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26

499

Tables

500

Table 1. Patient characteristics

Characteristic

N (%)

Age, years – median (range)

57 (32-76)

Sex

Male

8 (35)

Female

15 (65)

ECOG Performance status

11 (48)

12 (52)

Primary tumor site

Salivary gland

12 (52)

Nasal cavity/paranasal sinus

3 (13)

Ocular

3 (13)

Others

5 (22)

Histology

Adenoid cystic carcinoma

10 (43)

Adenocarcinoma, NOS

5 (22)

Salivary duct carcinoma

3 (13)

Sebaceous adenocarcinoma

2 (9)

Others

3 (13)

27

Disease status

Primary untreated metastatic

9 (39)

Recurrent, locoregional

1 (4)

Recurrent, metastatic ± locoregional

13 (57)

Organ involved

Lung

17 (74)

Liver

5 (22)

Bone

4 (17)

Cervical lymph node

4 (17)

Others

3 (13)

Previous treatment

21 (91)

Surgery

20 (87)

Irradiation

14 (61)

Definitive concurrent cetuximab with radiotherapy

1 (4)

Definitive concurrent S-1 with radiotherapy

1 (4)

Androgen blockade therapy with palliative intent

1 (4)

501

28

502

Table 2. Treatment efficacy.

Efficacy

N (%)

95% CI

Evaluable patients

22 (95.7)

CR

2 (9.1)

0.1-29.2

PR

8 (36.4)

17.2-59.3

SD

11 (50.0)

28.2-71.8

PD

1 (4.5)

0.0-22.8

Confirmed objective response (CR + PR)

10 (45.5)

24.4-68.8

Disease control rate (CR + PR + SD)

21 (95.5)

77.2-99.9

Median PFS, months

6.7

4.8-8.5

Median OS, months

20.1

14.3-25.9

Median time to response, months

1.4

0.6-7.3

Median duration of response, months

4.0

1.9-12.8

503

CR, complete response; PR, partial response; SD, stable disease; PD, progressive

504

disease; PFS, progression-free survival; OS, overall survival; CI, confidence interval

29

505

Table 3. Grade (Gr) 1 or worse adverse events in 10% or more of patients.

Adverse events

All Gr (%)

Gr2 (%)

Gr3 (%)

Gr4 (%)

Hematological

Anemia

23 (100)

9 (39)

5 (22)

Neutropenia

22 (96)

9 (39)

Platelet count decreased

15 (65)

1 (4)

9 (39)

8 (35)

1 (4)

Febrile neutropenia

12 (52)

Non-hematological

Fatigue

21 (91)

4 (18)

3 (13)

Appetite loss

21 (91)

8 (35)

3 (13)

1 (4)

Nausea

20 (87)

6 (26)

2 (9)

Hair loss

19 (83)

15 (65)

Constipation

14 (61)

5 (22)

1 (4)

Diarrhea

12 (52)

2 (9)

2 (9)

Peripheral neuropathy

11 (48)

5 (22)

1 (4)

Vomiting

8 (35)

3 (13)

Edema

7 (30)

4 (18)

Mucositis, oral

7 (30)

1 (4)

Hypoalbuminemia

23 (100)

9 (39)

1 (4)

Hyponatremia

21 (91)

5 (22)

30

Aspartate aminotransferase

16 (70)

1 (4)

1 (4)

Hypocalcemia

14 (61)

2 (9)

1 (4)

Hypomagnesemia

10 (48)

Alanine aminotransferase

10 (44)

1 (4)

2 (9)

Creatinine increased

8 (35)

2 (9)

Alkaline phosphatase

7 (30)

2 (9)

1 (4)

Hyperkalemia

4 (17)

Blood bilirubin increased

3 (13)

increased

increased

increased

506

31

507

Figure legends:

508

Fig.1 Best % change in target legions from baseline (n=22)

509

510

Fig.2 Kaplan–Meier curves. (A) Progression-free survival. (B) Overall survival (n=23)

511

512

Fig.3 Tile plot. Next-generation sequencing was performed with using multiplex PCR

513

for enrichment of cancer related gene loci covering hotspots of 50 cancer genes (Ion

514

AmpliSeq Cancer Hotspot Panel v2) and additional 4 hormonal genes (ESR1, ESR2,

515

PGR, and AR). ANOS, adenocarcinoma, not otherwise specified; SDC, salivary duct

516

carcinoma; SA sebaceous adenocarcinoma; MEC, mucoepidermoid carcinoma; AdCC,

517

adenoid cystic carcinoma; NUT, NUT midline carcinoma; CR, complete response; PR,

518

partial response; SD, stable disease.

32

40

30

20

10

ー1

-20

•一

-30

-40

-50

-60

-70

-80

-90

ー1

00

Adenoidc

ccarcinoma

Adenocarcinoma,

to

es

yductcarcinoma

Sebaceouscarcinoma

*O

eresponseasperResponse

Mucoepidermoidcarcinoma

nC

ai

nS

dTumors(

RECIST)

NUTm

ecarcinoma

n1.

cc

lcarcinoma

1.

642

000

Months

Months

40

30

20

10

40

30

20

10

e>l>﹄ns=e-0>O

642

0000

-e>!AJnseeJJ,UO!SSoJ60Jd

ogy

ANOS

ANOS

Sal

y S

li

vary

Primarys

Res

pons

PR

PR

ヒHBB

TP53

400T>A

Kn —

ALK

KRAS

GNAS

ESR2

ESR1

AR

PGR

SOC

SDC

SA

SA

Sa

iv

Ocular

Ocular

PR

PR

CR

CR

3.

64

2385G>A

472C>T

517G>T

502G>A

1.

67

2.

20

.77

1407417A>C

MEC

PR

AdCC

AdCC

Oro

pharynx

SD

Sa

PR

707G>A

Geneamplification(copynumber)

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NUT

Nasal

ar

SD

SD

Title: Docetaxel plus cisplatin in progressive recurrent and/or metastatic non-squamous-cell head and neck

cancer: a multicenter phase II trial

Medical Oncology

Authors: Yoshinori Imamura,1 Kaoru Tanaka,2 Naomi Kiyota,*1,3 Hidetoshi Hayashi,2 Ichiro Ota,4 Akihito

Arai,5 Shigemichi Iwae,6 Shujiro Minami,7 Katsunari Yane,8 Tomoko Yamazaki,9 Yoshiaki Nagatani,1

Masanori Toyoda,1 Takayuki Takahama,10 Kazuko Sakai,10 Kazuto Nishio,10 Naoki Otsuki,11 Ken-ichi

Nibu,11 and Hironobu Minami1,3

Affiliations: 1 Medical Oncology and Hematology, Kobe University Graduate School of Medicine, 7-5-1

Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan; 2Department of Medical Oncology, Kindai University

Faculty of Medicine, 377-2 Ohnohigashi, Osaka-Sayama, Osaka 589-8511, Japan; 3Cancer Center, Kobe

University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan;

Department of

Otolaryngology-Head and Neck Surgery, Nara Medical University, 840 Shijo-Cho, Kashihara, Nara 6348521, Japan; 5Department of Otolaryngology, Kyoto Prefectural University of Medicine, 465 Kajii-cho,

Kawaramachi-Hirokoji Kamigyo-ku, Kyoto 602-8566, Japan; 6Department of Head and Neck Surgery,

Hyogo Cancer Center, 13-70 Kitaoujicho, Akashi, Hyogo 673-8588, Japan; 7Department of Otolaryngology,

National Hospital Organization Tokyo Medical Center 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902,

Japan; 8Department of Otolaryngology, Nara Hospital, Faculty of Medicine, Kindai University, 1248-1

Otoda-cho, Ikoma, Nara 630-0293, Japan; 9Division of Head and Neck Medical Oncology, Miyagi Cancer

Center 47-1 Nodayama, Medeshimashiode, Natori, Miyagi 981-1293, Japan;

10

Department of Genome

Biology, Kindai University Faculty of Medicine 377-2 Ohnohigashi, Osaka-Sayama, Osaka 589-8511,

Japan; and 11Department of Otolaryngology-Head and Neck Surgery, Kobe University Hospital, 7-5-2

Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.

*Address for correspondence:

Naomi Kiyota, M.D., Ph.D.

Cancer Center, Kobe University Hospital

7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan

Tel.: +81-78-382-5820; Fax: (+81)78-382-5821

Email: nkiyota@med.kobe-u.ac.jp

Table S1. Target genes.

Ion AmpliSeq Cancer Hotspot Panel v2

ABL1

AKT1

ALK

APC

ATM

BRAF

CDH1

CDKN2A

CSF1R

CTNNB1

EGFR

ERBB2

ERBB4

EZH2

FBXW7

FGFR1

FGFR2

FGFR3

FLT3

GNA11

GNAS

GNAQ

HNF1A

HRAS

IDH1

IDH2

JAK2

JAK3

KDR

KIT

KRAS

MET

MLH1

MPL

NOTCH1

NPM1

NRAS

PDGFRA

PIK3CA

PTEN

PTPN11

RB1

RET

SMAD4

SMARCB1

SMO

SRC

STK11

TP53

VHL

AR

PGR

ERBB2

An original focused panel

ESR1

ESR2

EGFR

KIT

Table S2. Overall response according to primary tumor site and histology.

Overall response

Salivary gland

Number of responses/total number of patients

AdCC

ANOS

SDC

SA

MEC

NUT

AcCC

Total

2/4

2/3

2/3

0/1

6/11

1/3

Nasal

cavity/paranasal

1/3

sinus

Ocular

0/1

2/2*

2/3

1/1

0/1

1/2

Oropharynx

0/1

0/1

0/2

Ear

0/1

0/1

Total

3/10

2/4

2/3

2/2

1/1

0/1

0/1

10/22

Oral cavity/lip

AdCC, adenoid cystic carcinoma; ANOS, adenocarcinoma, not otherwise specified; SDC, salivary duct

carcinoma; SA sebaceous adenocarcinoma; MEC, mucoepidermoid carcinoma; NUT, NUT midline

carcinoma; AcCC, acinic cell carcinoma.

*Complete response

...