer and is part of an alliance between Merck KGaA, Darmstadt, Germany, and Pfizer

• Medical writing support was provided by ClinicalThinking and was funded by Merck KGaA and Pfizer

17Alice T. Shaw, MD, PhD

United States

Massachusetts General Hospital, Boston, MA

Tennessee Oncology, Nashville, TN

Winship Cancer Institute, Atlanta, GA

Spain

Hospital Universitari de la Vall d’Hebron,

Barcelona

Institut Catala d’Oncologia de Badalona

South Korea

Asan Medical Center, Seoul

National Cancer Center, Goyang-si

Samsung Medical Center, Seoul

Australia

Chris O’Brien Lifehouse, Camperdown, NSW

Peter MacCallum Cancer Center, Melbourne, VIC

The Prince Charles Hospital, Chermside, TAS

Japan

Aichi Cancer Center, Nagoya

National Hospital Organization Kyushu Cancer

Center, Fukuoka

The Cancer Institute Hospital of JFCR, Tokyo